The optical function of keratoprostheses.

The optical function of acrylic cylinders used in keratoprostheses is demonstrated by using a water-filled minicamera as a model of the aphakic human eye. Lengths and diameters of the optical cylinders are important factors influencing the visual fields. The dimensions to be chosen, depends on the thickness of the cornea and the supporting tissues. The most suitable combination of visual field, magnification and diameter of the retinal image field is obtained with optical cylinders with a concave posterior surface. Using a fixed radius of curvature of the posterior surface, the radius of the anterior surfaces are calculated to make the eye emmetropic. With such a cylinder of length 4.5 mm and diameter 2.1 mm a circular visual field of 48 degrees is obtained. With cylinder length 6.0 mm the visual field is at least 35 degrees. The retinal image is about 19% larger than that of the normal phakic eye. Cylinder length exceeding 6.0 mm require a greater diameter to provide an adequate visual field. With cylinder lengths up to 6.0 mm and diameters not less than 2.1 mm, the diameter of the retinal image field is at least 12.0 mm. Accidental obliquity of the optical cylinder or off-center implantation give the possibility of undesired projection of the image field outside the macula. The obliquity or degree of off-center implantation tolerance is calculated. The retinal image may be improved by darkening the side of the cylinder.


Selenium content of whole blood and serum in adults and children of different ages from different parts of Finland.

A low level of selenium (Se) in the blood and serum of Finns was demonstrated. Inhabitants in the central, eastern and southeastern districts of the country had particularly low levels selenium. However, the Se level of Lapps and the people of the Aland archipelago seemed to be significantly higher than the level of other Finns. In general, the Se levels in th serum were lower than the values for whole blood. Furthermore, the levels were lower in children than in adults. The significance of these findings in the pathogenesis of some human diseases is discussed.


Effects on rat liver acetaldehyde dehydrogenases in vitro and in vivo by coprine, the disulfiram-like constituent of Coprinus atramentarius.

Coprine, the disulfiram-like constituent of the mushroom Coprinus atramentarius was found to inhibit the low-Km dehydrogenase in rat liver and to increase the acetaldehyde level in blood during ethanol metabolism in vivo. Coprine did not inhibit the low-Km enzyme in vitro, but the hydrolytic product of coprine, 1-aminocyclo-propanol, was a potent inhibitor both in vitro and in vivo. A rapid onset of inhibition was observed after administration of coprine and the inhibition was long-lasting. It is suggested that 1-aminocyclopropanol is responsible for the inhibition caused by coprine in vivo.


Pharmacology of cis(Z)-clopenthixol decanoate, a depot neuroleptic.

The duration and intensity of the neuroleptic effect of cis(Z)-clopenthixol decanoate in Viscoleo have been compared with those of cis(Z)-clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)-clopenthixol, 2 HCl had a strong, but short-lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)-clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)-clopenthixol decanoate whereas cis(Z)-clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)-clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.


The renal handling of lithium: relation between lithium clearance, sodium clearance and urine flow in rats with diabetes insipidus.

In order to study the renal handling of lithium, I examined the relation between the lithium clearance and the urine flow in rats which had hereditary lack of vasopressin production and which had been given a test dose of lithium. The two variables were altered by varying the sodium intake. Rats with a low, medium and high sodium intake had a mean lithium clearance of 0.04, 0.22, and 0.40 ml/min./100 g body weight, respectively. When the sodium intake was increased from a medium to a high level, the lithium clearance and the urine flow rose in proportion to each other (r=0.90). When the sodium intake was decreased from a medium to a low level, the lithium clearance fell relatively more than the urine flow so that the proportion between the two was changed. The experiments show that when vasopressin-induced alterations of the urine flow are excluded and when the sodium intake is not extremely low, proportionality may occur between the lithium clearance and the urine flow. This suggests that the lithium clearance varies in proportion to and is determined by the delivery of sodium from the proximal tubules.


The effect of calcium and beat interval on the contractile force and refractoriness of the isolated rat atrium in the absence and presence of nifedipine: a possible mechanism for the negative staircase phenomenon.

An increase in the calcium concentration of the Ringer solution increased the contractile force and reduced the effective refractory period of the isolated rat left atrium paced at a frequency of 60 per min. An increase in the frequency of stimulation decreased the contractile force (negative staircase) and reduced the effective refractory period; these effects being most pronounced at the highest calcium levels. A calcium-antagonistic drug, nifedipine, decreased the contractile force and the effective refractory period. The effect of an increased frequency of stimulation on the contractile force at different calcium levels in the absence and presence of nifedipine paralleled its effect on the effective refractory period. This observation suggests that both these phenomena are caused by a decreased quantity of inflowing calcium ions during the period of exciation, and thus might explain the absence of positive staircase in the rat myocardium.


The effect of intracisternally injected ouabain on perilymph electrolyte concentrations.

A means for altering the ionic composition of perilymph utilizing the cochlear aqueduct and cerebrospinal fluid in chinchillas is introduced. A decrease in sodium and an increase in potassium concentration in perilymph was observed after ouabain was injected into cerebrospinal fluid. The time course of changes in the perilymph paralleled the CSF change but with a time lag which had not reached equilibrium within 60 minutes.


Respiratory and cardiovascular effects of 3-methylxanthine, a metabolite of theophylline.

The effects of 3-methylxanthine (3-MX), a major metabolite of theophylline in man, were studied and compared with those of theophylline in isolated preparations of human and guinea-pig airways, isolated guinea-pig hearts, and in anaesthetized cats. 3-MX was pharmacologically active, producing effects similar to those of theophylline. The guinea-pig and human airways preparations were relaxed; the rate and force of contraction of guinea-pig hearts were increased. In anaesthetized cats, 3-MX decreased the respiratory overflow and arterial blood pressure, and increased the heart rate. Theophylline was always more potent (between 1 and 5 times) than 3-MX. It is suggested that 3-MX may contribute to the effects of theophylline during long-term treatment.


Phlebography, urography and lymphography in the diagnosis of metastases from testicular tumors.

The value of lymphography from the foot, urography and phlebography of the inferior vena cava and the left renal and testicular veins in the search for retroperitoneal metastases was investigated in 120 patients with testicular tumors. Phlebography of the left renal and testicular veins was a valuable supplement to the other examinations, so that the combined use of all these methods is recommended in demonstrating metastases and in evaluating the extent of growth and effect of treatment.


Milk and lactose-hydrolyzed milk.

Seven females 18 to 26 years old (mean 23 years) who were lactose malabsorbers as determined by a lactose tolerance test were given two different test meals: 5 ml/kg body weight reconstituted nonfat dry milk and 5 ml/kg body weight reconsituted nonfat dry milk in which 92% of the lactose had been hydrolyzed to glucose and galactose. Lactose malabsorption was determined by the breath H2 test. Tests were done in duplicate for a total of 28 tests. Whether a 3-hr test period of a 5-hr test period was used, the average breath H2 response after the lactose-hydrolyzed nonfat dry milk test meals was significantly lower (P less than 0.002) than the average breath H2 response after the nonfat dry milk test meals. There were significant differences among individual responses (P lless than 0.06 for the 3-hr test period and P less than 0.09 for the 5-hr test period), and no significant differences between duplicate test days.


Endoaneurysmorrhaphy for visceral artery aneurysms.

The clinical histories and surgical management of two patients with mycotic aneurysms involving the hepatic and superior mesenteric arteries are presented. Endoaneurysmorrhaphy was used to successfully manage these patients. This technic permits the preservation of maximum blood flow to the abdominal viscera. The clinical features and surgical technic are discussed.


Phenylketonuria masked by low protein feeds.

Two patients with phenylketonuria (PKU) requiring treatment were fed on low protein milks. Both had blood phenylalanine levels below 1200 micronmol/l (20mg/100 ml) until given a phenylalanine challenge. Phenylalanine content of mature breast milk may provide intakes similar to those used in treating PKU. Diagnosis of PKU is unlikely to be missed if screening is carried out on the sixth or seventh day of life because of higher phenylalanine in breast milk during the first week. Interpretation of screening tests requires knowledge of the infants' feeds and a blood phenylalanine above 360 micronmol/l (6 mg/100 ml) in the absence of tyrosinaemia requires careful investigation.


[Light and electronmicroscopic examinations on granulosa and theca of preovulatory and freshly ruptured follicles of human ovaries (author's transl)].

In a first paper, the structural and functional relationship of granulosa and theca of follicles during early development stages was reported. On the special question of whether and from which moment these two tissue formations are involved in the steroidbiosynthesis, our electronmicroscopic examinations have given a further insight to this. Neither the granulosa nor the theca folliculi of primordial, primary and secondary follicles show definite morphologic submicroscopic criteria of the steriodbiosynthesis. In the resting tertiary follicle, the electronmicroscopy defines the theca cells as steroidbiosynthetic active cells, whereas the granulosa cells of this stages of follicle demonstrate the morphologic characteristics of protein-synthetic active cells. Our, under physiological conditions, systematically conducted light and electronmicroscopic studies of preovulatory and freshly ruptured follicles showed remarkable structural changes in the granulosa, as well as in the theca folliculi. For the follicle granulosa cells of the preovulatory follicle, the studies could demonstrate a structural transformation process of proteinsynthetic active to steroidbiosynthetic active cells. This transformation process can be seen in the nucleus. Especially recognizable is the continuous change from rough to smooth endoplasmatic reticulum in the cytoplasm of most of the follicle granulosa cells, which apart from that, often displayed whorle-like formations. Furthermore, we noticed striking changes of the paraplasmatic structures, especially of the fat, present in various stages in the cytoplasm of the follicle granulosa cells. We also noticed large mitochondria, which showed a lot of vesicular cristae. Numerous existing Golgi-fields contained many little homogenous fat-like droplets, which were surrounded by a thin osmiophilic membrane. This recognizable transformation process of the proteinsynthetic active granulosa cells to the steroid cells is quite completed in freshly ruptured follicles, according to our examinations. Although the theca cells have already been defined submicroscopically in the resting tertiary follicle as steroidbiosynthetic active cells, we see in this cellgroup in the preovulatory, as well as in the freshly ruptured follicle a remarkable conspicuous size-increase of the mitochondria. Apart from that, there are wide areas which are solely occupied by smooth endoplasmatic reticulum, whereas other structures, for example fat, are scarely seen. As our examinations have shown, there is a close relationship between the transformation process in the granulosa and the theca of preovulatory follicles and the theca of preovulatory follicles that, the increasing concentration of progesteron in serum, which begins prior to the ovulation can be regarded as a product of the follicle granulosa cells being transformed to steroid cells.


[Quantitative investigation of embryonal motor activity by ultrasonic time-motion technique (author's transl)].

Using ultrasonic A and B-mode equipment (Kreta-Technik, gray-scale) 80 time-position scans of active embryonal movements were recorded in 60 pregnancies between 8 and 14 weeks of amenorrhea. The quantitative analysis of the echograms comprised 14 parameters of embryonal motility. The extent and the velocity of body excursions within the amniotic cavity increased significantly with gestational age. Determinations of embryonal size by measurement of the thoracic diameter made possible an evaluation of energetic development in early pregnancy.


The effect of prostaglandin f2alpha on endocrine parameters in early pregnancy.

The luteolytic effect of prostaglandin f2alpha (PGF2alpha) has been well documented in a variety of primates. This property has not been proven in early human pregnancy. A study of the luteolytic activity of extraamnial administration of 5 mg PGF2alpha was carried out on 7 healthy women who were less than 6 weeks pregnant and on 4 women who were more than 9 weeks pregnant. Serum levels of 17beta-estradiol, 17-hydroxyprogesterone, progesterone and human chorionic gonadotropin (HCG) were measured by radioimmunoassay before, during and after the administration of PGF2alpha. Abortion was successfully induced in all the patients with early pregnancies, but in the control group of more mature pregnancies only one of the four women aborted. In the older pregnancies, the administration of 5 mg PGF2alpha caused no significant alteration in the serum levels of the measured hormones. In the younger pregnancies the serum concentration of 17beta-estradiol and progesterone decreased within hours after PGF2alpha administration. Serum 17-hydroxyprogesterone concentrations remained unchanged at a high level and declined significantly later in a manner similar to HCG. This discrepancy in the decline of 17-hydroxyprogesterone as opposed to progesterone and 17beta-estradiol may be explained by two mechanisms, the one mechanical, and the other secondary luteolytic. The marked increase of intrauterine pressure occurring within minutes after PGF2alpha instillation damages the fetoplacental unit. This leads to a decrease in the placental steroido-genesis and HCG production necessary for the maintenance of the corpus luteum.


[Can the search for early stages of cancer of the cervix uteri be improved? An empirical and theoretical study from sociology in medicine (author's transl)].

Using a standardised questionnaire, 7356 women, patients at the Erlanger Universitäts-Frauenklinik, were interviewed. Women with cervical cancer or carcinoma in situ of the cervix were compared with the remaining patients. Social factors are described which are more frequent with women with cervical cancer than with other women. The more such individual factors are added together, the greater the risk of developing a cervical cancer. Further, social factors are investigated which prevent women from going to prophylactic examinations. The more such factors are encountered, the greater the probability that a woman will not go to prophylactic examinations. Both results were to be expected from common-sense, but until now confirmation by empirical investigation was lacking. The greater the risk of getting cervical cancer, the greater the probability that screening will be avoided. This result show that cervical cancer is to be expected in the greater proportion of about 70% of women over the age of 30 who do not go for prophylactic examination, compared with the 30% who undergo prophylactic examination anually.


Morphologic association of lymphocytes with hepatocytes in chronic liver disease.

The interrelationship between lymphocytes and hepatocytes was examined by light and electron microscopy, using epoxy-resin embedded thick and thin sections of biopsy liver tissues from patients with chronic persistent hepatitis (CPH) and chronic active liver disease (CALD). Close apposition of lymphocytes with hepatocytes was classified according to morphologic features produced by surface contact, invagination, direct penetration, and aggregation. Lymphocytes in biopsy specimens from patients with CALD showed these morphologic patterns much more frequently than in those from patients with CPH. These small, infiltrating lymphocytes established intimate contact with hepatocytes through their multiple-surface projections. Hepatocyte degeneration appeared to occur in association with the structural contact. The morphologic association of lymphocytes with hepatocytes in CALD is consistent with the participation of cell-mediated immune processes.


Unusual gonadal stromal tumor of the testis. Case report with ultrastructural observations.

Ultrastructual observations on an unusual gonadal stromal tumor of the testis in a 4-year-old boy with gynecomastia revealed that the tumor cells lacked the abundant smooth endoplasmic reticulum usually found in neoplastic and nonneoplastic Sertoli and Leydig cells. The cells were rich in cytoplasmic microfilaments, with localized dense areas of the type seen in smooth muscle cells as well as intracytoplasmic lipid droplets. It  is concluded that the tumor cells show important similarities to the immature fusiform interstitial cells and the peritubular contractile cells present in the normal testis.


Sclerosing lipogranuloma of male genitalia. Review of 23 cases.

In 1950 the term "sclerosing lipogranuloma" was introduced to designate a praticular subcutaneous granulomatous reaction that was believed to be a "local reactive process following injury to adipose tissue." Subsequent reports have shown that exogenous lipid injections probably are responsible for this lesion. We have studied 23 cases involving penis, scrotum, spermatic cord, and perineum, nine of which had been previously reported. We have been able to identify paraffin hydrocarbons by means of infrared-absorption spectrophotometry in 21 of these cases. We belive this entity should be redefined as a "local reactive process following injection of exogenous lipids into the subcutaneous tissues." In conventional microscopical sections, the lesion must be differentiated from adenomatoid tumor, sclerosing liposarcoma, and lymphangioma.


[Clinical and radiological results after cruciate ligament repairs using the meniscus (author's transl)].

The postoperative clinical course and late x-ray results after plastic reconstruction of the cruciate ligament with a meniscus. Presented here are the postoperative results after plastic reconstruction of the anterior cruciate ligament with the medial meniscus. The periods of observation cover up to 29 years. 14 patients were personally re-examined, 3 were accounted for after answering a questionnaire. Only 2 cases showed severe instability and 13 cases gonarthrosis of varying degree. 13 cases were satisfied with the results of the operation. 16 patients were able to maintain their occupations, 5 changed their professions. The majority of patients is involved in athletic activity of wide variety, 6 participate in competitive sports.


Normal values of the ipsilateral acoustic stapedius reflex threshold.

It is frequently taken for granted that the acoustically evoked stapedius reflex is bilaterally symmetrical. Contrary to this, Møller described an asymmetry of the acoustic stapedius reflex with an ipsilaterally 2--14 dB lower threshold. The determination of normal values of the ipsilateral acoustic stapedius reflex threshold with a large number of patients is difficult as the intensity of the stimulus depends considerably on the position of the probe in the acoustic meatus and is therefore not defined with sufficient accuracy. For this reason we determined the values of the ipsilateral threshold by applying a stimulus sound of high intensity to the deaf ear of unilaterally completely deaf patients with a normal headphone, which can be calibrated much more accurately. After subtraction of the individual cross hearing loss, the exact ipsilateral intensity was obtained. By this method a stapedius reflex could be evoked with 49 of the 62 patients. By mathematical consideration of the data of the positive cases, as well as the maximum available intensities with the negative cases, determination of the median value of the ipsilateral threshold was possible: at 0.5 kHz 59 dB; at 1kHz 62.5 dB; at 2 kHz 67 dB; at 4 kHz approx. 67 dB. The difference between ipsilateral and contralateral stapedius reflex threshold was in the range of 15 dB. A new definition of the normal value for the ipsilateral measured Metz recruitment appears necessary.


Microridge cells in the larynx of the male white rat. Investigations by reflection scanning electron microscopy.

The laryngeal epithelium of male white rats is studied by reflection scanning electron microscopy (SEM). In addition to ciliated cells, microvilli cells, brush cells and goblet cells that are characteristic for normal respiratory epithelium the microridge or labyrinth cell can be seen in particular regions of the larynx. The apical surface of a typical labyrinth cell is characterized by a system of narrow standing microridges of about 0.05--0.15 micronm in diameter and interconnecting microridges with a diameter of about 0.01 micronm. The microridge system of a labyrinth cell originates from the fusion densely standing microvilli. Between microridge cells and microvilli cells all transition forms can be observed. The preferable localiziation of the microridge cell in the larynx and its possible function is discussed.


Scanning ultrastructure of the stria vascularis.

In the eleven years since the introduction of the first commercially available scanning electron microscope, a number of otologic studies have made use of this new technique. However, the literature contains only one report of scanning ultrastructure of the endolymphatic surface of the stria vascularis. We have studied the stria vascularis with a technique allowing examination of the mid-modiolar cut surface as well as the endolymphatic surface.


The morphology of the vestibular nerve in a patient with normal vestibular function and in patients with Ménière's disease.

The morphology of the vestibular nerve was studied in three fresh nerve specimens obtained by surgery from two patients with Ménière's disease and one patient with tinnitus after an attack of sudden deafness. The number of nerve fibres appeared light microscopically normal. The vestibular ganglion cells of the Ménière-specimens showed, as a characteristic finding advanced vesiculation of the cytoplasm. This change was confirmed by electron microscopy and the vacuoles appeared to consist of widened endoplasmic reticulum cisternae. Numerous primary lysosomes and lipofuscin granules were observed in all vestibular ganglion cells but their number appeared increased in the specimens from Ménière-patients. Some of the vestibular ganglion cells of these patients showed a filamentous appearance and the number of glycogen granules seemed reduced in all of them. All vestibular ganglion cells observed were unmyelinated. The degenerative changes observed might explain the typical elevation of the threshold for vestibular stimulation in Ménière's disease.


[A case of primary lymphosarcoma of the parotid gland].

A rare case of primitive parotid gland lymphosarcoma is described. The possibility of the occurrence of these rare neoplasias in the parotid region is discussed from the embryological and anatomical standpoints.


Histopathological research on eardrum perforations.

Basic information on the healing process of tympanic membrane perforations is scarce and sometimes contradictory. So the histological and histopathological course of the closure of tympanic membrane perforations was studied in experiments on mice and hamsters. From this investigations it seems evident that traumatic tympanic membrane perforations close nearly always spontaneously in animals. This fact must be kept in mind in the evaluation of techniques and results of tympanoplasties in animal experiments. Furthermore the squamous epithelium of the eardrum plays an important role in the regeneration of tympanic perforations. The closure of the connective tissue defect has always a tendency to lay behind the healing of the epithelial layer. This mechanism differs from the normal healing process of skin wounds where the squamous epithelium migrates over a newly formed granulation tissue layer. On the basis of these findings some practical considerations can be made on tympanoplasties in human.


Liability of ultrasound in maxillary sinus disease.

For the first time liability of of ultrasonography in diagnosing paranasal sinus disease was controlled in 256 patients with acute maxillary sinusitis as compared to irrigation findings and in 150 patients with persistent maxillary sinus disease using x-rays, sinoscopy and sinumanometry as controls. Confidence in diagnosing the presence of discharge ranges up 90%. In cases of total opacity of the sinus, ultrasonography helps differentiating mucosal swelling, tumor and discharge.


Anti-androgen-therapy in pachydermia of the female larynx--a new therapeutic possibility.

Case-report about a 56 year old white female patient with pachydermia laryngis and hirsutism, successfully treated with cyproterone-acetate, a testosterone antagonist. The significance of androgenic hormones for the development of epithelial changes in the female larynx is emphasized. The administration of antiandrogenic substances as a new therapeutic measure is discussed.


Delayed elimination of the ototoxic compound atoxyl from the inner ear.

Whether an active accumulation of ototoxic substances or their metabolites occurs in the cochlea, or whether there exists a delayed elimination of these products from the endo-and perilymphatic fluids, following a passive equilibrium between the blood and the body tissues, is still a subject for discussion. To investigate the cochlear distribution of an ototoxic substance and its elimination rate, compared to other organs in the body, atoxyl, with known ototoxic effects (Anniko and Wersäll, 1975a, b; Anniko, 1976a, b) was used as a test substance. The neutron activation analysis technique was used to measure the atoxyl concentration in various parts of the body (cochlea, blood, muscle, kidney and cortical femoral bone) after various lengths of time following a subcutaneous injection of 100 mg/kg b.w. of atoxyl. Atoxyl was retained in the cochlea for a long period and a delayed elimination occurred from the inner ear. The excretion of atoxyl was likely to appear via the kidneys.


Anomalous myelinated nerve fibers in the spiral ligament of the chinchilla cochlea.

A fascicle of myelinated nerve fibers has been found within spiral ligament tissue of the chinchilla cochlea. The presence of nerve fibers in this region of the cochlea has not been previously reported in any species and its occurrence in the chinchilla is thought to be anomalous.


[Studies on the detection of clonazepam and its main metabolites considering in particular thin-layer chromatography discrimination of nitrazepam and its major metabolic products (author's transl)].

The article describes analytical methods concerning screening tests for clonazepam and nitrazepam and the 7-amino derivatives. Further a detailed method is reported for the separation and identificatin of the benzodiazepine pair de. The method described permits a sharp separation and the nitro compounds with TiCl3 on the plate and forming the 7-acetamido derivatives by subsequent separation in the second dimension with ethyl acetate/acetic anhydride. The method described permits a sharp separation and highly sensitive detection by diazotization and coupling with Bratton-Marshall reagent. Amounts as low as 0.02 microng per spot can be detected. Besides preparation methods are reported for 7-aminoclonazepam, 7-acetaminoclonazepam, 2-amino-2'-chloro-5-nitrobenzophenone and 2,5-diamino-2'-chlorobenzophenone. Also spectral data (UV, IR, MS) and a literature review are given.


New broad-spectrum alkylthio cephalosporins.

A series of 7-substituted alkyl-thio-acylaminocephalosporins with the following general formula were prepared and tested for in vitro antibacterial activity: (formula: see text). We tried in our research to find any relationship between antibacterial activity and pharmacokinetic properties on the one hand, and chemical structure on the other. The most interesting products were also studied for their in vivo antibacterial activity in experimental acute systemic infections in the mouse.


[The reactions of human middle ear mucous membrane (author's transl)].

Healthy middle ear mucous membrane of newborns differs from the respiratory mucous membrane of the respiratory tract, in that it lacks a mucociliary epithelial pattern and because it has an absence of cells responsible for immunological resistance. Irritations over a short period of time and intensity cause a mucous membrane edema, which leaves behind, when the irritation disappeares, no permanent morphological changes in the structure of the mucous membrane. Severe irritations over a long period of time cause a characteristic change in the epithelium and submucosa: the single layered flat epithelium is replaced by respiratory epithelium; in the submucosa a proliferation of the connective tissue occurs simultaneously with the development of a local immunologically potent, cellular defense system. The actively secretive epithelial cells serve as the means whereby the antibodies are transported to the surface of the mucous membrane. Whereas at the time of mucous membrane edema, serum components (transsudate) are the primary source of the resulting "serotympanum", an increase in viscosity of the mucous allows one to recognize the active secretive work of the metaplastic epithelium. The biochemical composition of the various effusions givens a direct a direct indication of their origin: it is, however, no key to the cause! Only in the case of purulent secretions is it possible to recognize the cause by cellular or bacteriological identification. The same is valid for the norphological changes of the middle ear mucous membrane since the membrane will generally react in a similar manner, even though the types of irritation differ. When the stimulus which brought about the proliferation of the mucous membrane since the membrane will generally react in a similar manner, even though the types of irritation differ. When the stimulus which brought about the proliferation of the mucous membrane and the epithelial metaplasy disappears, the active production of mucous stops. However, a regression to the original condition does not take place: the mucous membrane remains ready to react!


Effect of histones on the intracellular metabolism of ascorbic acid.

Basic proteins are able to control the intracellular metabolism of ascorbic acid in human erythrocytes. The stimulating effect of ascorbic acid expressed by means of cellular peroxidase reactions of intact erythrocytes depends on the ascorbic acid and basic protein concentrations as well as on the structure of the histone molecule. Leukocyte and calf thymus histones can stimulate the intracellular metabolism of ascorbic acid in human erythrocytes, in contrast to the protamines which show an inhibitory effect in the above mentioned intracellular peroxidase metabolic system.


[2-Acetyl-2-methyl-1-phenyl-hydrazine: a frequently occuring artifact in processing biological material after ingestion of drugs containing antipyrine (author's transl)].

4-Hydroxy-antipyrine, the main metabolite of antipyrine is decomposed in alkaline medium to 2-acetyl-2-methyl-1-phenyl-hydrazine. Consequently this compound is often found in the working up of antipyrine-containing drugs.


[Anti-ulcer agent pirenzepine (LS 519)--a tricyclic compound with particular physico-chemical properties (author's transl)].

Compound 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one dihydrochloride (pirenzepine, L-S 519) represents a new type of drug in ulcer therapy. It has been selected for broad clinical investigations because of its outstanding pharmacological profile. Pirenzepine is devoid of any central activity despite certain structural similarities in relation to psychotropic tricyclic compounds. The extraordinary pharmacokinetic and pharmacodynamic behaviour of this compound can be easily derived from its inherent physicochemical properties: The inability to pass the blood-brain barrier as well as its inability to activate the unspecific and specific psychotropic receptors is due to thermodynamic factors.


[Determination of 3-(1'-phenylpropyl)-4-hydroxycoumarin by means of high-performance liquid chromatography (HPLC) (author's transl)].

Marcumar [3-(1-phenylpropyl)-4-hydroxycoumarin] was determined by means of high-performance liquid chromatography from serum extracts after the oral application of its sodium salt solution. 4-Hydroxycoumarin was used as the internal standard and rats were used as the test animals. Furthermore mixtures containing anticoagulants and anti-epileptics were also analysed with the help of high-performance liquid chromatography.


Fine structural aspects of the influence of lymphatic blockage on cold injury of the brain and skin, and the effects of benzo-pyrones.

The fine structural changes of cold injury, lymphoedema, or both have been studied in the cerebral cortices and facial skin of rats, with and without treatment by a mixture of two benzo-pyrones (coumarin and rutin sulphate salts). It was found that cold injury opens the endothelial junctions of the blood vessels and injures their plasma membranes, thus allowing plasma protein and fluid to enter the tissues, producing oedema. Hence the lymphatics of the skin and the prelymphatics of the brain become dilated, contain excess protein, and the junctions of the former become opened. Macrophages (together with astrocytes in the brain) appear to phagocytise some of the protein. Apart from the injuries to the blood vessels, lymphostasis causes similar effects. The two injuries in combination considerably enhance the effects of either by itself. The benzopyrones greatly reduce the amounts of protein and fluid, particularly in the tissues: the lymphatics lag behind these, especially if they are obstructed.


[The effect of benzopyrone on the bovine albumin induced exudative peritonitis in the rat (author's transl)].

The antiphlogistic effect of the benzopyrone drug "Venalot" could be proven in the model of the exsudative immune-peritonitis in the rat, caused by bovine serum-albumin. Under the action of the drug the exudate and the amount of proteins in the peritoneal fluid were reduced; an important reduction of the adhesions occurred, too. The differences between the mean values and observations in the control and in the treated group were statistically significant (P less than 0.001).


Experimental blood vascular and lymphatic occlusion in the rabbit ear and the effect of benzopyrones.

The effects of lymphostasis and its treatment by a mixture of benzopyrones were studied in the pinnae of rabbit ears. The blood and lymph circulations to the dorsal surfaces of the ears were largely interrupted by excising a portion of skin down to the perichondrium from one edge to the other. The untreated ears became very lymphoedematous, became necrotic and tell off between 7 and 34 days after the operation. The treated ears were much less lymphoedematous, both to the naked eye and by electron microscopy. Owing to the ubiquity of action of the benzopyrones, the phagocytic capacity of the macrophages is enhanced, removing the accumulating protein, the metabolic products and thus the oedematous fluid. This improves the tissue oxygenation, encouraging lymphatic and vascular regeneration and, to a lesser degree, recanalisation. Also, the red blood cells are protected against lactacidotic rigidification and they and the macrophages are given an increased chance of survival in the remaining stagnant areas by the enhancement of glucose up-take and transport. Upon these factors rests the ability of the tissue to survive. The fact that the ears in the treated groups did not fall off, gives a real indication of the potentiality of the benzopyrones.


[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.


The influence of triamterene on isoproterenol-induced and spontaneous myocardial calcium uptake in cardiomyopathic hamsters.

In this study the influence of 2,4,7-triamino-6-phenylpteridine (triamterene) on isoproterenol-induced myocardial accumulation of calcium in cardiomyopathic hamsters in the prenecrotic phase of their disease was investigated (acute experiments). When triamterene is administered in increasing doses simultaneously with the standard dose of 1 mg/kg isoproterenol, a dose-dependent decrease in the isoproterenol-induced calcium accumulation can be observed. A dose of 60 mg/kg triamterene is fully effective in preventing the isoproterenol-provoked myocardial calcium accumulation. In addition under the influence of isoproterenol the myocardial magnesium and potassium contents drop. This decrease can be also avoided when triamterene is administered simultaneously. The action of triamterene on spontaneous myocardial calcium accumulation was also studied in the cardiomyopathic hamsters, which beginning on their 30th day of life chronically received triamterene over a period of 27 days (twice daily 60 mg/kg p.o.). Usually the spontaneous calcium accumulation runs in parallel with progressive myocardial necrotization starting about the 40th day of life. The chronic experiment was unsuccessful; the myocardial calcium content was even higher in the triamterene-treated animals than in the controls. The failure of the long-term experiment seems to result from uremia due to high doses of triamterene with metabolic alterations that have not yet been clarified. Neverthless, triamterene seems to possess a cardioprotective effect against myocardial calcium overload. As the substance could also maintain normal intracellular potassium and magnesium contents in the acute isoproterenol experiments a combined application of triamterene and calcium antagonistic drugs is suggested. By this combination not only transmembrane calcium conductivity is reduced but also intracellular calcium binding sites might be blocked by normalized intracellular magnesium and potassium contents.


Pharmacological investigation of cardiovascular and haemodynamic effects of salts of ioxitalamic acid in anaesthetized dogs.

Aqueous solutions of salts of ioxitalamic acid were infected by intravenous, intracarotid, proximal intra-aortic, and intrafemoral route. We observed cardiovascular effects of small magnitude and short duration. They are composed of hypotension (intravenous and intracarotid route), hypotension followed by hypertension (intra-aortic route), changes of LVP, dLVP/dt and contractile strength parallel with those in blood pressure, bradycardia, increased femoral blood flow. Several factors seemed to be involved in the mechanism of these effects: vagal reflex, transient myocardial depression, peripheral vasodilating effect, increased volaemia. By all routes of administration used, the infection of non-iodinated solutions [NaCl, glucose, methylglucamine (MGL) and monoethanolamine (MEA) hydrochloride] of the same osmolarity as ioxitalamate solution, resulted in similar effects.


Influence of cortisone and cyclophosphamide on xanthine oxidase bacterial activation.

The xanthine oxidase increase in mice liver as response to infection was studied as a possible parameter useful for a better understanding of theimmunosuppression due to cyclophosphamide and cortisone. An impact of cortisone but not of cyclophosphamide on this mechanism was found; this may be useful in order to discriminate between the two different types of immunosuppressive drugs.


[The relevance of anticholinesterase properties to toxicity and neuromuscular effects of sulpiride (author's transl)].

N-[(1-Ethyl-pyrrolidin-2-yl)-methyl]-2-methoxy-5-sulf-amoyl-benzamide (sulpiride, Dogmatil) inhibits acetylcholinesterase of rat brain in a mixed-type manner (Ki 0.3 mM; Ki 1.8 mM) as well as serum cholinesterase of the rat competitively (Ki 0.37 mM). Using acetylthiocholine in concentrations below 0.1 mM and purified enzyme from Electrophorus, reaction becomes first-order kinetics. At 35 micronM sulpiride doubles half-life and is without effects below 3.5 micronM. Hydrolysis of acetylthiocholine in homogenates of stomach muscle from rats is not affected by sulpiride up to 20 micronM. Pretreatment of mice with 5 mg atropine/kg i.p. decreases i.p. LD50 of sulpiride to 67% of controls. The conclusion is drawn that neither toxicity nor hypermotility of stomach seen after sulpiride by other authors is due to the cholinesterase inhibiting properties of sulpiride.


[Penetration of the tympanum by active substances (author's transl)].

In a specially designed animal model the penetration of glucocorticoid and oxytetracycline through the intact tympanic membrane was studied. Dogs were anesthetised for up to 8 h, and the substances were administered to the external auditory meatus. The measured concentration of the applied glucocorticoid in the tympanum showed a level which can be expected to be therapeutically active. When treating the inflamed middle ear, an adjuvant therapy with the combination dexamethasone-21-isonicotinate/oxytetracycline/natamycine/;etracain (Incut) should be taken into consideration. Although oxytetracycline was administered as well, this substance could not be measured in the small samples due to technical reasons. To find out about penetration of o%ytetracycline will have to be the object of another series of experiments.


Antigangrenous effect of an odontological preparation.

Experiments were performed in order to compare the antigangrenous effect of Pyralvex Berna and its components (alcoholic salicylic acid solution and extractum rhei, resp.) with that of an antiphlogistic standard preparation (phenylbutazone). In this experimental model the tails of albino mice are put into water of 55 degrees C for 10 sec. This results in the loss of part of the tail within  the following days. In the present investigation, the tail of part of the animals was put into one of the solutions to be examined for 5 sec immediately after exposure to heat as well as on the following 5 days. In the controls 55.65% (on an average) of the original length of the tail were lost, in the animals treated with phenylbutazone 19.10% (on an average) and in the animals treated with Pyralvex 27.25% (on an average) were lost. Thus, the antigangrenous effect of Pyralvex was 77% of that of phenylbutazone. The statistical analysis of the results obtained in the 4th and 5th groups demonstrates that this effect is mainly due to extractum rhei, the antigangrenous effect of which is statistically not significantly different from the antigangrenous effect of Pyralvex (p greater than 0.4).


[Influence of the beta-receptor blocker nifenalol on insulin secretion in normal subjects and diabetic patients (author's transl)].

In 10 insulin-independent diabetic patients and 5 healthy volunteers the basal and glucose-stimulated insulin secretion was tested before and during oral treatment with the beta-blocker 1-(4-nitrophenyl)-2-isopropylaminoethanol (nifenalol, Inpea). In diabetic patients the insulin secretion was not changed by Inpea. The fasting blood sugar levels were slightly elevated in 8 of these patients. This result, which could not be ascertained statistically, may be due to a slight intrinsic activity of this beta-blocker. The normal subjects showed different responses. In one person the glucose tolerance deteriorated by Inpea.


[Studies on the effect of drugs on somatosensory cortical evoked potentials (author's transl)].

The effect of the following drugs in therapeutic doses on somatosensory cortical evoked potentials was studied: methamphetamine, chlorpromazine, imipramine, diazepam, phenobarbital, pethidine, and novaminesulfone. Physiological saline was used as control. Each of these compounds was studied in 5 healthy subjects. Three evoked potentials were recorded before, and another three after administration of the drug. Each potential was averaged from 1024 single stimuli. None of the drugs, led to marked changes of the evoked potential, i.e., all data (latencies, amplitudes) were within the double standard deviation of the data obtained in normal subjects in a previous study. Although no significant changes were seen, some trends could be observed: methamphetamine and imipramine produced a decrease in the latency of the first positive peak, chlorpromazine increased the latency of the third positive peak. The amplitude of the third peak was reduced under phenobarbital. It is concluded that the drugs investigated in the presents study do not produce significant changes in the somatosensory cortical evoked potential and therefore drug application may be continued when evoked potentials are used for diagnostic purposes.


[Problems in preclinical pharmacology when deciding on suitable animal species and animal tests models].

The significance of procedures used in animal experiments for the development of new pharmaceutical agents is demonstrated on selected examples. Particular attention is given to the different degrees of sensitivity in the various species to new compounds, which are dependent on several factors such as absorption, metabolism, distribution and excretion. Comparing findings obtained in animal experiments with unknown compounds to those of standard substances facilitates extrapolation to man.


[What may be learnt from short- and long term tests and from studies on cancerogenicity, teratogenicity and mutagenicity (author's transl)].

During the last 15 years the transferability of results from animal experiments to humans has been improved so that today certainly more than 70% of possible side effects can be predicted. Systemic hypersensitivity reactions cannot be predicted, however, since to date there are no safe animal experimental methods available. In spite of many decades of research in the field of animal experimental cancerogenesis the value of investigations of this kind for humans can be limited by the selection of unsuitable animal species, use of inadequate modes of administration or excessive doses. Similar aspects apply to reproduction toxicology; there are many examples in cancerology and teratology for false-positive and -negative results from animal experiments. In chemomutagenesis comparisons of in vivo cytogenetic investigations in somatic cells of animals and humans have revealed largely concurring results. However, only stable mutations found in generative cells are signs of a genetic danger. It will therefore have to be clarified which conclusions for generative cells should be drawn from changes in somatic cells. Furthermore, the elaboration of methods for the determination of the mutation of genes in the organism of mammals still requires intensive research.


[First-past Effect (author's transl)].

Metabolism or decay of a drug prior to, during or shortly after its enteral absorption necessarily reduces the amount of unchanged drug reaching the systemic circulation. This influences the pharmacokinetic properties of a drug and is called first-pass effect. Every drug metabolized in the liver theoretically undergoes a first-pass metabolism after enteral application. Whether it results in a pharmacokinetically obvious first-pass effect depends on extent and rate of this metabolic step. The pharmacokinetic relevance of a first-pass effect does not automatically mean also its therapeutic relevance. For the assessment of the therapeutic relevance of a first-pass effect, extent and slope of its dose-effect curve in man and the therapeutic index of a drug must be taken into accounts.


[Drug accumulation and dose finding (authors' transl)].

Accumulation following repeated doses is no individual behavior of a drug, but always happens if the rate of invasion of a drug exceeds its rate of evasion. Using parameters such as dosing interval and biological half-life of a drug, its rate of accumulation as well as the equilibrium drug concentration in the body can be calculated. The initial dose and the maintenance dose can be calculated in a similar way. For an individual case the reliability of data calculated on the basis of mean values for biological halflife may be limited by the statistical variation of means and by factors altering the elimination of the drug, e.g. pathological changes or the influence of drugs given additionally. Nevertheless, these data may serve as a guidance to the physician to help him find the individual dosage for  his patient.


[Methodical prerequisites in clinical pharmacology (author's transl)].

Clinical pharmacology being an experimental natural science, tries to answer clinical questions by means of thoroughly studied syntactic models. In doing so it is regularly confronted with the typical problems of any experimental science: the syntactic problem, the semantic problem, the problem of redundance. The syntactic problem is regarded as being solved by biometric means. The semantic problem reflects the developing state of scientific findings; insofar the solutions are of provisional character. To a large extent the problem of redundance seems to be a discretionary question.


[The role of the biometrician in dosage finding].

Biometrics is the science of mathematical models for biological processes and of methods for the design and analysis of biological experiments. By these tasks the role of the biometrician in the problem of dose-scheduling is determined. He has to develope mathematical models for the dose-response relationship and methods for the design and analysis of pharmacological and clinical experiments. In the paper the probit and logit model are discussed as examples of the mathematical approach to dose-response relationship. The problems of planning and analyzing bioassays are demonstrated. The pharmacological results can be applied to clinical investigations if they are related to standard drugs. The safety or risk of a drug can be measured by the therapeutic index, which is most important for the connection between pharmacological and clinical results. Finally the problem of repeated doses and accumulation is dealt with.


[Problems in dose finding from the view of the clinical pharmacologist (author's transl)].

The dose of a drug applied to a patient is determined by his physiological and pathological data, by specific properties of the drug and by the mode of application. The most important physiological data which influence the dose are body weight, sex, age, a pregnancy, genetic variations and circadian rhythm. Pathological findings such as organ insufficiencies (kidneys, heart, liver, endocrinium, transport protein in the blood, etc.) are also to be considered. Particularities of the drug kinetics (insignificant absorption, excessive biological half-life, specific affinities to tissues, etc.), of metabolism (first-pass effect, toxic metabolites, saturable detoxification, stress, etc.) or a high toxicity are other parameters of consequence. Finally attention has to be paid to the mode of application (p.o., i.v., etc.), to the kind of galenic preparation (liquid or solid, slow-releasing preparation, etc.), to interactions if using combinations of drugs and to a long-lasting pharmacotherapy. Aditional problems are encountered in clinical trials especially in early phases while determining the tolerable therapeutic dose.


[Problems in dose finding Practical examples presented on selected series of drugs: bronchospasmolytics, pharmacology (author's transl)].

The beta-adrenergic agents and the anticholinergics are cited as examples of the contribution of experimental pharmacology to determining dosage of bronchodilator drugs in man. With regard to animal species, data from dogs can be extrapolated better to man than data from guinea-pigs. As far as the modes of administration are concerned, results from inhalation studies can be extrapolated directly to man, without conversion. Greater caution is required for parenteral injection and oral administration. However, even here we have an example of effective oral dose in dogs, which correlates with the single dose in man when the difference in body-weight is taken into account. The guinea-pig is unsuitable for the oral testing.


[Dose finding for bronchospasmolytic drugs in clinical practice (authors' transl)].

The paper deals with methods of investigation, importance of provocation tests for investigations in healthy volunteers and patients, need for selection criteria, the "ideal" patient and methods of determining dose-response and time-response of effect and side-effects. The good correlation of the results in clinical and animal pharmacological studies and the problems of the correlation with pharmacokinetic data regarding the inhalation of bronchospasmolytic agents is discussed.


[Example of dose finding in practice. Pharmacology of an antiarrhythmic agent (author's transl)].

Results of the pharmacological investigation of a new antiarrhythmic drug are presented. In the isolated guinea pig ileum the substance of the procainamide-quinidine type reveals strong activity in prolonging the relative refractory period. The safety index as to antiarrhythmic and negative-inotropic properties in relatively high. In the aconitine arrhythmia of the rat the substance is effective after i.v. or oral administration. Furthermore, in these experiments it shows a long-lasting action with these two modes of application. From experimental data in the conscious and anesthetized dog the oral efficacy can also be derived. An oral dose of the new substance for the first application in humans is proposed which refers to its pharmacological activity compared with procainamide and to the human dose of this latter substance.


[Dose finding for clinical trials of antiarrhythmic substances (author's transl)].

Specific difficulties connected with clinical evaluation and especially dose finding for antiarrhythmic substances are discussed. They are mainly due to the differences in pathogenesis, clinical significance and to the inconsistency of the symptom arrhythmia. Therefore special cardiologic skills are required for performance and interpretation of respective studies. The importance of selection of patients and determination of plasma levels of the substance is demonstrated. Possible procedures for determination of the therapeutic dosage are described and the necessity of detailed documentation of side effects is stressed.


[Dose finding in antibacterial chemotherapy (author's transl)].

The therapy of bacterial infections is considered against the background of the relations existing within the system bacteria-man-chemical substance. The experimental conditions and the difficulties are discussed which are encountered in the determination of in vitro values and their transfer into therapy. On this background the basic equation of chemotherapy is discussed. The factors are given which reduce the strict validity of this basic equation and lead to the introduction of a safety factor when making a dose proposal.


[Finding the effective dose of diuretics in man (author's transl)].

After a short survey of the classes of diuretics the procedures are described which are available to find effective doses of newly synthetized compounds in animal experiments. The method of Lipschitz and its modifications used for screening in rats are discussed in more detail. From the practical view of the clinical pharmacologist an explanation is given of the problems encountered in planning a study, balancing fluid- and electrolyte intake and in the suggestions for dose extrapolations to man. The experimental development in animals and healthy humans is demonstrated by means of the new diuretic compound Hoe 747. A synoptic graph showing the estimated dose-response curves emphazises the fact that it is possible to extrapolate the first dose in man from animal data with sufficient precision.


[Problems of dose finding: sexual hormones (author's transl)].

1. Reproduction processes are differently regulated in different species. The gestagen/estrogen ratio is of paramount importance for the evaluation of gestagens. Steroids possessing inherent estrogenicity might act as estrogens in, e.g., rodents like rats and mice, but might be active as gestagens in women (e.g. norethinodrel). 2. There is a good and partly significant correlation between the activity of various gestagens in a number of experimental test models and clinical trials. The same is true for the antiovulatory activity of various gestagens in rats and women. Oral rat tests, however, are not relevant. Receptor tests are not at all suitable for dose finding. 3. Erroneously dissociated peripheral and central (inhibition of ovulation) activity of gestagens are found only if different animal species are used (e.g., test on gonadotropin inhibition in rats, gestagen test in rabbits). This is not the case if both kinds of tests are done in one species (e.g., ovulation inhibition test in rats and test on the peripheral progestational activity in rats). 4. As far as the combined oral contraceptives containing estrogens and gestagens are concerned, it seems that both components are involved in the inhibition of ovulation in rats and women. There is additive synergism. 5. Conclusions concerning the activity and duration of effect in the clinic can be drawn from the intensity and duration of the progestational effect in rabbits. 6. The oral and subcutaneous activity of estrogens in different tests in rats and mice is in parts very well correlated. This is also true for the antiovulatory activity. 7. Comparison of the estrogenic activity of ethinyl estradiol and mestranol in rats, mice and women still leaves the question unanswered whether ethinyl estradiol is more potent than mestranol. 8. Certain conclusions regarding the depot effect in the clinic can be drawn from the duration of the estrogenic activity in the Allen-Doisy test. This test is at least suitable for the selection of the optimal depot estrogen. 9. As concerns androgens, clinical dose finding is so difficult because there are no or only poor clinical parameters for androgenicity. The oral evaluation of androgens in rats and mice provides no evidence for whether or not an androgen is orally active in men. Frequently, one can only resort to conclusions form analogy. 10. The duration of androgenic activity in rats allows certain conclusions to be drawn regarding the duration of activity in men. Dose finding, however, is difficult. 11. Steroids in which the anabolic and androgenic activity in the levator ani muscle/accessory sexual gland test are dissociated (anabolics) do also show dissociation of these two partial activities in the clinic. 12. The levator ani muscle/accessory sexual gland test in rats allows also conclusions to be drawn as to the depot activity in the clinic. 13...


P-aminosalicylate metabolism in cancer patients sensitive and resistant to chemotherapy.

A reduced response of a tumour to chemotherapy may be due to the host's drug metabolism. To test this hypothesis, we measured the metabolism of a model drug, para-aminosalicylate (PAS). Volunteers and cancer patients ingested a single oral dose (2 g) of PAS and we measured the plasma disappearance curve of the drug and its metabolite. In 7 patients suffering from lymphosarcoma, acute or chronic leukaemia and resistant to cancer chemotherapy, we observed low plasma PAS concentrations, an increase in PAS acetylation and an increased number (and a higher frequency) of abnormal liver-function tests. In 14 patients with malignant blood disease, yet responding well to chemotherapy, the metabolism of PAS is similar to that of healthy controls of the same age and sex. The plasma half-life of PAS is similar in sensitive and resistant patients, but slightly longer than in volunteers. Finally, in urine collected 120 min after drug administration, we observed the same results as in plasma. In conclusion, cancer patients resistant to chemotherapy do not metabolize the model drug PAS as volunteers or sensitive patients do, and this might be relevant to the terminal stage of the disease.


The vitamin B6 status of pigs given a diet containing linseed meal.

1. Pigs consuming a diet containing 300 g linseed meal/kg and a pyridoxine supplement showed greater growth, nitrogen retention, blood packed cell volume and haemoglobin than those receiving only the basal diet. 2. Tryptophan-load tests on unsupplemented pigs revealed an increased excretion of kynurenine, Nalpha-acetylkynurenine and xanthurenic acid compared to those receiving additional pyridoxine. 3. The results suggest that the unsupplemented pigs were marginally deficient in vitamin B6. 4. When the same diet was fed to rats there was no evidence of vitamin B6 deficiency.


Dynamic structure of lipid bilayers studied by nanosecond fluorescence techniques.

Molecular motions in liposomes of dipalmitoyl-phosphatidylcholine (DPPC) were studied by nanosecond fluorescence techniques. As a fluorescent probe for the hydrocarbon region, 1,6-diphenyl-1,3,5-hexatriene (DPH) was used. Time courses of fluorescence intensity IT(t) and emission anisotropy r(t) of DPH embedded in DPPC liposomes were measured at various temperatures. The value of the fluorescence lifetime tau obtained froma single exponential decay of IT(t) was somewhat higher than that in liquid paraffin below the transition temperature Tt and decreased above Tt. Higher values of tau below Tt indicate the almost complete hydrophobic environment. The decay curves of r(t) were separated into two phases: an initial fast decreasing phase of the order of one nanosecond and a second almost constant phase. This indicates that the orientational motion of DPH in the hydrocarbon region is described by a wobbling diffusion restricted by a certain anisotropic potential. The results were analyzed on the model that the wobbling diffusion is confined in a cone with a uniform diffusion constant. Though temperature dependence of the cone angle was sigmoidal, that of the wobbling diffusion constant was like the exponential function. The change in the cone angle at Tt was sharper than that in the wobbling diffusion constant at Tt. Estimated values of the viscosity in the cone were an order of magnitude smaller than the values of "microviscosity"  which were estimated from the steady-state emission anisotropy without considering the restrictions on the rotational motion.


Lipid phase separation induced by a hydrophobic protein in phosphatidylserine--phosphatidylcholine vesicles.

Differential scanning calorimetry (DSC) was used to detect phase separation induced by hydrophobic myelin protein, lipophilin, in a mixture of phosphatidylserine (PS) and dipalmitoylphosphatidylcholine (DPPC). Preferential binding of PS to the boundary layer of lipophilin causes a decrease in the PS content of the remaining lamellar phase with a resultant shift in the phase-transition temperature to a higher temperature. The phase diagram for this mixture in the presence and absence of lipophilin is presented. From the phase diagram, it can be estimated that for an equimolar mixture of PS and DPPC, the boundary layer contains only PS, although for higher DPPC contents, some DPPC can also be found in the boundary layer. In the case where partial phase separation in induced in this mixture by Ca2+ alone, lipophilin increases the phase separation indicating that it also binds PS preferentially in the presence of Ca2+. Preferential binding of two other acidic lipids, phosphatidic acid and phosphatidyl-glycerol, to the boundary layer was also found, including a mixture where the acidic lipid was the higher melting component in the mixture.


Polysome-lamellae complexes in a case of nodular pleomorphic lymphoblastosarcoma.

The first case of PLC in a nondular pleomorphic lymphoblastosarcoma is reported. The PLC signification is at present unknown. In hematologic pathology, they are usually observed in HCL and scantly in different B-cells malignant proliferations.


Hashimoto's thyroiditis with immunoblastic lymphadenopathy and unusual "macaroni cells".

Light and electron microscopic study of the thyroid gland and an enlarged cervical lymph node in a 75-year-old woman with Hashimoto's thyroiditis disclosed immunoblastic proliferation in the lymph node, marked by collections of striking round cells positive to periodic acid-Schiff (PAS) staining, immunoblasts and plasmacytoid elements in a vascular, fibrous framework. The PAS-positive cells ("macaroni cells") were distended with whorls of angulated tubular material resembling endoplasmic reticulum. Parafollicular-cell hyperplasia and an atypical plasmacytoid focus were noted in the thyroid. Hashimoto's disease is known to be associated with malignant lymphoma, as are autoimmune and malignant diseases with immunoblastic lymphadenopathy. This is the first report of the association of Hashimoto's disease and immunoblastic lymphadenopathy. The atypical plasma cells have not previously been described.


Lymphosarcoma in Crohn's disease: report of a case.

In a patient who had a family history of ulcerative colitis and colonic carcinoma, a jejunal lymphosarcoma developed four years after resection for Crohn's disease of the small intestine. It is suggested that the association of lymphosarcoma with Crohn's disease is more than a chance association.


Metabolism of the apoproteins in pulmonary surfactant.

Two proteins having nominal molecular weights of 35,000 and 10,000 daltons are found in pulmonary surfactant. Although experiments on their immunological properties suggest that they share antigenic determinants, their metabolic relationship is unknown. To study this question we injected [14C]palmitic acid or L-[3H]leucine into the femoral vein of 59 puppies. We killed the animals 30 min to 68 h after injection and purified surface-active material from the endobronchial lavage fluid. We isolated the 35,000 apoprotein, the 10,000 apoprotein, and the saturated phosphatidylcholines in surfactant and measured their specific activities at various times after injection. We found that the 35,000 apoprotein appears in alveolar surfactant with the same time course as saturated phosphatidylcholine but is cleared more rapidly than is the lipid. The specific activity of the 10,000 apoprotein reaches a maximum after that seen for the 35,000 apoprotein and decays with the same turnover time as that of the lipid. The kinetic data suggest that the 10,000 apoprotein is a metabolic product of the 35,000 apoprotein. They are not consistent with the possibility that the 10,000 apoprotein is an artifact of nonspecific degradation during preparation.


Lesions of the menisci. Autopsy incidence in adults less than fifty-five years old.

The menisci were removed from the knees of seventy autopsy subjects less than fifty-five years old and 18.6% exhibited at least one horizontal cleavage lesion. Seven per cent of 200 autopsy subjects showed at least one discoid lateral meniscus, and it is suggested that neither these nor the horizontal cleavage lesions had caused symptoms during the lifetime of each subject. Microscopic signs of degeneration were seen in 76% of the grossly normal medial menisci examined. Medial menisci not only have a larger surface area than lateral menisci but are broader and thicker posteriorly. It may be that the greater thickness of the medial meniscus posteriorly renders it more vulnerable because there is less nutritional diffuse of synovial fluid.


Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves' disease.

Previous studies have suggested that there is an overproduction of triiodothyronine (T(3)) relative to thyroxine (T(4)) in patients with thyrotoxicosis associated with Graves' disease. To evaluate whether or not an increased ratio of T(3) to T(4) in thyroidal secretion could be contributing to this relative T(3) hyperproduction, T(3), T(4), and iodine were measured in thyroglobulin (Tg) from controls and patients with Graves' disease who had been treated either with propranolol only or with antithyroid drugs plus iodide before surgery. To avoid possible artifacts associated with pulse labeling and chromatography, T(3) and T(4) were determined by radioimmunoassay of Pronase hydrolysates of purified Tg. Results of analyses of Tg from six control patients and seven with Graves' disease, not receiving thiourea drugs or iodide, showed that the iodine content of Graves' disease Tg was not different from normal. Both contained 3.4 residues of T(4)/molecule Tg, but there was 0.39+/-0.08 (mean+/-SD) residue of T(3)/molecule Tg in Graves' Tg as opposed to 0.23+/-0.07 residue T(3) molecule Tg in controls matched for iodine content (P < 0.01). This difference resulted in a significantly lower T(4)/T(3) molar ratio (9+/-2) in Graves' Tg as opposed to control (15+/-2, P < 0.001). In Tg from patients with treated Graves' disease, iodine, T(3), and T(4) were reduced, but the reduction in the latter was more substantial, resulting in a T(4)/T(3) molar ratio of 3.4+/-1. Fractionation of Tg from all groups by RbCl density gradient ultracentrifugation indicated that at physiological levels of Tg iodination, the molar ratio of T(3)/Tg was consistently higher in Graves' disease. The specific mechanism for this difference is not known, but it is not due to iodine deficiency. If T(3) and T(4) are secreted in this altered ratio in patients with Graves' disease, the magnitude of the difference could explain the relative T(3) hyperproduction which is characteristic of this state.


Feeding polyunsaturated vegetable oils to lactating cows.

Holstein cows fed concentrate:hay diets also were fed for 14 days supplements of soybean oil plus casein, soybean oil protected from ruminal hydrogenation by encapsulation in a casein-formaldehyde matrix, cottonseed oil plus casein, or cottonseed oil protected with casein formaldehyde. The supplements were fed at rates to give a linoleic acid (18:2) intake of 225 g/day. Yields of milk and milk protein were not affected by treatment. Milk 18:2 was not increased by the unprotected soybean oil or cottonseed oil but was increased by protected soybean and cottonseed oil from a control of 2.3 to 5.7% of total milk fat. Milk 18:0 and 18:1 also increased. Compensatory declines were observed in milk 16:0 and 14:0 acids. In fecal fatty acids during the treatment periods, percentage of 18:2 of the total fat decreased and 18:0 markedly increased. These results indicate hydrogenation of the dietary oils in the alimentary tract or a differential absorption. Fecal 16:0 and 14:0 decreased.


Effect of a flavored milk option in a school lunch program.

An analysis of nutrient intake and of plate waste for four hundred elementary school children, when an option of chocolate milk was provided in the school lunch program, shows significantly higher intakes of calcium and riboflavin, lower intakes of iron, greater food waste, and significantly less waste of milk. Participation in the school lunch program was not affected by the announced availability of flavored milk in ten schools serving 3,700 children; however, significantly (p less than 0.01) more children bought milk alone.


Decreased dipalmitoyllecithin content found in lung specimens from patients with so-called shock-lung.

Lung specimens were obtained from 9 patients with shock lung (adult respiratory distress syndrome), immediately after death, and from 8 controls. They were analysed for phospholipid content anf for fatty acid composition of sphingomyelin and lecithin. We found an elevated phospholipid content in the affected lungs but a decreased dipalmitoyllecithin fraction of total lecithin as indicated by 127% elevated content of oleic acid in lecithin. As a consequence the relation between the palmitic acid and oleic acid moiety of lecithin shifted from 2.32 in the normal lungs to 1.64 in the diseased lungs. Since the content of dipalmitoyllecithin is closely related to the function of the surfactant system we conclude, that the alteration of surfactant function, observed in patients with adult respiratory distress syndrome may be at least in part a result of an altered surfactant metabolism, but we cannot rule out, that the findings represent an epiphenomenon in shock lung.


Lymphosarcoma in an infant northern fur seal (Callorhinus ursinus).

An infant northern fur seal (Callhorinus ursinus) died in a rookery on St. Paul Island, Pribilof Islands, Alaska. Grossly, slight enlargement of the mesenteric lymph nodes was seen. Microscopically, a lymphosarcoma composed of sheets of monomorphic lymphoid cells in sections of lymph node and tonsil was seen. Electron microscopy of formalin-fixed tissues revealed several structures that were possible of viral origin in the cytoplasm of the neoplastic cells.


Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study.

Twenty-nine patients with small cell carcinoma of the lung and without evidence of brain metastasis were randomized into two treatment groups consisting of 14 patients who received prophylactic cranial irradiation (PCI) and 15 who received none (non-PCI). All patients were treated with irradiation of the primary lesion and concomitant chemotherapy. The response rate and median survival of the two groups were not significantly different: 93% and 7.2 months in the non-PCI; 86% and 9.8 months in the PCI; P larger than or equal to .05. Brain metastasis occurred in 0/14 patients in the PCI and 4/15 in the non-PCI (P less than or equal to .05) and was the cause of major neurologic disability in each. Although PCI did not improve response rate or survival, brain metastasis with its attendant neurologic complications was effectively prevented.


Hypersomnolence and intermittent upper airway obstruction. Occurrence caused by micrognathia.

A patient with hypersomnolence, micrognathia, and respiratory insufficiency had been treated eight years for narcolepsy. Sleep apnea because of upper airway obstruction was found, and a tracheostomy was performed. Following this the hypersomnolence and respiratory insufficiency resolved. This case emphasizes the importance of carefully evaluating the condition of patients complaining of hypersomnolence to detect those with intermittent upper airway obstruction occurring during sleep.


Rectal biopsy in patients with Crohn's disease. Normal mucosa on sigmoidoscopic examination.

Of 99 patients with Crohn's disease whose rectal segment appeared normal on sigmoidoscopy, there was histologic inflammation in 45% and features characteristic of Crohn's disease in 30% of rectal biopsy specimens. Granulomas were found in 18% of patients, including 13% of those with ileitis, 13% of those with ileocolitis, and 37% of those with colitis. Eleven of the 17 granulomas were small undermarcated microgranulomas. Rectal biopsy specimens are of value to confirm the diagnosis in Crohn's disease and to determine the state of clinical activity even when the sigmoidoscopic appearance is normal.


Food asphyxiation in hospitalized patients.

During a five-year period, food asphyxiation caused 1.3% of all deaths of patients who came to autopsy at a hospital for chronic diseases. Patients died suddendly, during or shortly after meals. Acute myocardial infarction was mistakenly diagnosed in eight of the 14 patients until autopsy was performed. Sedation, old age, and poor dentition predisposed to aspiration. Food asphyxiation is a common problem whenever and wherever people eat. To minimize its occurrence in hospitalized patients, sedatives should be prescribed judiciously, and diets ordered appropriately. Physicians should learn the simple methods of extracting inhaled food.


Antibiotic use at Duke University Medical Center.

A study of antibiotic use at Duke University Medical Center in June 1973 showed that 34.2% of all patients received antibiotics (43.6% surgical, 21.4% medical patients). Cephalothins were most frequently ordered for surgical patients, ampicillin sodium and penicillin G or penicillin V with potassium for other patients. A retrospective analysis of 50 randomly selected patients, according to the Kunin's categories of use, showed 64% of total antibiotic therapy as not indicated or inappropriately administered in terms of drug or dosage. These results are similar to previous reports of antibiotic surveillance and further establish the need for continuing education of prescribing physicians.


Mortality from pneumonia and risk conditions during influenza epidemics. High influenza morbidity during nonepidemic years.

Increases in mortality from pneumonia and high-risk chronic diseases have not occurred during recent influenza epidemics. Excess mortality during the past four influenza epidemics in the United States is attributable to influenza reported as a primary cause of death, and the average excess was only about 4,000 deaths per epidemic. Most clinical influenza severe enough to cause hundreds of millions of days of bed disability during nonepidemic as well as epidemic years is not caused by the influenza viruses. During the nonepidemic year of 1973 to 1974, there were 61,841,000 episodes of clinical influenza severe enough to put people to bed for an average of 3.6 days. In my judgment there is now no basis for recommending annual administration of influenza vaccines to so-called high-risk groups and persons over 64 years of age.


Behavioral treatment of obesity. Limitations and results with the chronically obese.

Results of behavioral treatment for obese persons during the first 18 months of clinical operation are presented and other reports in the literature are reviewed. Baseline and follow-up data were gathered from a population of 144 female, chronically obese patients, most of whom were experiencing medical complications associated with obesity. Treatment results were disappointing in comparison with results of similar programs. Difference in patient population groups is offered as a possible explanation for this phenomenon. Covariant analyses of demographic and psychosocial variables failed to yield any clear predictors of weight loss; it is suggested  that biological factors may be important to treatment outcome for some overweight patients.


Pulmonary artery flow-guided catheters in the perioperative period. Indications and complications.

The risk factor of pulmonary artery catheterization was assessed in 392 critically ill patients. Major indications for catheterization in the operating room were marginal cardiovascular reserve, anticipated large fluid and blood loss, and hypotensive anesthesia. Immediate complications included cardiac arrhythmia, carotid artery puncture, and pneumotherax. Long-term complications included positive bacterial cultures, pulmonary infarction and neuropathy. None of the complications were directly responsible for the deaths in this series. Pulmonary artery monitoring in critically ill persons is a relatively safe procedure.


Spinal cord infarction following therapeutic renal artery embolization.

A patient with dialysis cachexia became paraparetic within hours of therapeutic renal artery embolization. At autopsy, emboli of absorbable gelatin sponge filled spinal arteries, accompanied by spinal cord infarcts. The renal arteries of patients with end-stage renal disease are smaller than normal becaue of intimal fibrosis associated with prolonged dialysis. Embolic material can reflux more readily in these patients than in patients with renal tumors.


Amyotrophic lateral sclerosis in a high selenium environment.

During a ten-year period, four cases of amyotrophic lateral sclerosis have been found in a sparsely populated county (population 4,000) in west-central South Dakota. The patients were unrelated male farmer-ranchers between 57 and 66 years of age, living within a 15-km radius of each other. The cases occurred in a region where naturally occurring selenium toxication is endemic in farm animals.


Estrogen receptor assay in the differential diagnosis of adenocarcinomas.

Estrogen receptor determination by the sucrose gradient method was applied to 295 tumor tissues of various origins. Estrogen receptor of the 8 S type was found only in adenocarcinoma of the breast, uterus, and ovary. Of 19 patients with metastatic carcinoma of unknown origin, four benefited from estrogen receptor study (ie, appropriate therapy could be initiated) and one was helped retrospectively on the clinical diagnosis. Estrogen receptor assays may also be useful in determining whether bilateral breast involvement represents two primary lesions or metastasis. Estrogen receptor studies should be included in evaluating cancers of unknown origin in female patients.


The spectrum of vitamin K deficiency.

The coagulopathy induced by vitamin K deficiency commonly results from our lack of awareness of the clinical setting associated with vitamin K deficiency. Thirteen cases are reviewed to illustrate the clinical correlates most frequently observed. Dietary deficiency was always present, but concomitant antibiotic therapy was not an absolute requirement. The postoperative patient is at high risk, as is the patient with cancer or renal failure. Abnormal bleeding was common, but significant hemorrhage occurred only in postoperative patients. Factor assays were helpful and occasionally necessary to make the diagnosis, but a therapeutic trial with parenteral vitamin K was often enough to provide the right diagnosis. Greater awareness of this deficiency syndrome is necessary to avoid the serious morbidity that often results.


Primary carcinoma of the appendix.

Primary adenocarcinoma of the appendix is a rare tumor. Fewer than 200 cases are on record. Correct preoperative diagnosis is virtually nonexistent. Two patients with adenocarcinoma of the appendix are described. Although appendectomy appears to be adequate treatment for carcinoid, right hemicolectomy is, in our opinion, the treatment of choice for mucinous cystadenocarcinoma, while it is mandatory in cases of adenocarcinoma of the colonic type.


Acute organic brain syndrome associated with gentamicin therapy.

Two patients receiving gentamicin sulfate experienced acute organic brain syndromes that subsided after use of the drug was discontinued. Among the various factors considered as possible causes, time sequences point to gentamicin as the most likely.


Tricyclic antidepressant overdose: incidence of symptoms.

Forty consecutively hospitalized patients who had overdosed primarily with a tricyclic antidepressant (TCA) were observed until discharge. The severity of the overdose was documented by serial measurements of plasma TCA levels. Nineteen of the patients became comatose, 16 required supportive respiration, and 2 died. Individual symptoms in the 13 patients having plasma TCA levels greater than 1,000 ng/ml are shown. Plasma TCA measurements more reliably define patients who are at risk for major medical complications following overdose than does the amount of drug ingested by history. In the absence of plasma measurements, a QRS duration of 100 msec or more on a routine ECG within the first 24 hours defined all patients with major TCA overdoses.


Theophylline concentrations in asthmatic patients after administration of aminophylline.

To test the efficacy of using a weight-derived formula to determine aminophylline dosages, 50 patients hospitalized for treatment of severe asthma were given intravenous aminophylline infusions at a rate of 0.9 mg/kg/hr to a maximum dosage of 1,500 mg/24 hr. Serum theophylline determinations done 12 to 96 hours after institution of this therapy showed levels greater than 20 mg/liter in 34% of these patients. Reliance on weight-derived formulas can be dangerous.


Cooperative study of hospital frequency and character of transient ischemic attacks. III. Variations in treatment.

Variations in therapy for patients with complaints suggesting transient ischemic attacks (TIAs) among six participating medical centers are described. Selected treatment, based on clinical interpretation of patient characteristics, varied widely among centers. Therefore, results cannot be attributed to specific treatment. Nevertheless, there was little difference between treatment categories and the likelihood of further TIAs. The mortality of the patients who had received anticoagulants was significantly higher (P less than .001) than those patients receiving other treatment. Possible reasons for these differences are discussed.


Emergency medicine as an academic discipline.

Because of an explosive increase in the use of emergency rooms in hospitals across the country, many hospitals have found it expedient to employ full-time emergency physicians. The demand for emergency physicians has prompted the development of training programs in emergency medicine in academic medical centers. The first such training program was instituted at The Medical College of Pennsylvania in 1970. The 32 current programs in the nation are filling a real need in providing manpower for hospital emergency rooms. With the increasing identification and distribution of emergency physicians, there has been an attempt to develop emergency medicine as a distinct discipline and to establish its legitimacy in the structure of academic medical centers. A variety of problems must be addressed to clarify the role of emergency medicine in the academic setting.


Planning for retirement: advice to physicians.

Retirement planning has become a legitimate concern of all physicians, especially those employed by agencies where retirement is compulsory. Faced with the possibility of retirement, whether forced or voluntary, and issues of competence and other related matters, many physicians are departing from the traditional pattern of working until they become incapacitated. The typical physician places high values on work and deprecates other activities. Busy practitioners who have spent little time with their families and in recreational pursuits find themselves unprepared for their altered status when they stop working. Little empirical information is available concerning physicians and retirement. Four proposed retirement patterns may help physicians plan successfully for retirement.


Systemic absorption of neomycin irrigating solution.

Systemic absorption of neomycin sulfate occurred in ten patients in whom neomycin wound irrigating solutions were used during total hip replacement. The use of neomycin in this manner may be associated with the risk of ototoxicity and nephrotoxicity.


Evaluation of a new antihypertensive agent: prazosin hydrochloride (Minipress).

Prazosin hydrochloride is an orally administered vasodilator that recently became available for the treatment of hypertension. It causes less tachycardia than hydralazine but may produce orthostatic hypotension, particularly after the initial dose. The role of prazosin in therapy is limited because of the risk of a first-dose syncopal reaction, and it appears to be indicated primarily in patients who cannot tolerate hydralazine hydrochloride or sympathetic depressant drugs. Like other antihypertensive agents, prazosin should be given with a diuretic.


Method for the isolation of surfactant from homogenates and lavages of lung of adult, newborn, and fetal rats.

A method is presented for the isolation of pulmonary surfactant from rat lung homogenates and lavages using differential discontinuous density gradient centrifugation. The isolated surfactant was characterized by electron microscopy, assay of enzyme markers for different subcellular organelles, and its chemical composition. Surfactant that was isolated from lung homogenates appeared to be free of other contaminating cellular organelles. Electron microscopic examination of surfactant isolated from whole homogenates showed the presence of lamellar bodies and tubular myelin figures and, hence, represented total lung surfactant. On the other hand, surfactant prepared from lung lavages had mostly tubular myelin figures and, thus, represented extracellular surfactant. Both preparations were rich in phospholipids, especially lecithins and phosphatidylglycerol, and showed high phospholipid to protein ratios. The method was used to study the quantity and composition of surfactant during lung development in rats. Surfactant was isolated from lung homogenates of fetuses at days 19 to 21 of gestation and from newborn and adult rats. During the period of 19 to 21 days of gestation, there is a 10- and 20-fold increase in the amount of protein- and phospholipids (milligrams per gram of wet lung), respectively. A further 2-fold increase occurs after birth. Phosphatidylcholines account for 65% of the total phospholipids at day 20, 71% on day 21, and 81% at term. A progressive increase in the phosphatidylcholine to sphingomyelin ratios and in the amount of phosphatidylglycerol occurs during this period. The amount of disaturated lecithins (expressed as percentage of total phosphatidylcholines) in the lung surfactant increases from 49% at day 20 to 53% at birth. There is no change in the amount of disaturated lecithins after the newborn stage. The present method for the isolation of lung surfactant is reproducible, is less time consuming, and can be used to isolate quantitatively surfactant from small lung aliquots.


Health and liability hazards in a veterinary hospital.

There is a wealth of information available to you concerning the methods and means of making the hospital a safer place for yourself, employees and clients. In addition, a book could be devoted to the safety of the animal patients. Your insurance carrier can help you spot som potentially dangerous conditions and suggest ways in which you can make the changes necessary to bring your hospital up to safety standards. Remember, a good preventive program is one of the best defenses against litigation.


Computed tomography of orbital lesions. A radiological study of 144 cases.

During the first two years with the 160 x 160 matrix EMI scanner 144 consecutive patients referred with suspicion of orbital disease were subjected to 190 computed tomography (CT) examinations. The X-ray attenuation and enhancement patterns of the various lesions were analyzed. In general it was difficult to correlate these parameters with the histopathological features. Hemangiomas, however, showed little enhancement and meningiomas a large degree of enhancement, while malignancies, lymphomas and pseudotumors were mainly intermediate. With orbital Graves' disease a low preinjection attenuation and a large enhancement (with normal striated neck muscle as a reference) was found in the external eye muscles. The diagnostic accuracy of CT (n=143) was compared to that of A/scan ultrasonography (US, n=80) and carotid angiography (n=40). CT showed the highest accuracy of the three methods, but CT differed only statistically from carotid angiography.


Interaction between bromocriptine and levodopa. Biochemical basis for an improved treatment for parkinsonism.

The present investigation examined the biochemical interaction of bromocriptine and levodopa with respect to monoamine and gamma-aminobutyric acid metabolism in the brain. Rats were treated with levodopa, 250 mg per kilogram of body weight intraperitoneally, with or without carbidopa, 25 mg per kilogram, 1 or 2 hours before sacrifice. Some were also given bromocriptine, 5.0 mg per kilogram, 4 hours before sacrifice. Rats were killed 1 and 2 hours after levodopa and brain levels of gamma-aminobutyric acid and monoamines, and their metabolites were measured. Dopamine levels and metabolism were not markedly altered when bromocriptine was added to levodopa treatment. The level of serotonin, which was reduced 25 to 40 percent by levodopa alone, was close to normal with the combination treatment. Serotonin metabolism was also enhanced by the addition of bromocriptine as shown by increased levels of 5-hydroxyindoleacetic acid. The results suggest that bromocriptine not only may improve the motor disorder of parkinsonism but also may reduce some side effects of levodopa therapy, such as depression, which could be due to serotonin depletion.


Absence of phosphatidylglycerol (PG) in respiratory distress syndrome in the newborn. Study of the minor surfactant phospholipids in newborns.

Phosphatidylglycerol (PG) was absent from lung effluent in 41 infants with respiratory distress syndrome of the newborn (RDS), whereas effluent from healthy control subjects of similar gestational age contained this phospholipid (4.9 +/- 2.4% of lipidphosphorus (P), n = 32). Control infants of 28 weeks of gestation or less with various respiratory disturbances other than RDS also had low PG (0.2 +/- 0.2% of lipid-P, n = 5). In RDS surfactant complex often could be isolated from the airways using differential and density gradient centrifugation. The material thus obtained had prominent phosphatidylinositol (PI) (13.6 +/- 2.8% of lipid-P, n = 6), but no PG. Of those 18 infants who had such surfactant even in the early stages of RDS, 13 were 35 weeks of gestation or more, 3 were offspring of diabetic mothers, and 2 had severe perinatal asphyxia. In healthy control subjects PG sometimes appeared first within an hour of birth, but in RDS PG did not appear until recovery from RDS. In RDS type II (transient tachypnea of the newborn) PG in lung effluent also was abnormally low (1.3 +/- 0.6% of lipid-P, n = 5) and PI was correspondingly prominent (9.7 +/- 3.6% of lipid-P, n = 5), indicating immaturity of surfactant similar to RDS. Surfactant with PG and PI has superior surface-active properties compared to that containing PI, but no PG. Surfactant without PG does not seem to stabilize the alveoli of the newborn as well as does surfactant with PG. The failure of PG appearance following birth therefore may precipitate RDS, especially beyond 35 weeks of gestation.


Fatty acids of phospholipids in human neonatal lung surfactant.

The fatty acid chains of lecithin, phosphatidyl ethanolamine (PE), and phosphatidyl dimethylethanolamine (PDME) in human neonatal alveolar washes were analyzed. Both alpha- and beta-palmitic acid increased with gestational age on all phospholipids analyzed. No evidence for high concentrations of myristic acid was found on any phospholipid. Babies who were stillborn or who had died of hyaline membrane disease (HMD) had lower proportions of beta-lecithin palmitic acid when compared with babies who breathed normally before death. In the HMD group these levels were significantly lower.


Retrolental fibroplasia and factors influencing oxygen transport.

The hospital records of 58 premature infants in whom proliferative retrolental fibroplasia (RLF) developed were matched with the records of 58 infants without RLF for birth weight, gestational age, and duration oxygen therapy. The two groups were compared for factors likely to influence tissue delivery of oxygen by blood. No significant difference was found in incidence of blood transfusions or exchange transfusions, use of phototherapy, or occurrence of acidosis.