[Occasional temperature rises following streptokinase infusions. Animal experiment findings].

The mechanism of the rises in temperature which have been observed in the clinic during long-term infusions with streptokinase (SK, Streptase-R) was clarified in animal experiments. After pyrogenic substances had been excluded as the possible cause of this side-effect and no rises in temperature in normal rabbits during SK infusions had been observed, this effect was imitated in animals immunised with SK. A clear fever reaction could be induced. Control experiments with rabbits which had been sensitised with human albumin, confirmed the hypothesis that the rise in body temperature is caused by anaphylactic fever. Neutralisation of the SK antibodies prevents the rise in temperature. Injecting high-titre gamma-globulin solution from animals immunised with SK, cannot suppress the fever reaction; this also applies to antihistamine (pheniramine-p-aminosalicylate) and hydrocortisone acetate therapy. During the lysis of thrombi induced by thrombin in the ear veins of rabbits, a rise in body temperature is obtained during the SK infusion and during treatment with a thrombolytic gel. Untreated control animals also showed the same rise in temperature during thrombolysis. The possibility that the fever reaction is set off by components of the dissolving thrombus is also discussed.


[Teratogenic effect of busulfan on testis cells of the rat (postnatal development)].

10-mg/kg of 1,4-bis-(methanesulfonyloxy)-butane (busulfan) are administered on various days of gestation to Wistar rats. The testes of the male pubs of these litters are examined histologically. Depending on the time of application of busulfan the cells of spermiogenesis are dimished and the meiosis is delayed. The Leydig cells are unchanged. In a second experiment, the weight of the seminal vesicles, LH and FSH in the serum show no differences versus the control group.


[Results of some clinical-pharmacological studies on ambroxol (NA 872)].

In the beginning objects and problems of clinical pharmacology were outlined. Results from experimental studies in animals with the metabolite VIII of bromhexine (N-[trans-4-hydroxy-cyclohexyl]=[2-amino-3,5-dibromo-benzyl]-amine, Ambroxol (NA 842)) are described in order to contribute to the understanding of this substance's mode of action. Hence NA 872 is an expectorant which fully meets all requirements expected from this category of druggs -- increase in sputum amount, easement in breathing, reducing the viscosity, and depression of coughing. The dose-effect rate of the substance was tested in 54 adults and 32 children. The average dose of 45.0 mg/kg for adults was determined as sufficient for the majority of patients. In the following test in 124 patients on dose tolerance and efficacy, the substance proved to be tolerated extremely well, to cause no adverse side effects while achieving good effects particularly with regard to improvement of expectoration. There was no casual relationship between some occurring changes in laboratory data and the application of the substance.


[Effect of papaverine hydrochloride on brain circulation. Studies using a scintillation camera computer system].

The effect of papaverihnydrochlorid (Panergon-R) on the cerebral circulation time was studied in 20 sclerotic patients by means of radionuclide circulography as established by a scintillation camera-computer system. After a 28-days period of treatment a mean effective change of circulation time of minus 10.6 +/- 4.8 percent was to be observed. This change was statistically significant.


[Blood, urine and bile levels of ampicillin during continuous intravenous infusion].

During and after continuous i.v. infusion of 0.25 g ampicillin (Binotal-R) per hour, serum and urine concentrations were determined in 6 healthy adults (volunteers) and in 12 geriatric patients with normal liver and kidney function. In old persons serum levels were higher and after the end of infusion decreased more slowly than in young adults. These data may be explained by a lower capillary permeability and renal clearance in older people. In patients with T-tube drainage after cholecystectomy, bile levels of ampicillin (during i.v. continuous infusion of 0.25 g/h) were equal to double those in serum. Recovery from the file was calculated as 0.1-0.2 percent.


[Comparison of pharmacokinetics of the combination trimethoprim and sulfamethoxazole in patients with liver diseases and healthy persons].

Pharmacokinetic characteristics of the antibacterial combination sulfamethoxazole (SMZ) plus trimethoprim (TMP) have been compared, following a single oral dose of 800 mg SMZ plus 160 mg TMP, between 3 groups of adult humans: A = 13 healthy persons, B = 4 patients with minor hepatic injury and C = 7 patients with severe, decompensated liver damage. The following data were determined: 1. the time tmax; 2. the maximum concentrations (cmax) of the two drugs reached in the plasma; 3. the half-life t1/2 of their elimination from the plasma; 4. their apparent distribution volume indicated in percent of body weight; 5. the share of metabolized SMZ in percent of total sulfonamide; 6. the concentration ratio of active SMZ to TMP, both total and unbound to plasma proteins; 7. the cumulative renal excretion of total sulfonamide and of non-metabolized TMP. Only the following differences between groups were observed: 1. The maximum plasma level of active SMZ as well as TMP was lower by an average factor of 1.5 to 2.0 in the two groups B and C as compared to group A. An analogous but diminishing difference lasted for the active SMZ up to the 24th, for TMP up to the 12th hour following medication. An influence of the liver disease on the absorption rate via alteration of the biliary conditions is envisaged as a possible explanation. 2. The elimination half-life of TMP, although lying in most of the liver patients within the range of healthy persons, was lengthened up to twice normal in some of the patients with severe liver damage. Such unusually long half-lives for TMP, however, are considered to be in the range of an individual peculiarity. 3. The renal excretion of TMP occurred in the liver-diseased patients on the average more slowly during the first 24 h and its cumulative value reached at the end of the 72 h observation time was somewhat lower than in the healthy persons. In group C at least this may be in connection with a concomitant reduction of the kidney function. None of the features indicated are considered to be of essential clinical importance, such as to discourage the use of the combination in cases of liver disease.


[Dose-response relationship of bumetanide in healthy subjects].

A diuretic effect is demonstrated following oral administration of 0.25 mg 3-n-butylamino-4-phenoxy-5-sulfamoylbenzoic acid (bumetanide, Burinex-R), the maximum response apparently not being reached by a dose of 0.5 mg. Within this range the dose-response curve is steep and approximately linear. The pattern of urinary volume and electrolyte excretion bears close resemblance to the "high-ceiling" diuretics known so far. Bumetanide differs from them by a markedly increased potency compared on the basis of molar dosage.


[Proinsulin and insulin secretion in obese females before and after administration of metformin].

In 49 normal and overweighty women the basal and reactive proinsulin and insulin level as well as serum cholesterol and triglycerides were determined before and after the application of N,N-dimethylbiguanide-hydrochloride (metformin, Glucophage retard-R). The proinsulin fraction of the basal total insulin is 70 percent in normal women. With increasing overweight the percentage of proinsulin decreases in favor of insulin. Stimulation with 100 g oral glucose, in analogy to the total insulin, significantly increased proinsulin levels, remaining, however, below the insulin levels. Accordingly the increased secretion of total insulin  in overweighty persons consists mostly of insulin and to a lesser degree of proinsulin. Additionally there exists a significant correlation between the triglycerides and the degree of overweight. After 4 weeks application of 1.7 g metformin daily the weight reduction reached on an average 1.4 kg, after 16 weeks 5.2 kg. In relation to the weight reduction lower proinsulin and insulin levels were noticed before and after stimulation with glucose. Even those test persons who did not lose weight under metformin showed lower proinsulin and insulin levels. It might be that metformin leads to a slow-down in glucose absorption and as a consequence to a decrease of insulin secretion. Lower triglyceride values after treatment with metformin not only were a sign of weight reduction: biguanides also influence the fat metabolism independently of the carbohydrate metabolism. Additional to the reduction diet the treatment with metformin seems to be very appropriate for overweighty patients with hyperinsulinism and hypertriglyceridemia.


[Experimental exophthalmos. Preliminary communication].

Pyrogallol and N1-(d,1-seryl)-N2-(2,3,4-trihydroxy-benzyl)-hydrazine (RO-4-4602), two inhibitors of catechol-O-methyl-transferase, produce exophthalmus in mice and rats. This exophthalmus can be suppressed by local application of guanethidine.


[New method for intranodular administration of 2,4-dinitro-1-chlorobenzene].

2,4-Dinitro-1-chlorobenzene (DNCB) proved to be an excellent stimulator for immunotherapy of melanom. Because of its poor solubility the therapy is limited to topical application. Our investigations have shown that an aqueous, injectable solution may be obtained by using dimethylsulfoxide (DMSO) that permits solubilization.


"A spoonful of sugar" - trans-alveolar nutrition.

In this initial study, it has been postulated that even the simple bronchial administration of isotonic glucose and insulin can maintain alveolar cell metabolism as measured by A.T.P. activity; further studies, using aerosolized glucose solutions, will test the validity of the hypothesis that alveolar metabolism can be maintained by the administration of substrate in aerosolized form by the alveolar route and will determine whether this form of substrate administration has clinical potential.


The indications for equine laparotomy--an analysis of 140 cases.

The indications for laparotomy in 140 horses are analysed, with particular emphasis on the operative or autopsy findings in 82 cases of colic. In cases of exploratory laparotomy, the overall recovery rate was only 28 per cent but 48 of the 82 animals were considered to have inoperable lesions. The recovery rate and causes of death for each indication are briefly reviewed.


Malabsorption in the horse associated with alimentary lymphosarcoma.

Three horses suffering from malabsorption were shown to have alimentary lymphosarcoma predominantly affecting the small intestine and the associated lymph nodes. The diffuse cellular infiltration in two of the case produced marked changes in the villous architecture reducing the available mucosal surface area, and, with lowered or barely detectable disaccharidase activities, contributed to the impairment of digestive-absorptive processes. One of the horses maintained a voracious appetite and was not diarrhoeic, but failed to gain weight, indicating differences in the production and utilisation of energy sources absorbed from the small and the large intestines. A large proportion of plasma cells in the infiltrate, and the resulting morphological changes in two of the cases bore a striking resemblance to features of alpha chain disease, an immunodeficiency disease of man, although immunological studies were not conducted on these horses.


Studies on the mechanism of action of continuous microdose quingestanol acetate.

The contraceptive mechanism of action of quingestanol acetate administered as a minipill was investigated in five healthy, ovulating women. Each woman served as her own control and was studied during a normal menstrual cycle followed by a cycle in which she received quingestanol acetate, 300 mug/day given orally beginning on cycle day 1, for 30 days. Urinary estrone, estradiol, estriol, total estrogens, pregnanediol; serum progesterone, follicle-stimulating hormone, and luteinizing hormone, together with cervical mucus properties (including viscosity, ferning, spinnbarkheit, cell content, pH, and proteins), sperm transport through mucus, vaginal cytology, and basal body temperature were studied serially during the control and study cycles. Endometrial biopsy specimens were obtained at the end of each cycle. The results indicated that all control cycles were ovulatory. In the treated cycles, endometrial morphology was slightly altered. There was also suppression of preovulatory follicle-stimulating hormone and luteinizing hormone peaks, alteration of urinary estrogens, and a decrease in serum progesterone during the luteal phase. Cervical mucus properties and sperm penetration were inhibited to varying degress during the treatment cycle. These findings suggested that at least three different factors, i.e., alteration of ovulation, disturbances of corpus luteum function, and cervical mucus changes causing inhibition of sperm penetration, were involved in the contraceptive mechanism of microdose quingestanol acetate.


An international perspective on strikes and strike threats by physicians: the case of Chile.

The program for health services developed by the government of Dr. Salvador Allende Gossens in Chile is outlined, as well as its early effects. A review of this development is necessary to an understanding of the systematic opposition of the organized medical profession to this program in particular, and to the broad socialist goals of the government in general. Three periods of activity by the medical profession are traced, beginning in September 1970 and culminating in September 1973 with the military coup and overthrow of the democratically elected government of Chile and the murder of its president, a physician. While the medical profession was opposed to the government program for community participation in health care and to changes in the models for delivery of care, and feared a changed status for the physician, clearly there were broader political links between the organized medical profession and the political opponents of the government which sought its overthrow.


The nature of the neuropsychological disability in autistic children.

In previous studies the author and her associates found that the IQs of autistic children can be measured and are also predictive of the child's future functioning. Contrary to earlier opinion, autistic children were found to have subnormal intelligence and more signs of neurological dysfunction than subnormal controls. In this study test data were reviewed to see what subtests differentiated a group of 66 autistic children from a group of 29 children with subnormal intelligence. Results indicated that "high autistic" children were similar to subnormal children on verbal subtests. However, subnormal children were superior to autistic children in some performance areas as in ball play. Findings are interpreted to suggest that autistic children with severe visual/motor disabilities as indicated by low ball play scores may be propelled into emotional withdrawal, even though they are only moderately retarded on verbal subtests.


Childhood psychosis. The problem of differential diagnosis.

In a study of 66 former child psychiatric patients, Form E-1 of Rimland's Diagnostic Check List (DCL) was found to be an effective instrument for differentiating autistic, other psychotic, and nonpsychotic disturbed children. Follow-up study revealed more favorable outcomes in nonpsychotic cases, with significant association between DCL scores and improvement following discharge. Scores indicative of autism on the DCL were also significantly associated with being of the Jewish faith.


Modifying the verbal expression of a child with autistic behaviors.

The Bell and Howell Language Master was used in conjunction with the Monterey Language Program to modify the verbal expression of a nine-year-old boy with autistic behaviors. The goal was to train the child to correctly name up to 10 pictures presented individually. Two training modes were used. For one, the therapist spoke at the time (live voice). For the other, she presented a tape recording of her voice via a Language Master. The results suggested that the child's responses to the Language Master were as good as, if not better than, his responses to the live-voice presentations. In addition, observation indicated that he responded more readily to the Language Master presentations. His spontaneous speech was also noted by independent observers to improve in his classroom and in his home. Possible reasons for the improvement in verbal expression are considered.


Concept usage in schizophrenic children.

This study compares concept usage and categorizing behavior among schizophrenic, normal, and brain-damaged children. Two sets of tasks were administered to each subject, the child being required to match an index object with one of a group of three choice objects. On the first task, the choice objects were related to the index object by class, function, or stimulus similarity; on the second task, the two choice objects were unrelated to the index object, while the remaining choice object was related by class or function. For both tasks the subjects were asked to state which of the choice objects was related to the index object, and why. Results indicated that the schizophrenic, normal, and brain-damaged children showed a significant improvement with increased age in utilizing class or function concepts. However, the schizophrenics, unlike the normal and brain-damaged children, did not benefit consistently from a reduction in stimulus competition. Within the schizophrenics, grouping by IQ revealed a dichotomous type of concept usage. Low IQ patients performed like the brain-damaged group; high IQ children failed to benefit from reduction in stimulus competition and produced more bizarre and irrelevant responses.


An operant procedure to teach an echolalic, autistic child to answer questions appropriately.

An operant conditioning procedure to teach an autistic patient with rapid immediate echolalia to answer questions correctly was devised. The procedure involved positively reinforcing the patient immediately after a correct response and preventing incorrect responses. It is simple to implement and eliminates some of the structure and constraints inherent in previously described operant methods. This allows the procedure to be administered by a variety of therapeutic personnel and parents and in a variety of living situations.


Uptake and efflux of serotonin from platelets of autistic and nonautistic children.

This study examined, in vitro, the uptake and efflux of serotonin by platelets from autistic children, nonautistic hospitalized comparison cases, and normal children. The autistic patients were carefully selected according to previously established diagnostic criteria. The hospitalized comparison children were utilized to assess possible environmental and dietary influences upon the results. Uptake methods were similar to those used by previous investigators. Two efflux procedures were utilized to explore the possibility that methodological factors accounted for previously reported differences between autistic and comparison groups. The results failed to indicate statistically significant differences in uptake or efflux between the autistic and the hospitalized comparison groups or the normals. Methodologic considerations which could possibly account for the failure to confirm previous findings are discussed in detail.


On the organic nature of some forms of schizoid or autistic psychopathy.

Representative case histories are presented to illustrate the typical clinical features of autistic psychopathy. These patients showed several clinical features compatible with organic encephalopathy. Physical signs suggesting the presence of an underlying cerebral dysgenesis were particularly frequent. These patients superficially resembled schizophrenics but differed in their delayed and peculiar intellectual development, the response of their behavior to external stimuli, and their frequent and severe motoric defects. From these observations and a review of the pertinent literature, we conclude that the patients described in this report have an organic deficiency of brain function, determined congenitally or in the early postnatal period.


Language, communication, and the use of symbols in normal and autistic children.

The characteristics of language and other forms of communication in normal and autistic children are described. The main basis of comparison is the extent to which each group can comprehend and use spoken and nonspoken language and also develop inner language. It is suggested that the central problem in early childhood autism is an impairment of complex symbolic function affecting all forms of communication. This problem can occur on its own, but, in the majority of cases, it is associated with other impairments of the central nervous system. The relationship of early childhood autism to mental retardation and to normal intellectual function is discussed.


The ecology of child treatment. A developmental/educational approach to the therapeutic milieu.

Many residential and day treatment programs for troubled children have experienced only limited success because of their inability to impact the child's total life sphere: family, peer group, school, and neighborhood. This has prompted the present move to deinstitutionalize children's mental health services--a movement which is sound in its underlying purpose, but which sometimes falls prey to the notion that merely altering the location of treatment from the ward or institution to the community setting will dramatically alter its results. It will not. This paper begins with the assumption that the focus of child treatment is as important as the locus and attempts to identify the critical elements in a therapeutic community-based program for the troubled child and his parents.


Changing diagnosis of childhood psychosis.

The case findings of thirty-three children given a diagnosis of psychosis during hospitalization in the '50s and '60s were reviewed and rediagnosed in 1973. Childhood schizophrenia was the original diagnosis in 58% of the cases but was the rediagnosis in only 18% of those same cases. Chronic brain syndrome with various reactions (psychotic reaction, nonpsychotic behavioral reaction, and mental retardation and autism) was the diagnosis in 27% of the cases, originally, but was given to 67% of the cases on rediagnosis. One-third of the children originally diagnosed as psychotic were rediagnosed as nonpsychotic. Approximately two-thirds of the children were nonpsychotic according to the DeMyer-Churchill guidelines.


Diagnosis of internal derangements of the knee. The role of arthroscopy.

In a prospective study of 100 patients with internal derangement of the knee, clinical diagnosis, arthrography, arthroscopy, and arthrotomy findings were compared. The clinical diagnosis was correct in seventy-two patients, correct but incomplete in ten, and incorrect in eighteen. Arthroscopy was accurate in ninety-four, influenced surgical therapy in fifty-five, and revealed unexpected disease in twenty-five patients. It was found to be critical for diagnosis in sixteen patients. Twenty-three additional patients were analyzed who underwent arthroscopy but not arthrotomy. Unnecessary operations were avoided in twenty-one of these twenty-three patients.


Interaction of phospholipid vesicles with cells.  Endocytosis and fusion as alternate mechanisms for the uptake of lipid-soluble and water-soluble molecules.

Depending on their phospholipid composition, liposomes are endocytosed by, or fuse with, the plasma membrane, of Acanthamoeba castellanii.  Unilamellar egg lecithin vesicles are endocytosed by amoeba at 28 degrees C with equal uptake of the phospholipid bilayer and the contents of the internal aqueous space of the vesicles.  Uptake is inhibited almost completely by incubation at 4 degrees C or in the presence of dinitrophenol.  After uptake at 28 degrees C, the vesicle phospholipid can be visualized by electron microscope autoradiography within cytoplasmic vacuoles.  In contrast, uptake of unilamellar dipalmitoyl lecithin vesicles and multilamellar dipalmitoyl lecithin liposomes is only partially inhibited at 4 degrees C, by dinitrophenol and by prior fixation of the amoebae with glutaraldehyde, each of which inhibits pinocytosis.  Vesicle contents are taken up only about 40% as well as the phospholipid bilayer.  Electron micrographs are compatible with the interpretation that dipalmitoyl lecithin vesicles fuse with the amoeba plasma membrane, adding their phospholipid to the cell surface, while their contents enter the cell cytoplasm.  Dimyristoyl lecithin vesicles behave like egg lecithin vesicles while distearoyl lecithin vesicles behave like dipalmitoyl lecithin vesicles.


Acute effects of corticosteroids on thyroid activity in Graves' disease.

We studied the effects of administration of dexamethasone, 2 mg orally every 6 hr for 4 doses, on circulating thyroid hormone levels in hyperthyroid Graves' disease patients and in normal subjects. Serum triiodothyronine (T3), thyroxine (T4) and thyroglobulin (Tg) fell significantly below baseline values within 24 to 48 h after the first dose of dexamethasone in hyperthyroid patients; the values returned to or toward baseline levels in the subsequent 5 to 6 days. Serum T3 fell transiently in normals but to a much smaller degree than in hyperthyroid patients; T4 and Tg showed no significant change. Dexamethasone had ni inhibitory effect on the thyroid response to exogenous TSH in the hyperthyroid patients. Studies in vitro demonstrated lack of any appreciable effect by dexamethasone or hydrocortisone on stimulation of human thyroid adenyl cyclase by TSH or immunoglobulin G(IgG) from patient with Graves' disease. The fall in serum T3 without a change in serum T4 in normals suggested an effect of dexamethasone on peripheral conversion of T4 to T3. However, the markedly greater, more persistent drop in T3 in the hyperthyroid patients, as well as the associated drop in T4 and Tg, suggested an additional effect of dexamethasone administration on thyroid secretion in these patients. Preservation of thyroidal response to TSH during dexamethasone administration both in vivo and in vitro indicated that dexamethasone had not impaired thyroidal cellular processes per se. The data were consistent with an effect of dexamethasone on thyroid stimulator. The putative stimulator does not appear to be normal pituitary thyrotropin (TSH), since TSH was not detected in serum of anyof the patients studied. Additionally, the changes observed were too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator. The data are consistent with the possibility that there may be a non-TSH non-IgG thyroid stimulator in Graves' disease.


Iodoamino acid content and distribution in normal and abnormal human thyroids.

Iodoamino acid content and distribution were measured in adenomas, nodular goiters, thyroiditis and carcinomas and compared to thyroids from patients who died suddenly and normal thyroid tissues originally adjacent to diseased tissue. Tissues were hydrolyzed with Pronase, derivatized and analyzed by gas chromatography as had previously been reported for rat thyroids. Considerable overlap in values was found among adenomas, nodular goiters and papillary and follicular carcinomas as compared to values in normal thyroid tissue, but low values were also found in several diseased tissues. MIT/DIT and T3/T4 ratios were essentially constant in most tissues, even when T4 values were low. MIT/DIT ratios were, however, high and iodothyronines undetectable in all Hurthle cell neoplasms, clearly differentiating them from other thyroid conditions.


Endotoxin as a cause of aseptic meningitis after radionuclide cisternography.

The role of pyrogens in aseptic meningitis after radionuclide cisternography was studied by means of the Limulus test, a sensitive detector of endotoxin. During a 15-month period, 39 reactions associated with cisternography were reported. Ten samples of specific lots of the radioactive drugs implicated in 20 of these reactions were tested and all reacted strongly positive to the Limulus test. The less sensitive rabbit pyrogen test was negative for these preparations when tested on a dose-per-weight basis. Our findings apparently provide clinical evidence for the observation made in animals that endotoxin is at least 1,000 times more toxic intrathecally than intravenously. The data implicate endotoxin contamination as a cause of adverse reactions to radionuclide cisternography. We conclude that the USP pyrogen test is insufficiently sensitive for intrathecal injectables and should be supplemented by the Limulus test.


Necrotizing enterocolitis in low-birth-weight infants fed an elemental formula.

The incidence of necrotizing enterocolitis in the newborn infant has increased within the same time period that increasing emphasis has been placed on oral alimentation of very small infants. A prospective investigation was conducted to determine the nutritional efficacy as well as the incidence of necrotizing enterocolitis of a standard cow milk formula compared with an elemental formula. Sixteen infants who weighed less than 1,200 gm were randomized and fed one of the two formulas. The clinical status of the two groups was similar. Seven of eight (87.5%) infants fed the elemental formula and two of eitht (25%) fed the standard cow milk formula developed necrotizing enterocolitis (p less than 0.02). The hypertonicity of the elemental diet may have contributed to the increased incidence of necrotizing enterocolitis in infants fed this formula.


Conformational effects on the activity of drugs. 5. Pharmacological properties of 2-(p-nitrophenyl)-4-isopropylmorpholine, a cyclic analog of INPEA.

2-(p-Nitrophenyl)-4-isopropylmorphine (V), an analog of 1-(p-nitrophenyl)-2-isopropylaminoethanol (INPEA, I) in which the OCHCHN chain of I is locked in a morpholine ring, loses the beta-receptor blocking activity of I on various isolated preparations. The same ineffectiveness is observed in the O-methyl (II), N-methyl (III), and N,O-dimethyl analog (IV) of I. However, some other properties which are present in I, such as inhibitory effect on acetylcholine or on 5-HT, intrinsic alpha-sympathomimetic activity, and potentiation of catecholamines, are maintained; this demonstrates a complete dissociation of these effects from beta-receptor blockade. The interactions with the alpha-adrenoceptors and with the uptake mechanism are discussed on the basis of the structure-activity relationship between I and its analogs II-V.


Distribution of anticancer agents in spontaneous animal tumors. II. Distribution of gallium in canine lymphosarcoma.

The physiologic disposition of pharmacologic doses of gallium was studied in control dogs and dogs with spontaneous lymphosarcoma. Gallium 67 (67Ga) was administered iv with carrier gallium added at a dose of 8 mg/kg. About 50% of the injected dose was excreted in the urine by 48 hours (mostly in the first 12 hr), whereas negligible amounts were excreted in bile. The distribution of 67Ga in normal tissues was similar in control and tumor-bearing dogs. The tissue-to-plasma concentrations of gallium were considerably greater than 1 in the kidney cortex, bone marrow, bone, small intestine, and liver 6-72 hours after administration of the drug. At comparable time periods, tissue-to-plasma ratios of gallium were less than 1 in skeletal muscle and brain. In dogs with lymphosarcoma there was neither selective uptake nor selective retention of gallium in comparison to most normal tissues. In fact, several normal tissues, particularly kidney cortex and bone marrow, concentrated gallium greatly in excess of tumors. Qualitatively similar findings were obtained in a dog with malignant melanoma. These findings were contrary to what one would predict from reports showing that carrier-free 67Ga is selectively concentrated in various human and animal tumors. This indicates the need for more extensive studies of the physiologic disposition of pharmacologic (antitumor) doses of gallium in humans and appropriate animal models.


DNA-dependent RNA polymerases of Ehrlich carcinoma, other murine ascites tumors, and murine normal tissues.

DNA-dependent RNA polymerase was solubilized from nuclei of Ehrlich ascites carcinoma (EAC) cells by sonic disruption in the presence of 0.3 M (NH4)2 SO4, and the multiple RNA polymerases were separated by chromatography on DEAE-Sephadex A-25. Elution with a nine-step gradient of (NH4)2 SO4 yielded five peaks of activity designated RNA polymerases Ia, Ib, IIa, IIb, and III, of which IIb was the most prominent. Linear-gradient elusion also yielded five peaks of the same designation, but Ia and Ib, as well as IIa and IIb, were not well separated. IIa and IIb were inhibited completely by 0.1 mug alpha-amanitin/ml, whereas the other forms were not. EAC RNA polymerases Ia, Ib, IIa, and IIb possessed Mg2+ ion, Mn2+ ion, and (NH4)2 SO4 optima, molecular weights, and thermal sensitivities similar to those reported for other mammalian DNA-dependent RNA polymerases. As measured by relative ribonucleoside monophosphate incorporation, with native calf thymus DNA template, EAC RNA polymerases Ia and Ib synthesized ribosomal RNA-like products, whereas forms IIa, IIb, and the parent enzyme mixture synthesized compounds that were more similar to DNA. No species specificity was found for DNA templates, and denatured DNA was consistently preferred to the native template by RNA polymerases IIa and IIb; the two kinds of template were about equally efficient for RNA polymerases Ia and Ib. Although EAC RNA polymerases Ia, IIa, and IIb were inhibited by daunomycin, form IIa was preferentially affected. 3',5'-Cyclic AMP, 3',5'-Cyclic GMP, and gibberellic acid, implicated as RNA polymerase regulators in other systems, were generally ineffective. The levels of nuclear RNA polymerase activities, per mg DNA, of 3 mouse ascites tumors (EAC, 6C3HED lymphosarcoma, and TA3 adenocarcinoma) were compared with those from 3 normal mouse tissues (kidney, liver, and spleen). On the average, the tumor cell nuclei contained (per mg of DNA) 8.9, 1.5, 2.7, 20.0, and 3.8 times the activities of RNA polymerases Ia, Ib, IIa, IIb, and III, respectively, as the normal cells, but the difference was significantly only for IIb.


Oyster-associated hepatitis. Failure of shellfish certification programs to prevent outbreaks.

During October and November 1973, outbreaks of hepatitis A associated with consumption of raw oysters occurred in Houston and in Calhoun, Ga. The oysters implicated in both outbreaks had been harvested in two Louisiana bays. Although the bays had been contaminated with polluted Mississippi River water two months before the oysters were harvested, at the time of harvesting the bays met national sanitation standards for shellfish growing and were certified for oyster fishing. These epidemics raise serious questions about the adequacy of shellfish sanitation monitoring systems currently in use.


Thyroid nodularity in children.

Of 5,179 school children surveyed in Utah, Nevada, and Arizona for thyroid abnormalities because of possible exposure to radiation from fallout, nodularity of the thyroid was found in 98 (1.8%). In 34, the nodularity represented lobulation associated with adolescent goiter, and in 31, thyroiditis. Two malignant neoplasms were found. In a normal childhood population in which nodularity is incidentally discovered on physical examination, the risk of nodularity being malignant is approximately 2%. Factors that favor exploration of thyroid nodules in children are discreteness, growth of the mass, singleness, and absence of other thyroid disease.


Gallium citrate Ga 67 scans in febrile patients.

Scanning with gallium citrate Ga 67 is a sensitive technique for the detection of localized inflammatory disease. In a group of 22 febrile patients, 17 had one or more abnormal areas of radioactive gallium localization. Eight patients showed localized areas of inflammation; five showed no area of local inflammation within the field of the scan. The remaining patients had excellent clinical and laboratory confirmation of neoplastic or inflammatory disease. These cases illustrate the usefulness of radioactive gallium in febrile patients in whom the cause of the fever cannot be otherwise determined.


Alcohol and malnutrition in the pathogenesis of liver disease..

Malnutrition is common among alcoholics because alcohol displaces protein-, vitamin-, and mineral-containing foods in the diet, and chronic alcohol consumption results in maldigestion and malabsorption of essential nutrients. In addition, alcohol exerts direct toxic effects on both the liver and gut, resulting in structural alterations in the intestine and the development of fatty liver, alcoholic hepatitis, and cirrhosis. Liver injury is preceded by an adaptive phase characterized by accelerated metabolism of drugs (including ethanol), and hyperlipemia, secondary to hypertrophy and hyperactivity of the smooth endoplasmic reticulum. Side effects include enhanced hepatotoxicity of CCI4 and possibly energy wastage. Alcoholics should not be led to beleive that correction or prevention of nutritional deficiency will prevent liver damage in the face of continued alcohol abuse.


Successful carotid endarterectomy for cerebrovascular insufficiency. Nineteen-year follow-up.

This is believed to be the first successful case of thromboendarterectomy for cerebrovascular insufficiency caused by atherosclerotic occlusion of the carotid artery, as well as the longest follow-up study. At the time of the patient's death from coronary occlusion, 19 years after operation, he had no cerebrovascular symptoms, and there was clinical evidence of maintenance of the restored circulation in the carotid artery.


Hypertension and unilateral parenchymal renal disease. Evidence for abnormal vasoconstriction-volume interaction.

Hypertension was not renin-dependent in the majority of 62 hypertensive patients with seemingly unilateral renal parenchymal disease, as indicated by plasma renin activity: low in 14 (23%), normal in 40 (56%), and high in only 8 (13%). By a weighted scoring system for analysis of differential renal-vein and peripheral renin levels, 70% (16 of 23) of these patients did not give scores predictive of cure by nephrectomy. Thus, occult bilateral disease reflected by attendant volume expansion and consequent reactive renin suppression may explain the well-known disappointing cure rate after uninephrectomy in this group. Since unilateral hypersecretion of renin with a completely normal contralateral kidney is rare in this group, abnormal renal-vein and peripheral renin values should be a prerequisite for advising nephrectomy, especially when the suspected kidney shows considerable excretory function.


Genetic disorders of human red blood cells.

Human red blood cells (RBCs) are subject to an enormous degree of genetic diversity. The variability that occurs may result in anemia, cyanosis, polycythemia, or may cause no hematologic alterations. Genetic abnormalities affecting hemoglobin include the sickling disorders, the unstable hemoglobinopathies, hemoglobinopathies associated with polycythemia or with methemoglobinemia, and the alpha- and beta-thalassemias. The most common enzymatic abnormality of RBCs is glucose-6-phosphate dehydrogenase deficiency, but defects of many other enzymes leading to hemolytic anemia have been identified. Deficiences of RBC enzymes may also be important in the diagnosis of nonhematologic disease and in the evaluation of dietary status.


Gastrointestinal dysfunction in immunoglobulin deficiency. Effect of corticosteroids and tetracycline.

Idiopathic late-onset immunoglobulin deficiency in a young man was associated with achlorhydria and a severe intestinal malabsorption syndrome that did not respond to conventional therapy. Combined therapy with high doses of prednisone and tetracycline hydrochloride resulted in weight gain, cessation of diarrhea, improved absorption of water, fat, and vitamin B12, and production of gastric acid after stimulation with histamine. Serum immunoglobulin levels, however, did not increase.


Acromegaly. Treatment by transsphenoidal microsurgery.

Serum growth hormone levels, thyroid function, and adrenal function were measured before and after surgery in 16 of 17 acromegalic patients undergoing undergoing transnasal transsphenoidal microsurgery of the pituitary. Thirteen patients have been followed up for 12 to 24 months; three patients have been followed up for three to six months. Serum growth hormone levels decreased to less than 5 ng/ml in seven of nine previously untreated patients; thyroid and adrenal function were preserved in eight of these nine patients. In seven patients treated previously by other modes of therapy, growth hormone levels after transsphenoidal surgery decreased to less than 5 ng/ml in three, to between 5 and 10 ng/ml in three, and from 98 to 41 ng/ml in one. Preoperative adrenal function was normal in six of these seven patients and was preserved in four; thyroid function was normal in five patients preoperatively and was preserved in three. Transsphenoidal microsurgery appears to offer an effective means of lowering growth hormone levels and a possiblity of preserving any remaining normal pituitary function. It may be considered for initial treatment in selected patients in whom more rapid arrest of acromegaly is indicated.


Pulmonary and articular sporotrichosis. Report of two cases.

Two rare forms of sporotrichosis were seen in one hospital within a two-year period. One, a case of primary sporotrichosis of the lung, represents the eighth case on record, to our knowledge. The other, a case of articular sporotrichosis, is not as rare, but is still uncommon manifestation of the disease. The problems in management of these two patients are of interest because of the challenge of conventional concepts of therapy.


Giardiasis.

The recent near-epidemic incidence of Giardia lamblia infection in visitors to the Soviet Union illustrates the importance of this intestinal flagellate as a cause of diarrhea in travelers worldwide. Clinical states range from the asymptomatic cyst-passing stage, to the chronic or subacute stage mimicking gallbladder or ulcer disease, to the transient or, rarer, persistent acute stage with steatorrhea and substantial weight loss. Symptoms may be related to IgA deficiency. Secondary lactose intolerance may follow eradication of the parasite. Diagnosis is usually based on repeated stool examinations or examination of duodenal contents. Quinacrine hydrochloride is the most effective treatment, but metronidazole and furazolidone are also useful. Contaminated water is the most likely source of infection.


Medical information bureau.

The Medical Information Bureau (MIB) is a nonprofit trade association with approximately 700 life insurance companies as members in the United States and Canada. A computer bank that contains primarily medical information is maintained by the MIB. Safeguards are taken to assure confidentiality, and there is no linkage with other computer banks. Information is submitted to the MIB only after the individuals involved give authorization, and they have access to their records and can make corrections if necessary. Dissemination of computer information is made only to member companies when they have a bona fide application or claim and then only with the consent of the person involved. Medical directors of member companies have the primary responsibility for maintaining integrity and seeing that their companies adhere to the rules of the MIB.


Giardia-induced malabsorption in pancreatitis.

This report deals with the onset of Giardia-induced, primary malabsorption in patients with chronic pancreatitis. To our knowledge, this association has been reported only once previously. A further review of the literature suggests that malnourished patients with chronic pancreatitis may be susceptible to G lamblia infection. Therapy for giardiasis rapidly reverses the diarrhea, malabsorption, and edema seen in these patients.


Furuncular myiasis.

We saw two cases of cutaneous myiasis from the larvae of the botfly, Dermatobia hominis. The first patient acquired the disease in Brazil, the second in Guatemala. The appearance is quite similar to furunculosis, but is not responsive to antibiotic therapy. Surgical excision is the treatment of choice.


Sporadic puerperal mastitis. An infection that need not interrupt lactation.

Sporadic (nonepidemic) acute puerperal mastitis was diagnosed 65 times over a period of 26 months in 2.5% of mothers who elected to nurse their infants. Staphylococcus auereus was cultured from the milk of 23 of 48 infected breasts, but from only one breast of 19 normal mothers. Forty-one women with mastitis continued to nurse without difficulty for an average of 13 weeks, although mastitis recurred in four women. Three breast abscesses resulted from the 65 infections (4.6%).


1-alpha-hydroxyvitamin D3 in chronic renal failure. A potent analogue of the kidney hormone, 1,25-dihydroxycholecalciferol.

In chronic renal disease, the synthesis of the kidney hormone, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), is impaired, thus contributing to the development of renal osteodystrophy. The clinical use of 1,25-(OH)2D3 is limited, due to the complexity and expense of its chemical synthesis. This study reports the use of 1-alpha-hydroxyvitamin D3 (1-alpha-OH-D3), an active analogue of 1,25-(OH)2D3, in eight patients with chronic renal failure, five of whom were undergoing long-term hemodialysis. The drug was given orally for 6 to 260 days at a dosage of 1mug to 4mug/day. Short-term (21 days) balance studies showed an increase in intestinal calcium absorption and a simultaneous fall in serum parathyroid hormone levels during administration of 1-alpha-OH-D3. In two long-term studies (160 and 260 days), roentgenographic improvement of renal osteodystrophy was seen after 45 and 185 days, respectively. The data indicate that 1-alpha-OH-D3 holds considerable promise for the prevention and treatment of renal osteodystrophy.


IUD-related hospitalizations. United States and Puerto Rico, 1973.

In a mail survey of physicians likely to be involved with intrauterine contraception in the United States and Puerto Rico, 49.2% of the physicians responded, describing 3,502 unduplicated reports of hospitalizations related to the use of intrauterine contraceptive devices (IUDs) during the first six months of 1973. We estimate from this response that approximately 7,900 IUD-related hospitalizations occurred during that period. Interviews with a probability sample of nonrespondents demonstrated that their IUD complication experience was not substantially different from that reported through the mail survey. Estimates of the number of IUDs worn in 1973 permit rate calculations of three to ten IUD-related hospitalizations per 1,000 woman-years of IUD use. The rate of hospitalizations attributable to the IUD is probably higher that that attributable to combination oral contraceptives.


Mortality associated with use of IUDs.

Five deaths associated with the use of an intrauterine contraceptive device (IUD) were reported during the first half of 1973 through a nationwide mail survey of physicians whose practices were likely to be involved with intrauterine contraception. Four of the five reported deaths involved serious infections, and two of these four occurred in relation to a pregnancy. Use of an IUD prior to death ranged from seven months to 3 1/2 years. The mortality attributable to IUDs is estimated to be lower than that attributable to combination oral contraceptives.


On awakening paralyzed during surgery. A syndrome of traumatic neurosis.

We have observed several cases of a traumatic neurotic syndrome in patients who awakened from light anesthesia while still unable to move. The subsequent symptoms of anxiety and irritability, preoccupation with death, and repetitive nightmares should lead the physician to suspect the condition even though the patient is reluctant to talk about it. A direct explanation of the situation often serves as a dramatic cure.


Bitemporal visual field defects in presumed multiple sclerosis.

Three patients with presumed multiple sclerosis had bitemporal hemianopia mimicking that caused by parasellar tumors; the visual loss was probably due to a plaque within the chiasm. The diagnosis of multiple sclerosis was made on the basis of a history of relapse and remission, signs and symptoms indicating involvement of different levels of the central nervous system, and normal neuroradiological studies. Extensive neuroradiological studies may be delayed or omitted in patients with established multiple sclerosis and nonprogressive bitemporal visual field defects if central visual acuity is not greatly reduced.


Cardiac pacemakers. Does radiation therapy affect performance?

Representative deman cardiac pacemakers were tested with several common radiation therapy devices and ancillary equipment. The experimental set-up essentially duplicated the dosimetric and electroconductive environment of the radiation therapy patient bearing a pacemaker. Observations of pulse width and interval confirmed that pacemaker output was generally not appreciably affected by the simulated treatments. Occasionally, changes were caused by ancillary equipment and start-up of treatment. We conclude that although interference hazards are sometimes seen, radiation therapy is not contraindicated in patients wearing pacemakers.


A large food-borne outbreak of hepatitis A. Possible transmission via oropharyngeal secretions.

In Minneapolis, 107 cases of hepatitis A were identified and traced primarily to consumption of cold sandwiches served for lunch in a department store's popular basement restaurant. A sandwich-maker in the restaurant was the index patient. The date of onset of her illness and the dates of food consumption and onset of illness of infrequent restaurant patrons were consistent with accepted periods of infectivity and incubation for hepatitis A. Because the sandwich-maker frequently touched her hands to her mouth when she worked, and because we could not find evidence for fecal, airborne, or other modes of transmission, we believe that she may have contaminated food with infectious oropharyngeal secretions. The secondary attack rate was much lower among household contacts who received immune serum globulin than among those who had not.


Effect of peyote on human chromosomes. Cytogenetic study of the Huichol Indians of Northern Mexico.

Fify-seven Huichol Indians with a lifelong individual history and a 1,600-year cultural tradition of ingestion of peyote, a mescaline-containing cactus possessing hallucinogenic properties, were compared with 50 Huichol Indian controls and ten laboratory controls for effects on lymphocyte chromosomes. The frequency of abnormalities in the experimental and control groups did not differ significantly. Our results indicate that multigenerational ingestion of peyote is not associated with abnormalities in lymphocyte chromosomes.


Unilateral exophthalmos. Occurrence after treatment for perichiasmatic neoplasms.

Unilateral exophthalmos developed shortly after treatment in three patients with chromophobe adenoma of the pituitary gland and craniopharyngioma. In two patients, the exophthalmos followed surgery, while in the third it did not appear until after radiation treatment. The pathogenesis of the exophthalmos in these cases in obscure. However, the other findings and subsequent course indicate that the exophthalmos is not due to recurrence of the neoplasm nor to a complication of therapy.


Injectable fluid silicone therapy. Human morbidity and mortality.

Four patients who had received silicone injections had the following complications: migration, hepatic disease manifested as granulomatous hepatitis (previously undescribed, to our knowledge), hypopigmentation, and death. Silicone should now be considered as a possible cause of hepatic granulomas in an appropriate host.


Nontoxic goiter-diffuse or nodular.

Nontoxic goiters are very common. A single hyperfunctioning nodule is never malignant. Treatment is required only if the patient is hyperthyroid. Most single hypofunctioning thyroid nodules are cool and most are benign; however, it is important to rule out malignancy. The presence of microcalcification is consistent with psammoma bodies and the presence of papillary cancer of the thyroid. An elevated plasma calcitonin level with a further increase in calcitonin after calcium infusion is usually characteristic of medullary cancer of the thyroid. Needle biopsy of the thyroid is recommended when an experienced surgeon and pathologist are available. The treatment of benign thyroid lesions may include a trial of fully suppressive doses of thyroxine.


Social background of 171 women attending a femal venereal disease clinic in Brisbane.

A survey over 12 months was carried out on 171 women and girls attending the State Health Department Women's Clinic in Brisbane. Each person was interviewed to obtain data on occupation and educational and family background, attitude to sex, knowledge of venereal disease and other pertinent attitudes. It was obvious that most patients came from lower socioeconomic groups and had little knowledge of venereal disease. The former finding may have been because women from the upper middle and professional classes seek private advice. The need for social workers in venereal disease clinics has been emphasized.


Iron nutrition in infancy: effect of an iron-fortified milk formula.

Iron nutrition in infants was studied in a double-blind trial with artificial milk formula. Statistically significant differences were observed with the iron-fortified formula. Not all haematological indices showed significant differences. The fragiligraph technique result was the only parameter showing differences not influenced by other variables examined.


Morphological changes in the nucleoli of peripheral-blood lymphocytes as prognostic criteria in the chemotherapy of malignant tumors.

By a simple cytochemical demonstration of RNA, the percentages of various nucleolar types, reflecting the activity of RNA synthesis in peripheral-blood lymphocytes, were established. The checkings were done in patients with advanced stages of malignant tumors processes with primary localization in the digestive tract, receiving cytostatic treatment with Cytembena Spofa and Cyclophosphamide Germed. Evidence has been brought that significant differences in the indicators investigated existed between a healthy population and patients with cancer before the start of the treatment. In the further course of the disease, during cytostatic treatment, peripheral lymphocytes underwent changes followed sooner of later by changes in the clinical state of the patients: a decrease in the percentage of activable (ring-shaped) nucleoli, and increase in the percentage of irreversibly inactivated nucleoli (micronucleoli) incapable of RNA synthesis, and an elevation of the nucleolar coefficient were followed by a deterioration of the patients' clinical state and a progression of the tumorous disease. With an opposite trend of the nucleolar-test findings (an increase in the percentage of nucleoli capable of RNA synthesis, a decrease in the percentage of nucleoli incapable of RNA synthesis, and a lowering of the nucleolar coefficient), the further development of the disease appeared to be favourable.


What are infants fed in the United States?

Estimates of calorie intake from various sources during infancy are presented in relation to age. The estimates, based on published reports and personal communications to the author, concern total calorie intake and its distribution between milk or formula and beikost (i.e., foods other than milk or formula fed to infants), relative prevalence of breast, formula- and milk-feedings, relative popularity of specific commercially prepared formulas, and percentage of calories consumed in the form of commercially prepared strained and junior foods and "table" foods.


The role of BCG vaccination in producing tumor immunity. An experimental study.

A transplantable hamster lymphoma was investigated to determine the role of BCG-immune macrophages in killing tumor cells. The suppression tumor cell growth was tested by the transfer of different combinations of lymphoid and tumor cells into 162 normal inbred (LHC) hamsters. The results demonstrated that the transfer of a combination of BCG-immune macrophages and tumor-immune lymphocytes to normal hamsters suppressed the growth of these tumor cells. We suggest that immunization with BCG increases the killing potential of macrophages, and that tumor-immune lymphocytes may cause these "activated" macrophages to release their toxic enzymes to cause necrosis of adjacent tumor cells.


A technique for thyroidectomy.

For several decades following the turn of the century, most thyroid surgery was necessary because of endemic goiter and Grave's disease. A lack of safe anesthesia and an inability to control hyperthyroidism preoperatively necessitated a rapid operating technique. This often meant blind resection of the bulbous anterior and lateral portions of the gland, resulting in considerable hemorrhage and injury to the recurrent laryngeal nerve in a significant number of cases. With the subsequent introduction of iodine into food and the use of radioactive iodine and the antithyroid drugs, surgery for these conditions was largely eliminated. Nevertheless, the thyroid surgeon of today still has a role in surgery of thyroid cysts, nodular goiter, and multinodular goiter either for cosmetic reasons or because of tracheal or esophageal obstruction. In addition, surgery is still required for nodular goiter with hyperthyroidism and thyroid cancers. Modern anesthetics and preoperative control of thyrotoxic patients afford the surgeon an opportunity for anatomic dissection of the thyroid. This article deals with an evolving technique for thyroidectomy individualized according to the pathophysiologic requirements of each case. The illustrations apply to a patient with a right lobe thyroid nodule. The variations in technique required for different thyroid disorders will be reviewed.


Effect of methylergobasine maleate on serum gonadotrophin and prolactin in humans.

Intramuscular injection of 0.2 mg methylergobasine maleate3) (Methergin, Sandoz) in women on day 3 post-partum, in regularly menstruating women and in adult men, is followed within 30 to 75 min by a 50% decrease in serum prolactin concentration: the levels remain low until 180 min and increase between 180 and 240 min. The amplitude of the decrease is the same when prolactin is measured in terms of the same serum prolactin standard by a homologous ovine assay and by a homologous human assay. However, in the case of regularly menstruating  women and of men serum prolactin concentration is some three times higher when estimated by the ovine assay than when estimated by the human assay. This difference between assay results obtained by the two radioimmunoassay methods could be due to heterogeneity of serum prolactin. However, non-specific effects of serum are not excluded. In regularly menstruating women and in men, intramuscular injection of 0.2 mg methylergobasine maleate is followed within 45 to 75 min by a 50% decrease in immunoreactive serum LH concentration without concomtant change in immunoreactive FSH. The depression of LH secretion lasts for 1 to 2 h. The circulating levels of HCG in post-partum women are not modified after intramuscular injection of Methergin. In humans as in animals and in in vitro studies, inhibition of prolactin and LH release induced by ergot drugs are likely due to both an indirect effect via the hypothalamus and to a direct effect on the pituitary cells.


Paradoxical effect of salmon calcitonin on serum calcium: studies in intact and thyroparathyroidectomized men and dogs.

Total serum calcium of normal men, a hypoparathyroid man, two thyroparathyroidectomized men, and intact and thyroparathyroidectomized dogs were studied at multiple intervals following the acute administration of synthetic salmon calcitonin. Calcitonin produced marked fluctuations in serum calcium in one normal man and a biphasic hypocalcaemic response in another. In four of five intact dogs, calcitonin caused absolute or relative hypercalcaemia. In contrast, administration of calcitonin to thyroparathyroidectomized dogs caused a hypocalcaemia with less fluctuations and with no periods of hypercalcaemia. It is possible that some of the paradoxical responses of serum calcium induced by exogenous calcitonin are due to overcompensation by parathyroid hormone. However, other mechanisms may be involved. Our findings indicate that when the disturbing influence is sufficiently great, the control of serum calcium is not as well modulated as previously suspected. In addition, our findings of paradoxically hypercalcaemic responses to calcitonin indicates that the pathophysiologic interpretation of serum calcium at any single moment in time following the administration of this hormone to either intact or thyroparathyroidectomized men or dogs is a precarious endeavour.


Studies in congenital generalized lipodystrophy.  VI. Suppressible and non-suppressible insulin-like activities of plasma.

1. Suppressible and non-suppressible insulin-like activities (ILA) of plasma from 3 patients with congenital generalized lipodystrophy have been studied, employing isolated fat cells from rat epididymal adipose tissue. 2. In all 3 patients the fasting ILA was markedly increased compared with the normal controls. In one of the patients (I.T.) total ILA rose to about 800 muU per ml during an iv glucose tolerance test. 3. The observed total ILA was in all cases (controls included) equal to or slightly higher than the previously determined immunoreactive plasma insulin (IRI). The exact determination of ILA was, however, hampered by a dilution effect, which was present even at high plasma dilutions. 4. In 2 of the patients addition of insulin antiserum inhibited plasma ILA by about 50%. In the third patient (I.T.), who exhibited the highest insulin level, at least 85% of the activity was suppressed by insulin antibodies. The levels of non-suppressible ILA were higher than in the controls in terms of muU per ml, but lower than in the controls when related to total ILA. 5. These findings strongly support our previous conclusion that the elevated plasma insulin seen in congenital generalized lipodystrophy is mainly due to true pancreatic insulin. 6. Since the effect of plasma insulin on isolated fat cells were freely expressed, i.e. suppressible ILA was equal to or slightly lower than IRI, the presence of a circulating insulin antagonist in this disease may be excluded.


[Value of determination of mononuclear blood cell proliferation in vitro in the diagnosis of lymphosarcoma].

The authors describe mitotic activity in non-stimulated cultures of mononuclear cells obtained from the peripheral blood of patients with lymphosarcoma. The investigations were carried out on 3 patients in stage 3rd and 4th of this disease and 5 patients in the stage of sarcomatous-cell leukaemia. During a period of 24-48 hours after setting up of culture a rise was observed in the number of blast cells and appearance of up to 10% of mitotic figures. This observation may be useful for differentiation of sarcomatous-cell leukaemia from chronic lymphocytic leukaemia in which cells obtained from the peripheral blood and cultured in vitro without addition of mitogen do not demonstrate mitotic activity.


Hemodialysis for acute anuric uric acid nephropathy.

A patient with acute oliguric uric acid nephropathy was treated with hemodialysis. Recovery in this disorder is based on treatment of both the uremic state and the intrarenal crystal obstruction. Hemodialysis with high uric acid clearance is much more efficient than other forms of therapy in this disorder.


Mechanism of release of endogenous cholecystokinin by jejunal amino acid perfusion in man.

Ertan et al have shown that the perfusion of the proximal jejunum with a mixture of amino acids (MAA) in physiological concentration releases endogenous cholecystokinin (CCK) in man. In the present experiment, we investigate the mechanism by which jejunal MAA perfusion mediates an increase in exocrine pancreatic and biliary secretions. The effects of a bolus of topical anesthetic (oxethazaine, 0.5 mg/kg of 0.4% solution) or the simultaneous jejunal perfusion of a topical anticholinergic agent (atropine, 1 mg/liter) were studied in the same five normal patients on different days. Suppression of the response to jejunal MAA perfusion but not to intravenous infusion of CCK or jejunal saline perfusion, was noted in these normal subjects following jejunal application of oxethazaine and atropine. These results suggest a local involvement of the cholinergic mechanism for the endogenous release of CCK, while exogenous CCK acts directly on the pancreatic cells.


Prevalence of hepatitis B antibody in prostitutes.

The possibility that hepatitis B is transmitted venereally was examined by determining the prevalence of hepatitis B antibody (anti-HB(S)) in populations with different levels of promiscuity. Of 258 prostitutes, 31% were anti-HB(S) positive, compared to 10% of 258 female age-matched blood donors, 10% of 48 nuns living in a convent and 15% of 94 nuns working as teachers. Prevalence of anti-HB(S) increased with increasing age. In the age group 40-49 years up to 72% of prostitutes were anti-HB(S) positive, whereas anti-HB(S) was found in only 23% of blood donors. The correlation of length of the registration period as a prostitute and frequency of venereal diseases to prevalence of anti-HB(S) supported the hypothesis that the agent of hepatitis B was transmitted sexually. This correlation was absent for echovirus type 12 and adenovirus type 10 antibody.


Cancer of the breast: Its outcome as measured by the rate of dying and causes of death.

Mortality forces in women with cancer of the breast were measured by calculating the rate of dying and determining the cause of death in women who develop breast cancer. In the Syracuse-Upstate Medical Center Cancer Registry, 1,513 patients were followed for 15 years. The death curve of this group assumed a major slope characteristic of a single exponential curve, with a half life of 5.9 years. The cause of death was examined in a randomly selected group of patients from the Ontario Cancer Foundation, Hamilton, Ontario, and a group from the Syracuse Registry dying after 10 years. In these 136 patients, 130 died of breast cancer. From the National Cancer Institute Cooperative Studies of 3,225 women undergoing treatment for primary breast cancer, 914 died during the study---705 of cancer of the breast and 209 of competing risks. These data suggest that 80-85% of all women who die after developing cancer of the breast die of their breast cancer. Modification of the time of dying (rate of dying) or cause of death should be used as objectives of management rather than 5-year survival figures.


Triiodothyronine-induced thyrotoxicosis in ophthalmic Graves disease.

A euthyroid woman with ophthalmic Graves disease developed endogenous hyperthyroidism coincident with T3 suppression test. There is a putative role of liothyronine administration in precipitating or activating hyperthyroidism. Aberrancies in T3 suppression testing in graves disease occur.


A method for determination of lecithin/sphingomyelin ratio in amniotic fluid.

A method is described for the evaluation of amniotic fluid lecithin/sphingomyelin (L/S) ratios. The acetone precipitation step is eliminated, resulting in higher concentrations of phospholipids. Silica gel-impregnated glass fiber papers are used for rapid chromatography. For spot detection, a bismuth reagent is used which is specific for lecithin and sphingomyelin. The method is simple, inexpensive, rapid and a reliable indicator of the L/S ratio, and useful in laboratories that are not equipped with a densitometer.


[Ultrasound localization of intrauterine contraceptive devices in the laboratory and in patients (author's transl)].

Three frequently used IUD's were studied in model experiments by ultrasound. The position of the IUD in the uterine cavity can be best outlined by longitudinal and transverse ultrasound section of the uterus in the anteflected or retroflected position. Only rarely can the position of the IUD be properly visualized if the uterus is in middle position and the applicator placed transversly. There is the possibility of misinterpretation of the string as an IUD. The data correlate well with ultrasound results of women wearing an IUD.


[Oocytes from polycystic human ovaries (author's transl)].

Little is known whether oocytes of polycystic ovaries, espacially those of the Stein-Leventhal-syndrome, are able to perform complete maturation. Therefore the maturation capacity of ova derived from biopsies of two patients with polycystic ovaries was investigated using the culture technique with subsequent meiotic preparations. A remarkably high number of 42 and 54 oocytes have been found. The degeneration rates were 76.20% in the polycystic and 85.20% in the Stein-Leventhal-ovaries. The degenerative changes mainly appeared as shrinkage of the ooplasm and partial or total loss of corona cells. 14.28 and 7.40% resp. showed no or incomplete maturation, whether ova remained in dictyotene stage or were found arrested shortly after resuming meiosis. Four oocytes from each of the two patients underwent normal meiosis. A biovular follicle, observed in the Stein-Leventhal-ovary, is particularly mentioned. It may be concluded, that the majority of the oocytes of polycystic ovaries is degenerate, but there are a few ova able to mature in vitro.


[The so-called "reserve cells" of the human cervical (author's transl)].

I. Basal cells occurring focally beneath the columnar epithelium of the endocervix are generally regarded as "reserve cells". Single "reserve cells" cannot be identified among the columnar epithelial cells. II. Single "reserve cells" would not be needed for the regeneration of the cervical mucosa, since the normal columnar, cells themselves are capable of undergoing mitotic division. During such mitoses the mitotic spindle is located above the regular row of nuclei, the axis of the spindle running parallel to the basement membrane and surface of the cell, so that the daughter cells separate in a horizontal direction. Consequently, the term "reserve cell" with its functional implication is misleading and should be replaced by a more descriptive term such as the "subcylindrical"cell. III. It seems that for development of focal groups of subcylindrical cells according to I the columnar cells must proliferate locally. That proliferation could occur with the axis of the mitotic spindle rotated 90 degrees to be perpendicular to the basement membrane. More likely, however, the columnar cells seem to undergo mitoses with their spindles parallel to the basement membrane and accumulate locally to form two layers. On further proliferation of the basal layer, with the mitotic spindles rotated 90 degrees to be perpendicular to the basement membrane and with desquamation of the overlying columnar cells, the than multilayered epithelium may differentiate by indirect metaplasia into squamous epithelium.


Endometriosis of the lung: case report.

The first case of a clinically and histologically verified miliary form of endometriosis of the lung is reported here. The cardinal symptom was a menstrually synchronised hemoptysis, which by treatment with high doses of progestins disappeared. After operative castration a complete remittence with normal chest X ray was attained. Pathogenesis and frequency were briefly described. The 11 previously published cases served as a basis. Taking into account experimental and clinical experience, we propound the opinion the endometriosis of the lung occurs via hematological spread as a result of uterine operations or pregnancy. The conditions under which endometrium survives in the lung remain uncertain. Large doses of gestagen drugs are to be recommended as therapy and should be this prove unsuccessful operative castration.


Results of in vitro sperm penetration tests in cervical mucus in the normal cycle and in mucus under the influence of the contraceptive pill.

Women who are either menstruating normally or taking a combined or sequential preparation for hormonal contraception were examined at intervals of 2 days with reference to the day of the cycle. The parameter studied was the in-vitro penetrability of the cervical mucus for sperms. Whilst the combined preparation completely blocked the cervical canal for the spermatozoa, the distance travelled by the spermatozoa under the influence of the sequential preparation was approximately the same as in the normal cycle. This study of the depth of penetration of the spermatozoa in relation to the hormonal situation was prompted not by contraceptive but rather by epidemiological considerations of cervical carcinoma.


How do oocytes disappear?

It has been study using transmission and scanner electron microscopy the mean procedures of dessaparence of the oocytes. On described three methods: 1. The necrosis of the oocytes. 2. The autolysis and fagocitosis by granulosa cells. 3. The migration of those to the superphicie and fall into the peritoneal cavity. Using the scanner electron microscopy in ovaries of fetus and newborn it seems the latest method to bee the most important during the intrauterine life. After the birth, this last phenomenon seems to disappear.


Cardiobacterium hominis endocarditis with cerebral mycotic aneurysm.

Cardiobacterium hominis, a recently recognized Gram-negative pathogen, was recovered in blood cultures from a 65-year-old man with indolent endocarditis of previously normal heart valves. Despite the low virulence of the organism, major cardiac damage required valvular replacement, and there were multiple cerebral emboli with development of a mycotic aneurysm. After bacteriological cure, he died of a ruptured aneurysm.


[Light and electron microscopic investigations on the chorionic plate of the human placenta at term (author's transl)].

The chorionic plate of the human placenta at term consists of amniotic epithelium, amniotic connective tissue, intermediate layer, chorionic connective tissue, cytotrophoblast, and syncytiotrophoblast. - The connective tissue layers are divided into unorientated (situated just below the amniotic epithelium and in direct contact with the trophoblast) and orientated layers (between the two unorientated connective tissue layers). Besides an accelular border below the amniotic epithelium the connective tissue includes fibrocytes, fibroblasts, histiocytes, and old Hofbauer cells in the intermediate layer. - From the edge of the chorionic plate to its centre, the number of well preserved cytotrophoblasts decreases; instead of them especially intercellular substances (subchorial fibrinoid) but also degenerating cells predominate. In the trophoblast layer rests of chorionic villi are localized. Among the intact cytotrophoblasts 4 types can be distinguished (less differentiated, well differentiated, spongiotrophoblast-like, and glycogen-rich cytotrophoblastic cells). They are interpreted as different developmental stages of one and the same cell population. - The syncytiotrophoblast is inter rupted at many places; only fragments can be observed. Then cytotrophoblastic cells or intercellular substances may form the border to the intervillous space.


Lymphosarcoma involving cranial nerves in a cat.

A case of lymphosarcoma involving some cranial nerves in a cat is described. Clinical diagnosis of the condition was complicated by a concurrent bilateral otitis media; however, at autopsy it was determined that the signs seen were a direct result of the involvement of 6 cranial nerves, and the anterior cervical ganglion, by the neoplasm.


Hyperbaric oxygen and pulmonary surface tension.

Previous work has shown that short-term exposure of cats to oxygen at high pressure (OHP), to the extent of overt convulsive seizures, has little or no effect on the lung appearance or lung weight but does alter the alveolar surfactants. More prolonged exposure results in hemorrhagic edema of the cat lung similar to that observed in rats after only short-term exposure. Previous work showed that sympathetic stimulation via the stellate ganglion and mechanical CNS injury results in altered surfactants attributed to increased intra-alveolar cholesterol. In the present study, cats exposed to OHP until the animals convulsed intermittently for 3 min (approximately 1 hour, 6 ATA) similarly showed altered surfactants with a high minimum surface tension and a 150% increase in intra-alveolar cholesterol. These changes also occurred in the absence of any gross lung injury. The results from the present study suggest that an important causal mechanism involved in the development of gross lung injury associated with prolonged OHP exposure is an initial increase in minimum surface tension due to increased intra-alveolar cholesterol.


Tumors in fish caught in polluted waters: possible explanations.

The largest excess in tumor incidence due to pollution (616%) was observed in the fish species: Ictalurus nebulosis (the brown bullhead). Extensive analysis of waters on the Fox River in Illinois disclosed a heavy chemical and physical organic and inorganic materials far exceeding State and Federal minimal safety standards. Additional tests showed the presence of numerous human viral agents in the Fox River. Certain chemicals in the water appear to be potential carcinogens for fish. Two types of leukemia were found in 11% of the Esox lucius caught in the Fox River. It is hypothesized that these leukemias might also be of viral etiology. Experiments were conducted on Esox lucius caught in the Fox River. It is hypothesized that these leukemias might also be of viral etiology. Experiments were conducted on Esox lucius (Northern Pike). Interest centered around the possible viral origin of lymphosarcoma of the jaw in that species. Cell-free filtrates of this tumor were inoculated into a test group of fish from pollution-free waters. At the end of seven weeks, lymphosarcoma developed in 89% of the fish inoculated with cell-free homogenates. Control fish receiving inoculation of either Hank's balanced salt solution (HBSS) or normal tissues and kept in separate tanks at all times did not develop lymphosarcomas.


Biohazards in the field of microbiology.

Eighty cases of laboratory infection observed in our institute during 25 years were summarized. They were mostly research workers. Cases include not only manifestation of disease but also incidence of allergic responses. Causal agents were viral 22, rickettsial 14, bacterial or fungi 33, and toxin 11. Air contamination was considered to be the main cause of the above biohazard. Therefore, most of those accidents must be avoided by careful installation of the laboratory. Special attention should be given in laboratories where field specimens are treated and experimental animals housed. It was pointed out that most of the autopsy halls in Japan are little equipped to protect biohazard.


Protection against biohazards in animal laboratories.

An outline of the animal facilities known as the "Quarters for Experimentally Infected Animals" of the Research Institute for Microbial Diseases, Osaka University, is presented as one example of the approaches used for protecting against biohazards in animal laboratories. The quarters are contained in a 2-story building which is in the form of small cubicles for housing the experimentally infected animals. Each cubicle is equipped with specially designed cabinet compartments in which the animal cages are placed. The anterior surface of the compartments consists of an outward inclining door. Vigorous air-mixing between compartments and the interiors of the cubicles can be avoided by this arrangement. The air for ventilation is sucked through a gap between the edge of the door and the wall of each compartment and the collected air is finally filtered through Cambridge "Aerosolve" and "Absolute" filters before being exhausted into the atmosphere. In the central corridor connecting each cubicle the air pressure is maintained at a higher level than that in the cubicle but lower than that outdoors. Thus, the air stream is always kept flowing from the outside to the inside of the cubicle and from the inside of the cubicle to the compartments but never vice versa. Each cubicle is equipped with an individual, pass-through autoclave. All soiled materials are sterilized before being removed from the cubicle. The drained water from each cubicle is chlorinated in a tank by chloride of lime. In these facilities experimentally infected animals can be handled with little danger of accidental contamination of personnel, other animals, or the external environment. The authors emphasize the importance of complete adherence to the rules in such animal facilities.


[The optimization of the availability of homologous quaternary ammonium compounds. 2. In vitro studies on the partition of homologous benzilic acid esters of dimethyl-(2-hydroxyethyl)-alkylammonium bromides].

The partition of homologous quaternary esters of benzilic acid is studied in a modified three-phase model according to Schulmann (water-n-octanol-water). The logarithms of the partition coefficients of the compounds increase linearly with increasing alkyl chain. The rate determining step for the interphase transport of hydrophilic compound is the diffusion through the organic diffusion layer. The rate constants for the transfer from the aqueous to the organic phase increase linearly with the corresponding partition coefficient, whereas the rate constants for the reverse reaction are not influenced. With increasing chain length the diffusion through the aqueous diffusion layer becomes rate determining for the interphase transport. Thus the rate constants for the transfer from the aqueous to the organic phase are independent of partition coefficients. The rate constants for the reverse transfer are inversely proportional to the corresponding partition coefficients. The half-lives of the transfer of the homologous compounds under sink conditions show a minimum between the heptyl and octyl derivative. The equilibration time decreases with increasing agitation, concentration and temperature. The significance of the results for biological problems is discussed.


Biopharmaceutical factors influencing LD50. Part II: Particle size.

The effect of particle size on the time elapsing between administration and loss of righting reflex and % of deaths by determining the LD50 has been studied in mice. The drug used was pentobarbituric acid. In one preparation the particle size was less than 44 mum and in the other preparation it was greater than 297 mum and less than 420 mum. For both preparations a 1% sodium carboxymethylcellulose solution was used as suspending medium. It was found that both the curve for loss of righting reflex and the log dose-response curve, and hence the LD50, were significantly shifted to the right. There is a reflex LRR between the suspended pentobarbituric acid and the equivalent amount of sodium pentobarbital, both in 1% sodium carboxymethylcellulose solution. In reporting LD50 data it is essential not only to state the exact composition of the vehicle (viscosity factor) but also to state the exact particle size or particle size range, because by using increasing particle size the LD50 decreases.


[Stability of oxyfedrine in pharmacological experiments in vitro].

15% of L-3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone-hydrochloride (oxyfedrine [OF]; ildamen¿) are degradated in Krebs-Henseleit solution under conditions which are necessary for recording a complete concentration-effect curve on guinea-pig papillary muscle (total time max. 100 min). Norephedrine and 3-methoxyacrylophenone are qualitatively analysed as products of degradation by thin-layer chromatography (TLC). Secondary reaction products of the primary degradation are not detectable under these conditions. The quantitative analysis of oxyfedrine, norephedrine and 3-methoxyacrylophenone was carried out by spectrophotometry. Comparatively oxyfedrine and norephedrine were analysed by direct quantitative TLC (measuring of reflectance). The same results were obtained, in principle, by both methods. The importance of this relatively slow degradation for pharmacological in vitro experiments on the mode of action of oxyfedrine is pointed out.


[A new method for calculating a compensation function in power series].

A new method for the derivation of a compensation function in power series is developed and compared with the linear regression of the logarithms. At the same time from the formulas of the linear regression corresponding formulas for the regression of power series without the need of logarithms are derived. Comparing the newly developed method of the "persistence report" with the linear regression of the logarithms it results that the new method often reaches a better approach of the values of the compensation function to the measured values; furthermore the new formulas are simpler and applicable without computers.


Effect of human plasma lipase on smooth muscle.

In the presence of serum albumin, the enzyme human plasma lipase produces a slow contraction of smooth muscle. This effect was not antagonized by antazoline or by atropine, and was completely abolished by heating the enzyme prepartion for 1 min at 60 degrees C. Calcium ions were found to potentiate the effect of plasma lipase on smooth muscle.


[On the absorption and excretion of raubasin in rats with particular reference to a method for the direct determination of the alkaloid].

A sensitive method has been developed for the determination of raubasin in biological fluids. The procedure involves preliminary solvent extraction of raubasin and its metabolites from alkaline body fluids into chloroform, followed by thin-layer chromatography and in situ fluorimetric quantitation. This method permits the quantitative assay of raubasin down to 0.02 mug with a standard deviation of less than 5%. Drug recovery from plasma is greater than 85%. The method has been applied to the measurement of raubasin concentrations found in rat plasma and urine after a single, oral dose of the alkaloid. A biliary elimination of the unchanged drug and of some metabolites has been demonstrated.


Some pharmacological properties of 2-aryl-1,3-indandione derivatives.

Some pharmacological properties of indandione derivatives have been studied in laboratory animals. These substances possess anti-inflammatory, analgesic and anti-coagulent effects, as already known for other indandione derivatives. In addition they possess anti-tussive effects in mice. Unfortunately many of these molecules have also ulcerogenic effects. This fact is disappointing for those indandione derivatives which already are in therapeutic use, as G/18 (Uridion¿) and Emandione¿. It appears that compounds which have two Br in R1 and R4 position possess at the same time low toxicity and no ulcerogenic effects in addition to anti-inflammatory (G/21) and also anti-coagulant (G/22) interesting activity.


Effects of ajmaline and N-propylajmaline on maximum follow frequency and contractility of the dog heart: short communication.

With intravenous infusion in the anesthetized dog N-propylajmaline (NPA) as compared to ajmaline leads to a significantly larger decrease in left ventricular dp/dtmax with equieffective reduction of maximum follow frequency by 25%, and, also in contrast to ajmaline, to a significant increase of left ventricular enddiastolic pressure.


An investigation and some parameters that affect the galactosamine model of hepatitis in the rat.

1. The effect of d-galactosamine hydrochloride on the livers of rats was observed by measuring serum transaminase levels and histological examination. 2. Galactosamine caused dose related liver cell damage when given i.p. and s.c. but was ineffective when given orally. 3. The time of maximum effect was 24--48 h after administration. 4. The liver cell damage was modified by the oestrus cycle in female rats. 5. Galactosamine when given in proportion to body weight tended to be less effective as body weight increased.


[Studies of the metabolism and excretion of silybin in the rat].

The metabolism and excretion of silybin (as N-methyl-glucamine salt) was investigated after intravenous and oral administration to rats. In the urine, silybin was excreted mostly in the unchanged form after intravenous as well as oral application, whilst in the bile it appeared above all in the form of metabolites. By hydrolysis with arylsulfatase/beta-glucuronidase, the metabolites were identified as sulfate and glucuronide conjugates of silybin and dehyrosilybin; the latter appeared in small quantities as a dehydrated product of silybin. After intravenous injection of 20 mg silybin per kg body weight, the excreted amount of silybin after 48 h was 8%, whereas 76% was eliminated in the bile within the same period of time. After oral application of 2--20 mg silybin/kg body weight 20% after 40 mg/kg 35% and after 120 mg/kg 20% of the administered silybin was excreted in the bile during 48 h. The maximum excretion rate was achieved at application of 20 mg/kg p.o. after 1 h. At this dosage, 2--5% was eliminated within the same time in the urine. The excretion of silybin mainly took place (more than 80% of the total of excreted bilybin) in the bile, both after oral and intravenous administration.


Influence of sulpiride on gastrointestinal motility: experimental radiological study in the dog.

A radiological study has been carried out in the dog to control the influence of N-ethyl-2(2-methoxy-5-sulfamido-benzamidomethyl)-pyrrolidine (sulpiride) on the motility of the gastrointestinal tract. The drug was administered orally and parenterally at different doses for each pharmaceutical form and for such route of doses for each pharmaceutical form and for each route of administration. In doses which were considered optimal, the results have demonstrated that sulpiride exerts hypertonic and hyperphasic effects on the smooth musculature of the gastrointestinal tract. Consequently, there is a reduction of the transit time and of the emptying of the opaque meal in the various sectors of the gastrointestinal tract, which is in the order of about 50% with respect to normal. Using doses which are inferior to those considered optimal, no significant results were obtained, while following higher doses the action of sulpiride is manifested by an inhibitory effect on gastrointestinal motility.


[The physiology of the isolated dog pancreas--the influence of the actual blood glucose level on the blood circulation in the pancreas].

1. Glucose loading tests were undertaken on isolated pancreas or pancreas-duodenal preparations. 2. In 75% of cases a vasodilatation can be observed which leads to enhanced blood circulation under constant pressure in the isolated organ. 3. This vasodilatation persists until the level of blood sugar has normalized. 4. The experiment being carried out on an isolated organ, external factors such as the vagus nerve, do not become active.


Morphological changes after simultaneous administration of isoproterenol (ISO) and K+,MG2+-Aspartate (KMg-ASP) as a physiological Ca2+ antagonist.

Calcium antagonistic compounds including physiological ions of K and Mg are supposed to protect the heart against the deleterious effect of calcium overload. Pretreatment with K,Mg-aspartate in a single i.v. dose of 100 mg/kg was performed in dogs 5--10 min prior to isoproterenol chloride injection in a single dose of 7 mg/kh s.c. Administration of K,Mg-aspartate alone in the above-mentioned dose produced reversible changes of mitochondria after 2--6 hr. K,Mg-aspartate pretreatment applied prior to isoproterenol application revealed summarization of both K,Mg-aspartate and isoproterenol-produced changes after 2--6 h without significantly preventing hypoxic-like alterations. However, the final result after 24 h was good improvement of ultrastructure generally resembling metabolic regeneration and/or enhanced metabolic activity.


Comparative studies concerning the suitability of European hamsters and Syrian golden hamsters for investigations on smoke exposure.

The suitability of the European hamster and the Syrian golden hamster for experiments with tobacco smoke has been tested under various conditions by exposure of the animals to total smoke and the gas vapour phase of two cigarettes. Respiration rate, tidal volume and CO-Hb concentrations were measured before and after the exposures. The results demonstrate that the European hamster tolerates smoke inhalation under all conditions studied better than the Syrian golden hamster. In addition, the haemoglobin of the European hamster showed a markedly lower affinity for carbon monoxide than that of the Syrian golden hamster. In the European hamster, therefore, the danger of CO poisoning after repeated exposures to tobacco is much smaller than in the Syrian golden hamster. The European hamster can be regarded as a more suitable model for investigations with highly concentrated and prolonged smoke inhalations.


Pharmacological properties of 6,7-tetramethylene-5-phenyl-1,2-dihydro-3H-thieno[2,3-e](1,4)-diazepin-2-one (QM-6008, thiadipone), a new psychotropic drug.

The pharmacological actions of 6,7-tetramethylene-5-phenyl-1,2,-dihydro-3H-thieno]2,3-e](1,4)-diazepin-2-one (QM-6008, thiadiapone), a new psychotropic drug, have been studied. QM-6008 shares many of the psychosedative effects in rodents of benzodiazepines. The electroencephalographic actions in rats and rabbits of QM-6008 and chlordiazepoxide are also rather similar. This new compounds is endowed with clear conflict attenuating properties in an approach-avoidance schedule and can be considered, in consequence, as a new potentially useful anxiolytic drug. In other operant conditioning procedures in rats--Variable Interval and Discriminated Avoidance--QM-6008 induces an increase in response rate which is not generally shared by chlordiazepoxide. The psychopharmacological data collected in the present work leal to classify this new thienodiazepine derviative within the fram of tranquilizers of the benxodaizapine type. The sedative effects of QM-6008 appear howerer to be less potent and the psychostimulatn effects more markde than those ofchlordiazeposide.


[Quantitative determination of the main metabolites of acetylsalicylic acid. 1. A method for the quantitative determination of salicylic acid and its metabolites. Studies in healthy individuals].

For special purposes a combination of methods is described which allows to determine salicylic acid (including acetylsalicylic acid) and its main metabolites in blood plasma and urine separately and quantitatively. Salicylic acid (SA) and salicyluric acid (SU) are extracted from the acidified fluid with ether and afterwards reextracted in an aqueous phase. By fluorometry at different wavelengths, it is possible to differentiate between SA and SU. The conjugates of SA and SU are hydrolyzed with sulfuric acid and then extracted in the form of SA and SU. The four analyses (SA, SU and their conjugates) are of satisfying accuracy and sensitivity. To test the validity of the method in vivo, the concentrations of SA and its conjugates were determined in the plasma and urines of healthy volunteers. By a simplified, but nevertheless accurate, modification of the described method total salicylate in the urine can be determined.


Pharmacokinetic analysis of ampicillin concentration in neonates: comparison of two pharmacokinetic models and of two numerical methods.

Ampicillin blood levels after i.m. injection were analysed according to a one and a two-compartment pharmacokinetic model. The two-compartment model gave no substantially better fit to the data than a one-compartment model. To fit the one-compartment model two computer programs based on different numerical methods, were tested. The BMD program gave satisfactory results in all cases.


Conformation and motion of the choline head group in bilayers of dipalmitoyl-3-sn-phosphatidylcholine.

The conformation and motion of the choline head group in lipid bilayers above and below the gel-to-liquid crystal transition point are studied by means of deuterium and phosphorus magnetic resonance. For this purpose dipalmitoyl-3-sn-phosphatidylcholine is selectively deuterated at various positions on the choline and glycerol constituents. The residual deuteron quadrupole couplings and the phosphorus chemical-shift anisotropy of the corresponding lipid-water mixtures yield quantitative information on the segmental motions. The choline methyl group is only slightly hindered in its movement, but the motional freedom becomes increasingly restricted the closer the segment is located to the glycerol backbone. The average value of the OC-CN bond rotation angle changes with temperature. Increasing the temperature rotates the choline methyl group into the vicinity of the phosphorus atom. The choline group as a whole is thus characterized by a flexible, temperature-dependent structure. Its orientation in space is not fixed, either parallel or perpendicular to the bilayer surface. Instead all segments execute angular oscillations with varying degrees of restriction around the normal on the bilayer surface. The gel-to-liquid crystal phase transition at 41 degrees is clearly reflected in the deuterium and phosphorus resonance spectra of the choline moiety, while no change is observed at 34 degrees. The calorimetric pretransition at 34 degrees seems not to be associated with a conformational change in the choline group.