Microbial process translation--laboratory to pilot plant at the Frederick Cancer Research Center.

In summary, operations in the FCRC pilot plant have included training an operating staff, operability trials, equipment modification and repair, and supplementation of the original equipment to gain greater versatility. In addition to effort spent on proving and improving the capacity of the pilot plant, development studies and production operations involving translation of laboratory operations to pilot level or volume have included: 1. Development of a production process for interferon as described above. As a by-product of the interferon program, samples of cell culture have been studied in the Basic Research Division of FCRC for the production of lymphokines. 2. Production of starting materials (cell paste) for carboxypeptidase G1, using three different organisms, and production of refined material from the FCRC 252 organism as described herein. 3. Production of large quantities of crude phenylalanine ammonia lyase in the form of cell paste for Prof. Creed Abell at the University of Texas, Medical Branch, at Galveston,. 4. Production of a crude staphylococcal nuclease for the program of Dr. David Sachs, National Cancer Institute, Bethesda, Maryland. 5. Developmental studies and limited production of a crude cysteine desulfhydrase according to the protocols of Dr. J. Uren, Sidney Farber Cancer Center, Boston, Massachusetts. 6. Preliminary production studies on the agent produced by Culture FCRC 14, discovered in the CFL search program. 7. Developmental fermentation studies on the antitumor antibiotic, piperazinedione 593A [6], in preparation for production of quantities of this antibiotic to support clinical studies under the auspices of the National Cancer Institute.


Criteria for selection of new analogs of antitumor antibiotics.

If a new analog of a known antitumor antibiotic is to justify interest, it must be demonstrated to possess either quantitative or qualitative superiority over the parent compound in pharmacologic, toxicologic, immunologic, tumor cytotoxic, or other biologic properties that are therapeutically favorable. The most commonly used criterion is in vivo activity in are therapeutically favorable. The most commonly used criterion is in vivo activity in experimental tumor systems. This may be demonstrated in primary screening systems or in secondary screening systems, or in refractory tumor systems, or in one or more tumors of a human xenograft panel. Data on adriamycin and bleomycin analogs give evidence of some of these approaches. An additional criterion for selection of analogs involves the demonstration of a broader spectrum of effectiveness against a panel of experimental systems. Actinomycin D is used as an exampled. There are a variety of factors that may be employed in determining further clinical interest for analogs of known antitumor antibiotics. It is important to delineate the limiting characteristics in the clinical application of the parent antitumor antibiotic and to the choose the appropriate systems to identify and characterize new analogs and investigate them in depth in order to determine whether they may provide some advantage either in antitumor selectivity or in the diminution of host toxicity with retention of antitumor effectiveness.


Characterization of leucine and methionine enkephalin and their interaction with morphine on the guinea pig ileal longitudinal muscle.

Using naloxone as the antagonist, a comparison of pA2 values obtained from the guinea pig ileal longitudinal muscle preparation revealed that both leucine (leu-) enkephalin and methionine (met-) enkephalin can be classified as pure narcotic agonists with pA2 values similar to that of morphine but different from that of nalorphine. In addition, cross tolerance to both met- and leu-enkephal in could be demonstrated on an ileal strip made tolerant to morphine by implantation of morphine pellets to a guinea pig for 72 hours. Pretreatment of a naive muscle strip to three increasing concentrations of leu-enkephalin was found to markedly decrease the IC50 of morphine and to sensitize the ileal strip to naloxone as was evidenced by an increase in the morphine-naloxone pA2 value. Met-enkephalin or morphine pretreatment had no effect on subsequent morphine IC50 determinations but similarly increased the morphine-naloxone pA2 value. These results suggest that although both leu- and met-enkephalin may be classified as pure narcotic agonists, their interaction with morphine on the ileal strip is markedly different. Leu-enkephalin may be an important physiological modulator of narcotic efficacy.


Identification of six substituted 4''-hydroxy-metabolites of of delta1-tetrahydrocannabinol in mouse liver.

4''-Hydroxylation is shown to be a major metabolic route for delta1-tetrahydrocannabinol (delta1-THC) in the mouse. Metabolites were extracted from the livers of mice treated with delta1-THC and examined by combined gas chromatography-mass spectrometry. The 7-hydroxy-6alpha,7-dihydroxy-, 6-oxo- and 7-hydroxy-6-oxo- derivatives of 4''-hydroxy-delta1-THC together with the 4''-hydroxy- and 4'',6alpha-dihydroxy-derivatives of delta1-THC-7-oic acid were identified. Only the diol, 4'',7-dihydroxy-delta1-THC has been reported previously.


Cardiovascular effects of novel amphetamine analogs in anesthetized rats.

In albino, adult Sprague Dawley rats, anesthetized with urethane intraperitoneally, the effects of the exo- and endo-isomers of 2-amino-5,8-dimethoxybenzonorbornene were studied on arterial blood pressure and heart rate. Both compounds produced an immediate rise in systemic arterial pressure followed by an immediate maximal depressor response. The depressor effect was sustained beyond 30 minute duration, but declined in intensity with time to nearly preinjection levels. Both compounds decreased heart rate in varying degrees. Evidence of marked bradycardia and onset of toxicity was observed at doses of 12.8 mg/kg (exo) and 19.2 mg/kg (endo). The biphasic response seen after intravenous injection of the compounds suggests an initial vasoconstrictory followed by a vasodilatory effect.


Effects of pre- and post-treatment with EXP 561 on the amine-depleting effects of p-chloroamphetamine and 6-hydroxydopamine in rats.

EXP 561, 4-phenyl-bicyclo(2,2,2)octan-1-amine hydrochloride monohydrate, antagonized brain serotonin depletion by p-chloroamphetamine and heart norepinephrine depletion by 6-hydroxydopamine in rats. The antagonism of p-chloroamphetamine action occurred with post- as well as pre-treatment with EXP 561. Simultaneous injection of EXP 561 with p-chloroamphetamine initially antagonized serotonin depletion but the effect diminished by 24 hrs. The antagonism of 6-hydroxydopamine action could be produced only by pre-treatment with EXP 561, post-treatment having no effect. When EXP 561 was injected simultaneously with 6-hydroxydopamine, its antagonistic effect did not decline with time. The duplications of these findings for the interpretation of data on uptake inhibitor antagonism of amine depletors are discussed.


Perineural microtubule inhibitors induce degenerative atrophy of central nociceptive terminals in the Rolando substance.

Short-term perineural application of a microtubule inhibitor around a peripheral nerve induces degenerative atrophy of primary central nociceptive terminals in the Rolando substance. Consequences of the local microtubule inhibitor treatment are identical, both at light- and electron microscopic levels, with those that follow transection of a peripheral nerve. Degenerative atrophy in the Rolando substance is due to arrested axoplasmic transport in, and not to Wallerian degeneration of, the peripheral axons since (1) locally applied vinblastine and vincristone do not induce peripheral degeneration at all and (2) even though local colchicine treatment may cause Wallerian degeneration of thick myelinated axons, thin Adelta and C fibers do not undergo degeneration after colchicine treatment. The intriguing possibility to use this approach in the treatment of intractable pain is discussed.


Inhibition of aldehyde dehydrogenase by propiolaldehyde, a possible metabolite of pargyline.

Pargyline (Eutonyl) inhibited aldehyde dehydrogenase (AlDH) in vivo in rats as adduced by the elevation of ethanol-derived blood acetaldehyde (AcH), but had no effect in vitro on the enzyme in intact mitochondria. SKF-525A, an inhibitor of the hepatic microsomal P-450 enzyme system, completely prevented the pargyline-induced elevation of blood AcH in vivo, further implicating a metabolite of pargyline as the active inhibitor of AlDH. Of the potential pargyline metabolites tested, N-benzylpropargylamine and propargyl alcohol--like pargyline itself--readily inhibited AlDH in vivo but were without effect on the enzyme in vitro. These data implicated propiolaldehyde, a theoretically possible product of metabolism of all three of the above compounds, as the active metabolite responsible for AlDH inhibition. Indeed, propiolaldehyde at a concentration of 200 micron essentially completely inhibited the low Km AlDH of intact rat liver mitochondria.


Prostaglandin biosynthesis in platelets: demonstration and role of prostaglandin H2 leads to E2 isomerase.

Double-labeled [3H/14C]-prostaglandin endoperoxide H2 was used to assess the presence in platelets of enzymatic activity for conversion of the endoperoxides to prostaglandin E2. This enzymatic activity (prostaglandin H2 leads to E2 isomerase) involves the selective removal of a hydrogen from the C-9 carbon atom of the endoperoxide molecule and is subject to an isotope discriminatory effect against tritium-labeled molecules. Rabbit washed platelet suspension was pre-incubated for 1 min, with imidazole (1 mM) to inhibit thromboxane A2 generation and [3H/14C]--prostaglandin H2 was added. Analysis of the [3H] and [14C] radioactive products in incubations with native vs. heat denatured platelets indicated that native platelets convert the endoperoxide enzymatically to mainly prostaglandin E2. Thus, although arachidonic acid released endogenously or added exogenously to platelets is converted mainly to thromboxane B2 and 120H-17:3 acid, platelets appear to possess prostaglandin H2 leads to E2 isomerase activity which becomes manifested when thromboxane synthetase activity is inhibited.


Production of antibody toward asbestos.

Unlike normal rabbit control globulins, experimental globulins from rabbits injected with BSA-coated asbestos were found to bind with asbestos. One evidence of such binding is a decreased rate of sedimentation of asbestos in solution. Other evidence has been obtained in experiments with fluorescein-labelled reagents. These results are taken to be indicative of the presence of anti-asbestos antibody in the experimental globulins.


Trans-delta-9-tetrahydrocannabinol: effects on macromolecular content of mouse liver tissue.

Mice were starved for 72 hours then injected with a total of 50 mg/kg THC over 48 hours during which time the animals were fed ad libitum. At the end of the 48 hours, the mice were sacrificed and the livers were analyzed quantitatively for DNA, RNA, protein, and glycogen. It was determined that the THC had no effect on the DNA or glycogen levels. The amount of RNA increased significantly when compared to controls while protein levels decreased by 50%.


The effect of dantrolene sodium on the efflux of Ca45 from rat heavy sarcoplasmic reticulum.

The effect of dantrolene on calcium (Ca2+) efflux was studied using SR vesicles isolated at 8,000 X G from rat skeletal muscle. Dantrolene concentrations of 4 to 9 X 10(-5) M suppressed the efflux of Ca45 from the isolated vesicles in a dose-related way during the first 5 minutes of incubation. The residual Ca2+ in the sarcotubular vesicles was inversely related to the dantrolene concentrations of 4, 6 and 9 X 10(-5) M. The addition of 10mM caffeine to the efflux media offset the suppressive effects of the lower concentrations of dantrolene on Ca2+ efflux. Only dantrolene concentrations of 9 X 10(-5)M resulted in significant retention of Ca2+ in the vesicles in the presence of 10mM caffeine.


Potentiation of the toxicity of adriamycin by propranolol.

Both propranolol and adriamycin are biochemically known to inhibit mitochondrial CoQ10-enzymes of myocardial tissue in vitro. Both propranolol and adriamycin are clinically known to cause cardiotoxicity. At two dose levels of propranolol which caused no deaths to mice when administered alone, significant potentiation (p less than 0.01) of the lethality of adriamycin to mice was observed. These data, projected to the clinical situation, seem to contraindicate the administration of the beta-blocker, propranolol, for the hypertension of a cancer patient who is being treated with adriamycin.


Chromosome banding studies in cattle.

A recent advance in the field of cytogenetics has been the ability to stain differentially specific areas or bands on the fixed chromosome. In terms of clinical and paraclinical work C- and G-bands have been of most value to date in allowing precise identification of chromosome homologues even in species such as cattle, where the vast majority of chromosomes are of a similar morphology. These methods have allowed at the gross level of the chromosome the precise identification of a number of Robertsonian translocations and certain aneuploids. In this study 1/29 Robertsonian translocations were found in three separate breeds. Also a 14/20 and a 6/16 Robertsonian translocation were identified as was a 61XXY sterile bull. In the future these techniques will allow the identification of as yet unidentified anomalies in cattle such as reciprocal translocations and paracentric inversions. Since many anomalies have been correlated with such clinical problems as early embryonic death, abortion, congenital anomalies and reduced reproductive efficiency in the mammalia, it is important to use cytogenetics as an additional laboratory aid in such investigations.


A method for collecting lachrymal fluid from cattle.

The bovine lachrymal duct was catheterised with an expanded polyvinyl catheter and lachrymal fluid was collected for periods of up to 8 h, 45 min. The method was simple and allowed the flow rate of lachrymal fluid to be measured.


Relationship of parakeet/Netherlands/449/75 virus to other avian paramyxoviruses.

Serological and physico-chemical properties of parakeet/Netherlands/449/75 (449) virus indicated a close relationship to paramyxovirus/Turkey/Wisconsin/68.


The effect of mebendazole in food on Echinococcus granulosus and Taenia hydatigena infections in dogs.

A limited, but controlled trial with mebendazole incorporated in a prepared food and with tablets given with this food showed that with the former there was an overall reduction in the expected dog population harbouring Echinococcus granulosus and Taenia hydatigena. Neither treatment was fully effective.


The effect of an antibiotic of the streptothricin family against Echinococcus granulosus and Taenia hydatigena infections in dogs.

The effect of an antibiotic of the streptothricin class on Echinococcus granulosus and Taenia hydatigena infections has been investigated in a trial involving 160 dogs. The drug showed significant activity in freeing dogs from Thydatigena, but the evidence for similar activity against E granulosus was less well marked. Vomiting and diarrhoea were common sequelae of dosing. The preparation tested consisted of four chemical components and the cestocidal value of each was not determined.


The effect of diuredosan on Echinococcus granulosus and Taenia hydatigena infections in dogs.

Diuredosan has been tested against Echinococcus granulosus and Taenia hydatigena infections in dogs. The drug showed significant activity against T hydatigena, but there was no significant dose response curve against E granulosus in this trial. Two treatments at 50 mg/kg or 100 mg/kg, however, reduced the number of dogs infected with hydatid worms. Worms were still present in some dogs after three treatments at 50 mg/kg. Vomiting and diarrhoea were relatively common sequelae at and above 50 mg/kg.


Attempted protection of zebu cattle against trypanosomiasis using a multi-stabilate vaccine.

The protective value of double vaccination with 11 recently isolated stabilates of Trypanosoma congolense given either as live or dead organisms, followed by trypanocidal therapy, was assessed in zebu cattle subsequently challenged by nine of the original stabilates. Both vaccination regimens failed to prevent the animals becoming parasitaemic and eventually succumbing to the infection, although the mean survival times and prepatent periods of the calves which received the live vaccine were longer than those of both the groups which had received the dead vaccine and the challenge controls.


Blood and tissue content of the iso-enzymes of lactate dehydrogenase in the thoroughbred.

The occasions, position and relative concentration of LDH iso-enzymes in the blood tissues of the thoroughbred horse were determined. Locomotor muscles possess a high concentration of LDH 5 whereas non-locomotor muscles have a low concentration of this iso-enzyme.


The relationship of age and stage of gestation to the incidence of embryo death in dairy cattle.

Milk progesterone concentrations were measured thrice-weekly in approximately 200 autumn-calving cows of NIRD dairy herds in each of two successive years, about 100 being common to both years. From this, it was concluded that embryo death, later than the 14th day after artificial insemination occurred in about 10% of cows of each year. Most of the deaths occurred around the 35th day after AI, the time when the fetal membranes are becoming attached to the uterine wall. The incidence of embryo death around this time increases with age of cow.


Genetic resistance to helminths: a possible relationship between haemoglobin type and the immune responses of sheep to non-parasitic antigens.

The results of some preliminary studies on a possible association between haemoglobin type and the antibody responses of sheep to a variety of non-parasitic antigens are described. Sheep with haemoglobin AA showed a significantly better response to human serum albumin than animals of the same breed with haemoglobin BB. There was also suggestive evidence of a better response by haemoglobin AA types to rabbit red cells and horse gamma globulin. These results indicate that the greater resistance of these sheep to gastrointestinal nematodes is reflection of their superior immunological competence.


Changes of plasma uric acid levels in horses after galloping.

Two horses were alternately galloped and cantered at 48 h intervals in a cross over trial. Galloping produced a rise in plasma lactic and uric acids. The lactic acid decreased in concentration whereas the uric acid increased in the hour after exercise. Plasma phosphate levels were depressed 1 h after galloping. There was no significant variation in these parameters after cantering. Possible reasons for these changes are discussed.


Incidence and preliminary characterisation of a hitherto unreported, serologically distinct, avian paramyxovirus isolated in Hong Kong.

Twenty-seven apparent paramyxoviruses, unrelated to known avian paramyxoviruses, were isolated at a Hong Kong dressing plant from the trachea or cloaca of birds originating from Hong Kong and the People's Republic of China. A total of 2443 apparently healthy ducks, geese and fowls was sampled and isolation frequencies were 1.3%, 1.0% and 0.5% respectively. Twenty of the isolates were from the cloaca; 11 were obtained in association with Newcastle disease virus and one with an avian influenza virus. The majority of the isolations were made in the winter months. All 27 isolates were serologically related although 11 representative isolates differed slightly in haemagglutinin properties. A representative isolate was not pathogenic for chickens. A serological survey of poultry indicated a relatively low incidence of infection.


The absence of Trypanosoma congolense from the lymph of an infected sheep.

The lymph draining the prefemoral lymph node of a sheep infected with Trypanosoma congolense was examined over a period of 10 days. Only six trypanosomes were detected in 1500 ml of this fluid during this time, in spite of the animal having about 65,000 organisms/ml in its blood. It is concluded that the suggestion that T congolense is a strict plasma parasite is essentially proven for this specific situation.


Ultrastructure of livers of broiler chickens fed diets containing rapeseed meal.

The ultrastructure of the livers of four-week-old White Rock broiler chickens fed diets containing 50% rapeseed meal was examined. Multifocal hepatocytic necrosis was observed in most of the birds fed the experimental diets. Early degenerative changes were swelling of mitochondria and vacuolations of various sizes in the cytoplasm of the hepatocytes. The reticulum fibres seen as bundles of cross striated fibrils were disorganised at the sites of the focal necrosis. Alteration of interfibrillar matrix were considered to be reason for the negative silver stain in the necrotic foci at light microscopic level reported previously. Disruption of the liver framework at the necrotic foci appeared to have caused a rupture of the sinusoids in the birds showing the haemorrhagic syndrome.


Resistance of the rat to reinfection with Fasciola hepatica and the possible involvement of intestinal eosinophil leucocytes.

Rats infected three weeks previously with 30 Fasciola hepatica cysts were shown to be highly resistant to oral reinfection, as measured by the recovery of immature flukes from the peritoneal cavity 48 h after challenge and confirmed by liver recoveries three weeks after challenge. Eosinophils were prevalent in the lamina propria of the small intestine three weeks after primary infection and increased markedly after challenge.


Vaccination against Bordetella bronchiseptica infection in dogs using a heat-killed bacterial vaccine.

A group of eight-week-old dogs was inoculated with a heat-killed suspension of Bordetella bronchiseptica by the intramuscular route on two occasions at an interval of two weeks. All vaccinated animals developed high circulating agglutinin titres by two weeks after the second inoculation at which time the vaccinated dogs and a comparable group of unvaccinated animals were challenged by exposure to an aerosol of live B bronchiseptica. Both vaccinated and unvaccinated dogs subsequently developed clinical respiratory disease characterised by persistent coughing but the onset of disease in vaccinated animals was delayed by up to five days when compared with the controls. B bronchiseptica was isolated from the nasal cavity, tracheobronchial tree and lung parenchyma of vaccinated and control dogs.


Vaccination against canine bordetellosis using an aluminum hydroxide adjuvant vaccine.

Six collie dogs, eight weeks old, were inoculated intramuscularly with an aluminium hydroxide adjuvanted preparation of killed Bordetella bronchiseptica; the inoculation was repeated after two weeks. Two weeks after the second inoculation, the vaccinated dogs and a comparable group of six unvaccinated animals were challenged by exposure to an aerosol of pathogenic B bronchiseptica. All six unvaccinated control dogs developed respiratory disease characterised by persistent coughing. In contrast, four of the vaccinated dogs remained free from clinical respiratory disease while, in the other two dogs, disease was less severe and of shorter duration than in controls. At necropsy, there were only slight changes in the lungs of vaccinated dogs but in controls there was a severe tracheobronchitis with areas of exudative pneumonia. Bacteriological examination showed a marked reduction in the numbers of B bronchiseptica isolated from the respiratory tract of vaccinated animals compared with controls. An aluminium hydroxide adjuvant vaccine may be of value in controlling naturally occurring respiratory disease in dogs in which B bronchiseptica is involved.


Adipose tissue cells in cold-acclimatised sheep.

The morphology and lipid content of adipose tissue from sheep subjected to cold acclimatisation were examined. In two sheep the perirenal adipose tissue contained virtually no triglyceride (less than 2 mg/100 mg wet tissue) and the appearance on electron microscopy was typical of that of a depleted white fat cell. The morphological, chemical and physiological evidence indicates that, in the sheep, white adipose tissue does not revert to brown adipose tissue during depletion resulting from cold acclimatisation.


A 14/20 Robertsonian translocation in Swiss Simmental cattle.

A chromosomal abnormality identified as a 14/20 Robertsonian translocation by measurement and banding studies has been found randomly in several Swiss Simmental cattle. These cases have all been traced back to one ancestral bull. The testicular function of three unselected male offspring, two heterozygotes and one normal was studied. All possessed apparently normal spermatogenesis. In a meiotic study no alteration of overall chiasma counts were found at diakinesis in the heterozygous bulls compared with the normal, while the presence of a trivalent confirmed the diagnosis of a Robertsonian translocation. Also in the heterozygotes a small number of secondary spermatocytes were identified but they were too few to draw any firm conclusions regarding alterations in non disjunction rate.


Experimental bovine anaplasmosis: clinico-pathological and nutritional studies.

Groups of Brahman-cross steers maintained on two nutritional planes were infected intravenously with a stabilate of Anaplasma marginale. In general, animals on the higher plane of nutrition were more severely affected. Fever was the first clinical sign of anaplasmosis but, like anaemia, was absent in the mildest cases. When present anaemia appeared two to three weeks after infection. There was a corresponding increase in erythrocyte sedimentation rates when read after 24 h but not at 1 h. The haemolytic nature of the anaemia was indicated by a significant increase in unconjugated bilirubin during the acute phase. Some visceral damage was suggested by a significant increase of serum aspartate amino-transferase (GOT) especially in severely affected animals of the 'high' nutrition group but no significant change occurred in levels of alanine amino-transferase (GPT).


Changes in IgG2 levels with age in British cattle.

IgG1, IgG2 and IgM levels were measured in serum samples from 282 cattle of various ages and the results analysed by least squares. There were marked increases with age in IgG2 levels in bulls, and in dairy cattle in the absence of culling for disease or low production traits. There was about a 300% increase between one year and eight years of age for IgG2 compared with the small increase of about 20% for IgG1 but there was no apparent effect of age on IgM levels. There were no differences between Hereford and Friesian bulls for any of the immunoglobulins but there were environmental differences, between AI centres, for IgG1 and IgM. No animals were found to be immunodeficient but IgG2 levels ranged widely from 1 mg/ml to 35 mg/ml in different bulls.


Experimental infection of ducklings with Mycoplasma gallisepticum and Mycoplasma anatis.

Two groups of day-old ducklings were infected with Mycoplasma gallisepticum and M anatis respectively by air sac inoculation. Clinical disease was not produced but air sacculitis was produced by both infections. M gallisepticum could be recovered readily from respiratory tissue 10 and 30 days after infections but RSA tests were negative. M anatis was not reisolated from these tissues or from the cloaca but a positive RSA test was observed on the serum of a few ducklings.


Physiological effects of lowered blood oxygen affinity in dogs.

Ten adult Labrador retrievers were studied under control conditions and while blood oxygen affinity was lowered by intravenous infusions of glycolytic intermediates. Blood P50 was increased from 32.4 +/- 1.3 mm Hg (mean +/- SD) to 34.3 +/- 1.2 mm Hg, a highly significant increase (P less than 0.001). Blood oxygen capacity, mixed venous oxygen tension and arterial PCO2 were not significantly different in the two conditions. Cardiac output (Q) was lower with the higher P50 (89 +/- 16 ml/kg/min) than in the control state (111 +/- 31 ml/kg/min) but the difference was not statistically significant. The arteriovenous oxygen concentration difference (CaO2 - C-V(O2)) was significantly increased (P less than 0.05) from 4.4 +/- 0.6 vol % to 4.9 +/- 0.8 vol %. Oxygen consumption, the product of Q and (CaO2 - C-V(O2)), was the same in the two conditions: 4.9 +/- 1.3 ml/kg/min (control) versus 4.4 +/- 0.9 ml/kg/min. The animals responded to lowered blood oxygen affinity with increased oxygen extraction by peripheral tissues and a concomitant, although not statistically significant, fall in cardiac output.


Interspecies variation in lung lavage and tissue saturated phosphatidylcholine.

We measured the saturated phosphatidylcholine in lung lavage fluid and in lung tissue after lavage in five vertebrate species. The amount of saturated phosphatidylcholine recovered by lung lavage and from lung tissue showed a direct log linear correlation with species alveolar surface area. The saturated phosphatidylcholine content of lung lavage fluid per square meter of alveolar surface area varied in the sequence: mouse greater than rat greater than rabbit greater than dog greater than cat, and showed a direct correlation with species respiratory rate. We compared the lavage (presumably mainly alveolar) and tissue saturated phosphatidylcholine with the theoretical minimum amount required to produce a monomolecular layer over an area equal to the computed alveolar surface area. The data suggest that there is an alveolar and a tissue reserve of saturated phosphatidylcholine. The size of the alveolar reserve varied in the sequence: mouse greater than rat greater than rabbit greater than dog greater than cat. We conclude that in each species studied there is an alveolar and tissue reserve of saturated phosphatidylcholine and that both reserves are larger in animals with rapid ventilatory rates and small alveoli than in animals with slower breathing rates and larger alveoli.


Chicken intrapulmonary chemoreceptors: discharge at static levels of intrapulmonary carbon dioxide and their location.

We studied 54 intrapulmonary chemoreceptors in the unidirectionally ventilated left lungs of 12 thoracotomized cockerels. We ligated the left pulmonary artery to eliminate CO2 contributed by mixed venous blood. At zero PCO2 many units discharge irregularly, and some cease discharging after several seconds. Discharge frequencies at 13.7 torr PCO2 and above are described by logarithmic regressions. The slopes and intercepts of the logarithmic regressions are correlated so that the average response can be written: frequency = 3.86 -B . 1n (24.5 PCO2-1). Afferent activity above 6.8 torr PCO2 is described by 0.073 + 78.6 exp (-0.11 PCO2) -63.3 exp (-0.15 PCO2). For each unit, receptive site PCO2 in a perfused lung was assumed to be the PCO2 in the unperfused lung which gave the same discharge frequency. Location of the receptor was determined as the fraction of ventilation-perfusion region which had the same PCO2 as receptive site PCO2. Two major concentrations of receptors accounted for 85% of the total, one near the entering gas and one near the middle of the gas-exchange region. Sensitivity of individual receptors did not vary systematically with location.


Properties of apneusis produced by reversible cold block of the rostral pons.

Reversible cold block of the rostral pons was used to compare properties of normal and apneustic respiration in anesthetized, vagotomized, artificially ventilated cats. During apneusis we observed high frequency oscillations (HFO) in phrenic nerve activity which were reduced in frequency compared with those during a normal inspiration. Apneusis produced by mid-pontine transection or punctate pneumotaxic center (PC) lesion produced similar HFO changes. The minimal intensity of superior laryngeal nerve electrical stimulation needed to terminate a breath was higher early in an apneusis than at the same time during a normal breath. Later in apneusis the intensity required became constant and was approximately the same as that needed to end a normal inspiration at its natural termination. With intact vagi lung inflation produced a greater prolongation of expiration during apneustic respiration than during normal respiration. Apneustic type activity was observed in both phrenic and vagal inspiratory motoneurons. We suggest that: (1) HFO are generated without the PC, but the PC elevates the oscillation frequency; and (2) apneusis may result in part from a delayed activation of the normal inspiratory off-switch mechanism.


Occlusion pressure in acute bronchospasm induced by methylcholine.

We measured resting minute ventilation, the pressure developed by the inspiratory muscles during the first 0.1 sec of inspiratory effect against an occluded airway (P0.1), FRC and airway resistance in normal subjects during bronchoconstriction induced by methylcholine inhalation and again after the bronchoconstriction had been reversed by inhaled isoproterenol. Methylcholine resulted in a 2- to 3-fold increase in airway resistance, FRC rose in 5/6 subjects and ventilation changed in variable fashion. P0.1 increased in all subjects with methylcholine and decreased after isoproterenol. When the subjects were considred as a group, P0.1 correlated positively with airway resistance. Normal subjects respond to bronchoconstriction as they do to external resistance loading, by increasing inspiratory muscle activity. During bronchoconstriction, all subjects demonstrated an increase of breathing frequency and a decrease in the duration of expiration; inspiratory duration did not change significantly. This response may have been due to activity of pulmonary irritant receptors. Breathing frequency and expiratory duration returned to control levels with isoproterenol, so we could not show that this response was independent of changes in lung mechanics.


Intrapulmonary and systemic CO2-chemoreceptor interaction in the control of avian respiration.

Experiments on anesthetized chickens were conducted to study interactions between afferent activity from the intrapulmonary and systemic CO2-sensitive chemoreceptors in the generation of respiratory amplitude (RA) and respiratory frequency (f). The thoracoabdominal cavity was opened, air sacs ruptured and each lung independently and unidirectionally ventilated. Intrapulmonary chemoreceptor activity was altered by changing the PCO2 of the ventilatory gas (PICO2) to the vascularly isolated right lung (VIL); systemic chemoreceptor activity was altered by changing the PICO2 to the denervated left gas exchange lung (GEL). Respiratory amplitude and frequency responses to changes in intrapulmonary PCO2 were determined at four levels of systemic arterial PCO2 (PaCO2). The results indicate that elevating PaCO2 shifts the pulmonary CO2-response curves for both RA and f to the left and increases the sensitivity of the RA-CO2 response curve but decreases the sensitivity of the f-CO2 response curve. We conclude that (1) interaction occurs between intrapulmonary and systemic afferent activity in the generation of RA and f, (2) the nature of the interaction is synergism with respect to RA and interference with respect to f, and (3) the interaction is greater during hypocapnia than hypercapnia.


Growth and decay of pulmonary function in healthy blacks and whites.

We recorded maximum expiratory flow-volume curves in 3046 healthy persons, blacks and whites, age 7 and over--a representative population of lifetime nonsmokers except for some black adult males, who were healthy smokers or ex-smokers. We computed regression equations for lung function measurements (FVC, FEV1.0, FEV10/FVC, PEF, MEF 50% and MEF 25%) as a function of age, height and weight terms for eight subgroups (by sex and race, and for children or adults). Objective statistical criteria were used to select the optimal equations. Simple linear regressions on age and height are inaccurate, in particular for young adults and for the elderly. Weight affects most function measurements: lung function first increases with weight ('muscularity effect') and decreases with further increases in weight ('obesity effect'). The regression equations allow more accurate prediction of normal lung function. In addition, the lower 95% confidence limits are closer to the predicted values and are valid regardless of height, weight and age within each subgroup.


Central and direct vagal dependent control of expiratory duration in anaesthetized rabbits.

In anaesthetized rabbits, total or partial (only inflation reflex nearly abolished) DC current vagal block was performed during inspiration (ITB and IPB), or expiration (ETB and EPB), or throughout the breathing cycle (CTB and CPB). During CTB inspiratory (Ti) and expiratory duration (Te) increased as after vagotomy. With ITB Ti equally Tivag; Te increased, but remained shorter than Tevag. During ETB, Ti was unchanged, Te increased, but remained shorter than Tevag. The sum of deltaTe during ITB and ETB equalled deltaTevag. During CPB and IPB, Ti and Te behaved as during ITB. With EPB, Ti was unchanged and Te shortened. Preferential stimulation of large myelinated fibers in the central vagal stumps during expiration lengthened Te. Inspiratory stimulation shortened both Ti and Te, restored breath timing of ETB, but not that of pre-vagotomy control. Hence, Te of eupneic breaths should depend on a central mechanism relating Te to preceding Ti and on expiratory vagal discharge, having both a small lengthening (from stretch receptors) and a variable shortening effect (from irritant receptors). Both central and peripheral mechanisms are affected by CO2 breathing.


I. Pulmonary-CO2 ventilatory reflex in dogs: effective range of CO2 and results of vagal cooling.

Bartoli et al. (1974) found in dogs with constant PaCO2 that an increase in PCO2 in the vascularly isolated lungs increased ventilatory drive by a vagal reflex. We have examined the range of lung PCO2 over which the reflex operates. In anaesthetized dogs we ventilated the lungs separately with O2, maintaining gas exchange with the right lung. When we occluded the left pulmonary artery, left lung PCO2 fell to 2--4 mm Hg, and phrenic nerve firing decreased significantly. Phrenic activity increased again when left lung PCO2 was raised in steps to 19, 32 and finally to 50 mm Hg. PaCO2 was unchanged. Phrenic responses were abolished by cutting the left vagus nerve or by cooling it to 7--8 degrees C. The largest increase in phrenic activity occurred when left lung PCO2 was increased from 2 to 19 mm Hg, and the smallest when PCO2 was raised from 32 to 50 mm Hg. Hence the significance of the pulmonary-CO2 ventilatory reflex may lie in depression of ventilatory drive when pulmonary CO2 falls below normal, rather than in stimulation of breathing when pulmonary CO2 increases above normal.


II. Effect of CO2 on afferent vagal endings in the canine lung.

We have attempted to identify the afferent endings responsible for the pulmonary-CO2 ventilatory reflex. We recorded afferent vagal impulses arising from the left lung in anesthetized dogs with separately ventilated lungs. When the left pulmonary artery was occluded, left lung PCO2 fell to 3 mm Hg and slowly-adapting pulmonary stretch receptor activity increased 46%. Firing declined to its original intensity when left lung PCO2 was raised in steps by administration of CO2, firing decreasing most between 2 and 19 mm Hg, and least between 30 and 50 mm Hg. Irritant receptor activity also increased (from 2.8 to 7.4 impulses/sec) after pulmonary arterial occlusion, the effect being reversed by administration of CO2. These procedures caused trivial changes in pulmonary and bronchial C-fiber activity. Effects on both slowly-adapting stretch receptors and irritant receptors appeared to result from a direct action of CO2 on the endings themselves, rather than from mechanical changes in the lung. Changes in slowly-adapting stretch receptor activity provide an adequate explanation for the pulmonary-CO2 ventilatory reflex, the relationship between impulse frequency and lung PCO2 suggesting that these afferents may have a role in limiting CO2 loss under conditions causing hypocapnia, but be less effective in stimulating breathing during hypercapnia.


Uneven perfusion and ventilation within lung regions studied with nitrogen-13.

The clearance of nitrogen-13 (13N) from the upper, mid and lower zones was measured with a gamma camera during spontaneous breathing in 10 seated subjects. The clearance was monitored after (a) an intravenous injection of 13N dissolved in saline and (b) equilibration with 13N gas in closed circuit. Subjects breathed air first, and then a 30 or 11% oxygen mixture. For any region, the time for 90% elimination (T90) was related to the volume expired by the whole lung during that time (VE90). For the mid and lower zones, the clearance was faster (VE90 smaller) after intravenous 13N than after equilibration with 13N gas. This difference persisted when 30% or 11% oxygen was inspired. For the lung overall, the physiological dead space for a mean tidal volume of 884 ml was 277 ml for intravenous 13N clearance, and 384 ml for 13N clearance after equilibration. The conclusions drawn for this study are (1) ventilation in relation to volume is uneven within lung regions (2) intraregional perfusion in relation to volume is also uneven (3) at a local level the well-ventilated units are better perfused (4) these inhomogeneities are not affected by raising or lowering the inspired oxygen concentration.


Lung architecture volume and static mechanics in five species of lizards.

Compared with mammals, lizards have large, highly compliant lungs and a compliant body wall. High lung compliance is not necessarily associated with high body wall compliance but rather with the degree of development of the caudal and ventral dilatations of the lung. Comparison of the midinflation distance between inflation and deflation curves on standard volume--pressure diagrams indicates hysteresis may have an intrapulmonary component related to the degree of lung partitioning and an extrapulmonary component, attributable to forces hindering the free movement of the lung in the body cavity. Simultaneous consideration of lung structure, mechanical properties and certain nonrespiratory functions such as buoyancy and display indicate that the function of the lung in gas exchange may be only one of several factors important in determining lung structure in lizards.


Lung reflexes in rabbits during pulmonary stretch receptor block by sulphur dioxide.

Anaesthetized rabbits were given 200 ppm sulphur dioxide to breathe for 10 min. This abolished activity in 23 of 26 pulmonary stretch receptors, while leaving that of lung irritant receptors unimpaired. The Breuer-Hering reflex was abolished and breathing became deeper and slower. Inspiratory time (tI) was increased and expiratory time (tE) decreased. Subsequent vagotomy increased tidal volume (VT), tI and tE. In animals with stretch receptors blocked, injections of phenyl diguanide and histamine still increased breathing frequency and decreased VT, indicating that reflexes from lung irritant and J-receptors were intact. Inhalation of 8% CO2 caused a bigger increase in frequency and tidal volume in rabbits with stretch receptor block compared with controls or those after vagotomy. Induction of pneumothorax with stretch receptor block transiently prolonged tI and shortened tE; removal of the pneumothorax also transiently shortened tE and usually also decreased tI. The results suggest that lung irritant receptors reflexly shorten tE in all our experimental conditions, but have various effects on tI which may depend on the timing of the irritant receptor discharge and refractoriness of the inspiratory response.


Oxygen uptake and transport during hypoxic exposure in the sturgeon Acipenser transmontanus.

Gill ventilation, stroke volume and frequency, %O2 utilization and oxygen uptake, and dorsal aortic blood oxygen tension, content, pH and oxygen affinity have been determined during normoxia and during a range of hypoxic exposures in the sturgeon, Acipenser Transmontanus. In air-equilibrated water gill ventilation was 350 ml/kg/min, % utilization was 35--40%, and oxygen uptake at 15 degrees C was 55--60 ml O2/kg/h. Dorsal aortic blood PO2 was 90 mm Hg and blood O2 content at a normal pHa of 7.84 was 7.0 vol%. Vg fell considerably through a reduction in branchial stroke volume when PIO2 was reduced from 150 to 100 mm Hg. Although % utilization remained unchanged, VO2 was halved, clearly identifying Acipenser as an O2 conformer with a critical O2 tension just below air saturation. At a PIO2 of 60 mm Hg VO2 was only 15% of that at normoxic levels falling to only 5% at a PIO2 of 30 mm Hg. There was no hypoxic bradycardia. There was no repayment of an oxygen debt even after severe hypoxic exposure in Acipenser, and pHa remained unchanged under all experimental conditions, a response incompatible with lactate or succinate production. It is concluded that the sturgeon reduces total energy expenditure during hypoxic exposure, rather than switching from aerobic to anaerobic metabolism.


Interrelation between Bohr and temperature effects on the oxygen dissociation curve in men and women.

For both sexes (7 males, 7 females) the fixed acid Bohr coefficient BCFA (delta PO2/deltapH) and the temperature coefficient TC (deltalogPO2/deltaT) were investigated in whole blood as function of oxygen saturation (SO2). BCFA which yielded maxima at midsaturation were generally lower at increased temperature (41 degrees C) and in females. Values for 50% SO2 amount to: -0.46 +/- 0.04 SD (males) and -0.37 +/- 0.06 (females) at 37 degrees C, -0.38 +/- 0.09 (MALes) and -0.31 +/- 0.04 (females) at 41 degrees C. TC, too, was generally lower in females, decreased in both sexes at falling pH, but showed no O2-saturation dependency. Mean values were 0.024 +/- 0.008 (males) and 0.017 +/- 0.003 (females) at pH 7.4, 0.019 +/- 0.008 (males) and 0.012 +/- 0.006 (females) at pH 7.2. Sex differences of both TC and BC could also be confirmed in additional experiments. While the interrelation of BC and TC and the variable saturation effect on the coefficients may be referred to known theories about ionization heats of oxylabile groups and nonuniform reactions of the single Hb4(O2)n fractions, respectively, no clear explanation was found for the sex influence.


Gas exchange of the fertile hen's egg: components of resistance.

The resistance to diffusion of respiratory gases falls by 50% from day 10 to day 18 in the incubating fertile hen's egg (Temple and Metcalfe, 1970). We have calculated the change in the components of this resistance with respect to incubation age. The egg shell resistance remains unchanged. The chorioallantoic membrane (including capillary endothelium) resistance decreases dramatically from day 10 to day 14 and then remains relatively unchanged. The resistance offered by the blood is unchanged from day 10 to day 12, it decreases by day 14 due to an increase in oxygen capacity and continues to decline at days 16 and 18 because of the combined effects of a continued increase in oxygen capacity and an increase in capillary volume.


Nasal resistance during infancy.

Nasal Resistance (Rn) was measured in 30 Caucasian and 13 Negro infants during the 1st year of life, using an adaptation of the posterior rhinomanometric method. Concurrent measurements of Thoracic Gas Volume (TGV) and Airway Resistance during nose breathing (Raw (n) were made using the plethysmographic technique. The percentage contribution of Rn to Raw (n) was significantly higher in the Caucasian infants (mean 49.2 +/- 7.5 (SD)%), than in the Negro infants (mean 31.1 +/- 6.8 (SD)%), which probably resulted from anatomical differences in nasal structure. In each infant, Rn was subtracted from Raw (n) in order to assess resistance, and its reciprocal, conductance (Gaw), during mouth breathing. A strong linear relationship was found to exist between Gaw (m) and TGV throughout the first year of life (r = 0.92), with no significant difference between Negro and Caucasian infants. Specific Airway Conductance during mouth breathing (SGaw (m) = Gaw (m)/TGV) was found to be considerably higher during infancy than at any other time during life, which may help to at least partially compensate for the fact that newborn infants are obligatory nose breathers.


Temporal differences in the detection of resistive and elastic loads to breathing.

Two series of experiments were conducted on 8 healthy subjects to test for temporal differences in the detection of added resistive and elastic loads. In one series of experiments, 5 resistive loads were presented for single inspirations for a total of 10 presentations each. Subjects pressed a signal marker as soon as possible if they detected the load. In the second series, 5 elastic loads were tested using the same protocol The detection time (Tdet) for threshold resistive loads (deltaR50) occurred in mid-inspiration near Vmax whereas the Tdet for threshold D loads (delta E50) occurred near the end of inspiration. The differences in the detection times were significant (P less than 0.001). With suprathreshold loads, detection times progressively decreased reaching a minimum value with total occlusion. These results demonstrate unique temporal differences in the patterns of sensory information generated by added resistive and elastic loads and suggest that the intensity of the information is flow dependent for resistive loads and volume dependent for elastic loads.


Breathing pattern in men during inspiratory elastic loads.

Breathing pattern was studied in men during inspiratory elastic load applied throughout breathing cycle (CL) or inspiration only (DL). VT decreased similarly under both loads: 40% during 1st loaded breath (1st), 25% after 1 min (min); so did Ti (15% at 1st, 25% at min); Te decreased by 35% under CL, 25% under DL, at both times. Under DL expiratory flow started after a lag of about 0.4 sec, required to raise alveolar pressure above atmospheric. In all subjects the inspiratory muscles activity increased at 1st and in 6 out of 8 the ventilatory response at min was essentially neurogenic. At 1st all subjects recruited expiratory muscles, decreasing FRC by 100--300 ml under DL' in most this phenomenon was negligible at min. Rate of decrease of inspiratory muscle pressure during period of zero flow under DL was proportional to end-inspiratory muscle pressure (Pmuse.i.) and to Pmuse.i./Ti. At beginning of expiration dPmus/dt was greater under DL: under this period difference of Pmus between CL and DL seems mainly due to muscle intrinsic properties.


An obstructive apnea in the suckling opossum.

Pressure plethysmographic measurement of ventilation and electromyographic measurement of diaphragm activation in unanesthetized suckling opossums revealed spontaneous episodes of obstructive apnea. To better understand this phenomenon, intact animals were tested under different conditions of respiratory drive and during activation of pulmonary reflexes. Results showed that obstructed breaths were usually initiated with the lungs at or near the end-inspiratory level, and they occurred more frequently during air or oxygen breathing as compared with inhalation of hypercapnic or asphyxiant test gases. The latter two gas mixtures caused increases in ventilation; but depression of breathing resulting from pentobarbital anesthesia was not accompanied by obstructed breaths. It was initially considered that a reflex laryngeal response with changes in lung volume or lung irritation might trigger obstructive apnea; but pulmonary inflation and deflation as well as ammonia inhalation did not typically produce such an effect. The results indicate that mechanisms for obstructive apnea in the suckling opossum must account for the limited incidence of obstructed breaths during both ventilatory chemostimulation and anesthetic respiratory depression.


Human gas exchange during water immersion.

We measured lung volumes, closing volume (CV), alveolo-arterial oxygen difference (P(A-a)O2) and steady-state diffusing lung capacity per liter ventilation (DLCO/V) in 18 men immersed up to the neck in water. The subjects were divided into 3 groups, according to relative changes in P(A-a)O2 and DLCO/V. In group 1 (n = 6), P(A-a)O2 decreased and DLCO/V increased, probably because of the hemodynamic changes induced by immersion. Their end expiratory level was above closing volume in water. In group 3 (n = 6), P(A-a)O2 increased and DLCO/V decreased, probably as a result of a decrease in ventilation in the dependent parts of the lung, considering that breathing range (ERV + VT) was less than closing volume. In group 2 (n = 6), P(A-a)O2 increased significantly and DLCO/V, only slightly. Tidal volume was only partially included in closing volume. The increase in exchange surface area was probably unable to compensate for the arterial hypoxia brought on by the decrease in ventilation in the dependent parts of the lung. The relationship between end expiratory level and closing volume, which seemed to explain the results observed during immersion, was itself a consequence of the subjects' age and body build.


Topographical distribution of VA/Q in elderly subjects using Krypton-81m.

The topography of ventilation-perfusion (VA/Q) ratios was measured in seven elderly (aged 58--69) subjects, seated erect, using the short-life (t1/2 = 13 sec) radioisotope Krypton-81m. 81mKr was inhaled (for ventilation) or infused intravenously (for perfusion) continuously for 1--2 min periods, during spontaneous ventilation, while radio-activity was recorded on a large-field gamma camera interfaced to a computer. The VA/Q ratio was computed for 15 horizontal slices of the left lung. VA/Q distribution was similar to that of young subjects. No decrease of basal VA/Q was seen; thus, if there are any changes of ventilation in the lower part of the lung in the elderly, they are matched by equal alterations of perfusion. There was no significant change when 60% oxygen was breathed. The progressive fall in arterial oxygen tension which occurs in erect subjects with increasing age does not appear to be caused by inter-regional differences of ventilation and perfusion.


Effect of ventilation with different gas mixtures on experimental lung air embolism.

In six anesthetized, curarized and mechanically ventilated dogs, air was infused via a jugular vein at 0.1 cm3/kg/min for 25 min. This induced a progressive increase in pulmonary artery pressure (Pap) while arterial PO2 (PaO2) and end tidal PCO2 (PETCO2) decreased. Systemic arterial pressure, dynamic lung compliance and total pulmonary resistances were not affected. Changes tended to plateau by 20 min with a peak increase in Pap of 80 +/- 13% and decrease in PaO2 and PETCO2 of 22.2 +/- 2.8% and 14.5 +/- 2.1% respectively. When embolization was stopped these values returned to control levels within 30 min. During air infusion (at 20 min) some dogs were switched from ventilation with air to ventilation with the following gas mixtures: SF680%-O220%, He80%-O220%, N2O80%-O220%. During the final 5 min of air infusion. He and, to a greater extent, N2O breathing results in an immediate and marked further increase in Pap and decrease in PaO2 and PETCO2. In contrast SF6 produced rapid improvement in these parameters with return to near control levels. The recovery time after stopping infusion was greatly shortened with SF6 but was unaffected by He or N2O. These results are explained by different rates of gas transfer between the intravascular bubbles and the various alveolar gases. These findings show that ventilation with SF6 results in marked improvement in the gas exchange abnormalities produced by air embolism.


Arterial PO2 and PCO2 stimulus threshold for carotid chemoreceptors and breathing.

The PaO2 and PaCO2 stimulus thresholds for activity of carotid chemoreceptors and for ventilation were investigated in twenty anesthetized adult cats at sea level. Over the range studied PaCO2 threshold for carotid chemoreceptors decreased with increasing intensity of hypoxia showing stimulus interaction. Once begun, the carotid chemoreceptor activity increased gradually at a rate that was inversely related to initial PaO2. The greater the initial hypoxia the greater was the carotid chemoreceptor activity at which the first inspiration occurred, apnea was shorter and inspiratory PaCO2 threshold lower. Hypoxia per se depressed the central mechanism for the resumption of inspiration. We conclude that (1) carotid chemoreceptor PaO2-PaCO2 stimulus thresholds are largely interdependent; (2) these receptors are activated at a lower PaO2-PaCO2 stimulus strength than ventilation is; (3) an increased input from peripheral chemoreceptors initiates breathing at a lower PaCO2 indicating that central chemoreceptor threshold is lower than the PCO2 threshold for inspiration; (4) a finite total input from the receptors is needed to start ventilation.


Experimentally induced antagonism of chemical and thermal reflexes in the respiratory system of fully conscious chickens.

The joint response of the respiratory and panting centres of fully-conscious unidirectionally-ventilated chickens to simultaneous combinations of hyperthermia and hypo-/hypercapnia was examined. The response was monitored by changes in the rate and amplitude of movements of the body wall and gular apparatus respectively. The response to a combination of hyperthermia plus hypercapnia bore indications of a linear summation of the individual responses of the panting centre and respiratory centre to the respective thermal and chemical stimuli. A more complex response was elicited by a combination of hyperthermia plus hypocapnia. In this case the inhibition of respiratory movements induced by the hypocapnia (hypocapnic apnea) permitted a more forceful manifestation of the component of the thermoreflex which acts via the hyoid muscles and which is responsible for the synchronous 'gular flutterin'. The rate of gular fluttering increased by up to 150% as compared to normal panting. The experimental procedure therefore provided a technique for breaking the central linkage which normally constrains the rhythm of the hyoid muscles to the more dominant rhythm of the respiratory muscles.


[Pseudo-tumoral softening of the cerebellum].

The author establish an onerall picture of cerebellar infarction with brain stem compression after reviewing 63 cases published in the literature and 4 personal observations. The frequency of this affection can be compared with that of cerebellar hematomas. Diagnosis is based on its predominance in males, the early age at which it appears, its rapid and typical onset, and the delayed signs of brain stem compression. Conventional neuroradiological procedures show an expanded cerebellar volume, and the scanner can specify the ischaemic nature of the lesion. As soon as changes in consciousness occur surgical decompression is necessary, first by external drainage of C.S.F. and later, if necessary, by direct access to the postdrior fossa.


[Disorders of heat and water regulation. Proliferative reticulo granulomatous process of hypothalamic origin (author's transl)].

The authors report the anatomical and clinical findings in a 65 year old patient with a lesion in the hypothalamus presenting mainly as disorders in heat and water regulation. Disorders in heat regulation dominated the clinical picture, in relation to a poikilothermia. Conservation of reactivity to pyrogenic bacteria is debatable. Inappropriate secretion of antidiuretic hormone (ISADH) by a direct effect on the supraoptico-hypophyseal aixs can account for the water and electrolyte disturbances. The anatomical lesions, due to hypothalamic changes, can be included in the circumscribed proliferative reticuloses of the CNS having a pseudo-inflammatory histological appearance.


Metabolism of interferon (facts and fancy).

Although the knowledge of the interferon metabolism is still incomplete, two organs are emerging as elective sites. The kidney and probably the liver may share a major role but only future research will define quantitatively their importance. Many aspects of interferon activity upon cellular processes and its possible function as a 'chalone-type' substance are reviewed.


Biology of the human myeloma cell population. I.Macromolecular characteristics.

Several human myeloma cell populations were studied using a combination of cytochemical (Unna-Pappenheim and naphthol yellow staining, Feulgen reaction) and autoradiographical (uridine, leucine, thymidine uptake and actinomycin binding) techniques. Progressive differentiation of the myeloma population was associated with: 1. a loss of proliferative activity, 2. decreased transcriptional capacity, 3. decreased RNA and protein synthesis, 4. increased RNA and protein concentrations, 5. greater stability of the protein synthesis template. The existence of a pre-myelomatous compartment is suggested in the light of these results and those of previous kinetic studies in vivo.


Biology of the human myeloma cell population. II. Cytokinetic characteristics.

A kinetic study of five human myeloma cell populations before and after chemotherapy using cytochemical and autoradiographical techniques showed: 1. a large number of cells, with a DNA content intermediate between 2c and 4c, that did not incorporate thymidine ('U' cells) and were indicative of ineffective myelomapoiesis; 2. non cell cycle-specific (cyclophosphamide) followed by cell cycle-specific (vincristine) treatment led to an increase in the 3H-thymidine labelling index (LI) and activation of macromolecular synthesis (increased uridine and leucine uptake and actinomycin binding capacity) pointing to early cell recruitment. A high percentage of 'U' cells can be found even after therapy. The LI variations make it clear that recruitment after therapy is overestimated by at least 40% due to ineffective myelomapoiesis. In the light of this and previous personal studies, we propose a kinetic pattern: the myeloma population may be seen as a highly differentiating population whose non-proliferating cells cannot re-enter the cycle. By contrast, the acute leukemia populations are unable to differentiate, and the non-proliferating cells (G0) can be recalled into the cell cycle.


Evidence for the involvement of the IgE-basophil-mastocyte system in human acute post-streptococcal glomerulonephritis.

Several findings reveal the involvement of the IgE-basophil-mastocyte-platelet-activating-factor (PAF) system in human acute post-streptococcal glomerulonephritis. In the acute phases of the disease there is a transient, marked reduction in the circulating metachromatically staining basophils, indicating an in vivo basophil degranulation. The blood reservoirs of PAF are depleted. The number of metachromatic mastocytes in renal biopsy samples was very low and morphological aspects of degranulation were present. In vitro, we demonstrated basophil degranulation and PAF release in presence of exogenous streptococcal Ags after recovery. These findings suggest that the IgE-basophil-mastocyte-PAF system may play a role in human pathology, as has been shown in immune complex (Ic) deposition in acute serum sickness in rabbits.


An automated method for evaluation of the thyroid uptake of 99mTc-pertechnetate.

A method for evaluating the thyroid uptake function, based on the work of De Garreta, Williams, Glass, Atkins, Higgins et al., was developed using 99mTc-pertechnetate and a scintillation camera connected to a minicomputer system. The method has the advantages of a single visit, a low-dose examination, and the reliability of a full automated technique. The clinical results of the studies performed to date are in close correlation with those obtained from the radioactive iodine uptake test, and in good agreement with the findings of the above-mentioned authors.


Erythrocyte deformability in a red cell ageing model.

The authors studied the effect of a period of storage on erythrocyte deformability in blood samples collected from 31 healthy subjects. A significant reduction in erythrocyte deformability was recorded over the course of time. The study was designed to determine whether pentoxifylline produces a dose-dependent increase in erythrocyte deformability in red cells from ageing blood. The effect of theophylline and prednisolone on this parameter was also studied. A dose-dependent increase in erythrocyte deformability was established for pentoxifylline and was measurable immediately after addition of the substance. Theophylline increased erythrocyte deformability but not to a degree which differed significantly from the controls. Prednisolone elicited a slight reduction in erythrocyte deformability, but again the change was not significant by comparison with the controls. None of the substances brought about any change in the rate of red cell ageing.


Inhibitory effects of vibrations on contractility of isolated rabbit papillary muscle.

The effects of vibrations on myocardial contractility have been tested in isolated rabbit papillary muscles. Sinusoidal longitudinal oscillations were found to inhibit active force in the paced preparation to an extent which depended on vibration amplitude and frequency. The inhibitory effect of vibrations on myocardial contraction resembled that previously seen in other types of muscle. Vibration during the inactive phase did not alter passive muscle tension. When the vibrator was controlled by phonocardiographic recordings from a normal subject or from patients with congenital aortic stenosis, pronounced inhibition was obtained only by vibrations corresponding to a systolic murmur. It is concluded that the myocardium is sensitive to oscillating length changes. If the ventricular muscle in vivo is exposed to vibrations during systole the cardiac function might be seriously interfered with.


Myocardial depressant effect of vibrations in the isolated rabbit heart.

A working rabbit heart preparation was developed in which vibrations could be induced in the left ventricular outflow tract. The vibrations were produced by a special vibrator from which a metal pin was connected to a thin metal plate sutured onto the left ventricle. Vibrations of 0.3, 0.6 and 1.2 mm amplitude and frequencies of 50, 80 and 100 Hz were used. Increasing amplitudes or frequencies resulted in more pronounced reduction of cardiac output, aortic flow and left ventricular peak systolic pressure. The left ventricular end diastolic pressure increased at higher amplitudes or frequencies. The coronary flow was not significantly changed. It is suggested that vibrations of the ventricular wall might be a myocardial depressant factor of importance in valvular heart disease.


Changes in plasma volume and extracellular fluid volume after addition of prazosin to propranolol treatment in patients with hypertension.

In fifteen patients with hypertension, inadequately controlled during treatment with propranolol alone (mean dosage 333 mg/day), plasma volume (PV) and extracellular fluid volume (ECV) were determined. After addition of prazosin for 3 months (mean dosage 9 mg/day) there was a significant increase in PV and ECV, on average 8 and 5%, respectively. The decrease in supine blood pressure, systolic as well as diastolic, was very modest, on average 11 mmHg (SD +/- 12) and 4 mmHg (SD +/- 7), respectively. The changes in standing blood pressure were more pronounced. It is assumed that the expansion of PV and ECV contributes to the inadequate blood pressure response found in the present study.


Hypoxanthine in cerebrospinal fluid in children.

In forty-five children the hypoxanthine concentration in cerebrospinal fluid (CSF) was measured (fifty-two samples). In newborn infants (nineteen patients) the hypoxanthine levels were higher in patients with clinical conditions associated with hypoxia (idiopathic respiratory distress syndrome, asphyxia, apneic attacks) than in patients without clinical hypoxia (P less than 0.01). In hypoxic patients the hypoxanthine concentration varied between 5 and 28 mu mol/l. In children outside the neonatal period the hypoxanthine concentration in CSF varied considerably in different diseases. High levels were registered in meningitis prior to treatment, febrile convulsions and in lymphoblastic leukaemia, probably reflecting tissue hypoxia and an increased tissue catabolism.


Optimum laboratory test combinations for thyroid function studies, selected by discriminant analysis.

In 430 patients with a variety of thyroid disorders, linear discriminant analysis was used to select laboratory test combinations giving optimum diagnostic efficiency in thyroid function studies. Unexpectedly, TSH was found valuable in the diagnosis of hyperthyroidism and T3 in hypothyroidism. These test combinations were found optimal for the separation of euthyroidism/hyperthyroidism: T3, TSH and T4; euthyroidism/hypothyroidism: Combined free thyroid hormone index (FTI) and TSH; and hyperthyroidism/euthyroidism/hypothyroidism: T3, TSH, T4, FTI and T3U. The latter test combination had a total efficiency of 94%. Cholesterol, achilles reflex time, PBI and radioiodine uptake measurement contributed little to the discrimination.


Aldosterone in primary hypertension relationship to plasma renin activity and urinary electrolytes and a comparison with normotensive subjects.

Plasma aldosterone (PA) and urinary aldosterone (Aldo-U) concentrations were studied in 123 patients with primary (essential) hypertension during basal (1 h supine rest), upright and frusemide (80 mg orally) stimulated conditions, and were related to urinary sodium and potassium excretions, supine and sitting blood pressure (BP) and the relationship to plasma renin activity (PRA). As controls, 120 normotensive subjects, matched for age and sex, were investigated identically during strictly defined out-patient conditions. No differences regarding the different mean PA levels, urinary electrolyte excretion or the urinary sodium: potassium ratio were observed between the hypertensive and the normotensive populations. However, the hypertensive subjects had significantly higher mean Aldo-U excretions than the controls. Correlations between PA and the corresponding PRA were consistently significant in the normotensive control group but weak to non-existent in the hypertensive subjects. No relationships at all could be found between the different PRA and Aldo-U values in the hypertensive population but significant correlations were noted in the control group. These findings point to a disturbed function of the renin-angiotensin-aldosterone (RAA) system even in primary hypertension.


Determination of renal blood flow by thermodilution method.

The single bolus thermodilution method for measurement of renal vein blood flow was tested. In model experiments the thermodilution method was compared with graduated cylinder measurements over a flow range from 50 to 1050 ml/min. There was a good correlation between the two methods (r = 0.98) with a mean of differences of 5.2%. In eighteen patients measurements were performed in duplicate in thirty-one renal veins. Comparison was made between the first (x) and second (u) measurement--performed within 3 min. The correlation between the two was very good (r = 0.99; y = 1.03x - 11.48). In twelve patients bilateral renal vein blood flow measurements were performed simultaneous to blood flow measurement by PAH clearance. The correlation between total flow measured by thermodilution (y) and by the clearance method (x) was good (r = 0.98; y = 0.79x + 221). It is concluded that the thermodilution method requires catheterization of the renal veins, but is otherwise simple to perform, is inexpensive and gives reliable results. It is particularly advantageous when repeated measurements in the study of acute changes in renal haemodynamics is desirable.


Serological diagnosis of acute hepatitis B infection.

The value of different serological assays of hepatitis B virus associated antigens and antibodies was tested in forty-eight consecutive cases of acute hepatitis negative for HBsAg by agargel diffusion. The tests included radioimmunoassay of HBsAg, IgM and IgG anti-HBs and counter-immunoelectrophoresis for anti-HBc detection. Twelve cases were identified as hepatitis B (25%). Eleven cases were positive for HBsAg by RIA, and only one case was detected by an increasing titre of antibodies alone. Further seventeen patients had an unchanged antibody titre to one or more antigens. It is concluded that a sensitive test for HBsAg is the most important tool for diagnosing acute hepatitis B infection.


Determination of thiosulphate in urine.

A method is described for the determination of thiosulphate in urine. After removal of interfering compounds, including endogenous thiocyanate by ion exchange, thiosulphate is converted to thiocyanate in the presence of cyanide and cupric ions. The thiocyanate formed is concentrated by ion exchange, eluted with an acid solution of ferric ions and the ferric thiocyanate complex determined colorimetrically. Healthy human subjects excreted 31.7 +/- 12.8 mumol/24 h (mean +/- SD) thiosulphate.


Porphyrin production and liver involvement in a patient with erythropoietic protoporphyria.

The clinical and biochemical findings in a patient with erythropoietic protoporphyria are described. The patient had an extreme accumulation of protoporphyria in his erythrocytes and there was a thirty-fold increase in stool protoporphyrin. The patient also had elevated protoporphyrin in serum, bone marrow and liver. The porphyrins of the red blood cells, bone marrow and serum had fluorescence spectra different from that of the liver. Urine showed increased copra-, hepta- and uroporphyrins. Ferrochelatase activity in the bone marrow was less than 20% of that of non-porphyric controls. In spite of the extremely high levels of red cell protoporphyrin, the patient was clinically healthy with modest changes in liver function tests and liver histology. The results are discussed in relation to the development of liver damage and the recent findings of the effect of porphyrins on cell metabolism.


Skeletal muscle characteristics and carbohydrate metabolism after glucose loading in hypokalaemic periodic paralysis.

A prolonged glucose load was administered to four patients with hypokalaemic periodic paralysis and four healthy control sujbects. Muscle ATP and CP concentrations as well as lactate dehydrogenase, hexokinase and phosphorylase activities were similar in those two groups, but succinate dehydrogenase was approximately 50% higher in the control muscles. Muscles fibre composition was almost identical in the two groups, whereas patients had a higher degree of capillarization. Complete muscle weakness was produced in all patients, accompanied by hypokalaemia. Glucose loading resulted in elevated insulin levels and a minor rise in blood glucose level was seen in the patients compared to the control subjects. Glucose loading decreased hexokinase activity in controls, but increased this in the patients. At similar times, muscle and blood lactate levels and blood pyruvate values were generally higher in the patients over the course of the experiment. Initial glycogen concentrations were higher in patients, but glucose loading did not result in greatly increased glycogen values. These data suggest that patients with hypokalaemic periodic paralysis have an enhanced metabolism of carbohydrates and that insulin seems to be an important factor leading to the onset of muscle weakness.


Muscle glycogen concentration during recovery after prolonged severe exercise in fasting subjects.

The influence of 12 h of fasting after prolonged severe exercise on the muscle glycogen concentration was studed in 5 normal subjects. The subjects exercised in the post absorptive state at 70% of max. Vo2 till exhaustion, then rested for 12 h. No food was allowed during recovery. Blood samples and muscle biopsies were obtained before exercise, immediately after the cessation of exercise, and after 2, 4, 6, 9 and 12 h of recovery. Muscle glycogen content decreased from 70.4 +/- 3.0 to 21.6 +/- 3.9 mmol glucosyl units/kg w.w. in response to exercise. After 4 h of recovery muscle glycogen had increased to 28.8 +/- 3.6 mmol glucosyl units/kg (P less than 0.025). During the next 8 h of recovery no further increase in glycogen concentration was observed. Mean plasma glucose concentration was observed. Mean plasma glucose concentration decreased from 5.25 +/- 0.16 to 4.37 +/- 0.18 mmol/l during exercise (P less than 0.001). No change in the plasma glucose level was observed during recovery. Immunoreactive insulin (IRI) concentration decreased from 15.9 +/- 1.0 to 10.2 +/- 0.5 micromicron/ml (P less than 0.001) during exercise, and remained at this level during recovery. It is concluded that some muscle glycogen repletion may occur after prolonged, severe exercise even under fasting conditions. It is suggested that this may proceed through an increased hepatic gluconeogenesis.


The kinetics of myoglobin in old volunteers and in patients with acute myocardial infarction.

Following pre-treatment with potassium iodide, [125I]myoglobin was administered intravenously to six old volunteers. Blood and urine samples were taken at regular intervals. Serum radioactivity was shown to be myoglobin-bound. Three rates of elimination were observed, with half-lives of 20 min, 3 h 20 min, and 18 h 30 min. The first two rates corresponded to distribution volumes of 5.2 and 211. The third rate was of zero order and had eliminated around 10% of administered radioactivity after 6 h. At this time 60% of administered radioactivity had been recovered from the urine. Around 80% appeared as non-protein bound 125I, while 10% was protein-bound. The latter fraction was not precipitable with antiserum against myoglobin, which suggests that this fraction was deconjugated globin. Only insignificant amounts were excreted as myoglobin. The elimination constants were larger than those found in patients with acute myocardial infarction (AMI), measured by the disappearance rate of endogenous myoglobin.


Factors limiting renal proximal tubular reabsorption at high glomerular filtration rate.

To examine the factors limiting proximal reabsorption, distal reabsorption was inhibited by continuous infusion of ethacrynic acid in anaesthetized dogs. During combined infusion of ethacrynic acid and 0.9% saline, autoregulation of renal blood flow is impaired and glomerular filtration rate (GFR) can be varied by lowering or raising renal perfusion pressure. During lowering of GFR reabsorption of bicarbonate, chloride and sodium varied in proportion to reduction in GFR (glomerulotubular balance), but during elevation of GFR the increase in the filtered load of all three ions was excreted and a maximal rate of reabsorption was approached. Administration of acetazolamide reduced the reabsorption of bicarbonate, chloride and sodium in the ratio 1:2:3, whether GFR was at control, reduced (74% of control) or increased (124% of control). Renal blood flow was 80--90% greater at high than at low GFR. These observations indicate that bicarbonate concentration increases along the proximal tubules during elevation of GFR, until plasma bicarbonate concentration is approached at the distal end of the proximal tubules. From then on, bicarbonate reabsorption cannot be further raised by increasing GFR. Proximal tubular sodium reabsoption reaches a maximum at high GFR because NaCl reabsorption varies in proportion to bicarbonate reabsorption.


The applicability of the thermodilution method for determination of pulmonary blood flow and pulmonary vascular resistance in infants and children with ventricular septal defects.

The thermodilution method is accepted for measuring cardiac output in adults without shunts. It has been shown to work in animals the same size as newborn infants and has recently been used in children with congenital heart defects. We have proved its clinical applicability in determining the pulmonary blood flow, in twenty-five infants and children with VSD. The pulmonary vascular resistance can be calculated more accurately than by the Fick principle with an assumed O2 consumption, which has often had to be done in earlier studies.


Change in P wave terminal force and systolic time intervals during exercise in patients with coronary artery disease.

P wave terminal force (Ptf) and systolic time intervals (STI) were determined non-invasively from electrocardiogram, phonocardiogram and carotid pulse wave in fifteen men with coronary artery disease, before and during exercise. Left ventricular end diastolic pressure (LVEDP) and stroke volume (SV) were determined at catheterization simultaneously with the non-invasive recordings. Pre-ejection period (PEP) shortened in eleven patients, left ventricular ejection time (LVET) shortened in eight and Ptf and PEP/LVET decreased in ten patients during exercise. Ptf was significantly correlated to LVEDP both at rest (r = -0.66) and during exercise (r = -0.79). The change in Ptf and LVEDP was less correlated (r = -0.52). The change in LVET (r = -0.50), the change in PEP (r = 0.62) and in the index PEP/LVET (r = 0.65) was correlated to the change in SV. The use of both Ptf and STI may be of value in estimating left ventricular function during exercise in patients with coronary artery disease.


Radioimmunoassay of triiodothyronine and thyroxine in capillary blood.

A radioimmunoassay technique for the estimation of T3 and T4 levels in capillary blood is described and evaluated in comparison to a simultaneously drawn and equally analyzed sample from the cubital vein. A total number of 236 samples thus received from the capillary and the vein from euthyroid, hypo- and hyper-thyroid patients were collected. For both T3 and T4 a good correlation (r = 0.94) was obtained. The clinical implication would especially be for paediatric practice.


Endoscopic retrograde cholangio-pancreatography in pancreatic cancer and chronic pancreatitis. Differences in morphologic changes in the pancreatic duct and the bile duct.

The radiological findings in ERCP in 49 patients (ERP 49 patients and ERC 24 patients) with pancreatic diseases were evaluated blindly (24 patients with chronic pancreatitis and 25 patients with pancreatic cancer as a final diagnosis). Obstructions of the main pancreatic duct were found in 16 out of 24 patients with chronic pancreatitis and in 24 out of 25 patients with pancreatic cancer. Irregularity of obstructions was seen significantly more often in patients with cancer. Cholangiography demonstrated obstructions of the distal part of the common bile duct in both groups of patients, but irregularity of obstructions was exclusively seen in the cancer group. Though characteristic radiological features were demonstrated, a safe diagnosis must probably still rely on biopsy.


Passage of molecules through the wall of the gastrointestinal tract. I. A simple experimental model.

We describe here a simple experimental model for studying how the structural integrity of the intestinal wall is related to the transmural passage of molecules into the circulation. The model is based on the deposition of fluorescently labeled dextran in the intestine and its eventual recovery in the portal blood and mesenteric lymph. The fluorescent compound can be determined with sensitivity and ease by using fluorescence spectrometry. As judged from chromatography on Sephadex G-100, the compound was not degraded or otherwise chemically altered on its route of passage. The rate of passage was inversely proportional to the molecular size. The model may prove useful for studying factors that influence the transmission of macromolecules across the intestinal wall. Such a transmission probably underlies the pathogenesis of a variety of diseases.


Malabsorption of fat and vitamin B12 before and after intestinal resection for Crohn's disease.

Intestinal absorption of fat and vitamin B12 was studied prospectively in 136 patients with Crohn's disease localized to the ileum and/or the colon. Fecal fat was measured in 3-day periods on a high fat diet, and vitamin B12 absorption was assessed by the Schilling test. When related to the extent of the ileal disease there was a poor correlation to both fecal fat excretion and the result from the Schilling tests, but an exponential and highly significant correlation was found between the results of both tests and the length of the resected ileal segment. Accepting a change in either direction not exceeding 10% of the preoperative test value as unchanged, three-fifths of the patients deteriorated and one-fifth improved in fat-absorption, whereas half the patients deteriorated and one-third improved in vitamin-B12 absorption after surgery. When related to the length of the ileum resected, the test results were about the same in patients subjected to a restorative procedure sparing the major part of the colon and in ileostomy patients. Absorption of fat and vitamin B12 did not change with time elapsing from operation, indicating that there were no compensatory mechanisms as regards absorption of these substances.


The inhibitory effect of secretin and glucagon on pressure responses to cholecystokinin-pancreozymin in isolated guinea-pig stomach.

Pressure responses in guinea-pig antral and fundal pouches were investigated in vitro. Secretin and glucagon in concentrations that did not significantly alter spontaneous activity significantly reduced antral responses to cholecystokinin, but had no depressive effect on the fundal responses. The antral inhibition of CCK-PZ may be specific, since responses to acetylcholine were unaffected by secretin and glucagon. The changes produced by secretin and glucagon in the antral dose-response curve to CCK-PZ suggest that the inhibition might be of a non-competitive type.


The endoscopic, radiological, and surgical findings in chronic duodenal ulceration.

A prospective study of the endoscopic, radiological, and surgical features of chronic duodenal ulceration has been performed. Double contrast barium meal and upper gastrointestinal endoscopy were both performed within five days of elective surgery for chronic duodenal ulceration on 50 patients. The surgical diagnosis correlated with endoscopy in 88% and radiology in 82%, but if both techniques were employed, an accurate pre-operative diagnosis was achieved in 96% of cases. There was poorer correlation in determining the position of the ulcer within the bulb, with only 41% correlation between all three parameters and complete disagreement in 24%. Surgery correlated with endoscopy in 71% but with radiology in only 41%. The correlation between endoscopy and surgery in the diagnosis of duodenitis was only 42%, suggesting that this should be a histological diagnosis. This study suggests that endoscopy is slightly more precise than radiology in the diagnosis of chronic duodenal ulceration, but with a combination of the two techniques almost 100% accuracy can be achieved.


Fecal beta-sitosterol in patients with diverticular disease of the colon and in vegetarians.

Fecal sterol analysis showed that excretion of beta-sitosterol, a major component of poorly absorbable dietary vegetable sterols, is subnormal in patients with diverticular disease of the colon. Thus, the patients had evidently consumed a diet low in plant materials. The finding agrees with the current opinion that diverticular disease of the colon is associated with dietary fibre deficiency and suggests that fecal beta-sitosterol provides a rough measure of the vegetable intake. In vegetarians the beta-sitosterol excretion was actually high.


Enteric hyperoxaluria: dependence on small intestinal resection, colectomy, and steatorrhoea in chronic inflammatory bowel disease.

The importance of intestinal resection, exclusion of the colon, and steatorrhoea for secondary hyperoxaluria was studied in 81 patients with Crohn's disease and 12 patients with ileostomy after colectomy for ulcerative colitis during a metabolic regime including a fixed oral supply of fat, calcium, and oxalate. Hyperoxaluria (greater than 48 mg (greater than 0.5 mmol) per 24 h) was present in 21 patients with Crohn's disease. All but one half or more of the colon preserved. Renal oxalate excretion was related to the amount of ileum resected. 14C-oxalate absorption was significantly higher in patients with ileal resection and the whole colon preserved than in patients with ileal resection plus hemicolectomy, despite the fact that the latter group had the most extensive ileal resections. Faecal fat and oxalate excretion agreed well in patients without ileostomy (r = 0.76, p less than 0.001), and renal oxalate excretion was significantly higher in patients with steatorrhea and the colon preserved than in patients without steatorrhoea. In all 93 patients 14C-oxalate absorption and renal oxalate excretion was positively correlated with a coefficient of correlation of 0.76 (p less than 0.001). No correlation was present between 47Ca- and 14C-oxalate absorption. The study confirm that a preserved colon is necessary for secondary hyperoxaluria and stresses the importance of ileal resection and steatorrhoea.


Obstructive jaundice in pancreatitis investigated by percutaneous transhepatic cholangiography.

Obstructive jaundice is a rare complication of alcoholic pancreatitis. In three patients with persistent jaundice, percutaneous transhepatic cholangiography demonstrated either stenosis and dislocation of the common bile duct due to pancreatic pseudocysts or stenosis due to pancreatic fibrosis. These stenoses were easily differentiated from obstructions due to tumours or common duct stones. We suggest that percutaneous transhepatic cholangiography is valuable in pancreatitis with jaundice.


Stereomicroscopic examination of stained rectal biopsies.

The normal mucosal surface morphology in the rectum has been described by investigation of 15 rectal biopsies using a semimacroscopic technique. The structures of the mucosal surface were rendered visible by staining the biopsies as whole mounts with Alcian Green. A regular pattern of the crypt openings was found, and the goblet cells were observed in and just around the crypt openings. The density of crypt openings was calculated as the number of crypt openings per square millimetre (104 +/- 23 openings per mm2, mean and S.D.). Histologic examinations of the same biopsies were performed, and the density of crypt tubules was calculated from serial, horizontal sections (130 +/- 34 tubules per mm2, mean and S.D.). The ratio of crypt openings/crypt tubules was 1:1.25, indicating some branching of the mucosal glands in the rectum.


Experimental studies on fluid pathophysiology in small intestinal obstruction in the rat. V. Effects of intraluminal hyperosmolality and simultaneous intravenous infusions on the experimentally obstructed and decompressed small intestine.

An influx of fluid into the lumen of the intestine similar to that seen in simple obstructional ileus may be provoked by introducing a hyperosmolal glucose solution into the bowel. In the otherwise intact small intestine the effect of this influx of fluid will be in accordance with a simple dilution curve. The intestinal mucosa thus functions in the manner of a semipermeable membrane permitting only hypo-osmolal fluids to enter the intestinal lumen and in amounts independent of parenteral fluid infusions, regardless of osmolality. This relationship persists even after the intestine has been totally obstructed for 3 days. The influx of fluid has the same principal characteristics, and the only limiting factor on the magnitude of this fluid shift to the intestine is the lack of fluids resulting from the marked dehydration of the organism due to ileus. Prerequisites for this are normal epithelial function and normal mucosal circulation. Thus it is clear that the organism in general and the small intestine in particular, even when exposed to prolonged obstruction, are still able to counteract intraluminal hyperosmolality by dilution with hypo-osmolal fluid.


Indomethacin treatment of acute experimental pancreatitis in the rat.

Indomethacin given orally or intramuscularly before or shortly after induction of acute sodium-taurocholate or olive-oil-induced pancreatitis in rats reduced the lethality. Neither the enzyme content of serum, ascites, and pancreatic tissue nor the damage to the organ itself were changed under the influence of indomethacin. Thus a modification of systemic effects of acute pancreatitis may be responsible for the beneficial effect of indomethacin.


Cimetidine treatment of protein-losing gastropathy (Ménétrier's disease). A clinical and pathophysiological study.

In a 47-year-old male with Ménétrier's disease (protein-losing gastropathy) the histamine-H2-receptor antagonist Cimetidine stops the protein loss and improves the clinical condition. Gastric perfusion studies on net and bidirectional ionic fluxes, protein secretion rates, and permeability, with simultaneous recording of the transmural electrical potential difference indicate that Cimetidine decreases a paracellular protein secretion by 'tightening' the tight junctions of the gastric epithelium.


The secondary cytotoxic response to trinitrophenyl (TNP) modified syngeneic lymphocytes: effectors generated in vitro differ from those generated in vivo.

Following priming in vivo, a secondary cytotoxic response to TNP modified syngeneic lymphocytes can be generated by restimulation either in vivo or in vitro. The secondary effectors generated in vivo show H-2 restricted cytotoxicity, in that only TNP modified syngeneic targets are lysed. However, the secondary effectors generated in vitro lyse both TNP modified syngeneic targets and TNP modified congenic targets which differ only at the major histocompatibility complex.


Comparison of the effector cells in human spontaneous cellular cytotoxicity and antibody-dependent cellular cytotoxicity: differential sensitivity of effector cells to in vivo and in vitro corticosteroids.

The effector cells mediating antibody dependent cellular cytotoxicity (ADCC) and spontaneous cellular cytotoxicity (SCC) in humans have been reported to possess similar characteristics. Multiple cell separation techniques were employed in an attempt to physically separate and distinguish the effector cells in these two types of cellular cytotoxicity. Subpopulations of mononuclear cells obtained by a variety of fractionation procedures which either enriched or depleted monocytes, lymphocytes bearing a receptor for sheep erythrocytes (SRBC), a receptor for complement (CRL) or an Fc receptor for IgG always had similar effects on both ADCC and SCC. Aggregated gamma globulin blockade of Fc receptors produced similar dose-dependent depressions of ADCC and SCC. Despite our inability to physically separate the effector cells of ADCC and SCC, administration of in vivo dexamethasone caused a relative increase in ADCC but a profound decrease in SCC. Furthermore, in vitro dexamethasone in pharmacologic and suprapharmacologic concentrations caused no change in ADCC but significantly decreased SCC. This study demonstrates that although the effector cells cannot be physically separated, ADCC and SCC are differentially sensitive to corticosteroids and are hence functionally distinct either on the basis of different subsets of effector cells with similar surface markers or different mechanisms of cytotoxicity by the same effector cell.


Corynebacterium parvum-induced peritoneal exudate cells with rapid cytolytic activity against tumour cells are non-phagocytic cells with characteristics of natural killer cells.

Peritoneal exudate cells taken from mice 3 days after intraperitoneal treatment with Corynebacterium parvum (Cp) have been shown to kill specifically certain tumour targets in vitro. We have analysed in detail such Cp-induced cytotoxic cells as to their cellular characteristics, considering the fact that size and charge characteristics of cellular subgroups are useful markers in describing their representative characteristics. We could thus show that the cytolytic cell could not be classified as a macrophage. They behaved, in every manner analysed, exactly as the previously defined natural killer cells found in the lymphoid organs of normal mice.


Lymphocyte subpopulations in man: no selective loss during isolation from defibrinated blood.

Human lymphocytes isolated from defibrinated blood are characterized especially in relation to the total yield of lymphocytes and their subpopulations identified by membrane markers. The defibrination per se gives a significant loss of monocytes and granulocytes but no loss of lymphocytes, indicating that no selective loss of lymphocytes occurs. In a comparison of heparin-stabilized and defibrinated blood no difference in yield is found during every single step of the isolation procedure. Quantitation of E-RFC and SmIg-positive lymphocytes gives no differences in comparing the respective isolated suspensions of mononuclear cells. The observed difference in EA- and EAC-RFC can freely be ascribed to the difference in monocyte contamination. Further, no correlation is found between total lymphocyte yield and the relative number of the subpopulations identified, i.e. E-RFC, SmIg-positive, Fc-receptor- and complement-receptor-bearing lymphocytes. Hence it is concluded that defibrinated blood is optimal as blood source for the isolation of mononuclear cells when lymphocyte subpopulations are studied and enumerated.