Candidosis: the most common postmortem cerebral mycosis in an endemic fungal area.

To determine the recent postmortem character of cerebral mycoses, 1,752 consecutive complete autopsies done in the endemic fungal area of central Kentucky from 1964 through 1973 were reviewed. Fourteen patients (0.8%) had histologically confirmed fungal infections in the brain. The most prevalent fungus was Candida spp. which was observed in six patients. Cryptococcosis was recognized in three patients; histoplasmosis in two; zygomycosis in two; and blastomycosis in one. In every patient these fungi were also seen in tissues outside the central nervous system and were identified microbiologically in nine. Unlike the pathogenic yeasts, Candida spp. and the zygomycetes produced intracerebral lesions without any significant meningeal reactions. Cerebral candidosis was recognized only at autopsy in patients compromised by previous multiple antibiotic therapy for gram-negative infections. On the other hand, immunosuppression was associated more commonly with the non-candidal fungal infections. An experimental model for systemic candidosis in adult Sprague-Dawley rats likewise demonstrated its difficult antemorten recognition even with cerebral lesions. Although clinical consequences from candidemia seem often inapparent, the associated intracerebral lesions may further compromise the altered host. Their frequency and significance remain to be elucidated.


Spinal cysticercosis.

Cysticercosis of the spinal cord is rare. A case is reported in a 40-year-old Hindu. Compression of the spinal cord by the cyst which was located in the arachnoid membrane resulted in a paraplegia. Removal of the cyst resulted in marked improvement.


Use of air bubble illuminator as an adjunct for surgery in the sitting position.

The use and construction of a simple device to illuminate air bubbles in an intravenous tubing connected to the right atrial catheter when air embolism is suspected is described. This had been effective in clearly demonstrating even small air bubbles in more than 25 cases.


Cerebral arterial spasm. Part 8: The treatment of delayed cerebral arterial spasm in human beings.

Three patients who had neurological deficits from delayed cerebral arterial spasm following rupture of posterior communicating artery aneurysms were treated with continuous, simultaneous, intravenous injections of phenylephrine and nitroprusside. The results were determined by cerebral angiography before and after treatment. A dramatic increase in the cross-sectional area of the large cerebral arteries was found after treatment. The clinical implications of this treatment are discussed.


Microsurgical pterional approach to aneurysms of the basilar bifurcation.

The authors describe a microsurgical frontolateral pterional approach to aneurysms of the basilar bifurcation. Results of surgery in 38 patients are presented.


Intra-aneurysmal pressure difference in human saccular aneurysms.

Intra-aneurysmal pressure and piezometric head differences with respect to common carotid values have been recorded by unidirectional and differential transducers in two patients undergoing craniotomy for aneurysms of the anterior communicating and middle cerebral arteries. Recordings were taken under normal systemic arterial pressure during temporary occlusion of the common carotid artery, during intra operative carotid arteriography and under controlled arterial hypotension. Predominance of the common carotid pressure head and piezometric head over the aneurysmal value was found in the two cases.


Decompressive craniectomy for the encephalopathy of Reye's syndrome.

Report of the successful use of a decompressive craniectomy for the encephalopathy of Reye's syndrome with increased intracranial pressure. The patient had failed to respond to all medical management.


[Dynamics of calcium metabolism in lactating cows when the calcium content of the rations is reduced (author's transl)].

From twenty-eight balance trials and supplementary findings on the state of health, milk production, body weight and composition of the bone, blood, saliva, milk, urine and faeces it is concluded that four cows of the Dutch-Friesian breed can conveniently live and produce for seven and, including the preliminary period, for sixteen months on a ration consisting of straw, potatoes and concentrates having an average calcium content (including calcium in drinking water) of 0.22 per cent (varying from 0.17 to 0.25 per cent) in the dry matter. There was found to be an inverse relationship between the calcium content of the ration and the absorption coefficient. The absorption coefficient of calcium ranged from 28.7 to 83.8 per cent when the calcium content of the ration varied from 0.44 to 0.17 per cent. For sixteen months, the calcium-phosphorus ratio of the ration varied from 0.4 to 0.8. Bone biopsy was successfully performed using a universal drill.


[A case of fowl cholera (Pasteurella multocida) in six-week-old broilers (author's transl)].

An outbreak of fowl cholera in a broiler-house with 6,000 six-week-old broilers is reported. The birds were affected with respiratory disease when they were four weeks old. Eight days after recovery, at an age of six weeks, 50 per cent of the birds were severly ill. The birds were reluctant to move and unable to drink. Four hundred birds died in one day. Post-mortem examination revealed marked swelling of the kidney and arthritis of all the hocks and knee joints in all fifteen birds studied. Pure cultures of Pasteurella multocida were isolated from all joints, the heart, the liver and the kidney. Treatment with chloramphenicol resulted in recovery of the birds which were slaughtered under the supervision of the Veterinary Services of the Ministry of Agriculture and Fisheries in the Netherlands. The disease was not observed in the two other broiler-houses on the same farm, which housed 11,000 and 12,500 broilers of the same age. The findings are discussed.


[Second examination in meat inspection (author's transl)].

A second examination at the expense of the party adjudged to be in error is based on Section 13 of the Meat Inspection Act in the Netherlands, which has been elaborated in Sections 51 and 51a of the Meat Inspection Order. The procedure to be adopted by the second veterinary-surgeon inspector, however, has not been stipulated. The need for clear instructions is stressed. The present paper was designed to promote objectivity and uniformity in second inspections to provide legal security for the owner of the slaughtered animal as well as for the first veterinary-surgeon inspector.


Effects of combined use of droperidol with pentazocine and with fentanyl on pulmonary hemodynamics.

The effects of droperidol combined with pentazocine and with fentanyl on the pulmonary hemodynamics were investigated in intact dogs anesthetized with urethanechloralose, and the results were compared with those of each analgesic alone. Mean pulmonary arterial pressure and pulmonary driving pressure remained almost unchanged after droperidol and pentazocine. Pulmonary vascular resistance decreased significantly, and pulmonary vascular compliance and its radium tended to increase. These results indicate that droperidol counteracts the vasoconstrictive action of pentazocine on the pulmonary hemodynamics. On the contrary, almost all the parameters of the pulmonary hemodynamics after droperidol and fentanyl changed to similar directions to those after fentanyl alone. Droperidol seemed not to modify but to exaggerate the pulmonary circulatory effects of fentanyl.


Positive chronotropic and negative inotropic effects induced by potassium chloride in the isolated canine atrium.

The effects of potassium chloride on inotropic and chronotropic activity were investigated in five isolated canine atrium preparations which were suspended in a bath and perfused with arterial blood from the carotid artery of the heparinized support dog. Potassium chloride administered into the cannulated sinus node artery in a dose range of 100 mug-1 mg produced a dose-related negative inotropic and a positive chronotropic effect. These effects were not influenced by treatment with either atropine or propranolol. From these results, it is concluded that potassium had a direct negative effect on atrial contractility and a direct positive effect on atrial rate.


Significance of Laurén's classification in chemotherapy of gastric carcinoma.

The effects of anticancer agents were studied on the basis of survival rates following surgery for gastric carcinomas in different histologic types of Laurén's classification. It was revealed that Laurén's classification would provide an index to the use of anticancer agents to a certain extent. Anticancer agents were effective against diffuse gastric carcinoma, and should therefore be intensively used for treatment of this malignancy. For female patients with diffuse gastric carcinoma, careful selection of adequate anticancer agents is highly necessary. Anticancer agents were less effective against intestinal-type carcinoma, and it would therefore be necessary to use anticancer agents on the aged male patients with this malignancy by taking his age and side effects of the agents into consideration.


Comparative studies on dysplasia of esophageal epithelium in four prefectures of Japan (Miyagi, Nara, Wakayama and Aomori) with reference to risk of carcinoma.

Distal two-thirds of the esophagus without macroscopically detectable malignant lesions from a total of 248 autopsy cases were examined for epithelial dysplasia on histological sections from serial blocks. The autopsy specimens had been obtained from Miyagi. Nara and Wakayama prefectures known for high incidence of esophageal carcinoma in Japan, and Aomori prefecture where the incidence of the disease is low. Epithelial dysplasia was classified into mild, moderate, and severe including carcinoma in situ according to the grade of epithelial atypism. Of 248 cases 91 (36.7%) had epithelial dysplasia and 30 (12.1%) had moderate and severe dysplasia. In one of the cases of severe dysplasia, in situ carcinoma was diagnosed. Lesions of dysplasia of the resected specimen were displayed in a diagram for the distribution of the abnormal epithelium. Cases of higher grade dysplasia tended more extensive in area and were slightly dominant in the distal third of the esophagus. Possible relationships of dysplasia with long-standing irritation to the esophagus and with precancerous lesions were discussed.


Pericentric inversion of chromosome No. 8.

Chromosome studies of an infant with multiple malformations were made by means of the trypsin-Giemsa banding as well as conventional Giemsa staining methods. The propositus showed 46, XY +3, -C, and it was indicated that the abnormal metacentric chromosome was induced by the pericentric inversion of chromosome No. 8, in which chromosomal breakage had occurred most likely at the bands 8p23 and 8q23. The probable formula of the inversion is 46, XY, inv (8) (p23q23). Karyotypic analyses of the parents revealed no abnormalities, and the inversion therefore occurred spontaneously. Clinical features of the porpositus are postulated to be caused by a loss of very small portions of the chromosomal material with the occurrence of the pericentric inversion.


Effect of immunization with an allogeneic tumor on the growth of primary methylcholanthrene-induced sarcomas in rats.

Making use of common antigenicity among allogeneic tumors, the immunotherapy against primary 3-methylcholanthrene(MCA)-induced sarcomas in rats was attempted. At the time when MCA-induced sarcomas reached approximately 1 cm in diameter, allogeneic Usubuchi sarcoma cells were injected 5 times into the subcutaneous tissue of rats. In most cases, inhibitory effect on the growth of the tumor was observed in the early period, but none of 29 cases treated resulted in final regression. Twenty-nine non-treated cases showed uniformly progressive growth from the beginning. This result seems to indicate the possibility of using allogeneic tumor(s) for the immunotherapy against human cancer.


Production of spontaneous diabetic rats by repetition of selective breeding.

This study was conducted under a working hypothesis that the repeating of selective breeding of normal rats with a slight impairment of glucose tolerance would produce spontaneous diabetes rats. This is the second report, 18 rats were selected by an oral glucose tolerance test from 211 normal Wistar rats obtained from an experimental animal farm. By the breeding 162 F1 rats were obtained. By the selective breeding in this way, 204 F2, 174 F3 and 215 F4 rats were obtained. The mean glucose tolerance curve became more diabetic with the increasing number of generations. The percentage of cases of a positive test for urine sugar during the glucose tolerance test increases with the number of generation. The results indicate the possibility of production of spontaneous diabetes from normal rats by the repetition of the selective breeding.


Morphometric studies on the rat liver in biliary obstruction.

The common bile ducts of the Wistar rats were ligated and severed, and liver biopsies were done weekly for 7 postoperative weeks. Light and electron microscopic specimens were prepared for the morphometric studies. The volume ratio of the hepatic parenchyma decline with the lapse of time after bile duct ligation. However, elevated mean sectional area of the nucleus, increased mitotic index and unchanged estimated weight of the hepatic parenchyma after biliary obstruction suggested that lost hepatocytes were compensated by regeneration. Mitochondrial swelling and curling of the cristae were noted in biliary obstruction in general. Moreover, both the number and volume ratio of the mitochondria were increased corresponding to the duration of biliary obstruction. These changes were interpreted as an adaptation process to mitochondrial dysfunction.


Increased peroxidase activity in Pendred's syndrome with hypothyroidism.

An 8-year-old boy with goiter and bilateral nerve deafness had a 46% discharge of radioiodine after thiocyanate administration. He was clinically euthyroid. Although the serum total T4 was low (2.4 mug/100 ml) and TSH was significantly high (181 muU/ml), the serum total T3 was normal (152 ng/100ml). It was considered that the increased release of TSH by the feedback mechanism in response to the low T4 resulted in a quite normal level of serum T3. The thyroid gland demonstrated a low stable iodine content, an increase in MIT/DIT ration and a decrease in iodothyronine. The thyroglobulin behaved normally in Sephadex G-200 chromatography and immunoreaction. Thyroid tissue exhibited increased peroxidase activity as measured by I3 formation. Increased peroxidase activity may be related to the observed increase in serum level of TSH.


Natural history of diabetes mellitus with special reference to age of onset and vascular complications.

Age and sex distribution of diabetics, seasonal incidence of diabetes, grade of hyperglycemia, frequency of vascular complications and daily living conditions were studied of 2771 diabetic patients experienced at five clinics. The cases consisted of 1587 male and 1184 female diabetics. The distribution of age of diabetes onset revealed that males predominate among diabetics but females predominate among child diabetics, and that the precentage of child was extremely low. This pattern was emphasized as characteristic of Japanese diabetic population. Distribution of fasting blood sugar at the diagnosis of diabetes was compared among the age groups of diabetes-onset and the results showed that percentage of the value exceeding 300 mg/100 ml was highest in the under 10 year-onset cases and decreased with age. The frequency of diabetic retinopathy and of ischemic ECG changes was analysed from the view point of age of diabetes onset and also the duration of the disease. The frequency of the retinopathy at the diabetes-onset was zero in the under 10 year-onset cases, 4.2% in the 10s-onset cases and increased with age. The longer the duration of the disease the higher the frequency of the retinopathy was. This increase along with the duration was most remarkable in the 10s- and 20s-onset cases and less remarkable in the 30s-onset cases. The retinopathy was significantly more frequent in female diabetics. Daily of the patients were studied by a questionnaire and the analysis of 1022 cases with diabetes of more than three years revealed that cases of patients working uneventfully and/or feeling fit were most frequent among the 30s- or 40s-onset cases and that cases of bed-disability were frequent among the cases whose diabetes was found in their twenties or younger. This study showed that the prognosis of the patients is quite different according to whether their diabetes occurred before of after 30 years of age.


Optic nerve innervation of so-called interneurons of the rat lateral geniculate body.

In urethane-anesthetized rats, neurons responding to electrical stimulation of the optic nerve (ON) with bursts of spikes were searched for in the region of the thalamic reticular nucleus close to the dorsal nucleus of the lateral geniculate body (LGBd). These neurons were identical with those which had been presumed to be inhibitory internerons (I-cells) of LGBd. Conduction velocityes of ON fibers innervating I-cells were determined by measuring differences in response latency between stimulations of two separate sites along the contralateral ON. The velocity ranged from 1.9 to 7.3 m/sec with an average of 4.6 m/sec, indicating that among the three groups of ON fibers with different velocities, only the slowest group is involved in activation of I-Cells. Calculation of synaptic delays revealed that one group of I-cells was excited monosynaptically and another, disynaptically. Experiments on rats with the visual cortex chronically ablated provided evidence that the disynaptically excited I-cells received ON impulses via axon collaterals of principal cells of LGBd. The region  of the thalamic reticular nucleus containing I-cells was found to receive inputs not only from the contralateral but also from ipsilateral ON.


Atrophie blanche examined with thermography.

Atrophie blanche developed in a 25-year-old man with systemic lupus erythematosus is reported. A thermographic examination was applied to estimate skin temperature, and the temperature was low on areas where lesions were distributed.


Errors of parameters of distribution functions for spherical bodies stochastically estimated on a random test plane.

The parameters of some distribution functions for the radius of spherical bodies randomly dispersed in a three-dimensional space can be estimated on a random test plane of unit surface area. In this estimation the set of measured Nao, delta and (delta2) or that of Nlambdao, lambda and (lambda2) is used. They are number of circles, arithmetical mean and secondary moment of circle diameters or number of chords delivered by intersection of a test line of unit length with circles, arithmetical mean and secondary moment of chord length, respectively. Provided that the region of measurement is sufficiently large, intraregional errors of these quantities expressed as the squares of coefficient of variation C are approximately: [C(Nao)]omega2=1/Nao, [C(delta)omega2=(32/3pi2)(Q3/Q2(2))(1/Nao) and [C(delta2)]omega2=(6/5)(Q5/Q3(2))(1/Nao); [C(Nlambdao)]omega2=1/MNlambdao, [C(lambda)]omega2=(9/8)(Q4Q2/Q3(2))(1/MNlambdao) and [C(lambda2)]omega2=(4/3)(Q6Q2/Q4(2))(1/MNlambdao). In these expressions Qn is a quotient defined by (Dn)/Dn, D and n being sphere diameter and a positive integer, respectively. The first three expressions may be used in these forms as the errors for the total region containing spheres. In the second three expressions M is the number of random test lines of unit length. When M is small, they can stand for the errors of the total region. In the case of large M, however, interregional errors or errors of sampling have to be added to them. The geometrical parameter of a distribution function of D is estimated from (delta2)/delta2 or (lambda2)/lambda2. The error of this ratio W is given by: [C(W)]2=[C(X2)-2C(X)]2, where X stands for delta or lambda.


Errors of parameters of distribution functions for spherical bodies stochastically estimated with parallel test lines of regular and narrow intervals.

The parameters of some distribution functions for the radius of spherical bodies randomly dispersed in a three-dimensional space can be estimated with a grating of parallel test lines of regular intervals superposed on a test plane of unit surface area. The interval of the test lines is set narrower than the mean diameter of the circles on the test plane. The errors of number Nlambdao of chords per test line of unit length, arithmetical mean lambda and secondary moment (lambda2) of the length of individual chords are: [C(Nlambdao)*]2=(4/9pi)(Q3/Q2(2))(1/M2lambdaNlambdao)+(4/pi)(lambda/Nlambdao), [C(lambda)*]2=(pi/4)[(32/3pi2) - 1](1/M2lambdaNlambdao)+[(4/pi)-(3pi/8)(Q2(2)/Q3)](lambda/Nlambdao) and [C(lambda2)*]2 = (1024/2025pi)(Q5Q3/Q4(2))(1/M2lambdaNlambdao)+4[(4/pi)-(3pi/8)(Q2(2)/Q3)](lambda/Nlambdao). The first and second terms of the right sides of these expressions represent intraregional and interregional errors, respectively; * denotes the error for the total region; M is the expectation of the number of test lines of unit length covering the test plane; and Qn a quotient (Dn)/Dn of sphere diameter D, n being a positive integer. Intraregional errors are inversely proportional to M2 with the grating, while they are inversely proportional only to M with random test lines. The use of regularly arranged test lines is consequently effective in minimizing intraregional errors.


[Radiosensitivity of malignant melanoma].

Based on case histories of 67 patients with malignant melanomas (14 primary tumors and 53 metastases to the lymph nodes) who underwent sole irradiation, the correlation between the total dose needed for a local healing and the period of treatment has been investigated. It appeared that excessively high doses are not necessary for healing. A dose of about 5500 rd in 35 days is regarded as sufficient. In long-term treatment, however, the total dose has to be increased more than, for example, with squamous cell carcinoma.


[Radiation pneumonitis and radiation fibrosis following systemic irradiation of thoracic lymph nodes in Hodgkin's disease].

146 of 226 patients suffering from Hodgkin's disease were submitted to a high voltage therapy in the chest using the method of single fields. In order to be in a position to judge the appearance and the development of a modification of the pulmonary parenchyma induced by radiations, the authors evaluated the data of 69 patients who could be checked up in relatively small intervals during at least one year after the radiotherapy. Dilatations of interpleural and hilar lymphomas or pulmonary infiltrates have to be considered as one of the most important causes of atypical pneumonia and fibrosis induced by radiation. 12 patients out of 35 (i.e. 35,3%) with intrathoracic lymphomatosis granulomatosa presented atypical pneumonias which mostly were not very serious, and four patients (i.e. 11,8%) had fibroses. If the mediastine was irradiated systematically for the purpose of prophylaxis, no pulmonary reaction was observed that could be demonstrated by means of X-rays.


[Late recurrences in Hodgkin's disease following radiotherapy].

1. From 1950 to 1970, 92 patients with Hodgkin's disease stage I and II were treated by irradiation at the Universitäts-Strahlenklinik Marburg. Staging was performed without diagnostic laparotomy. More than a third might be staged wrong. 2. The over-all survival rates for both, stage I and II, are 65% after five years, 40% after ten years. 15% of the patients are expected to be cured. 3. Three late recurrences after 12 or 13 years are contradictory to the definition of cure in Hodgkin's disease, as a ten years lasting relapse-free interval after primary treatment. In two further cases lymphogranulomatosis developed 7 and 12 years after operation and irradiation of mediastinal tumors, which were histologically classified as lymphadenitis and polymorphcellular sarcoma, but here and there showed the features of lymphogranulomatosis. Two further cases of lymphogranulomatosis were seen with extraordinary long remissions of 11 and 17 years. 4. On the understanding that the primary tumor disease had been cured, we can look at the recurrences as at second tumor disease. Then a tumor-disposition in these patients must be discussed. 5. The occurrence of the prognostically advantageous histologic type of nodular sclerosis, the age of the patients between 27 and 37 years at the first manifestation of the disorder, and the tolerance of peripheral localisation of the tumor disease lead to the conclusion that histologic type and course show the ratio between tumor disease and immunologic situation of the patient. Probably, the histologic features might be the expression of this situation.


[Extracorporeal blood irradiation using telecesium apparatus. II. Morphological studies in patients with chronic lymphadenosis].

The second communication of our experiences with extracorporeal blood irradiation comprises a systematical investigation of the conditions in blood picture and, in one case, of the morphological findings within lymph node punctures, during long-term treatment of two selected patients with a rather different course of the disease. One of the cases showed a typical pattern of chronic lymphadenosis which was to be influenced fairly well; the other case revealed an aggressive tendency with only a feeble response to extracorporeal blood irradiation. By means of toluidine blue staining, until now being used for the verification of nucleoli and their different shapes only in experimentations on animals, a good correlation of the nucleole analysis in the peripheral blood picture and in the lymph node biopsies with the clinical progress of the disease has been observed. Thus, this simple cytological method combined with customary clinical examinations may serve as a criterion for the judgement on the course of the disease and on the therapeutic success.


[Results of combined drug and radiotherapy in bronchial carcinoma].

90 out of 191 patients with bronchial carcinomas were treated exclusively with telecobalt (focal dose ofer 4,500 rad), 78 patients were given an additional treatment with Proresid, and 23 patients were additionally treated with 5-fluorouracil under so-called synchronization conditions. As far as the Proresid is concerned, the combination with the chemotherapy did not bring about an amelioration of the survival rates compared to the results of the radiotherapy alone. The survival rate of the patients treated with cobalt 60 and with 5-fluorouracil even showed a considerable decrease, so that the described combination therapies are not longer used in our institute.


Radionuclide scanning of the spleen. Technical modification, normal variants and dimensions.

In order to cut down the time needed for the preparation of the thermally damaged erythrocytes, the effect of heat was combined with the use of a higher concentration of ACD. Heating of the 51Cr tagged red cells was performed in a water bath, at 50 degrees C for 15 minutes, in the presence of ACD in the ratio of one ml ACD for every 3 ml blood. Using this technique, the obtained splenic scans in 20 normal individuals were excellent in quality. In the posterior view, the spleen was oval with an oblique long axis in 65% of the cases and transverse long axis in another 15%. In the remaining 20% the spleen was globular. The average measurements of the spleen were 10.5 X 7,1 cm, with a circumference of 29.8 cm. By planimetry, the surface area of the spleen averaged (59 +/- 12.4) cm2 (Mean +/- 1 S.D.) In the lateral projection, the surface area of the splenic scan was larger by an average of 40% than the picture obtained through the posterior approach in all the six examined subjects.


Thermoluminescence dosimetry in clinical radiation dose measurements.

A simple method using thermoluminescent dosimeters (TLD) to measure the doses where large shaped fields are used as mantle, breast and chest wall will be described. Measurements of doses in the gastrointestinal tract while treating nasopharynx, postcricoid and upper third of esophagus as well as in the rectum while treating cervix with intracavitary radium will be also discussed.


Water (electrolyte) balance after abdominal therapeutic treatment.

Total body water, plasma volume and Na space have been studied in 34 patients receiving external radiotherapy on the pelvic region. Determinations were made on the same patients before, and half-way treatment; in a few cases, some determinations were also repeated after the end of treatment. The results failed to show any appreciable modification of the different parameters studied.


Effect of low dose x-irradiation on the succinate dehydrogenase activity of guinea pig, rat and mouse tissues.

The histochemical changes in succinate dehydrogenase (SDH) were investigated in pectoralis major muscle of guinea pig, rat and mouse after low level X-irradiation (72 R and 240 R) and compared with control animals. Biochemical studies were carried out on liver, kidney, muscle (pectoralis major), adrenal and spleen of these animals after low dose local X-irradiation and compared with control animals. Changes in SDH activity were studied up to 72-h post-irradiation, which shows that low dose local X-irradiation leads to increased enzymic activity. The increase in enzymic activity was remarkable in mouse tissues as compared with guinea pig and rat. Adrenals of all the three animals showed significant activation after all the doses of radiation studied. The significance of these results, with special reference to oxidative metabolism, has been discussed.


[Healing results of pseudomucinous ovarian carcinoma depending on therapy].

A report is given on 57 patients with pseudomucinous ovarian carcinomas. The prognosis of the disease depends on two decisive factors, if the FIGO stages are not taken into consideration: 1. the operation which should be executed as radically as possible, 2. the intraperitoneal instillation of radiogold which shall be repeated two times. The following therapeutic results were realized under this treatment: a five-year survival rate of 76,9% and a ten-year survival rate of 72.7%. There were no serious side-effects of the radiogold therapy since the introduction of routine peritoneographies before instillation of 198Au.


Use of a low-ionic-strength medium in manual tests for antibody detection.

The present observations confirm the value of suspending red blood cells in a low-ionic-strength medium in the first stage of the indirect antiglobulin test; that is, during the period of incubation with antibody-containing serum. The main advantage of this procedure is to shorten the time of incubation. In this respect a low-ionic-strength medium appears to be superior to albumin as a suspending medium for the red blood cells. A further advantage is to increase the uptake of certain antibodies; this effect was pronounced with selected Rh antibodies believed to be of low affinity.


Frozen autologous platelets in the supportive care of patients with leukemia.

Multiple units of platelet concentrate obtained by intensive plateletpheresis of patients with leukemia in remission were pooled and frozen using 4 to 5 per cent dimethylsulfoxide and retransfused during periods of thrombocytopenia. Plateletpheresis was well tolerated by all donors and an average platelet yield per unit of 0.99 X 10(11) (n = 155) was obtained. The results of 107 transfusions to 36 patients are presented. An average of 32.4 per cent of the platelets were lost during the freeze-thaw process. Freezing loss was lowest at a freezing rate of one degree C per minute, at a lower final concentration of platelets, and when polyolefin bags were used. The mean corrected posttransfusion count increment was 6,400/mul (range 600-19,000 xm2/10(11) platelets transfused). In vivo results did not correlate with freezing rate but were statistically significantly better at lower platelet (approximately 0.16 X 10(11) platelets/10 ml) concentrations. Eleven patients, including some who were refractory to random donor platelets were supported entirely with autologous platelets during reinduction therapy for leukemia. When administered prophylactically the autologous platelets seemed to prevent hemorrhage during periods of thromobocytopenia although in most patients bleeding times were not corrected posttransfusion. This study demonstrates that frozen autologous platelets can be used in the supportive care of thrombocytopenic patients. Further technical improvements are necessary before platelet freezing becomes practical for widespread use.


The significance of red cell bound complement components in development of standards and quality assurance for the anti-complement components of antiglobulin sera.

Human red blood cells, sensitized with complement in vivo and by a variety of methods in vitro, (e.g. blood group antibody, low ionic strength, alternate pathway), were tested with a battery of anti-complement sera (anti-C3, -C3c, -C3d, -C4, -C4c). Red blood cells could be prepared by relatively simple methods to yield cells sensitized with C3 and C4, C3 but not C4, C4 but no C3, C3d with no C3c and C4d with no C4c. These cells are suitable for standarization and quality assurance of antiglobulin sera (AGS). Anti-C3d is necessary for optimal detection of sensitization of red blood cells by complement in vivo by the direct anti-globulin test (DAT). Anti-C3d may also be optimal for the indirect antiglobulin test (IAT) especially if incubation periods greater than one hour are employed. Potent anti-C4 and anti-C3 antisera made in the authors' laboratory resulted in numerous weakly positive antiglobulin tests when testing red blood cells from refrigerated clots (especially anti-C4) but red blood cells from refrigerated anticoagulated segments gave negative results. When red blood cells were incubated in normal serum at room temperature (as in the room temperature phase of a compatibility test), some positive results were again obtained with the potent anti-C4 and anti-C3 antisera. However, one commercial antiglobulin serum containing anti-complement antibodies that were at least as potent as any other commercial antiglobulin serum gave uniformly negative results under the above conditions. Anti-C4 antibodies may be omitted from anti-globulin sera without decreasing the efficacy of such antisera to be used in compatibility testing. Thus, positive results in the compatibility test due to detection of clinically insignificant cold antibodies in the IAT by the anti-complement antibodies in AGS, may be avoided if anti-C4 is omitted or is in low concentration and if the concentration of anti-C3d is carefully standardized. A higher concentration of anti-C3d could be used for compatibility tests if red blood cells from anticoagulated segments were used instead of those from clots and if a separate tube were used for the IAT at 37 C rather than using one tube for both room temperature and 37 C incubations.


Ultrastructural damage of leukocytes procured by the Leukopak: vulnerability of leukocytes to mechanical injury.

Because of the often observed undesired effects in patients transfused with leukocytes collected by continuous filtration leukapheresis (CFL), we have investigated the morphology of these cells in the hope that such studies may help evaluate their in vivo functions. Aliquots of CFL samples, procured by the Fenwal Leukopak and taken before and after tapping the filters, were examined. Leukocytes prepared by dextran sedimentation served as controls and were used to demonstrate the vulnerability of these cells to mechanical injury. The morphology of leukocytes harvested by filtration leukapheresis was markedly altered, ranging from formation of cytoplasmic projections and vacuoles to disintegration of entire cells. The severe changes were only observed in samples collected after the filters were tapped. The number of cells involved varied from donor to donor. In some cases more than half of the examined leukocytes showed signs of damage. Dextran sedimentation leukocytes retained their normal ultrastructure. However, substantial injuries were inflicted on dextran sedimentation collected leukocytes following brief periods of vortexing. Our results indicate that leukocytes are quite vulnerable to mechanical injury, and the major cause of damage found in Leukopak-isolated leukocytes is the tapping of the filters. The toxic reactions in some recipients transfused with Leukopak-collected leukocyte preparations may result from materials released from disrupted leukocytes. We believe that the employment of the continuous filtration to procure leukocytes with the present procedure should be reviewed.


Statewide support of thrombocytopenic patients with ABO matched single donor platelets.

Use of ABO matched, HLA nonmatched platelet units obtained from single donors by pheresis, using the Haemonetics 30 Cell Separator, has a lowered hepatitis risk, and possibly delays the onset of the refractory state. Pheresis also offers a method of obtaining HLA matched platelets for the already refractory patient. A mean of 4.2 X 10(11) platelets are collected in about 1 1/2 hours. ABO matched, HLA nonmatched platelets produced corrected increments of more than 2500/mm3 per 7 X 10(10) platelets infused in 67 per cent of transfusions to nonselected recipients. The procedure is simple, safe, and requires little time. It is a worthwhile large-scale program for a regional blood center to undertake in order to provide optimal therapy for thrombocytopenic patients.


Preparation of antihemophilic factor from indated plasma.

Four large-scale batches of Antihemophilic Factor (AHF, factor VIII) were prepared from plasma derived from 4 to 6-day-old blood applying a method developed for preparation of AHF from fresh frozen plasma. The AHF product was 6 to 9-fold concentrated over plasma with 7 to 10-fold purification and a recovery of 100 to 140 factor VIII units per liter of starting plasma. In terms of purity and yield, this is about half that of AHF obtained from fresh frozen plasma. The AHF concentrate was free of detectable thrombin and plasmin and the solubility of the dry product was comparable to that of the product derived from fresh plasma but the hemoglobin content was slightly increased. After further fractionation with polyethylene glycol (PEG 4000), a highly soluble AHF product 100-fold purified, and 30-fold concentrated, was obtained with 60% factor VIII recovery, which corresponds to a final yield of 60 to 85 factor VIII units per liter of starting plasma.


Additional studies concerning the metabolism of packed erythrocytes in CPD adenine.

Studies concerning the relationship between glucose level, hematocrit to which cells were packed (within three hours of initial collection) and adenosine triphosphate (ATP) concentration were undertaken in CPD supplemented with adenine (0.25 mM final concentration). It was found that apparently adequate ATP levels could be maintained in 90 per cent hematocrit packed units at 42 days only if glucose was present in amounts 1.5 times or greater than that provided by CPD. Less tight packing of the units to 70 and 80 per cent hematocrit maintained ATP at greater than 50 per cent of the initial level for a full 42 days of storage when 1.25 times the usual glucose concentration was present in the initial anticoagulant. No difference in 2,3-diphosphoglycerate or pH was found in any of the modified media under study.


Delayed overt hemolytic transfusion reaction due to anti-U antibody.

A patient is described who developed a delayed hemolytic transfusion reaction, 11 days posttransfusion, caused by anti-U. This case illustrates the difficulty that can occur in distinguishing a delayed transfusion reaction from autoimmune hemolytic disease when the antibody involved is directed against a high incidence blood group antigen.


Anti-Rd (Radin) following the transfusion of a Radin positive unit of blood.

Anti-Rd (Radin) was first described in association with five cases of hemolytic disease of the newborn. The authors report an anti-Rd that was demonstrated following the transfusion of a Radin positive unit of blood. The antibody appears to be of the IgG immunoglobulin class and increased in titer following the transfusion.


A walking blood donor program for seriously ill premature infants.

Premature infants with hyaline membrane disease and related disorders are frequently hypovolemic. Furthermore, they frequently require repeated phlebotomies for laboratory evaluation of electrolytes, pH, oxygen tension, and other parameters. Adequate care of such infants is aided by small transfusions of heparinized blood. The walking donor program at the Sacramento Medical Center premature nursery furnishes these transfusions without exposing the infants to the hazards of receiving blood from many different donors. The program is described in detail, and the shortcomings of some of the alternative programs are pointed out.


[Morphochemical differentiation of neurons of the lateral geniculate body of the rabbit brain following early visual deprivation].

To study the propertes of the external geniculate body neuron's protein concentration and protein content were measured cytophotometrically in the cytoplasm of the above neurons in normal and visual deprivided animals 2.5 months after the birth. The results obtained suggest the increasing of protein concentration and protein content in the cytoplasm of neurons and the decreasing of protein concentration in surrounding structures. These changes varied depending on the neuron volume during the deprivation. It is supposed, that some groups of neurons exist in the external geniculate body with different degrees of specificity in respect to vision impulsation. Mechanisms of a possible rearrangement of the neuron metabolism in the external geniculate body during the deprivation are discussed.


[Loosely bound proteins and membrane ultrastructure of erythrocyte ghosts].

The loosely bound erythrocyte ghost proteins, extracted by distilled water, 5 mM EDTA, tris-HCI buffer at pH 8.5, veronal-acetate buffer at pH 8.5 and by a 1.5% solution of acetic acid, were studied electrophoretically using a polyacrilamid gel with 0.1% sodium docecyl sulphate. 20% proteins with m.v.12 000-120 000 polypeptid chains were released from ghosts transferred from phosphate buffer to distilled water. 5 mM EDTA extracts, in addition, a m. w. 215000 protein. The increase of the negative change brought about the extraction of proteins of the molecular weight equal to 12 000-250 000. After extraction of 12% or more loosely bound proteins the reduction of membrane-attached materials was seen with the electron microscope. Shifts of pH from 6.3 to 7.4 and the treatment with 5mM EDTA resulted in reduction of the premembrane material, ghosts sticking together after the latter procedure.


Optimizing recovery of platelets in platelet rich plasma by the simplex strategy.

A Simplex is an empirical, geometric feedback strategy which progressively programs a series of experiments according to the results of the preceeding experiments. It leads to definition of conditions which maximize or minimize the result of experiments in two or more variables. When applied to study a laboratory method it dictates simultaneous variation of the conditions of an experiment, differing from the usual approach in which variables are altered sequentially and arbitrarily. A two variable Simplex (force and duration of centrifugation) has been applied to maximize platelet recovery in platelet rich plasma (PRP). The technique of Simplex is described. Maximal recovery of platelets in PRP was reached by centrifugation at 2160 X g for 2.7 minutes. To confirm the correctness of this result, platelet concentrates were prepared from PRP's separated by three different methods: 1) conditions determined by Simplex, 2) American National Red Cross recommended method (2820 X g for two minutes), and 3) Canadian Red Cross recommended method (995 X g for nine minutes). Mean recovery of 78 per cent was obtained by Simplex, significantly higher than 61 per cent with the American National Red Cross method (p greater than .005) and higher than 69 per cent with the Canadian Red Cross method. Simplex strategy is recommended as a simple, powerful technique for determining optimal experimental or laboratory conditions.


[Comparison of the electrical and isotope characteristics of ionic transport through bilateral phospholipid membranes].

Simultaneous measurements of electrochemical characteristics and tracer  fluxes have been made using large spherical bilayer lipid membranes (1-2 cm2 area). The results obtained show the predominant contribution of electrically silent chloride molecules to the fluxes through unmodified membranes. In cases of valinomycin modified (valinomycin concentration=10(-7)M) membranes (in 0.1 M solutions of KCl, RbCl and CsCl) the fluxes are determined exclusively by cations. The membrane permeability for 22Na, in 0.1 NaCl solution, does not depend on the valinomycin concentration. The selectivity sequences obtained by electrochemical and tracer methods are compared and discussed.


[The "anomalous" relationship between the concentration of potassium in the medium and the membrane potential of muscle fibers with a decreased intracellular potassium concentration. III. Change in the membrane potential during prolonged muscle incubation in saccharose-sulfate media containing 2.5 or 75 mM of potassium].

At the external potassium concentration 2.5 mM, The value Em--Ek diminishes, but at 75 mM it increases, although the potassium fluxes are nearly balanced and nosignificant changes in internal potassium occur. The contribution of other ions to the electrogenesis is examined. An attempt is made to describe the movement of these ions by the Goldman equations. The permeability coeficients should have been much higher than potassium coefficient, and besides it should be admitted that the coefficients and the internal activity of ions discussed may vary with time.


[Bone marrow cells of mice immunized with different rabies vaccines].

Cytogenetic studies of bone marrow cells of mice after inoculated differently with viral vaccines (fixed rabies virus, antirabic vaccine with the remainder virulence and fully inactivated with ultraviolet light antirabic vaccine) showed that all the vaccines, except the fully inactivated one, caused temporary damages of chromosomes interfering with the process of the first mitotic divisions after the beginning of immunization. The live fixed rabies virus caused a secondary, more significant increase in the frequency of chromosome aberrations at later periods of investigation (30-60 days after starting the experiments). The fluorescent antibody technique detected the specific fixed rabies virus antigen in the bone marrow cells of immunized animals within 3-90 days.


The maximum surgical blood order schedule and surgical blood use in the United States.

The outdating of units of blood can be reduced by decreasing the amount of time they spend in an assigned or crossmatched status. This reduction can be achieved in a hospital by establishing a maximum surgical blood order schedule (MSBOS) which reduces the excessive number of units of blood crossmatched preoperatively for patients undergoing elective surgery. The various steps which occurred in the development of a MSBOS in a large general hospital are detailed and the projected reduction in the number of crossmatched units which can be achieved with the MSBOS is illustrated. illustrated. The projected number of units of blood transfused to patients during their hospitalization for 50 common primary surgical procedures in the United States during 1974 is presented as a basis for defining maximum blood orders for each procedure.


Motivation of voluntary plasmapheresis donors.

A totally voluntary plasmapheresis program recruits 900 individual donors per year at a cancer institute, where 500 to 900 units of platelets are transfused each month. Staff and donors use a film and brochures to recruit donors from the local community. Television and radio spots, with donor recognition pins, certificates, receptions, and picnics are utilized. Donor motivation was studied by use of: 1) California Psychological Inventory--measures a variety of "normal" personality traits; 2) Study of values--measures theoretical, economic, aesthetic, social, political, religious values; 3) Internal-External Control Scale--measures degree to which a person blames self vs. external events for what happens to him; 4) Faith in People Scale--measures individual's confidence in his fellow man; 5) Anomia Scale--measure of feelings of self-to-others alienation; 6) Mach IV Scale--measure of persons tendency to manipulate others; and 7) Biographical Data Form. Results are presented for 25 male donor subjects studied, as they compare with normative data for the scales used. Donors appeared to have the same traits as do the general population, but appeared lower in Machiavellianism than non-plasmapheresis donors. Prospective study plans include additional subjects to provide appropriate control groups.


[The effect of cycloheximide on DNA replication. II. Antibiotic resistance following L cell treatment with hydroxyurea].

DNA replication in eukaryotic cells is closely associated with protein synthesis. When protein synthesis is specifically inhibited, DNA synthesis stops quickly too. No precise knowledge has been so far available concerning the reasons of this coupling. The data presented confirm an earlier established for Chlorella fact that the inhibition of DNA synthesis in L-cells, due to a several hours treatment with hidroxyurea, results in a consequent stability of DNA synthesis in these cells to a protein synthesis inhibitor--cyclohexamide.


[Ultrastructural organization and distribution of synapses of different size of the neurosecretory cells of the carp preoptic nucleus].

With electron microscope two types of synaptic buttons (SB) are found on the nuerosecretory cells (NSC) in the nucleus preopticus of the mature carp. SB type I contain dense core vesicles and synaptic vesicles, whereas SB type II have only the latter. SB type II is considered to be functionally more active. The density of SB on the NSC body surface varied inversely proportionally to the NSC size, being in average 1.7+/-0.2 on the section of one small NSC in the ventral part of the nucleus preopticus, and 1.0+/-0.1 on the section of a large one in the dorsal part (P less than 0.05). In large NSC type II SB are found more frequent than in small NSC, the synaptic apparatus of NSC in the dorsal part of the nucleus preopticus is in a more active stage, than of NSP in the ventral part. The structural organization of the complex SB-NSC of large cells is more complicated compared to that of small cells. The large cells are supposed to be more differentiated and functionally more active. The synapses of NSC of the nucleus preopticus of the carp are supposed to belong usually to axons of monaminergic neurons.


[Lipid droplets and their possible pathways of origin in rat pituicytes].

Callan's hypothesis of the constant movement of the chromomere DNA axis was checked with the method of 3H-uridine radioautography. The hypothesis was not corroborated as the RNA synthesis proceeded in chromomeres of lampbrush chromosomes on the stationary axis with formation of transcriptional units. Data on localization and count of transcriptional units are discussed with regard to structural and functional organization of chromomere in meiotic chromosomes of eukaryotes.


[The effect of vitamin E and rancid fish liver oil on the spinal cord motoneurons of white rats].

Using the "August" white rats, the influence of alpha-tocoferol (5 mg dose per day per animal) and of its antagonist--rancid fish oil (5% ratio in the food) on the cytophysiological properties of motoneurones was studied. Tocoferol caused a functional exhaustion of motoneurones. The rancid fish liver oil caused abnormalities in the specific function of motoneurones. Vitamin E administered after castration brought about further removal of changes, evoked by castration, whereas the rancid fish liver oil introduced after castration was seen to enhance distrophical lesions.


[In vivo and in vitro cytospectrophotometric studies of DNA in the cells of human neuroectrodermal brain tumors].

A rather distinct correlation in the content and distribution of DNA with the grade of malignancy was estabilished for the following series: normal astrocytes, and oligodendrocytes, typical astrocyfomas and oligodendrogliomas atypical astrocytomas and oligodendrogliomas. For glioblastomas this correlation is impaired, because the polymorphic variant of glioblastoma is characterized by particularly great disturbances in the content and distribution of DNA in the form of polyploidy and aneuploidy which, in this case, reflects not only the grade of malignancy, but also a pronounced polymorphism of tumour cells. The content of DNA in rapidly growing malignant tumours is not only an expressions of real deviation to the side of polyploidy and the mitotic cycle. In neuroectodermal tumours growing in the condition of cell culture, the similar regularity was observed, although the phenomena of aneuploidy were more distinctly expressed in the majority of tumours.


[A cytophotometric study of granules forming in frog erythrocytes during incubation in solutions of neutral red and novocaine].

Granules arising in the cytoplasm of Rana temporaria erythrocytes incubated in solutions containing either a stain (neutral red) or an alcaloid (novocaini) were studied cytophotometrically. The stuff concentrations in the granules were estimated under various conditions of incubations. The stuff concentrations in the granules appeared to be dozens- or hundreds--fold higher than in the incubation solutions. The average concentration in the granules did not depend either on the initial concentration of the stuff solution, or on the incubation time or on the volume of the incubation solution. The stuff concentration in the granule decreases with the increase in the granule size.


[Physiologic regeneration of corneal epithelium following exposure to constant magnetic fields of super-high intensity].

The mitotic index of mouse corneal epithelium was studied during and after 0.5-- 24 hours exposures to 9.9-39.4 kilooersteds constant magnetic fields. It was shown that 0.5, 1 and 3 hours exposures to a 39.4 kilooersteds constant magnetic field  inhibited the mitotic activity whereas 8 and 24 hours exposures caused its stimulation. The value and rate of mitotic index alterations decrease with a decrease of field strength. No changes were found in the frequency of aberrant mitoses or in the number of cells per one field of microscopic vison.


[An electron microscopic study of the interaction of polarized neoplastic fibroblasts of the L line with the substrate in tissue culture].

Neoplastic fibroblasts of L strain were studied 24 hours after attachment to the solid artifical substrate. The cells were oriented on sections perpendicular to the substrate plane. Transformed fibroblasts moved forward 24 hours after attachment, being polarized. The main difference between normal fibroblasts studied earlier and the transformed ones was observed in the area of the spread lamellar cytoplasm on the front edge of the cell. In this place in malignant cells, a diminition of size and number of bundles of microfilaments and zones of close junction with the substrate was seen. These elements lie close to each other in normal cells, and far from each other in malignant ones. Another difference between normal and transformed cells is that the latter have many microvilli in the lower part of the surface of lamellar cytoplasm. Ultrastructural differences between normal neoplasmic cells observed in this work may be the cause of the behaviour of neoplastic cells in tissue culture.


[A quantitative histochemical study of alkaline phosphatase isoenzyme kinetics in the thyroid gland, kidney and small intestine of white rats].

Microphotometric determination of alkaline phosphatase isoenzyme patterns in morphological structures of rat thyroid gland, kidney and small intestine were performed, using different concentration of L-levamisol and temperature-dependent enzyme inactivation. It was concluded that he constant of inhibition and degree of thermostability are closely connected with heterogeneity of alkaline phosphatase isoenzyme pattern in the organ.


[Late replicating human X-chromosome in the early S-period].

The early S-period in cultured human lymphocytes was studied using the premature chromosome condensation technique. In the lymphocytes, isolated from females but not from males, one uncondensed G1-chromosome was detected among "pulverized" chromosomes which remained unlabeled with H3-thymidine. This chromosome is regarded as an inactivated X-chromosome. The data obtained are in agreement with the phenomenon of the delayed onset of DNA replication in the inactivated X-chromosomes.


[Restoration of ability to proliferate and produce mitogenic factor by human lymphocytes in a serum-free medium following their purification].

The response of purified and "non-purified" human blood lymphocytes to phytoheamagglutinin (PHA) and their capacity to produce mitogenic factor upon PHA-stimulation in protein-free and serum-containing culture medium were investigated. Non-purified lymphocytes lost the capacity to react to the stimulation with PHA and to produce the mitogenic factor in protein-free culture medium. Purification of lymphocytes on the density gradient or passing them through a column made them resume their response to PHA and their capacity to produce the mitogenic factor in protein-free medium. It is assumed that the inhibition of the response to PHA in protein-free culture medium may be caused by polymorphonuclear leucocytes.


Alterations of the human vestibulo-ocular reflex in a simulated dive at 62 ATA.

In an attempt to investigate some aspects of the high pressure nervous syndrome, the vestibulo-ocular reflex (VOR) gain was measured in two professional divers undergoing a simulated dive at 62 ATA. The aquanauts in a seated position were rotated sinusoidally around the vertical axis at a frequency of about 0.3 Hz over a 20 degrees range. Tests were performed at regular intervals prior to, during, and after the compression/decompression period. The rotations were applied either in total darkness or with a visual target rotating with the chair or with a target fixed to the chair-supporting frame. An infrared photoelectric system monitored eye movements. The results showed no spontaneous nystagmus, but two definite changes in VOR gain: (1) a slight but significant increase related to pressure increase, which may be due to an increase of the vestibular system excitability or a decrease of the cerebellar inhibition exerted upon the vestibular nuclei, and (2) an intermittently appearing increase (VOR gain between 1 and 1.3) during brief periods. The latter finding, not related to pressure, was interpreted as the expression of an underwater-adapted mode that may developed in professional divers submitted to the intensive use of magnifying diving-optical systems.


A fluorocarbon emulsion with a high solubility for CO2.

A stable emulsion can be prepared by subjecting a mixture of 30% (by volume) FC-80 fluorocarbon; a 0.3-M THAM solution titrated to pH 7.4 with HCl; and 0.04 g F68 Pluronic surfactant per milliliter FC-80 to ultrasonic energy. The emulsion has a density of 1.24 g/ml; and absolute viscosity of 2.4 centipoise; and an approximate fluorocarbon-droplet diameter of 3mu. The approximate CO2 content of the emulsion at partial pressures ranging from 30 to 60 mm Hg is 132 ml (STPD)/liter + (5.5 X PCO2). The O2 content in ml (STPD)/liter equals 0.213 X PO2 (mm Hg).


Gas phase separation during decompression in man: ultrasound monitoring.

During two dive series, one to 132 fsw and one to 210 fsw, Doppler ultrasonic bubble detectors were used to monitor venous gas bubbles in divers during decompression and for 30 min thereafter. Various decompression schedules were used. Bubble scores were evaluated by independent listerners to tape recordings in a blind manner. A significant increase in bubble scores throughout the stages of decompression and postdecompression was demonstrated as well as a statistically significant relationship between bubble score and decompression sickness. A reduction in mean bubble score was found in divers who made an additional deep decompression stop that was unrelated to the extension of the decompression time. The implications of these findings are discussed.


Effects of a hyperbaric environment on respiratory and monoamine oxidase activities.

The effects of a prolonged hyperbaric environment (21 ATA He-O2, 200 +/- 30 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the respiratory activity of rat liver homogenates and the activity of monoamine oxidase in isolated rat-liver preparations. Exposure to a hyperbaric environment for 84 days caused selective in vitro inhibition of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, D-isocitrate, and alpha-ketoglutarate by rat-liver homogenates. The addition of NAD to the reaction mixture decreased the degree of such an inhibition. No effects on the in vitro activity of liver monoamine oxidase and its inhibition by pheniprazine were observed during exposure of animals to a prolonged high-pressure environment.


Alteration of high pressure nervous syndrome in rats by alteration of colonic temperature.

The components of the high pressure nervous syndrome (HPNS) have been clearly described previously. Animal studies of HPNS, however, have been characterized by nonstandardized definitions of the various HPNS parameters, based on visual observations. Where EEG's have been used in HPNS studies, the frequent occurrence of movement-induced artifact has made much of the data difficult to interpret. Because of these limitations, efforts to clarify the influence of environmental variables on the syndrome have led to varying results, especially with respect to the influence of temperature. The technique used in this study consistently yielded artifact-free EEGs from unanesthetized, moving rats during simulated heliox dives. Typical seizure patterns in the EEG recordings were combined with clinical seizure activity to define HPNS convulsion-threshold pressure (Pc). By manipulating body temperature artificially, three groups of rats were investigated--hypothermic, euthermic, and hyperthermic animals. An inverse relationship between body temperature and HPNS convulsion-threshold pressure was demonstrated.


The effect of high pressure on the hemolysis of red blood cells.

Investigations into the effects of pressure on the hypotonic hemolysis of human erythrocytes show that pressures up to 130 atm (1700 psi) do not potentiate the hemolysis as has previously been suggested. Furthermore, such pressures do not remove the protection against hypotonic hemolysis conferred by the presence of general anesthetics to more than a negligible extent.


Effects of nicotinic acid on plasma volume loss of experimental dysbarism.

Two groups of dogs anesthetized with sodium pentobarbital were subjected to compression of 60 psig for 60 min and decompressed at the rate of 10 psi/min without staging. Plasma volume was measured in each group by I131-tagged albumin dilution technique prior to compression, 10 min and 60 min after decompression. One group of animals received no other treatment and the other group received 15 mg/kg of body weight of nicotinic acid by intravenous injection immediately prior to compression and an additional 7.5 mg/kg of body weight of nicotinic acid 30 min after decompression. Both the untreated and the nicotinic acid-treated animals lost significant plasma volume at both the 10- and 60-min postdecompression measurements. Nicotinic acid-treated animals lost significantly less plasma.


Dysbaric osteonecrosis in mice.

The histopathology of dysbaric osteonecrosis and the influence of the number of exposures, compression rate, and obesity on the incidence and latency of the lesion were studied in 438 mice (2505 bones were examined). The animals were subjected to 75 psig air pressure for 2-6 hours (single or multiple exposures). Compression was rapid or stage. Decompression was safe. Osteonecrosis developed in the epiphysis of the tibia and/or femur in 34.1% of obese and in 5.8% of thin animals after a latent period of 2 to at least 12 months. It was concluded that: 1. dysbaric osteonecrosis appears to be independent of decompression sickness; 2. in obese mice the incidence is higher and the latent period shorter; 3. multiple exposures result in higher incidence and earlier lesions than single exposure; 4. the incidence is lower with stage than with rapid compression; 5. the pathogenesis of osteonecrosis may involve several factors (circulatory impairment by extravascular or intravascular bubbles, emboli, thrombi, vasoactive substances, gas-induced osmosis, autoimmunity) acting in concert or in sequence.


Changes in rat respiratory behavior under varying PCO2 levels and argon content in hyperbaric Ar-O2-CO2 atmospheres.

An anesthetized rat preparation has been used for breathing studies in hyperbaric Ar-O2-CO2 atmospheres in which total saturation pressure was varied in the range 1-19.1 ATA and PCO2 was set at levels of 0.0, 0.05 or 0.10 ATA. The variables monitored were respiration rate and an isotonic measure of diaphragm-twitch amplitude during contracture/relaxation (twitch index). The results indicate that: (1) hyperbaric Ar-O2 atmospheres are able to maintain the animal in stable condition for several hours; (2) elevation in PCO2 level produces enhancements in respiration rate and twitch index that are markedly dependent on the PAr level; (3) successive increases in PAr are able to lower progressively the effects on both breathing parameters produced by either 0.05 or 0.10 ATA of CO2, with full abolition of both effects of inhaled CO2 in the PAr range 14-19 ATA; and (4) the intrinsic ability of hyperbaric argon to abolish respiratory enhancement by CO2 is greater than that of hyperbaric helium. These results have been discussed in terms of possible CNS loci at which hyperbaric argon (or helium) is able to antagonize centrally induced effects from dissolved molecular species derived from inspired CO2, and in relation to the broader task of control of excitatory/inhibitory centers of the CNS during diving by manipulation of the partial pressures of diluent components of breathing-gas mixtures.


Exercise tolerance at 4 and 6 ATA.

Seven normal male subjects performed 5-min bicycle exercise ranging from 50-100% maximum oxygen uptake at 4 ATA and three were also studied at 6 ATA. At all pressures, the subjects breathed 0.2 ATA O2 plus nitrogen. All subjects were able to perform maximum work at all pressures. No pressure-dependent variations in heart rate, O2 uptake, or CO2 output were noted. At both 4 and 6 ATA, ventilation was decreased at exercise levels greater than 80% maximum O2 uptake. The magnitude of the decrease was not great, however, and signified only minor CO2 retention. In some instances exercise ventilation closely approached the 15-S maximum breathing capacity and these subjects noted severe dyspnea, possibly due to dynamic compression of large airways. In three subjects, respiratory frequency was measured as well as minute ventilation; this relationship did not change with depth. Subjects performing heavy exercise at 6 ATA noted disturbances of consciousness, presumably due to N2 narcosis.


Kinetics of fibrinogen and platelet adherence to biomaterials.

The initial task was to establish a conceptually and materially simple test procedure that could quantitate and evaluate the thrombogenic potential of a biomaterial surface. Since the primary events of thrombus formation on prosthetic surfaces are believed to involve the deposition of a plasma protein monolayer followed by platelet adhesion to its fibrinogen component, it seemed reasonable to focus on the binding kinetics of fibrinogen and platelets to a commonly used biomaterial. Employing solutions of 125I-fibrinogen in buffered saline, the adsorption characteristics of several types of biomedical tubing could be compared, and the competition and exchange among plasma proteins at surface binding sites of PVC were evaluated. Human platelets with 51Cr were found to adhere to PVC surfaces proportional to surface fibrinogen concentration, but only in the presence of plasma; the circulation of labelled platelets in buffered saline only resulted in significant adherence to the native surface, while surface fibrinogen was inhibitory. Physiological concentrations of albumin were the most effective in preventing both fibrinogen adsorption and platelet adherence. The most important consequence of this work, perhaps, is the many avenues of future experimentation discovered from this methodological approach, not only in the thrombogenic evaluation of a specific biomedical surface, but also in the delineation of thrombogenic sequelae in general.


Tin-protein binding kinetics in normal and uremic plasma and its effect on dialysis fluxes.

A high affinity of plasma protein for tin has been demonstrated by ultrafiltration studies. At physiologic concentrations, UF/P remained below 1%, consistent with more than 99% binding. Binding of tin was nearly complete despite a decrease in plasma protein concentration to 3.5 Gm% and an increase in plasma tin by 80 mg/L. This binding inhibits efflux of tin from plasma during dialysis while influx occurs readily. This may be a mechanism for accumulation of tin in patients undergoing maintenance hemodialysis. A mechanism for tin chelation could be clinically beneficial in the syndrome of dialysis dementia.


Essential amino acid metabolism in maintenance dialysis patients.

Oral and I.V. administration of a mixture of essential amino acids to normal and dialysis patients revealed: 1. First pass metabolism (FPM) occurred for all administered amino acids in both normal and dialysis patients, and was variable in both populations. however, FPM appeared lower for phenylalanine and higher for methionine in the dialysis group. 2. Net metabolic clearance rate was significantly lower (p less than 0.05) for leucine, isoleucine, threonine and phenylalanine, and tended to be lower for valine and lysine in the dialysis group. 3. With the exception of phenylalanine and valine the apparent volume of distribution did not differ between normals and maintenance dialysis patients. 4. These studies indicate the existence of a variety of significant abnormalities in the metabolism of specific essential amino acids, and suggests a defect in muscle metabolism of branched-chain amino acids in maintenance dialysis patients.


A new method for analysis of the adsorbed plasma protein layer on biomaterial surfaces.

The composition and dynamics of the protein film adsorbed onto surfaces from blood plasma remains unknown to biomaterials development. In situ radioiodination followed by elution and electrophoretic analysis has been demonstrated as a sensitive and versatile technique for analysis of these films. Iodine-125I was incorporated into protein using iodine monochloride. After film washing, and elution with sodium dodecylsulfate (SDS), proteins were subject to SDS gel electrophoresis for MW determination. Disulfide bond reduction with dithiothreitol was also employed to detect the presence of protein subunits. Fibrinogen, albumin and IgG were readily identified when adsorbed from a single protein solution onto teflon or silicone rubber. Electrophoretic analysis of the protein layer adsorbed from plasma revealed a complex pattern of up to 8 iodinated protein species. Iodinated protein with electrophoretic behavior consistent with fibrinogen and albumin was always found after plasma exposure, but proteins of apparent MW 7-10,000; 12,000; 25,000 and others remain unidentified. Adsorbed protein patterns varied with plasma source, type of material, and time of plasma exposure.


Deposition of platelets and fibrin on chemically modifide collagen hollow fibers.

A new technique was devised for interaction studies between human blood and chemically modified amorphous collagen surfaces. Blood is drawn directly from an antecubital vein, through saline-filled collagen hollow fibers, at either constant flow for varying time or constant time at varying flow. Platelets and fibrin were deposited more rapidly and in greater numbers on methylated surfaces and more slowly and to a lesser extent on succinylated surfaces than on native surfaces. Increasing blood flow was associated with increased fibrin formation. Adherent platelets spread over 3-8 mu of methylated surface, but retained a spherical shape (1-2 mu) on succinylated and native surfaces. Thus, charge modification of collagen significantly alters platelet adhesion, subsequent platelet morphology, and fibrin deposition. Methylated surfaces are thrombogenic and succinylated ones are relatively thrombo-resistant.


Platelets, foreign surfaces, and heparin.

These studies clearly indicate that heparin has 2 antagonistic effects in this platelet-foreign surface interaction; it acts directly on platelets to increase retention, while acting on the foreign surface to reduce platelet retention, perhaps by competing for cationic sites. This study also suggests that it is unlikely that heparin bonding confers reduced surface thrombogenicity by virtue of the ability to leach off that surface and that further studies in heparin bonding or other surface modification should consider the antiplatelet effect which can easily be studied in vitro.


An intrathoracic solenoid drive system for chronic left ventricular bypass.

The performance of an implantable Left Ventricular Assist System (LVAS), utilizing an advanced solenoid energy converter, has been extensively studied in vivo. For optimum system efficiency, reliability and responsiveness, the energy converter and blood pump are integrated into a single compact unit, which is implanted intrathoracically in an 80 Kg calf. The MK19 LVAS is battery operated and controlled by a miniature analog computer and is completely self-regulating. The maximum hemodynamic power provided by this circulatory assist system is 4 watts with cardiac outputs up to 10 L/min and a total system efficiency of 30%. LVAS function has been studied in a series of 19 calf experiments progressing through acute, model and chronic evaluations. Development of the implantation protocols and hemodynamic characterization were achieved in a series of 8 acute experiments. Long-term studies were conducted for periods up to 43 days in a series, including 2 control experiments using non-functional models and 9 functional LVAS chronic experiments. Aortic, left ventricular and left atrial pressures, pulmonary artery flow and pump outflow were monitored with chronically implanted transducers. A dedicated minicomputer provided real-time hemodynamic analysis and continuous surveillance of physiologic and LVAS parameters. In acute studies and in the immediate post-operative period of chronic experiments, synchronous LVAS operation reduced peak LV pressures to 30 mm Hg with cardiac outputs of 5 to 7 L/min. In chronic studies, with recovery of normal LV function, long-term synchronous operation was maintained, without capture of the total cardiac output and with significantly reduced ventricular unloading.


Creation of double-outlet left ventricles for left ventricular outflow obstructions: initial clinical results in six patients.

Operations for supravalvular, valvular, and subvalvular stenoses are frequently complicated by aortic insufficiency, recurrence, or aortic valve prosthetic malfunction. Without surgery, increasing left ventricular pressures, myocardial hypertrophy, congestive failure, and sudden death are common. Following an extended series of bovine experiments, we have created double-outlet left ventricles in 6 patients. All but one had been operated on previously for combined supravalvular, valvular, or subvalvular aortic stenosis or idiopathic hypertrophic subaortic stenosis. All left ventricular-ascending aortic gradients were markedly decreased and the deranged left ventricular physiologic indices returned toward normal following operation and discharge from the hospital. None of these patients is receiving Coumadin, and none has exhibited any deleterious effects from the fractionation of left ventricular output, cephalad and caudad. Our current prosthesis is a composite consisting of a special LTI carbon inlet tube with a left ventricular apical sewing ring and graft extension anastomosed to a Hancock prosthesis of appropriate size. The procedure is simple, reproducible, effective, and has much to recommend. Special conduits are now being fabricated for future use. In certain instances, this approach may have advantages over conventional primary aortic valvotomy in infants or valve replacement in adults.


The in vitro assessment of left ventricular flow patterns on the closure of a new mitral valve "bioprosthesis".

A new pulse duplication system, which we feel closely simulates not only the geometry but the pressure and flow phenomena in the left heart under phasic conditions, has been developed. A new mitral valve replacement, in a truncated cone or frustum configuration is being evaluated, utilizing this test facility. Flow patterns around the mitral valve appear to close the leaflets well prior to the onset of gradient reversal across the orifice.


Automatic control of the artificial heart.

An automatic control system has been developed to balance and control the output of an artificial heart. The system consisted of 2 linked negative feedback loops. The left ventricle was controlled by a Servo-Stroke Optimizer, which insured complete filling and full stroke operation of the left pump with each beat and changed the beat rate in accord with changes in aortic pressure. The right ventricle was controlled by a Servo-Variable Systolic Duration unit, which changed the stroke of the right ventricle to maintain the left atrial pressure within a preset band. In the initial animal studies, control pressures (aortic and left atrial pressure) were obtained from implanted transducers. More recently, a method has been devised whereby the control pressures were obtained from specific points on the left air line pressure wave, obviating the need for implanted transducers. The control system has been evaluated in a mock circulatory loop and in 9 calves with implanted artificial hearts. The system has provided balance of the 2 implanted ventricles and changes in flow rate in response to changes in peripheral resistance. The need for an operator to make manual adjustment to the power units has been considerably reduced. Further studies are indicated to evaluate the function of the control system in animals performing moderate-to-maximal exercise. Furthermore, the ultimate benefits of full stroke operation vs fill limited mode operation remain to be delineated.


Transapical left ventricular bypass (TALVB) without an auxiliary ventricle.

A simple transapical left ventricular bypass system employing a roller pump, transapical LV withdrawal catheter, and outflow filter for continuous blood filtration, has been developed and evaluated in unanesthetized sheep for periods beyond 2 wks. The system provides continuous partial LV bypass and is capable of totally maintaining the circulation in the presence of a vasodilator or when total bypass is desired. Blood damage is minimal and blood transfusions have not been required. The transapical withdrawal catheter has been left in the LV apex beyond 4 mos and demonstrates thrombus formation and myocardial histological changes which suggest this catheter should be removed after pumping or long-term anticoagulation provided.


Expanded polytetrafluoroethylene (PTFE) subcutaneous arteriovenous conduit: an improved vascular access for chronic hemodialysis.

The early results with 84 PTFE grafts used as subcutaneous A-V conduits for vascular access in 72 patients requiring chronic hemodialysis have been quite promising. Initial follow-up has revealed that these grafts functioned at least as well as the bovine heterograft, and the complications seen within the 2 groups being somewhat similar. Should the complications and rate of complications with PTFE be no greater than those seen with the bovine heterograft, then its availability, ease of handling and significant decrease in cost would make the PTFE graft a significant improvement as a means of creating vascular access for chronic hemodialysis.


Initial approach to blood access for the chronic hemodialysis patient--the bovine heterograft.

Experience with the modified bovine heterograft arteriovenous fistula for hemodialysis in 79 grafts in 73 patients over an 18 mo period is analyzed. An immediate (30 day) patency rate of 97.5%, and a 12 mo cumulative patency rate of 73.9% was observed. Early and late complication rates were acceptably low, despite early usage in 80% of cases. It is concluded that the bovine fistula provides an acceptable blood access route for the initial approach to the patient in urgent need of hemodialysis.


An upper arm A-V fistula for hemodialysis patients with distal access failures.

The technique of creating an upper arm side-to-side A-V fistula in patients with forearm vascular access failures has been described. The procedure has been used extensively in patients in Japan with a high degree of success. The limited U.S. experience has confirmed that the procedure results in trouble-free, reliable vascular access. It is proposed as an alternative approach for patients with forearm access failures.


A reassessment of the prognosis of diabetic patients treated by chronic hemodialysis (CHD).

Our early results in 25 diabetics treated by CHD prior to 1972, compared to results in a further 66 diabetics starting CHD since 1972, show an improvement in survival related to a reduction in deaths from myocardial infarction and sepsis. There has been a reduction in complications requiring hospital admission, related to a lower incidence of sepsis. Access survival has been markedly improved since the introduction of the bovine fistula.


Metabolic changes in diabetic uremic patients on hemodialysis.

By studying the metabolic values of a nondiabetic and diabetic uremic population we demonstrated the following: 1. Insulin is higher in diabetic than nondiabetic uremic patients. A slight arteriovenous difference across the dialyzer membrane suggests that insulin is dialyzable in small amounts in man. 2. C-peptides are highest in nondiabetics, lower in maturity onset diabetics, and lowest in juvenile diabetics. 3. Growth hormone is higher in diabetics than nondiabetics, decreased in both groups during hemodialysis, and returns to pre-dialysis levels 2 hrs after the completion of dialysis treatment. 4. Plasma triglycerides are elevated in both popualtions during the fasting state anddrop during hemodialysis, rising slowly towards the end of hemodialysis. 5. The majority of diabetics on hemodialysis have low renin levels and do not respond to volume reduction. In the high renin diabetics and high and low renin nondiabetics the plasma renin levels rise in response to volume reduction during hemodialysis. Renin is not dialyzable in man. 6. Thyroid function tests show that diabetic and nondiabetic patients have measurements in the low normal range. Our results reveal significant information concerning metabolic changes which take place in diabetic and nondiabetic uremic patients on hemodialysis and helps to characterize these populations. This report may have implications in better understanding the nature of the problems encountered in these populations and in their management (Table III).


The adsorption of sympathomimetic agents by activated carbon hemoperfusion.

Sympathomimetic agents with mixed and pure alpha and beta adrenergic activity are adsorbed by coconut shell activated carbon from blood, sufficiently rapidly to markedly reduce the activity of these agents. The results of this study suggest that the site of injection of sympathomimetic agents being considered for correcting hypotension during activated carbon hemoperfusion be selected to permit systemic mixing before circulation into the adsorption device.


Medical nephrectomy. The use of metallic salts for the control of massive proteinuria in the nephrotic syndrome.

Two patients with intractable massive proteinuria and uremia were followed and treated with standard mecial therapy and dialysis. After a period of study and demonstration of clinical deterioration both patients were given solutions containing sodium mercaptomerin. Within days there was a decline in urine protein excretion and a variable increase in serum protein concentration. The patients demonstrated an increase in blood pressure, which made hemodialysis treatment possible. No deleterious effects from the mercury salts were noted. These observations suggest that in selected cases nephrotoxic agents may be of value in decreasing massive proteinuria, and improving protein homeostasis in uremic patients. Table I: Possible advantages of medical nephrectomy. 1. Reversal of hypotension and shock 2. Ability to perform hemodialysis 3. No anesthesia or surgical risk 4. No angiography related complications 5. Preservation of endocrine function of kidney. Possible advantages of medical nephrectomy (Table I), are: 1) Correction of proteinuria and hypotension; 2) Ability to perform hemodialysis; 3) No anesthesia or surgical risk; 4) No angiography related complications; and 5) Preservation of remaining endocrine function of the kidney, including erythropoietic and vitamin D action. The ideal agent should be non-toxic to other organs and produce selective renal ablation. Obviously mercury is not the ideal agent, although in these cases it did not produce observable side effects. It appears that this agent should be used with caution and only in patients with irreversible renal failure.


Carbenicillin inactivation of aminoglycosides in patients with severe renal failure.

Carbenicillin appears to produce clinically important inactivation of aminoglycoside antibiotics in patients with severe renal failure. If combination carbenicillin/aminoglycoside therapy is used in patients with severe renal failure, the dose of carbenicillin must be adjusted to renal function and serum levels of both drugs should be monitored. Even with therapeutic serum carbenicillin levels (100-200 mug/ml), large doses of aminoglycosides may be required to achieve therapeutic serum levels and this may increase the risk of toxicity.


A comparison of three ventricles used for left ventricular bypass in the calf.

Long-term synchronized left ventricular bypass has been performed in calves using pneumatically powered pumps having a smooth lining fabricated of segmented polyurethane. Three different pump designs have been employed: a) sac pump, b) longitudinal tethered sac pump, and c) transverse tethered sac pump. Sizeable thrombi occurred in the apex of the sac and longitudinal tethered sac pumps. In the transverse tethered sac pumps, a considerably smaller thrombus was seen only at the flexion point on the inlet side of the pump. Thrombi occurred in areas of low flow velocity and were not prevented by anticoagulation or surface coating techniques. This study indicates the importance of ventricle design in the development of thrombus free pumps and suggests modifications to the present pumps to reduce or eliminate thrombus formation.


New methods for the in vitro investigations of the flow patterns in artificial hearts.

With the 3 applied methods one can investigate and obtain most of the interesting aspects of the flow within blood pumps: an integral picture of the flow, the development and position of stagnation flow, the time course of the velocity in points of special interest, the turbulence, and an integral picture of the mean boundary layer flow. The measurements have shown that the flow in the blood pumps is turbulent, the turbulence can be considered harmless, because its intensity is much weaker than that of a valve; there is a correspondence between the hotfilm method and the dye-washout method, and that there is a correspondence between the dye-washout method and the in vivo clot formation. Pumps, which have been designed according to these measurements, have been implanted in a series of calves. The pumps now have a smooth continuous inner surface and usually show no thrombus formation at all (anticoagulants are used) at the postmortem. Some animals do very well, such as the one in Figure 16 during his daily walk of 500 M on the treadmill. The animal is in its 45th day of survival and remains well to date.


Saving the aortic and pulmonary artery valves with total heart replacement.

The natural aortic and pulmonary artery valves can be saved with excision of the ventricles and inflow valves. These valves remain functional and unaltered with implantation of an artificial heart, when pumped for 96 and 122 days. The capacity of the artificial heart to meet the physiological needs of the animal, during exercise and body growth, over 3 and 4 mos has been documented. All of the parameters monitored in 2 experiments for 3 mos (and continuing) and 4 mos clearly demonstrates the efficacy of meeting the cardiac needs with an artificial heart.


Chronic evaluations of ventricular ejection phase dynamics during abdominal left ventricular assist device (ALVAD) pumping in the awake, unanesthetized calf.

In 1974, between 2 and 8% of the 50,000 adult patients undergoing cardiac surgery in this country succumbed in the early post-operative period from left ventricular failure, despite various methods of pharmacologic and/or mechanical support. Our laboratories have concentrated on the development, modification, evaluation, and validation of an abdominally positioned left ventricular assist device which has the potential of reducing these mortalities. Continuous testing in animals, for periods exceeding 2 mos, satisfied reliability, durability and longevity requirements. The cumulative results of these investigations were reviewed at the National Heart and Lung Institute on August 21, 1975. Authorization for clinical trials of the device according to specific criteria and protocols46 was approved on November 1, 1975. The ALVAD is now in the early stages of clinical testing. The results of the current experiments demonstrate that ventricular outflow impedance and prosthetic inflow impedance are the major determinants of left ventricular assist device hemodynamic effectiveness. By markedly reducing outflow impedance, the ALVAD profoundly lowers ventricular pressure-work and oxygen demands while simultaneously increasing ventricular performance and maintaining or augmenting systemic perfusion. Moreover, our studies indicate that improved device designs (intended for intermediate and long-term implantation) and maximal performance can be achieved by focusing on these central determinants.


Thermodynamics of native protein/foreign surface interactions. IV. Calorimetric and microelectrophoretic study of human fibrinogen sorption onto glass and LTI-carbon.

1. According to a working hypothesis put forward in the previous papers of this series2-4, the initial phases of native blood/foreign surface interactions have been considered within the framework of a physicochemical model of contact activation at the molecular level. The salient features of this hypothesis are: a) the arrival and adsorption of native plasma proteins on a contact surface overwhelmingly precedes that of the cellular blood components; b) the interaction energy that arises between a particular foreign surface and native plasma proteins settling on it, is a characteristic quantity depending upon the effective surface molecular structure as well as the nature of the proteins; c) the "intensity" of native protein/foreign surface interactions can be treated in terms of thermodynamic quantities since these energy terms are independent of the type of forces acting between protein and surface; and d) depending upon the degree to which the adsorption of a native protein is thermodynamically favored by enthalpy and/or entropy factors, the interaction energy can be utilized to induce conformational changes of varying degree in the sorbed protein. 2. Using glass and low temperature isotropic (LTI) carbon adsorbents, i.e., a known procoagulant and a relevant biomaterial, respectively, the adsorption properties and the potential surface-induced conformational changes of high-purity native human fibrinogen (clottability greater than or equal to 92%) were studied, at 25 degrees C, by 3 independent methods. In all of the experiments performed, a) both adsorbents were employed in the form of particles less than or equal to 1.0 mu representing specific surface areas of 9.85 M2/Gm and 27.7 (nominal) M2/Gm for the glass and LTI-carbon powders, respectively, and b) the fibrinogen was absorbed from a standaridized buffer (pH = 7.2, ionic strength 0.05) using the same fixed surface area/protein solution volume ratio with a given adsorbent. 3. The 25 degrees C adsorption isotherms of fibrinogen obtained for both the glass and LTI-carbon powder adsorbents are not amenable to Langmuir type analysis but indicate multilayer sorption with a possible change in binding mechanism after the completion of the first sorbed monolayer. The adsorptivities attained at first monolayer coverage were slightly greater on glass (approximately 0.76 mug/cm2) than on LTI-carbon (approximately 0.52 mug/cm2). 4. Using a custom-built, thermistorized, isothermal-jacketed microcalorimeter routinely capable of resolving temperature changes of 0.00001 degrees C in 100 ml of aqueous sample volume, the "intensity" of interaction between fibrinogen and each of the microparticulate adsorbents was studied by the direct measurement of the net overall enthalpy changes, hI(SLP)25 arising as a result of protein adsorption. From these values, the net heat of protein sorption has been determined...


Synthesis and characterization of blood compatible surfaces. Part I. Dynamic tube test applied to heparinized surfaces.

A 3 yr study has shown that this test procedure can monitor subtle differences in surface chemistry with a high degree of reproducibility. Based on the present studies, the test appears to be a valid screening tool for examining materials in a dynamic flow situation without the need for animal sacrifice often associated with blood testing. Also, due to the small amount of blood required, numerous samples can be run on the same animal which is extremely advantageous when comparing treatment methods. In addition, the simplicity of the test should make it easily adaptable to most blood testing laboratories.


The intravascular magnetic suspension of a test device for in vivo hemocompatibility evaluation of biomaterials.

To advance hemocompatibility evaluation techniques, a new in vivo method has been developed for the dynamic testing of candidate biomaterials in suitably-sized experimental animals. One of the salient features this method is that the material to be evaluated constitutes the blood contact surface of a slender body of revolution which is coaxially suspended in a large canine vessel by electromagnetic forces only. The insertion site of the specimen is distal and downstream to the test region, reducing the influence of thrombotic tissue substances. These experimental conditions also insure that the only chronically exposed foreign surface is that of the test material, whose interactions with blood components are not affected by contact with the vessel intima. As demonstrated in simulated Circulation Model experiments, macroscopic thromboembolic phenomena induced by the test material can be continuously monitored. Preliminary in vivo trials have verified the validity of the underlying principles; the feasibility of the required surgical techniques, and the adequate performance of the suspension system.


Treatment of bone disease in patients on chronic hemodialysis with dihydrotachysterol.

Nine out of 24 patients on chronic hemodialysis were found to have biochemical, radiologic and bone biopsy evidence of moderate to severe bone disease. Two patients had bone pain and muscle weakness, 2 had pseudofractures, and one patient had a pathologic fracture of the neck of the femur. Eight patients were treated with dihydrotachysterol (D.H.T.), 0.25 to 0.37 mg/day initially. Four patients required doses between 0.5 and 1.0 mg daily. The alkaline phosphatase decreased in all patients, returning to normal in 6 patients. The symptoms of bone pain and muscle weakness resolved, and the pseudofractures healed. Repeat bone biopsies were performed in 6 patients 12 mos or more after treatment with D.H.T. The osteoid area fell from 29.6 +/- 22.8 to 11.5 +/- 7.5% (p less than 0.025). Resorptive surface decreased in all patients. D.H.T., in doses of up to 1.0 mg/day, is effective in the treatment of both the osteitis fibrosa and the osteomalacic component of bone disease in patients on hemodialysis.


Measurement of the transmittance coefficient spectrum of Cuprophan and RP69 membranes: applications to middle molecule removal via ultrafiltration.

The transmittance coefficients of Cuprophan PT-150 and Rhone-Poulenc AN69 have been defined over a broad MW range. The results can be completely characterized by a simple Gaussian distribution employing 2 parameters, the selectivity and the mean molecular diameter. The selectivities of the membranes studies are identical. The mean MW at 50% cutoff for Cuprophan and RP69 are 2,500 and 11,500, respectively. A membrane model illustrating a semi-empirical correlation between permeability and transmittance has been developed.


Successful use of a totally heparin grafted hemodialysis system in sheep.

A total of 33 totally heparin-grafted dialysis systems using HFAK Cordis Dow Models 3 and 4 have been compared to a total of 23 nongrafted systems. The comparison of deltap, flow rate, FBVL and macroscopic inspection showed highly significant differences in favor of the heparin-grafted systems. The antithrombogenic performance of the totally heparin-grafted systems is mainly due to a small leakage of heparin during the experiments. A minimum of 1.35 X 10(-8) Gm/cm2/min of heparin is sufficient to prevent clotting at the blood-polymer interface.