[1st case of eosinophilic meningitis in Reunion, probably due to Angiostrongylus].

Report of the case of a six-year-old child who presented a meningitis with 40 % eosinophils in the cerebrospinal fluid and which spontaneously regressed. These clinical data and the serologic (positive test for many nematod antigens) and epidemiological findings (presence of Angiostrongylus larvae in terrestrial gasteropod) lead to the conclusion that we were in presence of the first case of eosinophil meningitis due to Angiostrongylus cantonensis reported in the island of la Réunion.


[Epidemiological study of onchocercosis in 5 villages of the valley of the Sanaga (Cameroon)].

The study carried out in five villages in the Sanaga Valley of Cameroon was concerned with the prevalence of the disease, the level of infection and an evaluation of the effect of the parasites on the health of the people. Entomological data were also collected. The study was concerned with the onchocerciasis found in the forest area where the disease is hyperendemic. The males are infected moreoften than the females. Among the adults the skin and lymphatic lesions are extremly important. It was found that as the visual acuity diminishes with age, from age forty many for the people are blind. The villages most affected are those situated near the Sanaga rapids where there is a concentration of the breeding sites of the vectors.


Activity of 10-chloro-5-(2-dimethylaminoethyl)-7H-indolo [2,3-c]-quinolin-6(5H)-one hydrochloride against experimental tumors in mice and rats.

10-Chloro-5-(2-dimethylaminoethyl)-7H-indolo [2,3-c]-quinolin-6(5H)-one hydrochloride (CIQ) was shown to exert significant antitumor activity against the Ehrlich carcinoma and sarcoma 180 transplantable tumors in mice by the intraperitoneal (ip) or oral (po) routes and when incorporated into diet. A solid tumor induced in BALB/c mice by the subcutaneous (sc) implantation of nonproducer murine sarcoma virus-transformed BALB/3T3 cells was also inhibited by CIQ after ip or po treatment but there was no effect against leukemia L1210 ascites or a transplantable murine renal adenocarcinoma. When tested in rats, CIQ significantly reduced the growth of Flexner-Jobling carcinoma, Murphy-Sturm lymphosarcoma and Walker 256 carcinosarcoma when administered by the ip or po routes. Pretreatment, but not posttreatment, with CIQ slightly inhibited the humoral antibody response of mice to sheep red blood cells. CIQ therefore differs from immunosuppressive agents such as imuran, methotrexate, cytosine arabinoside, or 6-mercaptopurine which affect the antibody response of mice to sheep erythrocytes when administered after immunization.


A flat capillary tube system for assessment of sperm movement in cervical mucus.

A new flat capillary tube system has been developed for studies of sperm movement in cervical mucus. The system is easy to use, employs readily obtainable components, and is amenable to small sample sizes characteristic of human cervical mucus. The system possesses good optical resolution and is suitable for visual assessment of sperm migration as well as more detailed studies of the movement characteristics of individual spermatozoa. The system subjects the mucus to a well-defined and controllable rate of shear deformation. Preliminary experiments have suggested that the swimmming speed of human sperm does not differ in flat capillary tubes of 200-micrometer and 400-micrometer depth.


Molecular basis of familial and acquired phagocytosis deficiency involving the tetrapeptide, thr-lys-pro-arg, tuftsin.

The biological activity and metabolism of the phagocytosis stimulating tetrapeptide (Thr-Lys-Pro-Arg) tuftsin, are discussed. Its effect is shown to be highly specific. It stimulates the phagocytic activity of the blood polymorphonuclear leukocyte. A unique familial deficiency of the tetrapeptide is described. In such patients, moderate to severe infections occur at high frequency. These are most pronounced in children. Biochemical and symptomatic evidence can readily be obtained in one or more children. At least one parent of either sex shows clinical signs or laboratory evidence of defective phagocytosis. Another type of deficiency results from removal of the spleen or from loss of specific function due to leukemic infiltration or embolism.


Kaposi's sarcoma in lymph nodes: histological study of lesions from 16 cases in Malawi.

Biopsy of lymph nodes containing Kaposi's sarcoma from 16 patients showed that the tumour is identical in appearance with that of Kaposi's sarcoma of the skin, regardless of the age of the patient or the mode of presentation. Spread of tumour along sinusoids throughout the lymph node was seen only in the cases of two children with generalised lymphadenopathy, but discrete deposits were present both in lymph nodes regional to skin lesions and in lymph nodes from patients who had presented with primary lymphadenopathy. The reaction of the remainder of incompletely involved nodes was variable. No transition was seen between Kaposi's sarcoma and malignant lymphoma.


Gm phenotypes in autoimmune thyroid disease.

The Gm phenotype Gm f,b or Gm f,n,b was found in all forty patients with Graves' disease studied, contrasted with thirty-five out of forty controls and twenty out of thirty-one patients with thyroiditis. The difference between the two groups with autoimmune thyroid disease was significant. These results suggest that thyroid stimulating antibodies may be allotypically restricted.


Influence of diet on growth in the rat.

Twenty-eight-day old male Sprague Dawley rats were fed, either ad libitum or in restricted amounts, isoenergetic diets containing 2%, 5%, 10%, 15%, 25%, or 50% lactalbumin protein and 5%, 11.9%, or 21.1% fat for 8 weeks and were then killed. Weekly food consumption and body weight, terminal weight, body water and lipid, and liver weight, DNA, RNA, protein, and lipid were measured. The growth rate increased progressively with each increase in the level of dietary protein up to 25% protein and then declined. Growth was also accelerated by a high fat diet but was retarded by restriction of energy intake. Total body lipid correlated directly with the level of fat in the diet. Multiple regression analysis of the type: Y = beta0 + beta1X1 + beta2X2 + B3X3 + B4X4 where Y = rate of weight gain X1 = dietary protein level, X2  = protein efficiency ratio, X3 = appetite factor, and X4 = energy/protein ratio, showed that the maximum rate of weight gain of 58.8 g/week occurred when the diet contained 23% protein. Growth rate declined when the diet contained a higher protein level.


Unchanged incidence of bronchopulmonary dysplasia in survivors of hyaline membrane disease.

To test the hypothesis that decreased mortality from severe HMD will result in increased morbidity from BPD, chest films of 30-day survivors of severe HMD were reviewed for evidence of Northway's Stage IV BPD. During July, 1970 to June, 1971, 20 survivors of severe HMD were identified; one case of Stage IV BPD was found in this group. During July 1974-June 1975, 80 survivors of severe HMD were identified; five infants had BPD. In spite of more survivors of severe HMD, no increase in the incidence of BPD could be demonstrated.


Bioavailability of acetazolamide tablets.

Plasma acetazolamide levels were measured by an enzymatic assay following single 250-mg oral tablet doses to 20 healthy volunteers; five different lots of acetazolamide tablets from a single manufacturer were used in a balanced incomplete block design. From the measured plasma levels, estimates of the bioavailability parameters (area under the plasma concentration versus time curve, time to peak plasma concentration, and peak plasm concentration) were obtained by least-squares digital computer fitting. No significant differences among the tablets were observed (alpha = 0.05) for the analysis of variance of the area under the curve or time to peak parameters. Two tablets, however, provided statistically higher peak plasma concentrations than the other three. Thus, lot-to-lot bioinequivalence of acetazolamide tablets was observed. Some in vitro tests employed showed general trends for correlation with the in vivo data. However, considerable refinement of these technique appears necessary for in vitro prediction of the observed lot-to-lot bioinequivalence.


Incidence of thyroid disorders in Connecticut.

A prospective study involving 1,544 patients who had annual physical examinations during a one-year period was conducted to determine the incidence of htyroid abnormalities in a practice of general internal medicine. A total of 5.8% abnormalities were found including nodular disease, thyroiditis, Graves' disease, hypothyroidism, simple goiter, and iatrogenic hyperthyroidism. No thyroid cancer was detected.


[The so-called shock lung, a disease of lung parenchyma (author's transl)].

Although the pathogenesis of the so-called shock lung is different, from the clinical point of view the syndrome is uniform. Regarding the morphology microcirculation, vascular permeability and surfactant of the lung in shock lung are discussed. The course of the alterations in lung parenchyma is uniform, independent of the different pathogenesis in a single case. Pathology and disturbtion of lung function are conform. The relation of the so-called shock lung to other diseases of lung parenchyma is discussed and finally a definition of the so-called shock-lung recommended.


Prolapse of the umbilical cord: a study of 69 cases.

Prolapse of the umbilical cord occurred 69 times in 30112 deliveries. The incidence was higher in abnormal presentations, particularly in compound presentation (11.1%), and in breech presentation (2.9%), especially when these occurred in association with prematurity. Twenty-five (36.2%) of the 69 infants died; 21 of these were dead at the time of diagnosis of cord prolapse, two died in the neonatal period of respiratory distress syndrome, and two died from complications of breech extraction. Reduction in perinatal mortality will be possible only if early diagnosis of cord prolapse can be made by means of vaginal examination or fetal heart monitoring, and the birth trauma associated with difficult vaginal delivery prevented.


A new antidepressant butriptyline: plasma levels and clinical response.

Ten patients who suffered from a primary depressive illness were treated with a new antidepressant drug butriptyline (150 mg/day). Six of the patients showed marked clinical improvement, as judged by depression rating scores, at the end of 22 days of treatment. No simple relationship was found between clinical response and plasma butriptyline concentration. Butriptyline is an effective antidepressant agent, well tolerated and with few side effects.


[Immunoblastic sarcoma: considerations on a recently observed case].

Supervening immunoblastic sarcoma in a patient with congenital immune deficiency is described. The literature suggests that this sarcoma may be a hyperimmune form similar to the GVHR described by Frizzera and the question whether or not angioimmunoblastic lymphadenopathy had previously occurred in the present case is discussed. The part played by the spleen and the effect of splenectomy on the progression of the disease are also examined.


[Local therapy of metastatic pleural effusions with zusammenfassung proteolytic enzymes (author's transl)].

From 1970 to 1976, 268 patients with pleural effusions underwent local therapy with the polyenzyme preparation Wobemugos; 235 patients were evaluable regarding the effectiveness of this therapy. In 115 of the cases, the primary tumour was carcinoma of the bronchus, in 86, carcinoma of the breast, in 9, mesothelioma and carcinoma of the ovary each, and in 16, other malignancies. There was a total remission of pleural effusions in 42% of the cases, a partial one in 41%, and no effect in 17%. In spite of the relatively large number of patients, some difficulties in interpreting the present results still remain and will be discussed in this paper.


[Clinical experiences with Holoxan in small cell carcinoma of the bronchus (author's transl)].

Clinical experiences obtained until now in the treatment of 47 patients with small cell carcinoma of the bronchus with Holoxan are reported. Special emphasis is laid to the results of a prospective randomized study; two groups of patients, one of them undergoing Holoxan therapy, the other receiving symptomatic treatment, have been investigated in respect of relationship between tumour remission, quality of life and survival time.


[Progress in the surgical treatment of cervix carcinoma].

The radioisotope radical operation may cause an improvement of results in carcinoma of the cervix stage I b, II, and IV. The increased yield of lymph nodes enables a more reliable prognosis in advanced cases. Recurrent tumors at the pelvic wall may be detected earlier by isotope nephrography.


Nonhyperoxic retrolental fibroplasia.

Retrolental fibroplasia (RLF) has most often been observed in preterm infants exposed to high ambient oxygen concentrations. This case report describes an infant near term who was never exposed to supplemental oxygen but in whom stage 4 RLF developed. The etiologic role of exchange transfusion is discussed.


[Changes in the acetylcholine concentration and acetylcholinesterase activity in the thyroid gland tissues and in serum cholinesterase activity in goiter].

A study was made of acetylcholine concentration and of the acetylcholinesterase activity in the thyroid gland tissue, as well as of the serum cholinesterase activity in the toxic goiter. This disease was accompanied by an elevation of the acetylcholine concentration and a fall of the eacetylcholinesterase activity. As to serum cholinesterase--it changed but little in this disease.


[Blood serum magnesium content and its excretion by the kidneys in thyrotoxicosis].

A study was made of magnesium content in the blood serum and the urine of 62 patients with thyrotoxicosis before and after the parenteral administration of magnesium sulfate (load dose). Blood serum magnesium content was diminished; as to its renal excretion--it failed to differ from that in the control group. The mentioned disturbances in magnesium content were more pronounced in patients with thyrotoxicosis for a long time.


[A method to measure the mean thickness and non-uniformity of non-uniform thin film by alpha-ray thickness gauge (author's transl)].

The alpha-ray thickness gauge is used to measure non-destructively the thicknesses of thin films, and up to the present day, a thin film with uniform thickness is only taken up as the object of alpha-ray thickness gauge. When the thickness is determined from the displacement between the absorption curves in the presence and absence of thin film, the absorption curve must be displaced in parallel. When many uniform particles were dispersed as sample, the shape of the absorption curve was calculated as the sum of many absorption curves corresponding to the thin films with different thicknesses. By the comparison of the calculated and measured absorption curves, the number of particles, or the mean superficial density can be determined. This means the extension of thickness measurement from uniform to non-uniform films. Furthermore, these particle models being applied to non-uniform thin film, the possibility of measuring the mean thickness and non-uniformity was discussed. As the result, if the maximum difference of the thickness was more than 0.2 mg/cm2, the non-uniformity was considered to distinguish by the usual equipment. In this paper, an alpha-ray thickness gauge using the absorption curve method was treated, but one can apply this easily to an alpha-ray thickness gauge using alpha-ray energy spectra before and after the penetration of thin film.


[Mean thickness measurement of distributed fine particles by using alpha-ray absorption curves (author's transl)].

The mean superficial density of fine particles, such as polystyrene latex particles or ion exchange resin particles, dispersed on a thin supporting film was measured by means of the thickness gauge which used the absorption curves of alpha-rays. The measured absorption curves coincided with the ones calculated from the particle diameter, density, number of particles per unit area and equivalent film thickness to an absorption gas of 1 mmHg. On the other hand, when the particle diameter exceeded a certain limit, the measured mean superficial density which was derived from the pressure displacement of absorption curve considerably differed from the true mean superficial density. This limit can be calculated from the shape of absorption curve, which depends on the alpha-ray spectrum emitted from the source. In the case of the 241Am source used in this study, the limit was about 450 microgram/cm2 for polystyrene latex particles. The mean superficial density of a sample can easily be obtained by measuring the pressure displacement of absorption curve when the maximum thickness difference is below the limit. However, when the maximum thickness difference exceeds the limit, it is necessary to estimate the whole shape of absorption curves.


[Determination of the thyroglobulin content in malignant and benign thyroid gland tumors as well as in thyrotoxic strumas using an immunological method].

A decreased content of the organospecific antigen (thyroglobulin) was found in the tissues of 70% of thyroid gland cancers and in about 50% of thyroid benign tumours and thyrotoxic goiters studied. These data testify to the fact that the antigenic simplification is not an obligatory and specific process for the malignant transformation of thyroid tissue. Among the neoplasms with decreased thyroglobulin content there were found tumours built up both of "A" and "C" cellular types, thus indicating the dual nature of the antigenic simplification of the thyroid tumours.


[Analysis of errors of radiation relay--errors of relay controller using the radiation scaler (author's transl)].

Radiation relay using the radiation scaler acts at the time when the output of the scaler comes to a set value. By this action, the stop valve in infusing line (or exhausting line) is closed and the increment (or decrement) of liquid level of tank is stopped. Same as radiation relay using CR rate meter, switching time of the relay of this system varies statistically due to the statistical property of radioactivity. In this paper, the probability density function of the switching time is calculated on the assumption that the pulse train is the Poisson process. Then, the relation between the switching time and the uncertainty in the stop level is examined under a constant incremental (or decremental) velocity of liquid level. Using these results, the minimum intensity of radiation which is necessary to obtain a given accuracy is calculated and the optimum scaling time is given to minimize the uncertainty corresponding to various velocity of liquid level.


Studies on the metabolism and toxicity of dinitrotoluenes--on excretion and distribution of tritium-labelled 2,4-dinitrotoluene (3H-2,4-DNT) in the rat.

In order to investigate the excretion and distribution of 2,4-DNT in the rat, 3H-2,4-DNT was synthesized by nitration reaction of 3H-toluene. About 21.3 per cent of the single orally administered radioactivity was excreted in the 1st day-faeces. The amounts of radioactivity in the 2nd day- and 3rd day-faeces were to be about 4.1 and 1.1 per cent, respectively. About 13.5 per cent of the radioactivity administered was excreted in the 1st day-urine, but after the 2nd day the excretion of radioactivity was to be trace. In all, about 46 per cent of the radioactivity administered was excreted in the faeces and urine during the 7 days. Seven days after administration relatively high levels of radioactivity were retained in adipose tissue, skin, and liver, however, the amounts of remaining radioactivity were to be only 1.5, 0.6 and 0.4 per cent, respectively. The amounts of radioactivity of the other organs were to be trace.


[In vivo behavior of 111In-DTPA in rat and mouse after intra-ventricular administration (author's transl)].

In vivo behavior of 111In-DTPA in rat and mouse after intra-ventricular administration was studied. Thus, 50 muCi and 35 muCi of 111In-DTPA was injected intra-ventricularly to rat and mouse respectively. At specific time intervals, the animals were sacrificed, then distribution in organs was determined by radioactivity counting and autoradiographic method. Urinary and fecal excretion were separately collected and excretion rates were estimated. Metabolites in urine of rat were examined with chromatography. A part of 111In-DTPA injected intra-ventricularly to the animals migrated to subarachnoid space, then radioactivity in cerebrospinal fluid effused into blood with about 1 hr initial half-life. Blood clearance was also rapid, about 1 hr after administration the blood level reached maximum and then decreased showing an initial half-life of about 1 hr. The predominant excretion route in rat was urinary and about 90% and 5% of administered dose were excreted within 48 hr through urine and feces respectively. Judging from the Rf-value of radioactivity peak on chromatograms, 111In-DTPA seems to be excreted without suffering any metabolic change. Concerning to the behavior of 111In-DTPA in male and female rat, no difference was observed, and the distribution pattern of 111In-DTPA in mouse was similar to that of rat.


[Studies on computer analysis of multi-frame renal images--multiple regional renograms and functional images (author's transl)].

A method of making the multiple regional renograms and simple functional images are described. Thirty-six EDTA (or DTPA) images has been transferred from a gamma camera to a small computer with the magnetic tape. Thirteen regional renograms from a kidney have been made by using the single pixel ROIs from these images, a continuous 13 pixels horizontal and/or vertical of the matrix are selected, in distinction from right and left kidney. Two functional images have been made by the multi-frame images as a peak arrival time and it's peak counts. Small change of the radioisotopic transportation in the kidney could be observed by the method, and change of the urodynamics could be extracted by two functional images. It will be actualize quantitative diagnosis to the renal function disorders.


Effects of the removal of the regional lymph nodes on the survival of mice bearing B16 melanoma or EAkR lymphosarcoma.

This work presents data concerning the effect of tumor excision accompanied or not by the removal of the regional lymph node (RLN) on the survival time of mice bearing the EAkR lymphosarcoma or the B16 melanoma. The operations were performed at various times to study this effect in relation to tumor size. Early tumorectomy, on day 6 for the EAkR lymphosarcoma, on day 10 for the B16 melanoma, significantly prolonged the survival time. The additional removal of the RLN abolished this beneficial effect. In the case of the EAkR lymphosarcoma. a beneficial effect on the survival time was, in contrast, observed after total excision of the tumor accompanied by RLN removal performed on day 8. The two surgical procedures were ineffective in increasing the survival time when they were applied after the 8th day for the EAkR lymphosarcoma and after the 10th day for the B16 melanoma. These results suggest that the preservation of the RLN may be favorable for the host, at least at an early stage of the tumor growth.


Treatment of murine EAkR lymphosarcoma by surgery combined with systemic or local active BCG immunotherapy applied repeatedly.

A combined treatment modality imcorporating surgery plus BCG immunotherapy was administered to (C57Bl/6 X DBA/2)F1 mice grafted with EAkR lymphosarcoma. A single preoperative local or postoperative systemic BCG administration cured 20-30% of the animals, but did not prolong the survival time of these groups. Repeated s.c. injections of BCG resulted in a significant increase in survival time compared to the group submitted to surgery alone. In contrast, multiple i.v. injections of BCG before and after surgery were no more effective than surgery alone and were less effective than a single postsurgical i.v. injection in producing cures. We have concluded that for local BCG therapy, multiple injections before and after surgery are more effective than a single injection. However, for systemic therapy, multiple injections are less effective than a single injection applied postoperatively.


Disseminated tuberculosis, bone marrow necrosis and lymphoma: a case report.

Tuberculosis often complicates lymphoma, and bone marrow necrosis has been described in disseminated tuberculosis. However, the association of lymphoma, disseminated tuberculosis and bone marrow necrosis is rare. We report a patient with this triple association. After a 3-week influenza-like illness the patient was admitted to hospital semicomatose with pancytopenia and hyponatraemia. During routine examination a bone marrow trephine biopsy revealed diffuse lymphomatous infiltration with scattered necrotic foci. On Ziehl-Neelsen staining these foci exhibited numerous acid-fast bacilli. The patient subsequently died and at autopsy was found to have widely disseminated non-reactive tuberculosis.


Malondialdehyde production by platelets during secondary aggregation.

A method is described for increasing the sensitivity of the thiobarbiturate assay for malondialdehyde by concentrating the coloured reaction product. The basal level of malondialdehyde-like material in plasma was found to be about 0.03 micrometer. Platelets synthesized malondialdehyde when stimulated by collagen or thrombin and also during the second phase of aggregation induced by ADP or adrenaline.


Depletion of platelet amine storage granules by the antithrombotic agent, suloctidil.

Suloctidil, a compound with antithrombotic properties in animal models, causes depletion of human platelet serotonin stores during 1-5 hr incubation with platelet-rich plasma in vitro. This effect is not attended by leakage of cytoplasmic nucleotides or by alterations in cyclic AMP metabolism, malondialdehyde production or energy balance. 5HT uptake was also inhibited but uptake of adenine was not. 5HT released by suloctidil appeared in the supernatant as oxidation products, though the amine also accumulated when re-uptake was blocked by imipramine.


Prostaglandin endoperoxide--thromboxane synthesis and dense granule secretion as positive feedback loops in the propagation of platelet responses during "the basic platelet reaction".

Platelets respond to a great variety of stimuli by a sequential display of shape change, aggregation, prostaglandin/thromboxane synthesis--dense granule secretion and alpha-granule secretion. It is suggested that these responses are independent of each other, and caused by an increase in the concentration of a second messenger, liberated to the cytoplasm through the interaction between an extracellular agonist and the platelet membrane. The extent of the propagation of responses is determined by the strength of the stimulus. Stimuli can be subdivided into 1) original, applied stimuli and 2) platelet-produced stimuli (substances secreted from dense granules, prostaglandins and thromboxanes); these stimuli may act synergistically. In this way the platelet has two apparently independent means of potentiating their response to external stimuli which act as two separate positive feedback loops.


Effects of sodium azide on platelet function.

Sodium azide in low concentrations (0.1-10 micrometer) was found to have inhibitory effects on human platelet function. Primary aggregation induced by ADP, epinephrine, thrombin and the ionophore A 23187 was decreased. To evaluate the effect of azide apart from secondary processes, the platelets were treated with indomethacin to prevent prostaglandin/thromboxane synthesis for all inducers; in addition, effects of secreted ADP, in the case of thrombin and A 23187, was prevented by the presence of creatine phosphate plus creatine phosphokinase ADP, epinephrine and A 23187, but not thrombin-induced primary aggregates, dispersed immediately upon addition of azide. Azide powerfully inhibited dense granule secretion induced by collagen, ADP and epinephrine as measured both by 14C-serotonin secretion and as judged by secondary aggregation. Shape change induced by ADP, thrombin or A 23187 was not affected. Azide had no effect on energy metabolism. Since the aggregation experiments were performed in the presence of indomethacin, and malondialdehyde formation from arachidonic acid was not affected by azide, it seemed unlikely that the inhibition by azide of platelet function was related to inhibition of synthesis of prostaglandins and thromboxanes. It is concluded that azide exerts its effects directly on the common pathway for platelet responses.


The role of platelets in the pathogenesis of thrombosis and hemorrhage in patients with thrombocytosis.

Some patients with thrombocytosis due to myeloproliferative diseases or other etiologies experience thromboembolic complications and others may bleed excessively. It seems unlikely that elevations in platelet count per se are a direct cause either of thrombosis or of hemorrhage. In an effort to ascertain whether variations in platelet function might determine whether an individual patient experiences thrombotic or hemorrhagic complications we have evaluated platelet function in 22 patients with thrombocytosis due to a variety of etiologies. The results of platelet counts, bleeding time determinations, and studies of platelet aggregation were similar in patients with thrombosis, in patients with bleeding and in patients with neither complication. Therefore, detailed studies of platelet coagulant activities were carried out in 8 patients. The results of platelet coagulant activity assays were normal in all 3 patients with thrombocytosis and neither thrombotic nor bleeding complications and an additional 3 patients with myeloproliferative diseases, normal platelet counts and no thrombohemorrhagic complications. In 2 patients with thrombotic complications significant elevation of platelet coagulant activities concerned with the early phases of intrinsic coagulation were observed whereas in 2 patients with severe hemorrhagic complications deficiencies of either contact forming activity or collagen-induced coagulant activities were evident. This preliminary study suggests the possibility that variations in platelet coagulant activities concerned with the early stages of intrinsic coagulation may determine whether patients with thrombocytosis will experience bleeding or thrombotic complications.


Cold-insoluble globulin (CIg), a circulating cell surface protein.

The history of the discovery and characterization of the cold-insoluble globulin of plasma (CIg) is reviewed. Subsequent growth of knowledge relating to its structure and function in plasma, in tissues, and on cell surfaces is examined.


Factors influencing leukocyte adherence in microvessels.

In vivo studies of the microcirculation of an untraumatized and unanesthetized animal preparation has shown that leukocyte adherence to vascular endothelium is an extremely rare occurrence. Induction of leukocyte adherence can be produced in a variety of ways including direct trauma to the vessels, remote tissue injury via laser irradiation, and denuding the epithelium overlying the observed vessels. The role of blood flow and local hemodynamics on the leukocyte adherence process is quite complex and still not fully understood. From the results reported it may be concluded that blood flow stasis will not produce leukocyte adherence but will augment pre-existing adherence. Studies using 2 quantitative measures of adherence, leukocyte flux and leukocyte velocity have shown these parameters to be affected differently by local hemodynamics. Initial adherence appears to be critically dependent on the magnitude of the blood shear stress at the vessel wall as evidenced by the lack of observable leukocyte flux above some threshold value. Subsequent behavior of the leukocytes as characterized by their average rolling velocity shows no apparent relationship to shear stress but, for low velocities, may be related to the linear blood velocity.


Reduction of coagulation factor XIII concentration in patients with myocardial infarction, cerebral infarction, and other thromboembolic disorders.

Coagulation factor XIII and plasma fibrinogen chromatographic assays have been performed serially in patients suffering from acute myocardial and cerebral infarction, and in others with disseminated intravascular coagulation. The findings were compared with 2 groups of "controls"; normal clinically-well subjects and hospitalized patients with cerebral infarction who exhibited minimal, stable, or improving neurological deficits. Substantial depression of factor XIII concentrations developed in the 3 patient groups, together with concomitant significant increases in the proportion and concentration of plasma high molecular weight fibrin(ogen) complexes (HMWFC). An inverse correlation (p less than 0.05) between coagulation factor XIII concentration and percentage of HMWFC was demonstrated in the early stages of the illness. These findings suggest that depression of coagulation factor XIII concentration in these states, is secondary to extravascular or intravascular coagulation and may reflect its degree.


Spurious prolongation of the activated partial thromboplastin time.

The clinical and laboratory data of 8 patients (4 males and 4 females) with circulating anticoagulant were presented. Based on prolonged APTT, failure to correct the APTT with 50% normal plasma and abnormal tissue thromboplastin inhibition test, the inhibitor was identified as "middle stage"--or the "lupus anticoagulant". Thrombokinetics showed the maximal rate of change in optical density (VmaxdeltaOD) of plasma, resulting from clot formation to be significantly less in the plasma of patients with the inhibitor than in normal plasma. This was not completely corrected by mixing the patients' plasma with 50% normal plasma.


Disseminated intravascular coagulation in status epilepticus.

Disseminated intravascular coagulation is here reported as a complication of status epilepticus. Other features of this case were rhabdomyolysis, hyperthermia, myoglobinuria and renal failure.


Human platelet storage organelles. A review.

Platelets contain numerous electron-dense subcellular organelles which have been referred to in the literature by various names such as alpha-granules, electron-dense and very electron-dense granules, lysosomes, dense bodies, etc. Most of the organelles are secretory granules, since induction of secretion by appropriate stimuli causes degranulation of platelets and the appearance of the granule contents in the extracellular medium. Among the substances that are known to be stored and secreted by platelets are: serotonin, ATP, ADP, calcium, pyrophosphate, acid hydrolases, fibrinogen, vascular permeability factor, beta-thromboglobulin, platelet factor 4 and growth factor. The recent literature concerning the localization of the secreted substances within specific platelet organelles is reviewed here. Results from electron microscopy and microprobe analysis, selective secretion experiments, subcellular fractionation studies and studies on platelets from patients with storage pool deficiency indicate that there are as many as four types of storage organelles in human platelets.


Thrombin-stimulated myosin phosphorylation in intact platelets and its possible involvement secretion.

A 20,000 dalton polypeptide, which is phosphorylated in intact platelets pre-incubated with 32P-PO4, has been identified as a platelet myosin light chain. Stimulation of intact platelets with thrombin produced a 5-fold increase in the amount of radioactive phosphate incorporated into the light chain. Myosin phosphorylation preceeded acid hydrolase secretion and occurred concomitantly with adenine nucleotide secretion. These results are suggestive of participation of contractile mechanisms in platelet secretion.


Measurement of nucleotide pools in platelets using high pressure liquid chromatography.

We have devised an improved high pressure liquid chromatographic technique whereby serotonin, nucleosides, cyclic nucleotides, namely cAMP and cGMP, and 5'mono-, 5'di-, and 5'tri-nucleotides can be analyzed. The cyclic nucleotides have been measured in picomolar quantities. All nucleotides can be quantitated in a single step separation in 75 min using a 0.0015 M phosphoric acids vs. 1M pH 4.8 ammonium phosphate gradient. 5/10 ml of platelet-rich plasma furnishes an adequate sample for complete analysis. Nucleotide levels in platelets from 16 normal donors expressed in 10(11) platelets are as follows: cAMP, 6.32 (4.15) nanomoles and AMP, 0.32 (0.14); ADP, 2.48 (0.67); ATP 3.78 (0.68); GDP 0.38 (0.07) and GTP, 0.45 (0.07) micromoles. ADP and ATP values are lower than those previously published. However, the total nucleotide level approaches published values. Upon aggregation with thrombin, approximately 50% of ADP and 40% ATP is releaseed. Release is complete by 2 min. Thrombin is the most potent releasing agent with collagen and ADP occupying an intermediate role and epinephrine being the least effective. Upon aggregation cyclic AMP levels diminish along the other nucleotides. Patients with asthma showed depression of ADP, ATP, GDP and GTP levels.


[Electron microscopic and morphometric study of the cellular composition of several forms of goiter in man].

According to the ultrastructural patterns four varieties of follicular cells are recognized in the cell population of the human goiter. The parenchyma of different goiters is composed of the same cell types and varieties. Goiters differ in percentages of these cells. The ultrastructure of the main cell form is correlated with the functional activity of the goiter. The "map" of cell composition of some forms of goiter is given, which may be used for a more exact diagnosis of the goiter, especially in the cases of discrepancy between the light microscopical morphological data and clinical picture of the desease.


[Scanning the subarachnoid space of the spinal cord following endolumbar and cisternal administration of colloid solutions of radioisotopes].

The patency of the subarachnoid space of the spinal cord was studied by means of radioisotopes in 82 patients, among whom 18 had tumors of the spinal cord, 22 had herniation of the intervertebral disk, 18 had complicated fractures of the spine, and 11 had inflammatory diseases of the spinal cord and its meninges. Colloidal solutions of 198Au, 111In, and 131I were used for endolumbar and cisternal infusion. Scanning of the vertebral canal provides for the diagnosis of the level, degree, and extent of its compression caused by various vertebro-medullary pathologic conditions. The method is sparing, minimum doses of isotopes are used, and no complications are produced.


The kinetics of imipramine-N-oxide in rats.

Rats were given imipramine-N-oxide as single intramuscular injection and then as repeated oral doses. Imipramine-N-oxide and the metabolites imipramine and desipramine were analysed in the blood cells, plasma and brain tissue. The concentration of imipramine-N-oxide increased simultaneously in the brain and blood, reaching a peak 45 minutes after a single dose. Imipramine was the quantitatively predominant metabolite in the blood cells and brain, while desipramine reached a higher concentration than imipramine in the plasma. Samples taken at different times after oral doses during continuous treatment showed fairly constant concentrations of imipramine-N-oxide and desipramine in the brain, whereas the concentration of imipramine was more fluctuating.


Inhibition by neuroleptics of uptake of 3H-GABA into rat brain synaptosomes.

Neuroleptics from various chemical groups and some amino acids were examined for GABA uptake-inhibiting properties in rat brain synaptosomes. The phenothiazine and thioxanthene neuroleptics inhibited GABA uptake by 50% in the concentration range of 10-30 micron. No difference in potency was found between the cis and the trans isomers of the thioxanthenes. Clozapine and particularly sulpiride were weak inhibitors of the GABA uptake process, whereas some of the butyrophenones examined exhibited rather potent effect. Secific GABA uptake inhibitors (nipecotic acid and guvacine) were as active as the most potent butyrophenones. As no significant correlation was obtained between GABA uptake-inhibiting effect of the neuroleptics and their clinical or pharmacological effects it is concluded that the influence on GABA uptake is not an important aspect of the neuroleptic action.


Effect of methotrexate on folate binding to a folate binding protein in cow's milk.

Folate in cow's milk was strongly bound to a minor whey protein. Methotrexate inhibited the folate binding in a log dosis dependent manner, but was a rather weak inhibitor. The binding mechanism of folate changed from a cooperative to a non-cooperative type in the presence of methotrexate. This model system could be used in investigations on human body fluids and tissues.


The mass in the neck.

A cervical mass should be approached in a systematic manner with a full knowledge of the possible etiologies and their consequences. The approach taken with a child differs markedly from that taken with an adult. Cervical masses in children are likely to be congenital or inflammatory. In adults, neoplastic masses are most common; most of these are metastatic. Indirect laryngoscopy, important in the search for the primary lesion, should be performed on all patients.


The relationship of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in primary thyroid failure.

Thyroid-stimulating hormone (TSH), serum thyroxine (T4) and triiodothyronine (T3) in sera of 100 patients with primary thyroid failure were measured by radioimmunoassay. Effective thyroxine ratio (ETR) was also measured in 69 of these sera. TSH was elevated in all, with a mean of 76.7 +/- 55 micromicron/ml (range 11 to 140 micromicron/ml, and was used to confirm the diagnosis. Mean T4 and T3 levels in the group were 1.8 +/- 1.5 microgram/100 ml (range less than 0.2 to 7.0 microgram/100 u.) and 76.7 +/- 76 ng/100 ml (range less than 10 to 600 ng/100 ml), respectively. Mean ETR was 0.81 +/- 0.05. A moderate inverse relationship was observed between TSH and T4 (r = 0.73), in contrast to TSH and T3 and TSH and ETR, which showed comparatively poor relationships (r = 0.41 and 0.43). This observation, in addition to the finding that 17 patients had subnormal T4 but normal or elevated T3, suggests that normal T3 levels alone may not be sufficient to maintain euthyroidism. In contrast, there were only three clinically hypothyroid patients who had elevated TSH, normal T4, but subnormal T3 levels. This study indicates that T4 and T3 may function together to maintain euthyroidism, and that in addition to serum TSH, T4 determination has more diagnostic value than serum T3 or ETR in these patients.


Isolation of Yersinia enterocolitica from raw milk.

Four enrichment procedures were used for examining 131 raw milk samples for the presence of Yersinia enterocolitica. Forty-two isolations were obtained from 19 pooled- (31.1 percent positive) and 10 individual-producer samples (14.3 percent positive). Enrichment by Butterfields phosphate buffer incubated at 4 degrees C for 14 days and then inoculation of modified Rappaport broth incubated at 23 degrees C for 5 days produced the greatest number of isolations. The majority of isolates were biotype 1, and many were atypical from clinical isolates in being rhamnose positive (47.6 percent), citrate positive (16.7 percent), and lactose positive (26.2 percent). Thirteen isolates were serotypable, belonging to seven different O serotypes, with O:5 occurring most frequently.


Persistent meningeal inflammation associated with intrathecal gentamicin.

A 30-year-old woman was treated with intraventricular gentamicin for Klebsiella meningitis. Cultures became sterile, but meningeal inflammation, associated with high central spinal fluid gentamicin levels, persisted until gentamicin was discontinued.


Control of fertility outcome in artificially inseminated gilts and old sows. 1: Electric stimulation of estrous sows. Its effect on insemination results.

Fifty gilts and 33 old sows which exhibited oestrous after bio-engineering treatment were electrically stimulated during insemination, using an A.C. mains-connected unit. The average voltages applied were 3.7 volt for gilts and between 2.5 and 2.8 volt for the old sows. The current was applied rectally, and the responsiveness differed individually. The treated animals then were compared to unstimulated controls, and the achievement in terms of born piglets was 1.18 more for gilts and 1.20 more for the old sows. Those better results were attributed to electric acceleration of sperm transport.


Leukapheresis and granulocyte transfusion.

Granulocytes for transfusion can now be obtained from normal donors by one of four techniques that involve either centrifugation or reversible adhesion of granulocytes to nylon fibers. The leukapheresis process appears to be safe for donors and standards for the selection and care of donors are being formulated. It appears desirable to transfuse granulocytes that are compatible in a leukoagglutination crossmatching, however, better methods for histocompatibility testing must be developed. Granulocyte transfusions clearly are of benefit to patients with Gram-negative sepsis and granulocyte counts of less than 500/cu mm for at least ten days. They may be valuable for granulocytopenic patients with other severe infections; however, there is no indication that granulocyte transfusions are indicated prophylactically or for febrile granulocytopenic patients without evidence of infection.


Effect of auto-oxidation products from cholesterol on aortic smooth muscle cells: an in vitro study.

Purified cholesterol is quite unstable when stored in air at room temperature. Products of cholesterol auto-oxidation were concentrated from several lots of USP-grade cholesterol by recrystallizing cholesterol from the methanol extract, retaining the mother liquor, and evaporating the residuum to dryness under vacuum. By application of thin-layer chromatography and gas-liquid chromatography, major, individual, oxidation compounds were identified and quantitated. Biological activities of these oxidation compounds were studied by using cultured rabbits' aortic smooth muscle cells. The concentrate of the auto-oxidation products of cholesterol showed remarkable in vitro cytotoxic effects, whereas purified cholesterol at the same concentration produced no toxic effects. The concentrate was further separated into six thin-layer chromatographical fractions. The results showed that 25-hydroxycholesterol and cholestane-3beta, 5alpha, 6beta-triol were probably responsible for the biological toxicity of the concentrate


Aneurysms of the septum primum in adults.

Sixteen aneurysms of the septum primum were found at autopsy among 1,578 adults. Most occurred in individuals in their fifth or sixth decade. All aneurysms were asymptomatic and none were diagnosed before death. Fourteen bulged into the right ventricle. The aneurysm may develop in patients with a raised intra-atrial pressure but most seemed associated with normal intra-atrial pressures. A particular morphology of the fossa ovalis region may predispose the septum to aneurysm formation. Echocardiographic and angiographic features of the aneurysm need definition to distinguish them from those caused by other lesions.


The origin of lipofuscin and possible consequences to the myocardium.

Examination by light and electron microscopy of human myocardium from necropsies and biopsy specimens has revealed evidence that mitochondria can be transformed into granules of lipofuscin. This pigment has been shown to arise from peroxidative destruction of polyunsaturated lipid membranes. A high rate of lipofuscin formation is indicated by the occurrence of brown atrophy of the heart in relatively young persons who died of conditions that were associated with inanition. Such lipofuscin formation suggests the importance of dietary antioxidants in preventing peroxidative damage to mitochondria. A by-product of lipid peroxidation, malonaldehyde, can react with nuclear DNA, blocking template activity. Nuclear damage of this kind could reduce the capacity for protein synthesis and limit mitochondrial and contractile protein replacement. Such a limitation would contribute to heart failure during stress. Peroxidative damage to the myocardium is cumulative and irreversible.


Lipomatous infiltrates of the heart.

Fatty masses of the heart usually arise in the interatrial septum and are uncommon. The autopsy files from LAC-USC Medical Center contain 15 such cases from 1952 through 1972. Although these masses are yellow and attain a large size, most are considered to represent lipomatous infiltrations rather than true lipomas since they usually lack encapsulation and do contain cardiac muscle in varying amounts. The lesion is most often associated with obesity. Surprisingly, even the large masses produce few clinical symptoms and none was suspected clinically, each being an incidental finding at necropsy. However, these masses do infiltrate the conduction system and can cause arrhythmias and sudden death. Echocardiography or other noninvasive techniques may bring attention to a lipomatous mass that may or may not be asymptomatic. This can result in a clinical dilemma in differential diagnosis and treatment since myxomas, rhabdomyomas, and sarcomas also arise in the interatrial septum.


Plasma erythropoietin levels in patients undergoing long-term hemodialysis.

The anemia of chronic renal disease has been attributed primarily to a decrease in erythropoietin (EP) production. Results of this study show that measurable levels of plasma EP can be demonstrated in a majority of patients with end-stage renal failure who are undergoing long-term hemodialysis. These levels were not related to the type of renal disease, nor were they greatly affected by androgenic therapy or by nephrectomy. Although EP elevations in such patients were somewhat less than in nonuremic patients with comparable anemia, the presence of measurable EP levels suggests that impaired end-organ response may play a role in the anemia of chronic renal failure.


Sternberg-Reed-like cells in a pleural effusion secondary to pulmonary emboli with infarction: a cytological observation.

Cells resembling Sternberg-Reed cells were observed in a pleural effusion that was caused by pulmonary embolus with infarction. Although Hodgkin's disease was suggested on the basis of abnormal pleural fluid cytological preparations, the subsequent evaluation and clinical course did not support that diagnosis. We conclude that first, the cytological diagnosis of Hodgkin's disease should only be made when Sternberg-Reed-like cells are seen in association with a compatible clinical and cytological picture, and second, the cytological diagnosis of Hodgkin's disease or other malignancy should be made with caution in cases in which pulmonary infarction is present.


[Lipids of plasmamembranes and of mitochondria in rat liver after intoxication with paraoxon (author's transl)].

0.426 mg/kg Paraoxon was applicated to female Sprague-Dawley rats. 4, 10 and 24 h after poisoning, cholesterol, glyceride and phospholipid content was measured in liver plasma membranes and mitochondria. After 4 h, cholesterol content of plasma membranes was significantly lower. Phospholipid content of plasma membranes was significantly higher than control values at all times of investigation, contents of neutral lipids and glycerides were also higher, but not significantly. In mitochondria, no significant difference of cholesterol content could be detected. Glyceride content was lower after 4 and 10 h, but phospholipid content higher at all experimental times. Differences found in cholesterol and phospholipid content of plasma membranes are discussed also in view of higher serum GOT, GPT and CPK activities known from other investigations. The differences in cholesterol and phospholipid content, their degree and their timing, which agrees with the timing of enzyme leakage, suggest that lipid composition of the plasma membrane may be one of the parameters which determine membrane permeability after organophosphate poisoning.


[Studies on the embryotoxicity of monolinuron and buturon in NMRI-mice (author's transl)].

The acute LD50 in virginal NMRI-Mice was found to be 2528 mg/kg for monolinuron and 1791 mg/kg for buturon. Pregnant female mice of the NMRI strain were administered orally 25--1000 mg monolinuron/kg (I) and 100-400 mg buturon/kg (II) on days 6--15 of gestation and, during defined phases of fetal development (days 10--13 after conception), 500 mg I/kg and 350 mg II/kg. Following administration of 10 doses, an increase of postimplantative losses and clear retardation of development in the upper dose range from 100 mg I/kg and 300 mg II/kg as well as a dose-dependent increase of the rate of cleft palates could be observed. High doses of both substances given from day 6--15 of pregnancy produced minor numbers of wavy and fused ribs as well as hypoplasia of the upper jaw after application of monolinuron and exenteria and exencephaly after buturon. Administration of monolinuron between days 10 and 13 of gestation resulted a minor and that of buturon a clear increase of the number of cleft palates. To evaluate postnatal development 200 and 500 mg I/kg, and 200 and 300 mg II/kg were administered orally on days 6--15 of gestation. In the higher doses, both substances produced an increased mortality among the offspring up to 3 weeks after birth, and a clear increase of the rate of cleft palates.


On nickel contents in urine and hair in a case of exposure to nickel carbonyl.

In an accidental case of exposure to nickel carbonyl with a few persons weak symptoms of illness were observed. Rapid and simple methods of flameless atomic absorption spectroscopy were applied for the determination of nickel in urinary samples and in sections of bundled hairs. The measurements showed in some cases remarkable increased Ni values well above normal levels. The data obtained will be amply discussed and can be used in part for a rough estimation of the biological half life of inhaled Ni.


Radioimmunological screening and gas chromatographic identification of diazepam in blood and serum.

A radioimmunoassay for the determination of diazepam in human blood and serum is presented. Diazepam is separated from the bulk of the biological material by adsorption at Amberlite XAD-2 and subsequent desorption with ethyl acetate. The extract thus obtained can be used directly for the determination od diazepam by radioimmunoassay and gas chromatography with electron capture detection. For the combined radioimmunological and gas chromatographic determination 0.5 ml of blood or serum are necessary, the lower detection limit being approx. 5 ng/ml for both of these procedures. A good reliability of the radioimmunoassay is established with respect to precision, accuracy and specificity. The quantitative results obtained by radioimmunoassay and gas chromatography correspond well with each other. The radioimmunological procedure enables the screening of more than 200 samples for diazepam by one technician within two working days.


Metabolic activations of polycyclic hydrocarbons. Structure-activity relationships.

Considerable evidence now points to 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrenes as ultimate mutagenic and carcinogenic forms of benzo(a)-pyrene. Quantum mechanical calculations have been performed to assess the possible general role of diol epoxides in polycyclic aromatic hydrocarbon (PAH) mutagenesis and carcinogenesis. The calculations enable a prediction of relative reactivity (ease of carbonium ion formation) for diol epoxides derived from a single PAH and also for diol epoxides from different PAHs. The calculated reactivity has so far been found to provide a good estimate of diol epoxide mutagenicity. Results of the metabolic activation of benzo(a)anthracene dihydrodiol derivatives and of the mutagenicity of benzo(a)anthracene diol epoxides are reported. Limitations inherent in predictions of polycyclic aromatic hydrocarbon carcinogenicity using a model based upon the calculated reactivity of a potential metabolite are discussed.


Structural modifications in contraceptive steroids altering their metabolism and toxicity.

Norethisterone and, to a lesser extent, d-norgestrel are metabolically activated by rat liver microsomal enzymes to intermediates which are capable of irreversibly binding to proteins. This microsomal activation in vitro depends on presence of NADPH and is inhibited by glutathione. Irreversible binding of metabolites of progesterone, nortestosterone acetate and cyproterone acetate is very low, compared to that of norethisterone metabolites. Phenol as a reference compound shows quantitatively a similar binding behaviour as norethisterone. Norethisterone-4beta,5beta-epoxide, a microsomal metabolite of norethisterone, binds non-enzymatically to albumin, at a rate of 380 pmol/mg albumin per hour (at 37 degrees). The corresponding rate for norgestrel-4beta,5beta-epoxide, 42 pmol/mg albumin per hour, indicates a considerably lower reactivity of norgestrel-epoxide. The non-SH-proteins concanavalin A and bovine gamma-globulin do not react with either norethisterone-epoxide or norgestrel-epoxide. Also, DNA and RNA show no binding reaction. Thus, the requirements for irreversible protein binding of the 19-nortestosterone progestagens norethisterone and norgestrel are similar to those found for oestrogens which, when activated by rat liver microsomes, only bind to proteins with SH-groups, not to DNA or RNA.


Metabolic activation of diethylstilbestrol and aminostilbene-derivatives.

Diethylstilbestrol and trans-4-dimethylaminostilbene are metabolically activated and several of their metabolites are able to react with cellular macromolecules. Some of the problems are discussed which are encountered in linking a particular metabolite with the mutagenic and carcinogenic properties of these compounds.


The significance of covalent binding of catechols to proteins in vivo.

When rats were dosed with 14 microgram/kg 3H-isoproterenol, 3H-radioactivity was measurable in the liver until 48 h. This amount was not different in livers of animals which have been pretreated with diethyl maleate. After exhaustive extraction, a significant amount of 3H-radioactivity from isoproterenol could be detected in the proteins of total liver (homogenate), of cytosol and of microsomes. In the cytosol fraction of diethyl maleate pretreated animals twice the amount of isoproterenol-radioactivity was found in the extracted proteins compared to controls. In the microsomal fraction there was no difference between diethyl maleate pretreated and control animals in the amount of radioactivity incorporated into proteins. In all fractions the radioactivity measurable in the extracted proteins declined with a half life time of about 24 h. The in vivo results on covalent binding of isoproterenol are compared to the irreversible protein binding of ethinyloestradiol in vivo. Quantitatively, these in vivo data are compared to the results on irreversible protein binding obtained during incubations of isoproterenol or ethinyloestradiol with rat liver microsomes.


Multiple forms of cytochrome P450 in the microsomal monooxygenase system.

The microsomal monooxygenase system is characterized by its broad substrate specificity which includes endogenous substrates as well as lipophilic drugs and chemicals. From in vitro investigations it was known that the relative reactivities and the pattern of products varied greatly with species, sex, age, diet or pretreatment with drugs of the animal. The suggestion that this was possibly due to a variety of cytochrome P450 enzymes rather than a single monooxygenase was recently confirmed by the isolation of several cytochrome P450 species with different although overlapping substrate specificities. In view of the consequences of a genetic and environment-dependent pattern on monooxygenases for drug metabolism and drug-mediated toxicity the methods of a quantitative assessment of the various forms are discussed.


Metabolic activation of chlorinated ethylenes: dependence of mutagenic effect on electrophilic reactivity of the metabolically formed epoxides.

In chlorinated ethylenes, the chlorine substitution exerts, by its electron withdrawal effect, a stabilization of the molecule which increases with the number auf chlorine residues. All chlorinated ethylenes are metabolically transformed, in a first step reaction, to epoxides which may rearrange to aldehydes or acyl chlorides, respectively, undergo hydrolysis to diols, conjugate with glutathione, or react, by alkylation, with cellular macromolecules. The electrophilicity of the epoxides is high with those having an unsymmetric chlorine substitution, and comparatively low with the others bearing symmetric chlorine residues. According to in vitro mutagenicity testing in a modified Ames system, the following rule on structure/activity-relationship has been worked out: mutagenic potential is bound to unsymmetric substitution and high chemical reactivity (as with vinyl chloride, vinylidene chloride, and trichloroethylene), symmetric substitution results in lower chemical reactivity and non-mutagenicity. So far, the rule is substantiated by positive carcinogenic effects in animal experiments with vinyl chloride, vinylidene chloride and trichloroethylene.


Retrolental fibroplasia: a new analysis of risk factors based on recent cases.

Over an 18-month period, four severe and eight mild cases of retrolental fibroplasia (RLF) were diagnosed. All infants had gestational age less than 34 weeks. While the  percentage of infants with RLF increased with decreasing gestational age, the severity of RLF was not related to birth weight or gestational age. These RLF infants were compared with premature infants having normal fundi. The arterial blood gas values in the first week of life were similar for the two groups. However, during the subsequent weeks of oxygen therapy, the infants who developed severe RLF had a significantly greater number of hours of capillary oxygen tension at undesirable levels (Pcap O2 greater than 50 mm Hg) than the mild RLF or control infants. These results suggest that infants may be at greatest risk of severe retinal damage from oxygen relatively late in the course of their oxygen therapy.


[Animal experiments on particulars of the time factor in the development and solving of pulmonary atelectasis caused by foreign body (author's transl)].

In literature are only older publications about the temporal beginning of the acute atelectasis after obstructive foreign body occlusion of the bronchial system which are operated at the open thorax. For this reason experiments on animals were made to find out the earliest beginning of an atelectasis by a simple bronchial occlusion as an imitation of a natural process of a foreign body aspiration. The alterations in each single phase of development showed regularly based on serial radiographies and by the autopsy macroscopic and microscopic that about 2 or 3 h after aspiration of an obstructive foreign body it will be reckoned with a complete atelectasis. Only now correlate the clinical result, the X-ray and the pathological-anatomical alterations. The histological picture of the complete atelectasis follows the macroscopic result only in longer temporal distance. Atelectasis occuring before the mentioned moment cannot be explained by an absorption of air from the alveolar tissue, but they depend on foreign body independent reflexes (= reflex contraction atelectasis). In other series of experiments the retroplasia of an atelectasis showed no regularity after the release of the bronchial occlusion, as the time of development, but it is possible to say that it takes more time of retroplasia the longer the atelectasis lasts. Dependent on that the respiratory exchange was jerky into the atelectatic lung after a resting period without prefering any lobes of lungs where localised atelectatic foci remain a longer time.


Deafness in an old English sheepdog. A case report.

The histopathological features of the inner ears in a case of deafness in an old English sheepdog reveal a cochleo-saccular (Scheibe) type of degeneration. However, also the hair cells in the vestibular part of the labyrinth were reduced in number though there appeared no clinical signs or symptoms of vestibular dysfunction. The present case is the so far only known old English sheepdog with a hearing loss reported in Sweden.


Experiences with the tracheoesophageal shunt method for vocal rehabilitation after total laryngectomy.

The tracheoesophageal (T-E) shunt technique reported by Komorn et al. (1973) was used for vocal rehabilitation in 8 laryngectomized patients including one case of hypopharyngeal cancer. It was proved that this technique was a simple one-stage procedure with a low incidence of complication. Four out of 7 patients, excluding one patient who died of another disease, acquired excellent speech without symptomatic aspiration. Two patients developed fairly good speech. One shunt was closed by aspiration. The shunt constructed by a flap measuring 2 x 4 cm, opened 1 cm below the distal end of the trachea, showed good results. The T-E shunt speech exceeds esophageal speech in duration and intelligibility.


Bioplast fibrin implants in nasoseptal perforation.

This study includes 9 cases of nasoseptal perforation following submucous septectomy. Sheets from Bioplast fibrin, an absorbable biomaterial, were implanted to prevent thepersistence of perforations. Postoperative mucosal growth on both implant surfaces ensured closure in 6 of the 9 cases. The method has the advantage of simplicity and it is commendable in the case of smaller defects when the mucosa is not markedly atrophic.


[The proof of age differences of slow acoustically evoked potentials of adults by a multivariate statistical analysis (author's transl)].

Many authors consider the nature of the slow acoustically evoked potentials to be partly a specific one. Therefore the AEP-time behavior probably contains more information about the functional state of the acoustical channel than it is got by the usual measurement of only 3 values (N1P2-amplitude, 2 latencies). A test of this hypothesis is possible with a multivariate mathematical procedure, which involves the whole AEP-time behavior. We are using the multivariate variance- and discriminant analysis. For the application of this statistical method random samples of patients with certain otologic diseases are needed. To avoid mistakes in grouping these samples some preliminary investigations had been necessary: This paper reports the results of multivariate investigations concerning age differences of the AEP in normal hearing adults. By means of the multivariate variance analysis the AEP of 3 age groups were examined (group 1: 15--34 years, group 2: 35--44 years, group 3: 45--60 years). At 1000 Hz as well as at 400 Hz significant differences between the group averages were found, which were not detectable by the usual N1P2-amplitude measurement. Furthermore with the discriminant analysis it is possible to perform a relatively reliable differentiation between the individual AEP of the age groups 1 and 3.


[Reaction time and Békésy audiometry (author's transl)].

Electrophysiological work has elaborated that subjects having positive recruitment exhibit shorter response latencies than non-recruiting subjects do. Correspondingly we have investigated in this paper, if subjectively measured reaction times also decrease in case of recruiting subjects. Our measurements have shown that the averaged reaction time (at 4 kHz) of recruiting subjects is significantly (p = 0.05) shorter than the value of a non-recruiting group. Because of the interindividual scattering of the results, however, measuring of reaction time ist not suitable to distinguish subjects with loudness recruitment from those having no recruitment. Comparison of reaction time and Békésy audiogram as recruitment test shows Békésy tracing to be more reliable. Finally the number of oscillations (N) per octave in Békésy tracing is discussed as a function of oscillation width (W). A general mathematical representation of this correlation is given by N = a.Wb. Constants a and b, depending on attenuation rate (2.5 dB/s) and frequency change rate (1 oct./min), are evaluated by statistical and graphical methods (a = 36.08, b = -0.71).


[Investigations on not cell-bound lipids in the pathologic maxillary sinus (author's transl)].

Lipids can be found sporadically in the maxillary sinus especially in connection with chronic sinusitis. Thus, the occurence of cholesterol is known for decades. Nevertheless most of the lipids in the excretions of maxillary sinus are unknown or less investigated still today. It may be that there is a lack of simple analytical methods. The intention of this paper is to demonstrate early results with TLC-separation and determination of lipids in the maxillary sinus excretions during sinusitis. The samples were collected from patients of the HNO-Klinik Würzburg in connection with a therapeutic rinsing of the sinus. The effluent was concentrated and then separated into three fractions by ultracentrifugation: 1. The sediment, consisting of cells and some other undefined organic material. 2. A supernatant clear solution, containing inorganic material, proteins, amino-acids, lipids... 3. Sporadically a very thin layer on the surface of the clear solution. Since fraction 3, which contains lipids too, could not be found each time, our attention was directed on the lipids of the clear solution, where most of these substances are attached to proteins. As well as in the sediment we found in the clear solution cholesterol, free fatty acids, triglycerides and very seldom cholesterol-esters. The concentration of cholesterol is nearly the same as that of free fatty acids. The frequency of occurrence of lipids is considerable which prevents us until now to correlate the lipid-content to some features of diagnosis, prognosis and therapy.


[Gentamycin in distributive balance between serum, perilymph and liquor in guinea-pig after dosage in therapeutical range (author's transl)].

Dosage of gentamycin in therapeutical range just as in higher doses results in a distributive balance between serum, perilymph and liquor under the condition of steady serum levels. After high doses the perilymph levels compared to the serum levels are relatively lower than after less doses. The distributive balance is reached after about 7 h in doses, which lead to concentrations of the serum levels of the supposed ototoxic critical range. Afterwards the concentration in the inner ear doesn't increase. In steady state, the concentration in serum is always higher than in perilymph, whereas the perilymph concentration is always higher than the one in liquor.


Interaction of light with the organ of Corti. I. Light guide effects in cochlear hair cells.

A cochlear postmortem preparation has been developed which allows for hydromechanical studies of the transilluminated organ of Corti. It was found that cochlear hair cells act as optical waveguides. This poperty of hair cells is important for optical cochlear investigations. It may be used in the study of the motion of single hair cells.


["On-line artefact rejection" at electric response audiometry (ERA). Use of an active, analog delay line as buffer in combination with a recognition of disturbing signals (author's transl)].

Some brief theoretical considerations about an artefact rejection basing upon the valuation of amplitudes are followed by a report on a new development of an "on-line artefact rejection" which uses an active analog delay line as buffer combined with a recognition of disturbing signals and can easily operate together with simple averagers. The advantages are shown and discussed by means of examples, but also the mistakes which can arise by too great limitations of the signal's level. Technical details are described briefly.


Regulating the "size of mesh" in drug screening from statistical point of view demonstrated by a 2-step procedure of in vivo testing of antiviral compounds.

The present paper indicates how to regulate the "size of mesh" in drug screening by sample size and/or by modification of the statistical procedure used. Such a regulation is demonstrated on a 2-step procedure of in vivo testing of antiviral compounds as an example, by changing the rules of decision with the parameter R0. From the computed probabilities of discarding substances with defined effectivities, curves have been drawn which allow to read off immediately sample sizes and R0-values for a desired "size of mesh".


Reactions of hydroxybenzofurans. VI. Syntheses of benzofuran chalcones, hydrazones and pyrazolines of potential biological activity.

Condensation of 5-acetyl-6-methoxy- (I) and 6-acetyl-5-methoxy-2,3-diphenylbenzofuran (II) with aromatic aldehydes gave the chalcones IIIa--f and IVa--f, respectively. Reaction of the chalcones IIIa--f and IVa--f with hydrazine hydrate-acetic acid mixture yielded the corresponding N-acetyl pyrazolines Va--f and VIa--f. The chalcones IIIa--f and IVa--f reacted with phenylhydrazine in ethanol to yield the corresponding phenylhydrazones VIIa--f and VIIIa--f. The latter hydrazones cyclize easily with boiling glacial acetic acid to the corresponding pyrazoline derivatives (IXa--f and Xa--f). The antibacterial activity of the chalcones and pyrazolines was investigated.


Anti-nociceptive substances from the roots of Angelica acutiloba.

Anti-nociceptive constituents of the Chinese crude drug Toki (the roots of Angelica acutiloba var. acutiloba Kitagawa) were investigated by means of chemical fractionation and bioassay. Seven active compounds that inhibit AcOH-induced writhing in mice have been isolated from Toki for the first time and identified as falcarinol, falcarindiol, falcarinolone (polyacetylenes), choline, scopoletin, umbelliferone and vanillic acid. Among these, the three polyacetylenes were found to be most active in the writhing test. Falcarindiol and choline also showed anti-nociceptive activities in the retrograde injection test of bradykinin into a carotid artery on rats.


The influence of D-penicillamine on cell proliferation. I. Quantitative investigations during an acute exudative inflammation in a model granuloma.

The influence of D-penicillamine (DPA) administration on a defined acute exudative inflammation in a model granuloma was investigated in a short-term experiment. The results indicate that DPA administration influences the metabolism of collagen but does not influence the proliferation behaviour of the fibroblasts. A significant increase in the number of fibroblasts can be explained in terms of an interaction of the loss of the soluble collagen with the number of fibroblasts necessary to maintain the total collagen level constant.


The cardiovascular effects of caffeine in various forms.

We have investigated the influence of various procedures which alter the solubility of caffeine on its physiological effects. Pretreatment of caffeine prior to injection by a) addition of sodium salicylate or sodium benzoate, b) increase in temperature or c) preliminary dissolution in hydrochloric acid, did not change the cardiovascular effects when injected i.v. at equivalent doses in urethane-anaesthetized rats. Addition of chlorogenic acid, a molecule found in coffee and other plants and reported to modify, by complexation, the physiological effects of caffeine, had no significant effect on the depressor responses to caffeine but did diminish caffeine-induced tachycardia at high doses of caffeine (10 and 30 mg/kg i.v.).


[Influence of high intravenous doses of D-penicillamine on toxic actions of cardiac glycosides in the guinea pig. Short communication (author's transl)].

Intravenous infusions of arrhythmogenic and lethal doses of ouabain and digoxin in anesthetized guinea pigs were not influenced by pretreatment with 1 g/kg D-penicillamine. The respective doses of proscillaridin and digitoxin, however, were significantly decreased by D-penicillamine. As could be demonstrated with proscillaridin this effect of D-penicillamine was dose-dependent between 0.25 and 1.0 g/kg. Obviously the strong plasma-protein binding of D-penicillamine leads to a displacement from binding sites of such cardiac glycosides which are also strongly bound to plasma proteins and thus reduces toxic doses of cardiac glycosides. Because of the extremely different doses of D-penicillamine in the animal experiments compared to those used therapeutically in man the present findings are irrelevant for clinical practice.


Study of the repercussions on blood of acute experimental inflammation in rats. I. Systemic effects induced by generalised inflammation with dextran.

Systemic effects resulting from dextran induced general inflammation in rats were studied. The phlogogenic agent was i.p. or i.v. injected. Dextran led to an increase in hematocrit values and erythrocyte counts. A decrease in blood total proteins, fibrinogen and sedimentation rate was observed, too. ADP mediated platelet aggregation was also decreased.


Pharmacology of halopredone acetate, a new topical antiinflammatory steroid.

The topical antiinflammatory activity of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon) has been compared with those of other steroids in a few bioassays in animals. At variance with the reference compounds, halopredone acetate, which exhibited variable potency according to the assay used never displayed substantial systemic effects when locally applied. Even after subcutaneous administration this new steroid did not interfere with adrenal function, carbohydrate and protein metabolism or sodium and potassium excretion. On the basis of the results reported, halopredone acetate may be considered a steroid with potentially high topical antiinflammatory activity and good tolerability.


Toxicological studies on halopredone acetate.

A toxicological study of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-dien-3,20-dione(halopredone acetate; Topicon), a new topical antiinflammatory steroid, administered a laboratory animals, was carried out in order to evaluate the safety of this compound. Halopredone acetate compared favorably with either hydrocortisone acetate or potent synthetic corticoids in acute and subacute toxicity studies in mice and rats. This compound did not induce gastric ulcers in rats after repeated administration and did not have any teratogenic effect in rats and rabbits. Also, repeated daily application for 4 months to the skins of mice from two different strains was well-tolerated.


[On structure-activity relationships of N'methyl-N'-beta-chloroethyl-benzaldehyde hydrazones (author's transl)].

The inhibition of uridine and thymidine in Ehrlich ascites cells is a basic property of the methylhydrazone structure and is reinforced by introducing a beta-chloroethyl group. This was shown by variation of the substituents at the N'-nitrogen atom of N'-methyl-N'-beta-chloroethyl-benzaldehyde hydrazone. Probably this action is due to an ethylenimmonium intermediate. This is derived from the observation that substituents which increase the nucleophilic property of the N'-nitrogen atom show a greater inhibitory effect in vitro. The therapeutic effect, however, is not enhanced when tested on the solid Ehrlich ascites tumor of mice. A better therapeutic effect resulted from introduction of chlorine atoms in positions 3 and 4 of the ring which inhbiits as well a probable metabolic hydroxylation of the ring.


Effects of hepatotoxic agents on hepatic microsomal metabolism of estrogens in the rat.

Different kinds of experimental liver damage in rats are evaluated as to associated changes in breakdown of natural estrogens. Acute or chronic treatment of rats with ethanol does not influence aromatic hydroxylation of estradiol, as indicated by liver microsomal replacement of tritium from 2,4,6,7-3H-estradiol. More severe liver damage by CCl4 or thioacetamide, which lowers hepatic cytochrome P-450, causes impairment of estrogen degradation: CCl4 dosage leads to a marked decrease in aromatic hydroxylation of estradiol. Whereas thioacetamide in a chronic application schedule has been previously reported to a decrease microsomal aromatic estrogen hydroxylation, a single dose of 300 mg/kg thioacetamide in rats causes increased microsomal formation of estrone from estradiol, which is regarded to be a better (i.e., more lipophilic) substrate for the microsomal estrogen 2-hydroxylase than is estradiol. The data show that hepatotoxic agents may act differentially on hepatic metabolism of endogenous steroids.


[Contribution to the pharmacology of a novel neuroleptic drug: flupenthixol (author's transl)].

Flupenthixol, which is chemically closely related to clopenthixol and fluphenamine, has the following properties: it reduces spontaneous motor activity, disturbs the behaviour, potentiates hexobarbital and chloral sleep, lowers central temperature and protects from death due to amphetamine; it is cataleptigenous and antagonizes apomorphic vomiting; it has marked adrenolytic and antihistaminic properties; its analgesic action is noteworthy. Flupenthixol presents the pharmacological profile of a neuroleptic drug.


[Development of new antiepileptics. II. Anticonvulsant effect of hydantoin derivatives].

From a series of N-substituted hydantoin derivatives, 1-phenyl-3-(o-chloro-p-sulfonamide-phenyl)-hydantoin was found to exhibit the best anticonvulsant activity against electroshock seizures. This substance showed also a weak activity against pentylenetetrazole seizures, as well as minor analgesic and sedative effects. The toxic effects are negligible; the lethal dose in mice was higher than 5000 mg/kg p.o. The other tested hydantoin derivatives showed much weaker anticonvulsant activities.


Spectrophotometric assay of nicotinic acid in blood. Assessment of its daily profile in humans.

A sensitive, simple, and specific spectrophotometric method is developed for estimating nicotinic acid in blood. The method depends upon reducing nicotinic acid by Zn/HCl to piperidine-3-carboxylic acid. The latter is complexed with CS2 and ammoniacal CuSO4 to form the yellow Cu-dithiocarbamate complex. The color is measured at 445 nm, obeys Beer's law (20--900 microgram/ml), and remains stable for more than 4 h. Efficiency of recoveries from standards and blood samples was tested and proved satisfactory at different levels of concentrations. The method shows good recovery (99.66%) and reasonable standard deviation (+/- 0.29%) in comparison with the cyanogen bromide method (98.3% and +/- 0.73%, respectively). The results obtained show a natural gradual decline in blood nicotinic acid level during the course of the day.


The binding of isoxazolyl penicillins to human serum proteins.

The binding of oxacillin, cloxacillin and flucloxacillin to human serum proteins was investigated with ultrafiltration methods and under the conditions of steady-state gel filtration and frontal analysis. In the different experiments very much lower rates of protein binding were found than had been expected according to the data in the literature. Partly the isoxazolyl penicillins are bound to the ultrafiltration membranes. The sources of error are discussed.


Biological properties and clinical application of propolis. VI. Investigation of the influence of ethanol extracts of propolis (EEP) on cartilaginous tissue regeneration.

Dressing of artificially formed losses of the cartilaginous tissue with the preparation containing ethanol extract of propolis (EEP) caused acceleration of regenerating processes in the lesioned cartilage. EEP inserted into the joint is well tolerated.


Chromosomal patterns of children born after induction of ovulation with bromocriptine.

We investigated a possible influence of 2-bromo-alpha-ergocryptine (bromocriptine, CB 154) on the human foetus. The chromosome patterns of the children born to mothers treated with bromocriptine before conception and in early pregnancy were examined. In 19 children no numerical or structural chromosomal anomalies which might be ascribed to the use of bromocriptine could be demonstrated.


Pharmacokinetics of five cephalosporins in healthy male volunteers.

This paper deals with data on the pharmacokinetics of cephazolin, cephalothin, cephapirin, cephaloridine and cephradine after i.m. injection of a single dose of 0.5 g in healthy male volunteers. Peak serum concentrations occurred 45 min after the administration and were 31.52 microgram/ml for cephazolin, 17.32 microgram/ml for cephaloridine, 13.98 microgram/ml for cephapirin, 9.51 microgram/ml for cephradine and 8.60 microgram/ml for cephalothin. The average half-lives were found to be 2.07, 1.80, 0.98, 1.24 and 0.97 h, respectively. The percentage of protein binding was found to be 82 for cephazolin, 59 for cephalothin, 51 for cephapirin, 31 for cephaloridine and only 10 for cephradine, half an hour after drug administration. The total urine recovery of the above cephalosporins, within 24 h, was 91.9% for cephradine, 81.9% for cephaloridine, 73.3% for cephazolin, 69.5% for cephapirin and 51.2% for cephalothin.


[Maltose as a substrate for inducing osmotic diuresis (author's transl)].

10 healthy men received an i.v. infusion of maltose at a dosage of 1.5 g/kg/h over a period of 1 h. No clinical side effects were observed. Total protein and albumin showed a significant drop. The glucose level remained constant. The concentration of maltose rose up to 495 +/- 77 mg/100 ml. The osmo-diuretic action of the solution was proven by a renal excretion of 289 +/- 57 ml water/h, 14.6 g maltose/h and 3.9 g glucose/h. The total carbohydrate elimination was 61.8 +/- 9.1 g/8 h, (44.5 +/- 13.5 maltose and 15.7 [+8.1--21,2] glucose). The specific action of maltose is an induction of glucosuria without hyperglycemia.


[Synthesis of Butyl 6alpha-Fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (Fluocortin Butylester) (author's transl)].

Among the metabolites of fluocortolone (1) there was found the alpha-keto acid 4a. This acid, as well as the esters 4b--4k were synthesized and the butyl ester 4c was chosen for local anti-inflammatory therapy.


[Structure elucidation of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester) (author's transl)].

The structure of butyl-6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) was elucidated by the spectrometric methods UV, IR, NMR and MS.


[On an improved device for measuring skin tearing strength. Technical description and experimental results obtained from rat skin following therapy with topical corticoids (author's transl)].

Technical details of an improved method for measuring tensile behaviour of normal and treated rat skin are described. The apparatus has been developed specifically for skin specimens so that the extending force and the adequate strain rate until rupture are designed especially for this purpose. Skin is to be mounted in the jaws of the instrument in horizontal position. Preliminary biological data have been worked out.


[Dermal and systemic side effects of fluocortin butylester. Comparative skin tearing experiments with active principles from commercial preparations].

Different concentrations of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester FCB, Vaspit) and of clobetasone-17-butyrate, clobetasole-17-propionate and hydrocortisone-17-butyrate have been administered topically in order to investigate dermal and systemic side effects. It could be shown that FCB exhibits by far the least side effects. A specially devised apparatus covering the site of substance application, guaranteed an exclusive dermal absorption. Side effects, therefore, cannot be ascribed to oral ingestion of the drugs.


[Metabolism of fluocortin butylester in the skin of guinea pigs and man (author's transl)].

The biotransformation of 3H labelled butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit, FCB) was examined in vivo in the intact and pre-damaged skin of guinea pigs and in vitro in excised skin from guinea pig and humans. The active ingredient was applied as 0.75% W/O-emulsion. At the end of the period of exposure the substance remaining on the skin was recovered with the aid of cotton wads or Tesa adhesive tape and the spectrum of metabolites in the skin and the rinsing fluid determined by thin-layer chromatography. FCB is only slowly degraded in the skin of guinea pigs and humans to produce its main metabolites 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadiene-21-acid and its derivative by decarboxylation 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-androstadiene-17beta-carboxylic acid. 4 h after application 80--85% unaltered active principle was still identifiable in the intac skin and approximately 70% in the damaged skin of the guinea pig. In the human skin the amount was approximately 90% 7 h after application. The amount of active ingredient in the perfusion medium was about 65% while the amount of steroid acids was about 25%. Despite the extremely low rate of absorption the slow ester hydrolysis of FCB in human skin results in a persistent, high level of active ingredient in the skin.


[Effect of fluocortin butylester (0.75%) as an ointment in the pyrexal erythema test on human skin (author's transl)].

The antiinflammatory efficacy of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) as a 0,75% ointment was tested in comparison with 1% hydrocortisone acetate ointment in the model of the pyrexal erythema. Fluocortin butylester appeared to be significantly superior to hydrocortisone acetate.


[The effect of fluocortin butylester on adrenal function in man (author's transl)].

The systemic corticoid effects of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-regnadien-21-oate (fluocortin butylester, Vaspit) in the form of 0.75% fluocortin butylester cream were tested under conditions which permit maximum absorption of the active principle. Over 8 days 40 g cream daily were applied to the entire body surface of 6 subjects and the trunk, thighs and upper arms covered with polythene foil. The plasma cortisol levels, elimination of free cortisol in the 24-h urine and eosinophilic leucocytes were compared intraindividually with the values before and three days after treatment. In addition 6 further subjects were treated with 0.1% hydrocortisone-17-butyrate cream, a preparation considered to have little systemic action. Fluocortin butylester showed no systemic corticoid effects. Cortisol secretion and eosinophilic leucocytes remained unaffected. In contrast the inhibiting effect of hydrocortisone-17-butyrate was evident in all parameters, especially in the morning plasma cortisol values. Under treatment with hydrocortisone-17-butyrate these dropped from 361 to 11 nmol/l. Under occlusion treatment with fluocortin butyl they remained constant (357 before, 320 nmol/l after treatment). The relevance of the method of examination is discussed.


[Studies on phototoxic and photoallergic effects of cream, ointment and fatty ointment of fluocortin butylester (author's transl)].

The phototoxic action of ointment and fatty ointment of butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) was examined by means of the epicutaneous test with subsequent UV-irradiation (Kromeyer lamp with Schott filter DG 18) in 20 patients with skin disorders. Photoallergic effects of fluocotrin butylester cream, ointment and fatty ointment were tested in a modified Draize test in which 198 subjects with normal skin participated. The subjects were sensitized in 10 epicutaneous tests conducted at intervals of 24 h and followed by irradiation (1500 W xenon lamp) with 2 MED. Treatment and irradiation were then repeated after a 2-week interval. This proceding permitted additional statements an phototoxicity of the administered preparations. No positive reactions occurred in either of the tests so that phototoxic effects can be excluded and a photoallergic potential is improbable.


Susceptibility to erythromycin of anaerobes of the genera Bacteroides, Fusobacterium, Sphaerophorus, Veillonella, Clostridium, Corynebacterium, Peptococcus, Peptostreptococcus.

The minimal inhibitory concentrations (MIC) of erythromycin were determined by broth dilution tests for 313 anaerobic strains, most of which were clinical isolates. All the gram-positive anaerobes tested (84 Peptococcaceae, including 21 Peptostreptococcus anaerobius and 15 Peptococcus variabilis; 65 Corynebacterium acnes and 29 Clostridium strains, including 13 C. perfringens) were sensitive (MIC values 0.012 through 3.12 microgram erythromycin/ml); so were 111 cultures of gram-negative anaerobes (52 Bacteroides fragilis, 12 B. thetaiotaomicron, 7 B. vulgatus, 13 B. oralis, 4 B. melaninogenicus, 10 Sphaerophorus necrophorus, 2 Veillonella sp., 11 members of other species). Erythromycin at concentrations of 6.25 through 200.0 microgram/ml was active against 24 strains (1 B. fragilis, 4 Fusobacterium fusiforme, 9 Sph. freundi, 10 Sph. varius). The present results are compared to the limited number of reports existing with regard to the susceptibility of anaerobes to erythromycin.


Quantum chemical studies on clonidine and related derivatives.

The ground state geometry of the protonated form of clonidine was established by CNDO/2 (complete neglect of differential overlap) calculations. For the interplanar angle of this molecule we found a value of about 40 degrees. The interplanar angles of a number of clonidine related derivatives, both bases and protonated forms, were calculated on the basis of the results obtained for clonidine by taking into account the bond lengths and van der Waals radii of the substituents present at the ortho positions of the phenyl ring. The preferred conformations of the free bases and protonated forms were used as inputs for the semi-empirical PPP-MO (Pariser, Parr and Pople molecular orbital) calculation procedure in order to obtain several quantum chemical parameters. Excellent correlations resulted in relating some of the calculated parameters with the experimentally determined pK'a of the molecules. The results show the ability of MO-calculations to predict the basicity in this series of congeneric molecules and furthermore support the reliability of the calculation procedure in providing the quantum chemical parameters reported in this paper.


On the cholinesterase inhibiting properties of two pyrrolidine derivatives.

The influence of cis-2-phenyl-1-pyrrolidino-cyclohexane (RX 67 668) and of cis-2-(3-hydroxyphenyl)-1-pyrrolidino-cyclohexane methobromide (RX 72 601) on acetylcholinesterase (AChE) and plasma cholinesterase (ChE) was investigated in vitro by means of a photometric assay technique with respect to their mechanism and constants of inhibition. The two compounds cause reversible inhibition of both AChE and ChE, the (I)50 and Ki for RX 67 668 being 2.5 x 10(-5) M and 4 x 10(-6) M (AChE), resp., and 2.0 x 10(-5) M and 8 x 10(-7) M (ChE), resp.; and for RX 72 601 7.9 x 10(-8) M and 3 x 10(-9) M (AChE), resp., and 3.2 x 10(-7) M and 1 x 10(-8) M (ChE), resp. The kinetic analysis of the inhibitory action disclosed a purely competitive mechanism. The inhibition of the two esterases is assumed to be induced by the formation of a readily dissociable enzyme-inhibitor complex due to the binding of the positively charged pyrrolidine moiety of the two substances to the anionic subsite of the active center, thus impairing the formation of an enzyme-substrate complex.


The influence of D-penicillamine on cell proliferation. II. Quantitative investigations during a chronic proliferative inflammation in a model granuloma.

The influence of D-penicillamine (DPA) on a defined chronic proliferative inflammation in a model granuloma was tested in a long-term experiment. A change in collagen metabolism was detected during the three weeks of DPA administration, whereas the proliferation of the fibroblast population remained unaffected.


Study of the repercussions on blood of acute experimental inflammation in rats. II. Blood changes in the course of carrageenin induced inflammation.

Repercussions on blood of inflammation induced by carrageenin injection in the four paws of rats were studied. Two stages were observed. 4 h after carrageenin injection, a high fall in leucocyte count and a small decrease in blood total proteins and blood fibrinogen were registered. ADP mediated platelet aggregation and sedimentation rate were not modified. 24 h after carrageenin injection, sedimentation rate and blood fibrinogen were increased; some platelet hyperaggregation with ADP was also observed.


Influence of central pretreatment with 6-hydroxydopamine on the hypotensive effect of clonidine.

Intracisternal (i.ci.) pretreatment of rabbits with 6-hydroxydopamine (6-OH-DA) (3 times 0.5 mg/kg) reduced the norepinephrine content of the brainstem significantly by 52% but did not diminish the hypotensive and bradycardiac action of 2-(2,6-dichloroanilino)-2-imidazoline (clonidine; Catapresan; Catapres) (doses 10, 30 and 100 microgram/kg i.v. and 1 microgram/kg i.ci.) in anaesthetized animals. Pretreatment with 6-OH-DA did not abolish the enhancement by clonidine (100 microgram/kg i.v.) of reflex bradycardia elicited by angiotensin 0.2 microgram/kg i.v. The conclusion is drawn that clonidine acts directly on central alpha-adrenergic receptors independent of storage and synthesis of endogenous catacholamines in the central adrenergic neurons.