An epidemiological study of viral hepatitis type B in Taichung, Taiwan based on detection of HBc antibody.

The city of Taichung (Taiwan) can be considered as one of the areas contaminated by HB virus. Using, as a control group, the population of three districts in Japan, i.e. 2,820 residents of the cities of Kumayama (Okayama prefecture), Bizen (Okayama prefecture), and Aki (Kochi prefecture), the extent of this problem was investigated by reference to HB antigens detected in 350 patients who presented at the Taichung hospital. The Taichung detection rates for HBs antigen, HBs antibody and HBc-antibody were 20.3%, 45.3%, and 96.9% respectively. In contrast to this, the results for the Japanese control areas were, in order, 1.2-2.9%, 14.3-22.2%, and 28.6-94.3%. The HBs antigen subtype in Taichung was predominantly adw (87.3%) rather than adr. It became clear that Taichung is, indeed, an area heavily contaminated with HB virus and, at the same time, that the number of patients with viral hepatitis type B is large.


Treating acne vulgaris.

While there is no single treatment plan that will work for every patient, acne can be controlled and long-term scarring can be minimized. Treatment must be individualized. Remember, there may be a "flare" when intensive therapy begins. Useful treatment methods include ultraviolet light, cleansers and soaps, peeling and drying agents, benzoyl peroxide preparations, abrasive soaps and scrubs, retinoic acid and oral antibiotics. The therapeutic choice depends upon the extent and severity of the disease.


Echocardiographic observations in patients with systemic infiltrative disease involving the heart.

Echocardiography was used to evaluate the heart in 19 patients with one of various systemic diseases known to be associated with infiltrative cardiomyopathy. Four patients had systemic amyloidosis, 10 had idiopathic hypereosinophilia and 5 had iron overload caused by multiple blood transfusions. Although 10 patients (53 percent) had no clinical evidence of cardiac disease, all 19 had echocardiographic abnormalities; the left ventricle was symmetrically thickened (more than 11 mm) and left ventricular mass was increased (more than 275 g) in all; the left ventricular transverse dimension was modestly increased (more than 52 mm) in 5 patients (26 percent) and the velocity of mitral valve closure in early diastole was reduced (less that 60 mm/sec) in 5 patients. Systolic function, as evidenced by ejection fraction, was well maintained (greater than 60 percent) in 18 of 19 patients. Thus, it appears that echocardiographic abnormalities can be detected in many patients with a systemic disease associated with infiltrative cardiomyopathy even before clinically evident heart disease develops.


Correlations of electrocardiography and echocardiography in determination of left ventricular wall thickness: Study of apparently normal subjects.

To examine the usefulness of the surface electrocardiogram in predicting left ventricular wall thickness as determined with echocardiography, standard echocardiograms, electrocardiograms and Frank lead vectorcardiograms were obtained in 30 volunteers. End-diastolic thickness of the interventricular septum and free posterior wall was measured from the echocardiogram and compared with the sum of the S wave in lead V1 plus the R wave in lead V6 (VS1+R6) and the magnitude of the Frank lead vector (Vf), a scalar dunction obtained from a simple analog device. The maximum of Vf, the summated vector (Vf), was highly correlated with VS1+R6 (r=0.84). There was significant correlation between the summated vector and VS1+R6 and the thickness of the interventricular septum (IVS) (r=0.73 and 0.66, respectively). The best least mean square fit for the population was Vf=1.7 IVS-0.39. There was no significant correlation between these variables and the end-diastolic thickness of the posterior wall. Volunteers who were athletically inclined or were joggers tended to have larger summated vector values and evidence of symmetric or asymmetric left ventricular hypertrophy in the echocardiogram. It therefore appears that the thickness of the interventricular septum has a greater influence on the summated vector and VS1+R6 that the echocardiographically assessed thickness of the free posterior wall of the left ventricle. The implications of these findings in the light of recent reports about the incidence of echocardiographically diagnosed left ventricular hypertrophy are discussed.


Down syndrome with congenital heart malformation.

Two hundred fifty-one patients with Down syndrome and congenital heart disease was based on clinical (41%), catheterization (38%), surgical (11%), or autopsy data (10%). The most common lesions were endocardial cushion defect (43%), ventricular septal defect (32%), secundum atrial septal defect (10%), tetralogy of Fallot (6%), and isolated patent ductus arteriosus (4%). Thirty percent had multiple cardiac defects. The most common associated lesions were patent ductus arteriosus (16%) and pulmonic stenosis (9%). Twenty-five percent of the patients uncerwent cardiac surgery. Motality in the 68 patients undergoing surgery was 26% for open heart procedures and 11% for closed heart surgery. In 32% of nonsurgically treated patients with large left-to-right shunts, irreversible pulmonary vascular disease developed. Improved medical and surgical care have decreased morbidity and mortality in these patients in recent years.


Mechanism of stress ulcer: influence of sodium taurocholate on gastric mucosal energy metabolism during hemorrhagic shock and on mitochondrial respiration and ATPase in gastric mucosa.

In previous reports from this laboratory, we have proposed that stress ulceration complicating hemorrhagic shock results from a gastric mucosal energy deficit due to shock-induced mucosal ischemia. We reasoned that if this hypothesis were correct, an agency known to augment the severity of stress ulceration would be expected to have an adverse effect on gastric mucosal energy metabolism. Others have shown that the severity of stress ulceration developing in animals subjected to hemorrhagic shock is increased by introducing bile salts into the stomach; conversely, the development of stress ulceration can be prevented by ligation of the pylorus or of the common bile duct. We have studied the influence of sodium tauurocholate on the respiration of gastric mucosal mitochondria and on gastric mucosal ATPase. We have also evaluated the influence of the intragastric introduction of taurocholate on the mucosal energy depletion produced by shock. The data presented in this report indicate that taurocholate uncouples oxidative phosphorylation of gastric mucosal mitochondria and inhibits gastric mucosal ATPase. The shock-induced gastric mucosal energy deficit was significantly more severe in the presence of added intragastric taurocholate.


Prevalence of hepatitis B infection among residents of an institution for the mentally retarded.

Data on prevalence of antibody to hepatitis B surface antigen (anti-HBs) and of hepatitis B surface antigen (HBsAg) among 95 matched pairs of Down's syndrome (DS) and other mentally retarded (OMR) patients in an institution were analyzed by age on admission and by length of residence. Passive hemagglutination test were used to determine anti-HBs. Anti-HBs prevalence increased with admission age among DS patients (26%, 42% and 56% for age groups less than or equal to 5, 6-15 and greater than 15 years, respectively) but decreased among OMR patients (85%, 71% and 78%), giving overall rates of 38% for DS and 77% for OMR which are significantly different (p less than .001). Anti-HBs prevalence increased with length of residence for OMR patients but was unchanged for DS patients. For both groups, the prevalence of hepatitis B (HB) infection (both anti-HBs and HBsAg) increased with length of residence and, overall, was nearly the same for DS and OMR patients. These observations are consistent with the hypothesis that, with respect to response to HB virus, younger DS patients are immunologically immature.


Assessment of counseling practices at the birth of a child with Down's syndrome.

An attempt was made to analyze 414 parents' perceptions of their experiences at the birth of their child with Down's syndrome. The interpretation of the results and the parents' comments suggest that the counseling of parents with a newborn Down's syndrome child demands tact, truthfulness, and empathetic guidance. The parents should be informed of the child's condition in a kind and sensitive manner as soon as the diagnosis of Down's syndrome has been made. Appropriate terminology should be employed, and both parents should be present when the physician tells them of their misfortune. Unconditional recommendations of institutionalization of the child with Down's syndrome should be practices of the past. The professionals' thoughtful considerations and mature counsel should assist constructively in shaping the child's future.


Predictive value of infant intelligence scales with multiply handicapped children.

The predictive value of infant intelligence scales with multiply handicapped children was investigated through the administration of a mental measure on two occasions to 28 children, divided into two age groups. A Pearson product-moment correlation coefficient of .69 (p less than .001) was obtained for the younger group and .83 (p less than .001) for the older group. When subjects were divided according to IQ level, a nonsignificant correlation coefficient was obtained for the high-IQ group and a significant correlation (r=.81, p less than .001) for the low-IQ group. These results indicated that infant intelligence tests are highly reliable predictors of later intellectual development when given to a population of multiply handicapped children.


Fetal pancreatic glucagon responses in glucose-intolerant nonhuman primate pregnancy.

Rhesus monkey pancreatic alpha-cell function in streptozotoc-induced glucose-intolerant pregnancy is similar to that in normal primate pregnancy. Specifically, basal maternal and fetal plasma glucagon levels equate, and the fetal alpha cell does not respond to the glucagonogenic stimulus of either intravenous alanine or insulin-induced hypoglycemia. This contrasts with the accelerated maturation of the fetal beta cell in glucose-intolerant pregnancy, and does not support the concept of functional coupling of the pancreatic islet by a common glucose-based process. Fetal plasma glucagon levels do increase after L-dopa injection to the fetus. These data indicate that alpha cell unresponsiveness is a function of the glucagon-releasing mechanism rather than inadequate hormonal synthesis.


The value of pre-therapy peritoneoscopy in localized ovarian cancer.

Because of the recent reports indicating the high incidence of unsuspected diaphragmatic metastases in presumed localized ovarian cancer, we have carried out peritoneoscopy on 14 consecutive patients referred with the diagnosis of Stage I or II ovarian cancer. Of the 14 women none was demonstrated to have diaphragmatic metastases, but 35 per cent were found to have cytologic washings demonstrating malignant cells. The significance of these findings is discussed.


Simplified treatment of large congenital ventral wall defects.

A preformed silicone polymer silo has been used in eleven infants with omphalocele and gastroschisis. This prosthesis has significant advantages over other forms of silo construction. Among these advantages are: (1) easy and rapid primary application; (2) a totally nonreactive and closed system which prevents peritoneum fluid loss and bacterial contamination; (3) a uniform constant stretching force applied to the abdominal wall which promotes expansion of the peritoneal cavity; and (4) the transparent material of the silo which permits constant evaluation of the contained viscera. These factors all contribute to a smoother operative and postoperative course than that which occurs with skin closure or the self-sutured prosthetic silos.


Immunologic approach to the treatment and prevention of gastrointestinal ulcers.

Reported clinical correlations between gastroduodenal ulcer and allergies point up the Arthus ulcer as a possible laboratory model for gastroduodenal ulcer. Successful immunological containment of gastroduodenal ulcer was achieved by utilizing Arthus ulcer dynamics in 12 patients over a two and one-half year period.


Thoracoabdominal motion in chronic obstructive pulmonary disease.

Studies of thoracoabdominal motion using the respiratory magnetometer were performed in 30 patients with chronic obstructive pulmonary disease. Volume equivalency of thoracic and abdominal deflections was established by using the concepts and methods developed by Konno and Mead. Twenty patients were ambulatory, although disabled, and 10 were in acute respiratory failure and were studied in a respiratory intensive care unit. Five of 20 ambulatory patients and 8 of 10 patients in acute respiratory failure showed inward abdominal motion coincident with outward rib cage motion during inspiration, suggesting ineffective diaphragmatic function. This pattern of thoracoabdominal motion was identical to that seen in 2 high quadriplegics with diaphragmatic paralysis when they were breathing entirely with their neck muscles. Inspiratory ascent of the diaphragm was confirmed fluoroscopically in 3 of the 5 ambulatory patients. Patients showing this pattern were generally severely disabled and had the largest residual volumes. Two abnormal patterns of thoracoabdominal motion were observed during the performance of maximal voluntary ventilation in the ambulatory patients. The first, seen in 9 of 20 patients, was characterized by reciprocal or paradoxical motion of rib cage and abdomen, with increase in rib cage volume associated with decrease in abdominal volume during inspiration. The second pattern, seen in 5 of 20 patients, showed complete disorganization of rib cage and abdominal motion, with no consistent or reproducible pattern. Thus, a significant proportion of patients with disabling chronic obstructive pulmonary disease show abnormalities in thoracoabdominal motion that are observable with the respiratory magnetometer and ofter by simple inspection. Most of these abnormalities suggest malfunction of respiratory muscles, particularly the diaphragm.


[Diagnostic of the heart tumors in newborn and children (author's transl)].

Heart tumors in children are rare. Though of benign pathology they are clinically malignant and should be diagnosed early and promptly treated by surgery in spite of the poor results usually obtained. Any heart enlargement in the absence of congenital heart disease accompanied by rhythm and conduction troubles must be considered as suspect. Five cases of heart tumor are reported and clinically described. Four occurred in newborns and the remaining one before the age of one. Heart enlargement was a constant finding. The ECG findings were: W.P.W. syndrome, intraventricular conduction troubles and ventricular tachycardia, wandering pacemaker (one case each) and ventricular hypertrophy with surprisingly low voltages in the corresponding chest leads (two cases).


Spontaneous recovery from nondepolarizing neuromuscular blockade: correlation between clinical and evoked responses.

The effects of nondepolarizing muscle relaxants were allowed to wear off spontaneously in 10 ASA class III and IV patients following major surgery. Neuromuscular and respiratory function were followed by clinical testing and by evoked muscle responses using a train of 4 (TOF) supramaximal stimuli. At a TOF of 70 percent (range 62 to 78%), all patients sustained eye-opening, hand-grasp, and tongue-protrusion, while 9/10 sustained head-lift. Vital capacity (VC) averaged 17 ml/kg when the TOF reached 70 percent. The increase in VC correlated with the increase in TOF (r = 0.88). There was no correlation between inspiratory force (IF) and TOF, but all patients achieved an IF equal to or greater than -22 cm H2O at 70 percent. Thus, TOF correlates well with clinical signs of neuromuscular and respiratory recovery in this group of patients and complements earlier studies in healthy anesthetized patients and nonmedicated volunteers.


Specific loss of stimulator activity following mixed lymphocyte reactions is due to cytotoxic cells.

Experiments were performed to test the hypothesis that stimulating antigens in the mixed lymphocyte reaction (MLR) are expressed in a restricted fashion on lymphocytes. Thus one-way MLR between spleen cells from congenic mouse strains differing at H-2 were treated with 5-bromo-2-deoxyuridine (BrdUrd) and light to inactivate dividing cells. The ability of the residual cells to act as responder or stimulator cells in a subsequent MLR was assessed. As expected, a specific loss of responder cell activity occurred under these conditions. Furthermore, such cells, following irradiation, would not stimulate fresh spleen cells from the strain against which they initially responded, but would stimulate spleen cells, following irradiation, would not stimulate fresh spleen cells from the strain against which they initially responded, but would stimulate spleen cells of unrelated mouse strains. This was shown to be due to the generation of cytotoxic T cells detectable in 51Cr release assays in the primary MLR, despite BrdUrd and light treatment and irradiation. Furthermore, loss of stimulator activity mapped to the H-2K region of the H-2 complex rather than the strong MLR-stimulating I-A or I-B subregions. These experiments provide no evidence of restricted expression of MLR-stimulating antigens on lymphocytes.


Adult thymectomy prevention of the appearance of suppressor T cells which depress contact sensitivity to picryl chloride and reversal of adult thymectomy effect by thymus extract.

Suppressor cells, which depress the passive transfer of contact sensitivity appear in the lymph nodes and spleen of mice injected with picryl sulfonic acid (PSA). These cells produce a soluble suppressor T cell product (s-TCP), and immune lymph node cells incubated in s-TCP fail to transfer contact sensitivity. This paper shows that the appearance of suppressor T cells following the injection of PSA was prevented by adult thymectomy (ATx). ATx also limited the production of s-TCP. However, ATx had no effect on the DNA synthesis which occurs in the lymph nodes of mice injected with PSA. The adverse effect of ATx on suppressor cells was completely reversed by a neonatal thymus graft placed under the renal capsule and partially reversed by grafts given 600 r in vitro and to a limited extent by grafts given 1000 r. The injection of thymus extract also reversed the effect of ATx whereas splenic extract was inactive. It is suggested that the suppressor T cell which depresses contact sensitivity is dependent on the presence of the thymus because it requires a thymus hormone, and not primarily because it belongs to a short-lived population which is rapidly renewed by cells coming from the thymus.


[Pulmonary reactions to non-infective antigenic contaminants].

There are different categories of non-infectious antigenic contaminants capable of provoking pulmonary reactions: thermophilic actinomycetales, fungi, vegetable particles, protein antigens, arthropods, drugs; their identification is based on their isolation, culture, and the study of their biochemical composition. The pulmonary reactions depend on the size and number of antigenic particles inhaled and by the underlying background. The immunological mechanisms brought into play a complex Arthus's phenomenon: in addition to the IgGs, the IgEs and the different factors of complement intervene; the recent acquisitions of immunomorphology enable better comprehension of the histogenesis of the pulmonary granuloma. The diagnosis of extrinsic allergic alveolitis is founded on well defined criteria of clinical, radiological, respiratory functional, immunological and histophthological order. These conditions are met with in agricultural, industrial and urban environments or are related to iatrogenic diseases. Many problems still remain obscure with regards to the pathogenesis and integration within the framework of immunological pneumonia of various conditions, and especially certain sarcoidosis.


[Biochemical aspects of testicular degeneration in the vitamin A deficient rat. 4. Permeability of the vascular walls].

Vitamin A deficiency modifies Na and K concentration values in oedematous testes. On one hand there is an increase of Na, on the other hand a decrease of K. Subcellular protein concentrations are impaired. Testicular fluid electrophoresis show it gets from plasma or lymph. No significant influence of ATPase (Na,+ K+) was demonstrable. Stimulation of lysosomal beta-glucuronidase can explain this fluid accumulation.


[The immunological mechanisms of psoriasis].

The occurrence of ANA in eluates of lymphocytes and polymorphonuclear leucocytes obtained in five untreated psoriasis patients could be demonstrated by means of the indirect immunofloruescence technique. These antibodies appear to be mainly directed against the nuclei of the basal cell layer, however, ANA directed against the nuclei of epidermal and dermal cells have also been encountered. The immunological mechanisms in psoriasis may therefore be looked upon as the result of an alteration in the structure of nucleic acid or nuclear protein of the basal layer cells. Finally psoriasis may be the result of an interplay of various exogenous factors and a special genetical make-up leading to the release of certain nuclear proteins initiating a delayed type immune response at the onset and an Arthus type reaction located in the upper layers of the epidermis at a later stage of the disease, and as a secundary phenomenon the derailment of keratinization. Moreover a slightly decreased mean percentage of circulating lymphocytes forming rosettes with sheep erythrocytes have been found in the patients studied. This slight decrease suggests a diminution of the T-lymphocyte control facilitating the antibody production by B-lymphocytes. The course of events in psoriasis is a self perpetuating inflammatory process.


Incidence study of Down's syndrome in Copenhagen, 1960-1971; with chromosome investigation.

The aim of the study was to obtain incidence figures for Down's syndrome throughout a period where a considerable change in the age distribution of child-bearing mothers has taken place and to study if the expected fall in incidence has occurred. In parts of the Copenhagen Metropolitan area 235 liveborn patients with Down's syndrome were ascertained in the period 1960 to 1971 in a population of 1-2 million with a total of 204771 births. All patients available were examined cytogenetically (75%). In 160 (90-4%) a regular trisomy 21 was observed. In 6-2% of the cases translocations and in 2-3% of the cases mosaics were found. Two double trisomies and a double trisomy mosaic were observed. Throughout the period 1960-71 the percentage of women over 30 years delivering children decreased from 23-4% in the beginning of the period to 16-2% at the end of the period. In the first part of the period 52-6% of the cases were born to mothers over 30, at the end of the period 40% of Down's syndrome mothers were of that age. However, the incidence was unchanged throughout the whole period, about 1-15 per 1000 births. For some age groups a steady rise in incidence of trisomy 21 cases was found throughout the whole period. These findings may be explained by better ascertainment of patients at the end of the period; however, environmental factors may also play a role.


Genetics of transplantation: the major histocompatibility complex.

A genetic region called the major histocompatibility complex of MHC (which plays an important role in the control of graft survival) has been defined in a large number of different species. Several different loci of the MHC have been described, including loci coding for transplantation antigens. These antigens can be divided into two categories: first, the SD antigens that were originally defined serologically and that appear to function as targets for the killer lymphocytes involved in the rejection of a graft and second, the LD antigens that were originally defined by lymphocyte response in the mixed leukocyte culture test and that stimulate helper T lymphocytes. In addition, there are genes for other antigens (referred to as immune response-associated or Ia antigens) and genes that control the ability of an animal to respond immunologically to antigenic stimuli, the immune response or Ir genes. There is evidence for epistatic interaction between these genes in that immune recognition of LD and SD antigens lead to a more pronounced development of cytotoxic (killer) cells than does stimulation by either antigen alone. In addition, the genetic control of immune responsiveness appears, at least in some systems, to reside in two very closely linked genes that may function better in the cis than in the transposition. This latter finding suggests a possible explanation for the strong linkage disequilibrium found between genes of the MHC. A number of new tests have been described to define the antigens of the MHC. Results of these tests have been used for studies of transplantation immunology but in addition to study the very strong associations that exist between some of the MHC antigens in man and various diseases.


The effect of atebrin on bacterial membrane adenosine triphosphatases in relation to the divalent cation used as substrate and/or activator.

The action of atebrin on purified adenosine triphosphatase (ATPase) from Micrococcus lysodeikticus was studied as well as on the membrane-bound and soluble ATPases from Escherichia coli and Bacillus megaterium. Atebrin inhibited the Ca(2+)-dependent activity of all these enzymes, and the inhibition was reversed by an excess of Ca(2+) ions. Kinetic studies carried out with the purified enzyme from M. lysodeikticus showed that the inhibition by atebrin was strongly cooperative, suggesting the complex nature of the process. On the other hand, atebrin stimulated the Mg(2+)ATPase activity of the M. lysodeikticus enzyme, displacing its adenosine 5'-triphosphate (ATP)/Mg(2+) optimum ratios, but inhibited the Mg(2+)-ATPase activity of E. coli provided that ATP was in excess over Mg(2+), i.e., that the ATP/Mg(2+) ratio was higher than its optimum. These results suggest that divalent cations influence the bacterial ATPases in different ways depending on the type of divalent ion and/or enzyme. The effect of atebrin on bacterial ATPases may reflect those differences, and its complex mechanism of action might be related to the existence of more than one site for divalent cations and/or distinct conformational states in these enzymes.


Liberation of protoplasts from mycelium of Neurospora crassa by means of enzymes obtained from autolyzed cultures of this fungus.

Spherical protoplast-like structures were released from Neuropsora crassa mycelia under the influence of cell-wall-lytic enzymes obtained from autolyzed cultures of this fungus, in 50 mM borate-citrate-phosphate buffer, pH 5.5 with 0.5-0.8 M mannitol for appropriate osmotic pressure. The protoplasts retain their morphological aspect for several days at 4 C, or for a longer time when they are washed by centrifugation and incubated with 0.8 M mannitol. The free protoplasts are sensitive to osmotic shock and lyse immediately when placed in distilled water; the vacuoles and other cytoplasmatic material remain intact for some time.


Significance of late reactions after bronchial challenge with house dust mite.

Sixty-nine children with moderately severe perennial asthma were submitted to bronchial provocation tests using aqueous extracts of Dermatophagoides pteronyssinus (house dust mite). 60 (87%) had immediate positive reactions. 73% also had late reactions occurring 4 to 8 hours after the challenge. A significant correlation was found between frequent attacks of asthma in the year before bronchial challange and the occurrence of late reactions. The late reaction was more prolonged and severe than the immediate reaction. The changes in lung mechanics during a late reaction were similar to those found in severe naturally occurring asthma. The possible relevance of the late reaction in antigen-induced asthma is discussed.


Myocardial changes in immature infants requiring prolonged ventilation.

Fourteen infants who had required prolonged ventilation with high concentrations of oxygen for 14 days or more, were studied at necropsy. 11 infants of immature gestation at birth had gross cardiac hypertrophy, defined as a heart weight greater than 2 SD above the mean for their age. No congenital malformation of valves or septum was found, and in the 7 youngest infants with hypertrophy, the ductus arteriosus was anatomically patent. 3 of these 7 infants had an accompanying nurmur. All 11 infants had severe bronchopulmonary dysplasia. The cardiac hypertrophy affected both ventricles and septum in an irregular fashion and was associated with areas of necrosis, progressing to coarse fibroelastotic scars. The intramural vessels showed marked intimal thickening but the main coronary vessels were normal. The 2 youngest infants with cardiac hypertrophy showed the presence of intravascular and endocardial platelet thrombi. In the 3 infants without cardiac hypertrophy less severe zones of necrosis and scarring were present, and only occasional bundles of hypertrophied muscle fibres were seen. In an attempt to understand these hitherto undescribed lesions, a group of 50 fresh stillbirths and 50 first-week neonatal deaths of comparable gestational age were studied. In 19 of these infants foci of myocardial fibre necrosis were present. It is suggested that the lesions in the older infants represent a more advanced and continuing stage of that seen in the younger infants, and that the foci of necrosis are the result of continuing hypoxia and related problems to a failing coronary circulation. The possibility of myocardial damage represents a serious hazard to the successful therapy of the immature asphyxiated infants.


Cutaneous and hepatic haemangiomata.

A 3-month-old infant presented with multiple cutaneous haemangiomata, and was found to have a cardiac murmur and hepatomegaly. The latter increased strikingly over the next 3 months, and was accompanied by cardiomegaly. Other usual signs of congestive cardiac failure were not present, however, and an arteriogram showed the presence of a grossly abnormal vascular pattern in the liver, confirming the clinical suspecions of hepatic haemangiomatosis. Two short courses of steroid therapy resulted in a marked but temporary decrease in liver size. After the age of one year, however, there was gradual regression of all abnormal clinical signs without further therapy.


On the physiology and biochemistry of the scalp and hair lipids.

Analyses were made of the scalp and hair lipids of 67 test persons. These were the most important results: 1. Seborrhoea is caused on one hand by a high secretion performance of the sebaceous glands. A further cause is that a longer period of time passes before a constant lipid amount is established.  2. There was an average of 19.32% of free fatty acids in the scalp and hair lipids on the 1st day after the hair was washed, and 38.68% on the 10th day. These results allow an assessment of the physiological significance of microbial lipolysis outside the secretory ducts of the sebaceous glands. 3. On the hairy head the percentage of free fatty acids in the scalp and hair lipids is independent of the amount of lipids. Such a difference in the concentration of fatty acids as is found between seborrhoea oleosa and seborrhoea sicca on hairless skin can not be found on the hairy head.


A monitor for the continuous assessment of left ventricular performance after open-heart operations.

A cardiac monitoring system has been developed that incorporated phasic aortic blood flow measurement by an extractable electromagnetic flow probe and high-fidelity arterial blood pressure recordings. Cardiac output, stroke volume, and peak aortic blood flow are measured continuously; using logarithmic amplifiers, the pressure-flow derivatives of left ventricular function, such as cardiac power and stroke work, are obtained beat by beat. This monitor is used to follow the postoperative course of patients undergoing cardiac operations and to evaluate the hemodynamic effect of therapeutic agents.


Composition and photoinduced biosynthesis of the carotenoids of a protoplast-like Neurospora crassa "slime" mutant.

A spheroplast-like "slime" mutant of Neurospora crassa (lacking a rigid cell wall) was found to synthesize an identical spectrum of carotenoids as wild type strains except for beta-carotene. Furthermore strict photoregulation of the biosynthesis of these pigments as well as the characteristics of photoinduced carotenogenesis were also nearly identical in the mutant and in the wild type.


The role of cerebral 5-hydroxytryptamine for convulsive threshold and anticonvulsant effect of acetazolamide in rats.

The effect of various substances modifying the activity of serotoninergic system on convulsive threshold and anticonvulsant effect of acetazolamide (ACA) in rats was studied using the electric test. The obtained results are suggestive of 5-hydroxytryptamine (5-HT) playing a significant role for convulsive threshold. On the other hand, the changes in the potency of anticonvulsant effect of ACA resulting from administration of substances altering the level of cerebral 5-HT seems to be secondary to the effect of these substances on convulsive threshold. Additionally, the ACA doses being effective as anticonvulsant were found to increase the cerebral level of 5-hydroxyindoleacetic acid (5-HIAA) and to accelerate the 5-HT turnover.


The role of serotonin in ephedrine-induced stereotypy and hypermotility.

The influence of serotonin agents on stereotypy and hypermotility induced with ephedrine was studied. P-Chlorophenylalanine (PCPA), an inhibitor of serotonin synthesis, had no influence on stereotypy. In reserpinized animals, this reaction was intensified only after high doses of ephedrine (100 and 120 mg/kg), but the precursor of 5-HT synthesis, tryptophan, strongly antagonized stereotypy. Ephedrine-induced hypermotility in mice and rats was potentiated by PCPA. It is suggested that serotonin ephedrine-induced effects, similarly to previous observations with amphetamine.


Evaluation of the influence of epoxide resins and their hardeners on the female body. I. Skin tests.

Skin tests of hypersensitivity were performed in 175 women and 16 men having direct contact during work with epoxide resinsand their hardeners. The tests were applied for 24 hours, and results were recorded after 24, 48 and 72 hours. The percentages of positive skin tests and numbers of skin lesions were found to increase with time of employment in contact with epoxide resins and their hardeners.


Fibrin thrombosis in monocrotaline pyrrole-induced cor pulmonale in rats.

Investigations were carried out to determine the lung lesions responsible for the development of pulmonary heart disease, cor pulmonale, in rats treated with monocrotaline pyrrole or monocrotaline. Animals with right ventricular hypertrophy showed microscopic lung alterations consisting of alveolar edema; fibrin thrombi with partial to complete occlusion of arteries, arterioles, capillaries, and veins; connective tissue proliferation of alveolar septae; cellular hyperplasia of septae; and medial hypertrophy of arterioles. Due to the high incidence of fibrin thrombi in animals with right ventricular hypertrophy, we believe that formation of fibrin thrombi plays a decisive role in the development of chemically induced cor pulmonale.


Congenital intracardiac band: a rare cause of nonrheumatic combined aortic and mitral regurgitation.

A patient had a congenital intracardiac band lying across the aortic valve that caused combined aortic and mitral valvular regurgitation. The band was excised, and the damaged aortic valve was replaced with a prosthesis. The case illustrates that not all congenital intracardiac bands are completely asymptomatic and not all bivalvular incompetence is rheumatic in origin.


Socialization patterns and sexual problems of the institutionalized chronically ill and physically disabled.

A post hoc survey of spontaneous remarks and actions bearing on social and sexual adjustment was done on 155 long-term physically disabled patients in a chronic-care hospital. Thirty-five percent were found to be involved in an active dyadic relationship; the great majority of these were between unmarried patients within the hospital. The remaining 65% were socially unattached. A large proportion of both socially attached and socially unattached patients acknowledged achieving some sort of sexual outlet. The importance of opportunity for sexual activity is discussed as it relates to traditional methods for dealing with the problems of personal confidence and physical competence of the physically disabled.


Treatment of full-thickness abdominal and chest wall losses with split-thickness skin grafting.

A 22-year-old man developed a large abdominal wall and sternal defect resulting from wound dehiscence. This was a sequel to two operations for gunshot wounds of the abdomen, the second one being for intraperitoneal abscess. The infected dehiscence was treated by the open method using povidoneiodine (Betadine) packs. As soon as the patient's condition permitted, split-thickness grafts were applied to the defect. One hundred percent success resulted, and convalescence of this critically ill patient was thereafter uninterrupted until discharge 31 days later. It is the authors' opinion that this method has a wider application than it is usually accredited.


[Comparative pathology of the choroid vessels in glaucoma, hypertension and arteriosclerosis].

Results of histological and histochemical studies of the choroid of the eyes of deceased old people who when alive suffered from glaucoma, hypertensive disease and atherosclerosis, are presented. It was established that hypertensive disease, general atherosclerosis, symptomatic hypertension brought about peculiar changes in the choroid vessels and stroma. There were revealed changes in the venous system of the choroid of the glaucomatous eyes, which testified to the presence of venous congestion in them, this apparently being one of pathogenetic factors in origination of primary glaucoma.


Vitreous surgery. XIV. Complications from sclerotomy in 89 consecutive cases.

All patients were examined preoperatively and postoperatively by indirect ophthalmoscopy and biomicroscopy with a three-mirror lens. The average follow-up was eight months. Our technique of sclerotomy consisted of an incision parallel to the limbus, measuring 1.5 times the diameter of the surgical instrument. The pars plana location was always verified with transillumination. A mattress suture over the lips of the sclerotomy was used to prevent any leakage during the procedure. The intraoperative complications included ciliary body laceration (1%), retinal tears (8%), and vitreous base incarceration in the wound. The postoperative complications consisted of retina dragged into the wound (4%), vitreous tract left by the instrument (6%), neovascular ingrowth (6%), and external symptoms from the Dacron (32%) or polyglycolic acid (5%) suture. The rate of complications is considered low for such high-risk surgery.


Intestinal, gastric body- and antral-type mucosal metaplasia in the gallbladder.

The material consisted of two intestinal, one gastric body-type and 14 antral-type cases of mucosal metaplasia in the gallbladder. Outside the mucosal areas mentioned, the epithelium of the gallbladder had undergone great changes. It usually consisted of goblet cells, enterochromaffin cells, superficial gastric-type epithelial islands and antral-type glands. Extensive areas contained non-sulphated acid mucin and neutral mucin. The areas of normal gallbladder epithelium were small.


[Group-allergic reaction spectrum and sensitization potency of benzylisothiocyanate].

Allergenicity of benzylisothiocyanate and group-allergic cross reactions. Comparative patch-test series made in pateints suffering from contact dermatitis induced by Sulbentin (Dibenzthion)-antimycotics and in guinea pigs, experimentally sensitized to benzylisothiocyanate (BITC), showed: BITC is a potent contact sensitizer and the real hapten in cases of Sulbentin-allergy. Of special importance in this molecule is the benzyl-group. Neither 4,4-diphenylmethandiisocyanate and isophorondiisocyanate (substances used in polyurethane production) nor the closely related methylisothiocyanate (decomposition product of some potato-selecting agents) produced any groupallergic cross reactions in the above-mentioned patients and guinea pigs.


[Contact dermatitides due to dichloropropiophenone].

Contact-allergy eczemas due to dichloropropiophenone. Following an exposition to p-beta-dichloropropiophenone (DCP) of less than one year nine skilled chemical plant workers were taken ill with an eczema from contact allergy, particularly badly seizing their faces, necks, hands and forearms. In all workers in question has been recognized a job connected skin disease with bodily impairment of 20 to 30%. The test concentration of DCP was determined at 0.01% (testing vehicle: oil). Nonexposed persons showed response only at 0.5% DCP concentration (50 times higher percentage!) by falling sick of an uncomplicated irritation erythema, strickly localized. With regard to the almost obligatory tendency towards sensitization there must be strict observation of the stringent measures of a labour protection, and moreover, in the future there should be established a closed system of automatic control.


Studies of energy-linked reactions. Net synthesis of adenosine triphosphate by isolated adenosine triphosphate synthase preparations: a role for lipoic acid and unsaturated fatty acids.

ATP synthase preparations [complex V, proton-translocatin ATPase (adenosine triphosphatase) and oligomycin-sensitive ATPase ] contain stoicheiometric amounts of lipoic acid residues (up to 6mol of lipoic acid/mol of ATPase complex) and catalyse net ATP synthesis in an uncoupler-and oligomycin-sensitive reaction utilizing dihydrolipoate, oleoyl-CoA and oleic acid, or in a reaction utilizing oleoyl-S-lipoate. The terminal reactions of oxidative phosphorylation are thus analogous to those of substrate-level phosphorylation.


Different fractions in the normal and hypertrophied rat ventricular myocardium: an analysis of two models of hypertrophy.

Long-term hemodynamic overload of the heart leads to an increase in myocardial mass. In most cases it is not known to what degree the single components in the myocardium (water, protein, nonprotein substance) increase. As an answer to the overloading of the myocardium, many authors have established an intensification in the synthesis of myocardial proteins. It is, however, little known which proteins are then more intensively created and accumulated. This study examines the dynamics of the protein and nonprotein content as well as of single protein fractions (sarcoplasmic, myofibrillar, and stromal) in both hypertrophied and normal tissue from rat myocardia. The results revealed that in Goldblatt rats, 4-24 weeks after stenosis of one renal artery, no noteworthy differences in the relationships of protein and nonprotein content were caused by hypertrophy (34-54%) due to left ventricular pressure overload. The same is true of the tissue from moderately hypertrophied myocardia (12-17%) of rats exercised for several weeks by swimming training. Determination of hydroxyproline concentration showed that significant differences in the content of the collagen tissue in relation to control animals of the same age occurred only in Goldblatt rats 24 weels after operation. However, greater alterations in the concentrations of various protein fractions could be registered. The increase in the concentration of myofibrillar proteins in hypertrophied myocardial tissue is of particular significance and is to be considered as an adaption of the muscle to the increased mechanical demands. Certain changes regarding the relation of the single components within the myofibrillar fraction (relation of actomyosin concentration to T-fraction; relation of both components to total fraction), whose cause and significance is as yet unclear, could be observed.


Avidity of antibodies in SLE: relation to severity of renal involvement.

The avidity of antibodies to DNA in the sera of 8 patients with SLE was determined by saturation analysis and Scatchard plots. Five of the patients had severe lupus nephritis; the other 3 had relatively mild or no kidney disease. The Scatchard plots revealed components with high relative avidity in the patients with severe nephritis (K values 4.4-10.4 X 10(5) M-1 for nDNA), compared with the patients who had mild or no kidney disease (K values 0.3-1.8 X 10(5) M-1 for nDNA). Avidity measurements may be helpful in the evaluation and treatment of patients with SLE.


Optical activity of disulfide bonds in proteins. 1. Studies on plasmin modified human somatotropin.

The reduction and alkylation of the two disulfide bonds in a preparation of human pituitary growth hormone which had been previously modified by limited proteolysis with the enzyme plasmin have been studied. Quantitative and selective reduction of the carboxyl-terminal disulfide, as well as total reduction of both disulfides, has been achieved in the absence of denaturants. Circular dichroism spectra of the various reduced and reduced-alkylated derivatives have provided sufficient information to allow an estimation of the individual contributions of each disulfide bond to the total optical activity of the protein. These contributions were found to represent a significant portion of the total optical activity between 290 and 250 nm. The carboxyl-termimal bond exhibits negative dichroism with an apparent center near 258 nm ([theta]M,258nm = 2100 deg cm2 dmol-1). By comparison, the contribution of the remaining disulfide is red-shifted to 273 nm, is also negative in sign, and somewhat more intense ([theta]M,273nm = 3200 deg cm2 dmol-1). Circular dichroism measurements have also been used to approximate the rate of reduction of the protein.


Purification of membrane attachment and inhibitory subunits of the proton translocating adenosine triphosphatase from Escherichia coli.

The portion of Escherichia coli adenosine triphosphatase (ATPase) which is peripheral to the membrane (ECFl) is composed of five separate polypeptides referred to as alpha, beta, gamma, delta, and epsilon. Treating purified ECFl with pyridine precipitated the three larger polypeptides (alpha, beta, and gamma), but the two smaller ones (delta and epsilon), which represent only about 10% of ECFl, remained in solution. After removing the pyridine, both delta and epsilon were active and both were obtained in essentially pure form after chromatography on a single molecular-seive column. epsilon strongly inhibited the ATPase activity of ECFl, indicating that epsilon has a regulatory role in the enzyme. epsilon inhibited ECFl missing delta, indicating that delta is not required for inhibition by epsilon. However, enzyme containing just the alpha and beta subunits, which was prepared by treating ECFl with a protease, was fully active hydrolytically but not at all sensitive to inhibition by epsilon. This result suggests that the gamma polypeptide is required for the inhibition of the ATPase by epsilon. delta restored the capacity of ECFl missing delta to recombine with ECFl-depleted membrane vesicles. The ECFl, which became attached to the vesicles by the added delta, was functional in energy transduction, as evidenced by the coupling of ATP hydrolysis to the transhydrogenase reaction in the vesicles. The rebinding of ECFl missing delta was directly proportional to the amount of delta added until all the ECFl receptors in the membranes were occupied. delta may be a stalk which connects the Fl headpiece to the membrane, since the attachment of ECFl to the membrane exhibited an absolute dependence on delta. Although delta is known to have an apparent molecular weight of about 20,000 by gel electrophoresis in the presence of sodium dodecyl sulfate, the active delta eluted from a molecular-seive column with an apparent molecular weight of about 35,000, suggesting that in the active form delta is a dimer or rather elongated in shape. The active epsilon subunit eluted from the same column with an apparent molecular weight of about 16,000.


Detection of a ouabain-induced structural change in the sodium, potassium-adenosine triphosphatase.

The structural consequences of ouabain interaction with a highly purified Na+K+-ATPase preparation, isolated from the outer medulla of porcine kidneys, were examined. The apparent heat capacity vs. temperature profile of the enzyme was obtained with a newly designed differential scanning calorimeter. The profile was characterized by a major endothermic transition at 55.3 degrees C. This transition appeared to correspond to irreversible protein denaturation since it was associated with loss of enzyme activity and the transition was not present in claorimetric profiles obtained after the initial scan of a sample. Interaction of ouabain with its receptor surface on the Na+, K+-ATPase shifted the endothermic transition from 55.3 to 59.5 degrees C and decreased the width of the transition. This indicated that the ouabain-Na+, K+-ATPase complex was more stable with respect to temperature and that the apparent cooperative nature of the transition was greater for the complex than for the untreated enzyme. The effects of the ouabain-enzyme interaction were examined with the fluorescence probe, 8-anilino-1-naphthalenesulfonic acid. The fluorescence of this dye in the presence of the enzyme was monitored as a function of temperature. These measurements also suggested that ouabain induces the formation of a more stable enzyme conformation. Incubation of the enzyme for 10 min at 53 degrees C with and without ouabain and measurement of remaining enzyme activity after the dissociation of bound ouabain confirmed the conclusions from the fluorescence and scanning calorimeter experiments.


Effect of neocarzinostatin-induced strand scission on the template activity of DNA for DNA polymerase I.

Neocarzinostatin (NCS), an antitumor protein antibiotic that causes strand scissions of DNA both in vitro and in vivo, is shown to lower the template activity of DNA for DNA polymerase Iin vitro. There is a correlation between the extent of strand scission and the degree of inhibition, maximal inhibition of the polymerase reaction being obtained under conditions promoting maximal strand scission. These effects can be related to the concentrations of NCS and of 2-mercaptoethanol and are maximized by pretreatment of the DNA with drug. Results from polymerase assays in which the amount of drug-treated DNA template was varied at a constant level of the enzyme suggest that the sites associated with NCS-induced breaks are nonfunctional in DNA synthesis but bind DNA polymerase I. The binding of the enzyme to the inactive sites is further confirmed using [203 Hg] polymerase. It is shown that the lowering of the template activity of DNA by NCS under conditions of strand scission is due to the generation of a large number of inactive sites that block, competitively, the binding of DNA polymerase to the active sites on the template. Furthermore, the inhibition of DNA synthesis, which depends on the extent of strand breakage and on the relative amounts of template and enzyme, can be reversed by increasing the levels of template or polymerase. The finding that DNA synthesis directed by poly [d(A-T)] is much more sensitive to NCS than that primed by poly [d(G-C)] suggests that the drug preferentially interacts at regions containing adenine and/or thymine residues.


Biosynthesis of the dimethylbenzene moiety of riboflavin and dimethylbenzimidazole: evidence for the involvement of C-1 of a pentose as a precursor.

The relative incorporations of specially labeled pyruvate, lactate, erythritol, D-erythrose, D-ribose, and D-glucose precursors into the dimethylbenzene carbon atoms of the 5,6-dimethylbenzimidazole unit of vitamin B12 by Propionibacterium shermanii have been determined. The incorporation data provide information regarding the putative four-carbon biosynthetic unit which is involved in the formation of 6,7-dimethyl-8-ribityllumazine and which is the source of the eight dimethylbenzene carbon atoms of both 5,6-dimethylbenzimidazole and riboflavin. The relative incorporations of the labeled lactate and pyruvate precursors are not consistent with either acetoin or 2,3-butanedione functioning as the four-carbon biosynthetic unit. The relative incorporations of the labeled hexose, pentose, and tetrose precursors indicate that the observed incorporation of C-1 of the pentose into the dimethylbenzene carbon atoms does not involve metabolism to a tetrose intermediate, but occurs more directly. It is concluded that the C-1 position of a pentose precursor is involved in the formation of the putative four-carbon biosynthetic unit.


Anthroylouabain: a specific fluorescent probe for the cardiac glycoside receptor of the Na-K ATPase.

Anthroylouabain (AO) was synthesized by reaction of anthracene-9-carboxylic chloride with ouabain. Nuclear magnetic resonance spectroscopy of AO suggests that the anthracene is esterfied to the rhamnose in the glycoside. AO inhibits Na-K ATPase from human red cells, eel electroplax and rabbit and dog kidney with a KI less than 1muM. AO bound to rabbit or dog kidney Na-K ATPase shows enhanced fluorescence and characteristic spectral shifts. AO binding requires Mg and is optimum in the presence of Mg + Pi or MgATP + Na; ouabain prevents AO binding and fluorescence enhancement if added before AO or reverses it if added after AO is bound. Na inhibits AO binding in the presence of Mg + Pi and K inhibits it in the presence of MgATP + Na. AO binding and dissociation rate constants measured by fluorescence agree qualitatively with reported measurements for ouabain, using other methods, although AO shows faster kinetics than ouabain. Dissociation constants obtained from kinetic measurements are 1.5 X 10(-7) and 1.8 X 10(-7) M for the MgATP + Na complex and Mg + Pi complex, respectively. KD from fluorescence titrations is 2.3 X 10(-7) M for the latter. The enzyme has 2-2.5 nmol of AO binding sites/mg of protein. No differences in the fluorescence parameters of the Mg + Pi or MgATP + Na complexes were observed, suggesting that the same enzyme conformation binds AO under both ligand conditions. Comparison of the AO fluorescence parameters in the enzyme with those of model systems suggests that the binding site is hydrophobic and/or viscous and shielded from H2O. The results indicate that AO is a specific fluorescent probe of the cardiac glycoside receptor of the Na-K ATPase. Possible applications are discussed.


Transient phase of adenosine triphosphate hydrolysis by myosin, heavy meromyosin, and subfragment 1.

The transient phase of adenosine triphosphate (ATP) hydrolysis (early burst) was investigated for myosin, heavy meromyosin (HMM), and subfragment 1 (S-1) over a range of temperatures and pH's. The burst size at pH 8,20 degrees C, is 0.8-0.85, based on steady-state and transient measurements. The equilibrium constant for the enzyme-substrate to enzyme-product transition is 0.85 +/- 0.05. It is concluded that both myosin heads undergo the rapid hydrolysis step and that there are no significant differences for S-1 vs. HMM or myosin. The transient data are fitted reasonably well by a single rate process, but available evidence is consistent with some heterogeneity and a range of rate constants differing by a factor of two. At pH 6.9 and 3 degrees C, the burst size is 0.5 and the hydrolysis is slower than the configuration change measured by fluorescence. The results are consistent with the kinetic scheme (see article). The lower burst at low temperature and pH can be partly explained by a reduction in the equilibrium constant, K3, and ATP can be synthesized on the enzyme by a pH-temperature jump.


Energy transduction in Escherichia coli. The effect of chaotropic agents on energy coupling in everted membrane vesicles from aerobic and anaerobic cultures.

1. The transduction of energy from the oxidation of substrates by the electron transport chain or from the hydrolysis of ATP by the Mg2+-ATPase was measured in everted membrane vesicles of Escherichia coli using the energy-dependent quenching of quinacrine fluorescence and the active transport of calcium. 2. Treatment of everted membranes derived from a wild-type strain with the chaotropic agents guanidine-HC1 and urea caused a loss of energy-linked functions and an increase in the permeability of the membrane to protons, as measured by the loss of respiratory-linked proton uptake. 3. The coupling of energy to the quenching of quinacrine fluorescence and calcium transport could be restored by treatment of the membranes with N,N'-dicyclohyexylcarbodiimide. 4. Chaotrope-treated membranes were found to lack Mg2+-ATPase activity. Binding of crude soluble Mg2+-ATPase to treated membranes restored energy-linked functions. 5. Membranes prepared from a wild-type strain grown under anaerobic conditions in the presence of nitrate retained respiration-linked quenching of quinacrine fluorescence and active transport of calcium after treatment with chaotropic agents. 6. Everted membrane vesicles prepared from an Mg2+-ATPase deficient strain lacked respiratory-driven functions when the cells were grown aerobically but were not distinguishable from membranes of the wild-type when both were grown under anaerobic conditions in the presence of nitrate. 7. It is concluded (a) that chaotropic agents solubilize a portion of the Mg2+-ATPase, causing an increase in the permeability of the membrane to protons and (b) that growth under anaerobic conditions in the presence of nitrate prevents the increase in proton permeability caused by genetic or chemical removal of the catalytic portion of the Mg2+-ATPase.


Control of brain slice respiration by (Na+ + K+)-activated adenosine triphosphate and the effects of enzyme inhibitors.

The involvement of membrane (Na+ + K+)-ATPase (Mg2+-dependent, (Na+ + K+)-activated ATP phosphohydrolase, E.C. 3.6.1.3) in the oxygen consumption of rat brain cortical slices was studied in order to determine whether (Na+ + K+)-ATPase activity in intact cells can be estimated from oxygen consumption. The stimulation of brain slice respiration with K+ required the simultaneous presence of Na+. Ouabain, a specific inhibitor of (Na+ + K+)-ATPase, significantly inhibited the (Na+ + K+)-stimulation of respiration. These observations suggest that the (Na+ + K+)-stimulation of brain slice respiration is related to ADP production as a result of (Na+ + K+)-ATPase activity. However, ouabain also inhibited non-K+ -stimulated respiration. Additionally, ouabain markedly reduced the stimulation of respiration by 2,4-dinitrophenol in a high (Na+ + K+)-medium. Thus, ouabain depresses brain slice respiration by reducing the availability of ADP through (Na+ + K+)-ATPase inhibition and acts additionally by increasing the intracellular Na+ concentration. These studies indicate that the use of ouabain results in an over-estimation of the respiration related to (Na+ + K+)-ATPase activity. This fraction of the respiration can be estimated more precisely from the difference between slice respiration in high Na+ and K+ media and that in choline, K+ media. Studies were performed with two (Na+ + K+)-ATPase inhibitors to determine whether administration of these agents to intact rats would produce changes in brain respiration and (Na+ + K+)-ATPase activity. The intraperitoneal injection of digitoxin in rats caused an inhibition of brain (Na+ + K+)-ATPase and related respiration, but chlorpromazine failed to alter either (Na+ + K+)-ATPase activity or related respiration.


Subunits of the calcium ion-pump system of sarcoplasmic reticulum.

Sarcoplasmic reticulum membranes with high content of Ca2+ -ATPase (80% of total protein) were dissolved in a non ionic medium and were submitted to isoelectric focusing in polyacrylamide gels. The membrane protein was resolved into six main bands whose isoelectric points range from 6 to 5. The mol. wt. of these peptides is about 100 000 as estimated by second dimension electrophoresis in sodium dodecyl sulfate-polyacrylamide system. The electrophoretic behaviour of the purified ATPase enzyme is similar to that of crude membranes.


Cell surface changes in diabetic rats. Studies of lectin binding to liver cell plasma membranes.

We have previously reported changes in the chemical composition of cell surface membranes in diabetic rats (Chandramoulis, V. and Carter, Jr., J. R. (1975) Diabetes 24, 257-262 [1]). To examine the possible implications of these changes for cell surface structures, we have measured the binding of labeled lectins and desialylated glycoproteins to plasma membranes prepared from the livers of streptozotocin--diabetic and control rats. Lectins were chosen which have affinities for different carbohydrate moieties. The binding of ricin and concanavalin A to liver cell membranes from the diabetic rats was significantly reduced, but no change in the binding of wheat germ agglutinin was noted. Binding of desialylated thyrozine--binding globulin, previously shown to be dependent on membrane sialic acid residues, ws strongly suggest that insulin deficiency leads to generalized changes in cell surfaced glycoproteins, at least in this animal model of diabetes.


Variation in sensitivity of the cardiac glycoside receptor characteristics of (Na+ + K+)-ATPase to lipolysis and temperature.

1. The rate of binding of [3H]ouabain to untreated membrane preparations of [Na+ +K+]-ATPase is a timperature--dependent process displaying a thermal transition close to 25degreesC. The apparent energies of activation which can be calculated above and below this transition are similar to, but not identical with, those previously reported for activation of the enzyme by cations. 2. Treatment of the enzyme preparation with detergents or lipolysis with phospholipase A eliminates the thermal transition resulting in linear Arrhenius plots. 3. The number of sites available for [3H]ouabain binding is not temperature dependent as the amount of [3H]ouabain bound at equillbrium is not changed between 10 and 37 degrees C. 4. Treatment of the enzyme with phospholipase A results in time-dependent changes in the number of binding sites for [3H]ouabain at equilibrium. 5. Treatment of the membrane enzyme preparations with detergents reveals additional [3H]ouabain binding sites which are extremely sensitive to lipolysis with phospholipase A. 6. There are a number of [3H]ouabain binding sites which remain resistant to lipolysis by phospholipase A in either untreated or detergent-treated membrane preparations. 7. It is suggested that [3H]ouabain binding sites exist in the membrane in at least two different environments, one of which is resistant the other sensitive to attack by phopholipase A.


The involvement of sarcotubular membranes in genetic muscular dystrophy.

Microsomal preparations from breast muscle of normal and dystrophic chickens are characterized with regard to ultrastructural features, protein composition, Ca2+ transport and ATPase activity. Dystrophic muscle yields a greater microsomal dry weight, with a reduced protein to lipid ratio. This is related to the presence of a considerable number of low density microsomes, in addition to seemingly normal microsomes. The low density microsomes display a reduced number of protein particles on freeze fracture faces. Electrophoretic analysis reveals nearly identical patterns in normal and dystrophic microsomes. Furthermore, normal and dystrophic microsomes sustain equal rates of Ca2+ transport and ATPase, demonstrating an identical protein specific activity. However, the dystrophic microsomes have a lower capacity to retain transported Ca2+. The high yield of low density microsomes with reduced capacity for Ca2+ uptake is attributed to the presence of membranes proliferated in the junctional and tubular sarcomere regions of the dystrophic muscle. It is suggested that proliferation of such membranes accounts for the altered excitation-contraction coupling and cable properties of genetically dystrophic muscle.


The localization of the MM isozyme of creatine phosphokinase on the surface membrane of myocardial cells and its functional coupling to ouabain-inhibited (Na+, K+)-ATPase.

A rat heart plasma membrane preparation isolated in a sucrose medium and some of its enzymatic properties have been investigated. It has been shown that a rat heart plasma membrane fraction contains high creatine phosphokinase activity which can not be diminished by repeated washing with sucrose solution. Creatine phosphokinase extracted from a plasma membrane fraction with potassium chloride and 0.01% deoxycholate solution is electrophoretically identical to MM isoenzyme of creatine phosphokinase. Under the conditions where (Na+,K+)-ATPase is activated by addition of Na+, K+ and MgATP, creatine phosphokinase of plasma membrane fraction is able to maintain a low ADP concentration in the medium if creatine phosphate is present. The rate of creatine release is dependent upon MgATP concentration in accordance with the kinetic parameters of the (Na+,K+)-ATPase and is significantly inhibited by ouabain (0.5 mM). The rate of creatine release is also dependent on creatine phosphate concentration in conformance with the kinetic parameters of MM isozyme of creatine phosphokinase. It is concluded that in intact heart cells the plasma membrane creatine phosphokinase may ensure effective utilization of creatine phosphate for immediate rephosphorylation of ADP produced in the (Na+,K+)-ATPase reaction.


Cooperative interactions between the contractile proteins of cardiac and skeletal muscle.

The calcium activation of the ATPase (ATP phosphohydrolase, EC 3.6.1.3) activity of cardiac actomyosin reconstituted from bovine cardiac myosin and a complex of actin-tropomyosin-troponin extracted from bovine cardiac muscle at 37 degrees C was studied and compared with similar proteins from rabbit fast skeletal muscle. The proteins of the actin complex were identified by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. Half-maximal activation of the cardiac actomyosin was seen at a calcium concentration of 1.2 +/- 0.002 (S.E. of mean) muM. A hybridized reconstituted actomyosin made with cardiac myosin and the actin-tropomyosin-troponin complex extracted from rabbit skeletal muscle was also activated by calcium but the half-maximal value was shifted to 0.65 +/- 0.02 (S.E. of mean) muM Ca2+. Homologous rabbit skeletal actomyosin showed half-maximal activation at 0.90 +/- 0.01 (S.E. of mean) muM Ca2+ and the value for a hybridized actomyosin made with rabbit skeletal myosin and the actin-complex from cardiac muscle was found at 1.4 +/- 0.03 (S.E. of mean) muM Ca2+ concentration. Kinetic analysis of the Ca2+ activated ATPase activity of reconstituted bovine cardiac actomyosin indicated some degree of cooperativity with respect to calcium. Double reciprocal plots of reconstituted actomyosins made with bovine cardiac actin complex were curvilinear and significantly different than those of reconstituted actomyosins made with the rabbit fast skeletal actin complex. The Ca2+-dependent cooperativity was of a mixed type as determined from Hill plots for homologous reconstituted bovine cardiac and rabbit fast skeletal actomyosin. The results show that cooperative interactions in reconstituted actomyosins were greater when the actin-tropomyosin-troponin complex was derived from cardiac than skeletal muscle.


Studies on the amino groups of myosin ATPase. III. Effect of nucleotides on the fluorescence of beta-naphthoquinone-4-sulfonate bound to amino groups of myosin.

beta-Naphthoquinone-4-sulfonate was used for chemical modification of amino groups of myosin. The reagent was found to affect also the sulfhydryl groups if the reaction was not prevented by previous disulfide exchange with cystamine. When cystamine protection was employed the ATPase (ATP phosphohydrolase, EC3.6.1.3) activity was enhanced in the presence of Mg2+ and decreased in the presence of K+ or Ca2+, a pattern typical of myosin with blocked essential amino groups. On addition of ATP or ADP a blueshift was observed in the fluorescent emission spectrum of beta-naphthoquinone-4-sulfonate bound by myosin, presumably owing to conformational changes in the environment of essential amino groups induced by the binding of nucleotides.


Fibrin digestion by thrombin. Comparison with plasmin-digested fibrinogen.

Solutions of plasminogen-free human fibrinogen alone or (1) treated with sodium p-chloromercuribenzoate in order to inactivate factor XIII, or (2) enriched with factor XIII, cysteine and CaC12, were clotted with plasmin-free human thrombin and incubated under sterile conditions. The clots dissolved gradually within 2 days (fibrin from sodium p-chloromercuribenzoate-treated fibrinogen) to 15 days (fibrin from factor XIII-enriched fibrinogen). This proteolytic process was not affected by soybean trypsin inhibitor but was completely inhibited by hirudin. Gel electrophoresis of the thrombin digests indicated the formation of bands equivalent to bands X, Y, D and E of plasmin digests of fibrinogen. The two latter bands, whose identity was confirmed by immunoelectrophoresis, appeared at a more advanced stage of proteolysis than the corresponding bands of plasmin digests. The number of isopeptide bonds present did not appear to affect the rate of release of acid-soluble peptides. Gel electrophoresis and the rate of release of acid-soluble peptides indicated that fewer bonds are hydrolysed by thrombin at the time of the complete solubilization of the clot than are split by plasmin when fibrinogen becomes unclottable by thrombin.


Depression, ECT, and erythrocyte adenosinetriphosphatase activity.

Erythrocyte membrane Na+-K+ ATPase and Ca++ATPase levels were investigated in 11 women treated with ECT for endogenous depression and 11 age-matched normal control subjects. Pretreatment ATPase levels in depressives were significantly lower than in controls, and increased to control levels after a course of ECT. These data are discussed in terms of the physiology of depressive illness and ECT.


Electronic trace of the mean axis of the heart.

A technique is described for tracing the mean electrical axis of the heart from an ECG waveform generator on a general purpose CRT, which could be used to teach medical students and might also be useful as an auxillary unit to investigate the possible applications of the mean electrical axis to the diagnosis of cardiac disorders.


On the role of enzyme cooperativity in metabolic oscillations: analysis of the Hill coefficient in a model for glycolytic periodicities.

The role of enzyme cooperativity in the mechanism of metabolic oscillations is analyzed in a concerted allosteric model for the phosphofructokinase reaction. This model of a dimer enzyme activated by the reaction product accounts quantitatively for glycolytic periodicities observed in yeast and muscle. The Hill coefficient characteristic of enzyme-substrate interactions is determined in the model, both at the steady state and in the course of sustained oscillations. Positive cooperativity is a prerequisite for periodic behavior. A necessary condition for oscillation  in a dimer K system is a Hill coefficient larger than 1.6 at the unstable stationary state. The analysis suggests that positive as well as negative effectors of phosphofructokinase inhibit glycolytic oscillations by inducing a decrease in enzyme cooperativity. The results are discussed with respect to glycolytic and other metabolic periodicities.


Semicontinuous flow centrifugation for the pheresis of immunocompetent cells and stem cells.

Mononuclear cells from human peripheral blood were purified by semicontinuous flow centrifugation (SCFC) using the Haemonetics model 30 blood cell separator; 64% +/- 7% of the mononuclear cells in 600 ml of peripheral blood were collected in a 30-ml volume. Analysis of sequential 5-ml aliquots of the mononuclear cell concentrate revealed that both immunocompetent cells and granulocytic progenitor cells (CFU-C) were proportional to the cell count throughout the buffy coat. In vitro pheresis of large volumes of human bone marrow resulted in recovery of 63% of the cells, 12% of the hemoglobin, and 84% of the CFU-C in 20% of the original volume. Further centrifugation eliminated 80% of the platelets without loss of cells or CFU-C. SCFC of peripheral blood or bone marrow selectively concentrated mononuclear cells and reduced the contamination by granulocytes and erythrocytes. Large numbers of mononuclear cells can thus be collected for studies in vitro or for cryopreservation and the autologous reconstitution of immunosuppressed or myelosuppressed patients undergoing intensive antitumor therapy.


The change of erythrocyte shape following action of different substances altering mg++-dependent ATPase activity (actomyosin-like protein).

It was found that some substances as aspartate, glutamate, atropine, physostigmine, ephedrine, caffeine and theophylline tended to alter the erythrocyte shape in the same concentration in which also the Mg++-dependent ATPase activity had been changed. The employment of various concentrations of barbiturate revealed that changes of the erythrocyte shape were dependent on its concentration. In the present study the relationship between Mg++-dependent ATPase and biconcave erythrocyte shape is discussed.


[Experimental study of a rostro-caudal systemization in the inferior olivary complex].

Injection of 3-acetylpyridine at a LD50 dose to albino rats produces in a few days the destruction of olivary neurons. But the caudal part of the olivary complex, particularly accessory olives, escapes the destruction by this antimetabolite of nicotinamide. Nicotinamide protects olives agains 3-acetylpyridine. However, a preliminary histoenzymological study of dehydrogenases demanding a coenzyme derived from nicotinamide has given no significant results. The authors invoke the necessity of a rostro-caudal systematization of the olivary complex, based on fine structure, connnections and metabolism of neurons.


Frequency-dependent changes in the cardiac sarcolemmal ATPase.

1 Effects of various frequencies (0.25, 0.5, 1.0, 1.5 or 2.0 Hz) of stimulation for various durations (2, 5, 10 or 15 min) on the contractile force of trabecular or papillary muscles of dog myocardium were investigated. 2 Effects of various frequencies (0, 0.25, 0.5, 1.0, 2.0 Hz) of various stimulus strengths (0.5, 1, 10 V) for various durations (2,5,10 or 15 min) on the Mg2+/-dependent Na+/--K+/--adenosinetriphosinetriphosphatase (ATPase) of isolated sarcolemmal fraction of dog myocardium were determined. 3 There was a frequency-dependent increase in the contractility and inhibition of the Na+/--K+/--ATPase within 2 minutes. 4 Frequency-dependent increase in the contractility and inhibition of Na+/--K+/--ATPase decreased as the duration of stimulation was increased. 5 The diminution in the inhibition of ATPase was associated with a decrease in the contractility with prolonged stimulation. 6 These results suggest that the frequency-dependent increase in the myocardial contractility might be mediated through an inhibition of the sarcolemmal ATPase.


Folie à quatre.

A case of folie à quatre is described affecting a proband and his wife, sister and brother. The three family members retained their symtoms of paranoid schizophrenia. The wife was not mentally ill and her delusions disappeared in time (folie imposée). Coincidentally, there were several cases of Huntington's chorea amongst her relatives. Different categories of folie à deux are demonstrated in the various family members and relationships.


Influence of severe hypercapnia upon cerebral cortical metabolism, CSF electrolyte concentrations and EEG in the cat.

The interconnections between EEG, intermediary and energy metabolism of the brain cortex and CSF potassium level are studied during severe hypercapnia in anaesthetized, artificially ventilated cats. Hypercapnic animals were ventilated with 40 to 50% to CO2 in oxygen. During severe hypercapnia the EEG becomes isoelectric. The CSF potassium concentration is raised and the changes in metabolism suggest an acidosis-induced inhibition of phosphofructokinase and, probably, of hexokinase. The energy charge potential remains unchanged whereas the cortical ATP concentration increases slightly. It is assumed that the changes in P-creatine and creatine levels are related to the pH-dependency of creatine phosphokinase. Recovery animals were ventilated with 40% CO2 in O2 and subsequently with room air. After termination of CO2 inhalation the EEG reappears, the CSF potassium concentration normalizes, and the inhibition of the glycolytic enzymes disappears. The energy charge potential shows a small decrease. It is not possible to trace back the disappearance of the EEG to only one of the recorded parameters. Cortical P-creatine levels, CSF potassium concentration, changes in membrane permeability and cortical amino acid concentrations are considered in this context.


Primary pelvic hydronephrosis in children: a retrospective survey.

A retrospective review of 63 children with primary pelvic hydronephrosis has revealed many features similar to those in adults. A plea is made for the greater use of pressure/flow studies in the renal pelvis in the assessment of hydronephrosis. The value of a modified and simplified nephroplasty as an adjunct to pyeloplasty in the more advanced obstructive cases is described and its greater use encouraged.


Urodynamics in the prune belly syndrome.

Urodynamic studies have been carried out in 10 boys with the prune belly syndrome. In spite of gross radiological changes the condition is compatible with normal voiding dynamics. Filling cystometrograms show a marked shift to the right. Pressure/flow studies may demonstrate an unbalanced voiding mechanism which can be treated by urethrotomy. Following urethrotomy urethral pressure profiles showed a significant fall, flow rates increased and residual urine volumes were reduced. Urological treatment in the prune belly syndrome should be directed at producing a bladder which empties well: a balanced voiding mechanism. Urodynamic investigations are helpful in achieving this aim. Residual urine determination and flow rates should be used in routine follow-up. Urethrotomy to lower bladder outflow resistance is advocated as one of the first steps in treating the unbalanced voiding mechanism that is often found in the prune belly syndrome.


Urodynamic assessment of bladder function.

Bladder function in micturition may be studied, without interference from the urethra, through 2 parameters, Piso and Q, which are measures respectively of the maximum pressure and of the maximum flow rate that the bladder can generate, i.e. of its intrinsic strength and speed. These parameters may be determined in a standard urodynamic investigation if the patient interrupts voiding for a short time with the external sphincter. The normal ranges of Piso and Q depend only slightly on age and sex and seem to be as follows: Piso, 50 to 100(+)cm H2O in both sexes; Q, 35 to 120 ml s-1 in males, 20 to 80 ml s-1 in females. There are significant differences in both parameters between different groups of patients. Many females, with stress or urge incontinence or with urgency, have bladders which seem to be weaker than normal (low Piso). The majority of proximally obstructed males, and many who have been surgically relieved of obstruction, have bladders which are significantly slower than normal but are of normal strength (low Q, normal Piso). Therefore the characteristic response of the detrusor to obstruction appears to be not the expected mechanical hypertrophy (Turner Warwick et al., 1973) but reduction in intrinsic speed. In contrast, a few proximally obstructed males and most males with a history of primary enuresis (persisting after 6 years of age) have bladders of normal speed and of strength significantly greater than normal (normal Q, high Piso), suggesting true mechanical hypertrophy of the detrusor. Females with a history of primary enuresis do not show this pattern so clearly. Since these sex- and disease-related differences must surely be of clinical significance, and since it is so easy to measure Piso and Q by the method given in section (e) of the Appendix, those who are concerned with clinical urodynamics are urged to investigate bladder function in this or some equivalent way (e.g. that proposed by Schäfer and Melchior (1975)).


A preliminary assessment of bladder distension in the treatment of enuretic children.

Urodynamic studies were performed in 22 enuretic children. Each child had previously been investigated to exclude gross psychological disturbance and organic disease and had been treated unsuccessfully in the past by conventional means. 16 of the 22 children showed evidence of bladder instability and were subjected to bladder distension. At follow-up, 4 children were in complete remission of symptoms, 6 had improved and 6 showed no change; the girls responded better than the boys. The interpretation of urodynamic studies, the significance of the results of bladder distension and the possible role of detrusor instability in the aetiology of enuresis are discussed.


Congestive cardiomyopathy in uraemic patients on long term haemodialysis.

Five uraemic patients who developed progressive cardiac failure with clinical evidence of congestive cardiomyopathy at the start or during haemodialysis treatment were studied. The diagnosis of cardiomyopathy, for which there was no apparent cause, was confirmed by angiocardiographic and haemodynamic studies. These showed a significant increase in left ventricular end-diastolic volume over normal values obtained in 12 patients without uraemia. The mean velocity of myocardial fibre shortening was significantly decreased, as was the index of normalised rigidity. Three of the five patients presented the complete picture of the disease. The other two also had considerable ventricular dilatation and a decreased index of normalised rigidity but normal ejection fraction and only moderately decreased myocardial contractility indices. This suggests that there may be primary involvement of normalised heart muscle rigidity followed by secondary changes in myocardial contractility in uraemic patients with congestive cardiomyopathy.


Neuroblasts-glia interaction in tissue culture as evidenced by the study of ectoenzymes. Ecto-ATPase activity of mouse neuroblastoma cells.

Ecto-ATPase and ecto-5'-nucleotidase activities of hamster astroblasts, clonal line NN, and mouse neuroblasts, clonal line Ml in coculture, have been studied. The originally low ecto-ATPase activity in both cell lines increased many fold when these cell lines were cocultured. An increase of ecto-ATPase activity was also found in coculture of neuroblastoma cells with chick fibroblasts. Neuroblastoma Ml cells were separated from coculture with hamster astroblasts after 7 days and 2 months. Reisolated M1 cell lines exhibited higher ecto-ATPase activity than the original M1 cell line. The M1 cell line separated after 2 months of coculture had higher ecto-ATPase activity than the M1 cell line separated after 7 days of coculture with hamster astroblasts. This higher ecto-ATPase activity continued for more than 20 replications after separation of the M1 cells from the glial cells.


Investigation of the quaternary structure of Neurospora pyruvate kinase by cross-linking with bifunctional reagents: the effect of substrates and allosteric ligands.

Pyruvate kinase (EC 2.7.1.40) of Neurospora, a tetramer composed of apparently identical subunits, has been shown to be a dimer of dimers by interprotomeric cross-linking experiments in which bifunctional reagents were used. An analysis of the polyacrylamide gel profiles of the enzyme after cross-linking with glutaraldehyde, dimethyl suberimidate, and dimethyl adipimidate shows that the extent of intersubunit cross-linking is influenced markedly by the ligand bound to the enzyme. Bifunctional cross-linking reagents with a shorter distance between the two functional groups form cross-links effectively in the unliganded enzyme. In the FDP-pyruvate kinase complex, cross-linking was observed over longer distances compared with the unliganded enzyme. It is demonstrated that covalent cross-linkers cah be used as sensitive indicators of conformational changes induced in pyruvate kinase by substrates and allosteric ligands.


Advances in the staging and treatment of ovarian cancer.

The age adjusted death rate for ovarian cancer has remained unchanged for the past 20 years. Recent data obtained by staging ovarian cancer patients with lymphangiography and peritoneoscopy demonstrated that many patients with apparently localized disease actually have occult dissemination within the abdomen. These new staging techniques plus the determination of the histologic grade of anaplasia may permit a more precise determination of a patient's prognosis and therefore better design of therapeutic stategy. Radiotherapeutic techniques are being adapted to attempt to treat some areas of occult disease. Numerous single chemotherapeutic agents are capable of producing objective tumor responses. Preliminary data suggest that combination chemotherapy can increase the objective response rate above that seen with single agents. Longer follow-up is necessary to determine whether combination chemotherapy can prolong survival.


Depressed responder and stimulator capacities of peripheral lymphocytes from patients with advanced breast cancer in the mixed lymphocyte culture.

Peripheral lymphoid cells of patients with carcinoma of the breast were examined for reactivity (responders) against allogeneic lymphoid cells in the one-way mixed lymphocyte culture. The latter cells were also tested for response against the patients' lymphocytes (stimulators). The responder and stimulator capacities of lymphoid cells of patients with advanced cancer were found to be significantly reduced compared to cells from healthy subjects. Such defects were not observed in disease-free women previously treated for primary carcinoma of the breast. The results support the view that there is an abnormality of the lymphocyte-monocyte pool of cells in patients with advanced cancer.


Biological and biochemical properties of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (NSC D 254157), a nitrosourea with reduced bone marrow toxicity.

1-(2-Chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), a water-soluble nitrosourea, differs from 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) by the placement of the cytotoxic group on C-1 of glucose. Its biological and biochemical properties are compared with those of chlorozotocin. At a 10% lethal dose (10 mg/kg i.p.), GANU demonstrates minimal myelosuppression. This dose failed to depress normal bone marrow DNA synthesis, in contrast to a 96% inhibition in L1210 DNA synthesis. In L1210 cell suspension, equimolar doses of GANU and chlorozotocin produced equivalent degrees of inhibition in DNA synthesis. GANU has significant L1210 activity in BALB/c X DBA/2 F1 mice treated on Day 2 of tumor growth. A 117% increased life-span and 15% 45-day survivors are atained with 15 mg/kg i.p., a 50% lethal dose. However, in concurrent studies using randomly selected littermate groups of mice, GANU proved less active than chlorozotocin which produced a 306% increased life-span (15 mg/kg i.p.). GANU and chlorozotocin have similar in vitro alkylating activity but the in vitro carbamoylating activity of GANU is sevenfold that of chlorozotocin. On a molar basis, the lethal toxicity of GANU is twice that of chlorozotocin. The significant carbamoylating activity of GANU may contribute to its greater toxicity and therefore limit the mumoles of alkylating agent that can be administered to the tumor. These structure-activity studies further confirm that the addition of a glucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.


Sequential laparoscopy and laparotomy combined with bone marrow biopsy in staging Hodgkin's disease.

In a series of 121 unselected, previously untreated patients with Hodgkin's disease staging laparoscopy combined with needle bone marrow biopsy detected the presence of extranodal disease in the liver or marrow or both in 9% of the patients. A spleen biopsy yielded positive findings in 13%. Subsequent laparotomy with open marrow biopsy performed in 110 patients with negative liver and marrow findings from the first combined procedure revealed the presence of extranodal hepatic lymphoma in two additional spleens. Surgical marrow biopsy was always interpretey. Although devoid of major complications, biopsy of the spleen is not recommended as a routine procedure in staging laparoscopy. This prospective sequential study confirms that laparoscopy plus needle marrow biopsy is a useful, rapid, safe, and economic procedure to establish stage IV disease in the large majority of patients with nodal involvement. Considering the recent more extensive use of chemotherapy for intermediate stages of Hodgkin's disease, our findings suggest that laparotomy with splenectomy needs a critical re-evaluation as a routine staging procedure for patients with no overt extranodal lymphoma.


Hepatic artery infusion of 5-FUDR after prior systemic 5-fluorouracil.

Twenty-one patients with disseminated colon carcinoma and clinically significant liver metastases were treated with 5-FUDR via hepatic artery infusion (HAI). All patients had previously received systemic chemotherapy consisting of either 5-fluorouracil aone or in combination with other agents. At the time of the initiation of the HAI, clinical disease in all patients was progressing. A PR of hepatic metastases was noted in eight patients (35%) with a median and mean duration of response of 4.5 and 5.0 months respectively. The median and mean survival from the start of HAI for responders was 8.0 and 9.0 months and for nonresponders was 1.0 and 1.6 months respectively. It appears that a significant response rate can be achieved with HAI of 5-FUDR in spite of previous exposure to fluorinated pyrimidines.


Common ECG changes in athletes.

The various ECG changes found in a group of 3,000 healthy athletes are discussed on the basis of eight representative ECG recordings. The common findings were sinus bradycardia, atrioventricular conduction disturbances, left and right ventricular hypertrophy according to the accepted voltage criteria, right axis deviation, intraventricular conduction disturbances (mainly in the right side of the heart), and various disturbances of the repolarization phase. The literature on this subject is reviewed, and the possible mechanisms involved in production of the various ECG changes are discussed. It is pointed out that in the absence of other evidence suggestive of cardiovascular disease, these changes should be considered as a normal variant and not lead to restriction of physical activity.


Regeneration of soleus muscles of rat autografted in toto as studied by electron microscopy.

Rat soleus muscles were autografted from right to left legs, and regeneration following necrosis of all original myofibres was studied after 7 to 250 days. The best regenerates were from grafts replacing all calf muscles and sutured to the tendon stumps. After 30 days the size of such regenerates was equal to those from minced gastrocnemius muscles: the cross sectional area of muscle tissue was 30% (1.7 mm2) and the number of fibres was 180% (4500) of normal soleus muscles; the fibre diameters were 10 to 40mum. To increase the number of myoblasts before grafting some muscles were injured by Ringer solution of 70 degrees C and transplanted after 2 days. Nevertheless, this did not influence regeneration. After 7 days clusters of myotubes occurred in the periphery of the muscle. These myotubes originated from myoblasts growing like endothelial cells on the inner face of the persisting basal lamina tubes of necrotic fibres. After 30 days the muscles were vascularized. Fibres formed in a common basal lamina detached and so looked "split". Satellite cells of new fibres came from undifferentiated cells associated with myotubes, i.e. from myoblasts. After 30 days and more regenerates contained three sorts of fibres. 1. Thin (5 to 20 mum) fibres resembling fetal muscle fibres. They were most prominent after 30 days, and probably not yet innervated. 2. Thin (10 mum) degenerating fibres as in long-time denervated muscles. 3. Thick (more than 30 mum) mature looking fibres which were innervated and revealed end-plates. Half of the grafts studied after 30 and 60 days contained unmyelinated and myelinated axons which had grown along strands of surviving Schwann cells. After 250 days, only two muscles were studied which both lacked innervation. Almost all regenerates contained muscle spindles, which, however, were not innervated. Within the persisting spindle capsules new muscle fibres had been formed from satellite cells of the former intrafusal fibres.


Isolation, characterization and localization of bovine adrenal medullary myosin.

Myosin was isolated in high purity from the bovine adrenal medulla by gel filtration and ion exchange chromatography. The purified myosin was analyzed by electrophoresis in gels containing SDS and found to contain a 200,000 molecular weight heavy chain and major light chains of molecular weights 20,000 and 17,000 in a 1:1:1 molar ratio. At high ionic strength the myosin had high Ca-ATPase and K-EDTA-ATPase activities and low Mg-ATPase activity. At low ionic strength, the Mg-ATPase was activated to a low level by rabbit muscle actin. The myosin was found to decorate F-actin in the absence, but not the presence of ATP. In low ionic strength solutions, the myosin assembled into characteristic bipolar filaments. The distribution of this myosin in the adrenal medulla and of cross-reacting myosin in several other bovine tissues was determined with the use of anti-medullary myosin immunoglobulin G as a specific stain that was detected by direct and indirect immunofluorescence. In the medulla strong staining was seen between the chords of chromaffin cells indicating that presence of a highly muscular vasculature that may perform functions analogous to those of the myoepithelium of exocrine glands. The chromaffin cells showed weak positive staining around the nuclei and in a pattern radiating toward adjacent blood vessels. Cells of the inner zone of the adrenal cortex showed strong staining in the peripheral cytoplasm while cells in the intermediate and outer zones did not stain. In a blood smear, platelets and the cytoplasm of leukocytes stained strongly while erythrocytes did not stain. In striated muscle and the gray and white matter of the cerebrum only the capillaries and larger vessels stained. In the liver the phagocytic cells bordering vascular sinuses staine strongly while the hepatocytes were separated from one another by a 2 micron trilaminar band possibly representing the microfilament web surrounding the bile canaliculi and associated with junctional complexes. The results suggest that myosin is present in several highly differentiated, non-motile tissue cells where it may play a role in secretion or other specialized functions.


Mistranslation in E. coli.

Flagellin, the protomeric subunit of bacterial flagella, contains no cysteine. We have detected the incorporation of trace quantities of 35S-cysteine into flagellin, highly purified and then resolved by SDS polyacrylamide gel electrophoresis, to measure mistranslation in vivo. Under normal conditions, this value is about 6 X 10(-4) pmoles cysteine per pmole flagellin. This value is greatly increased during growth in low concentrations of streptomycin and neomycin, antibiotics which are known to stimulate misreading in vitro. Of the specific types of misreading which streptomycin stimulates in vitro, only misreading of the CGU and CGC arginine codons could give rise to illegitimate incorporation of cysteine. In agreement, partial arginine starvation increases the incorporation of 35S-cysteine into flagellin in a relA- mutant, with or without streptomycin, but has no such effect in its isogenic relA+ partner- Assuming from these results that 35S-cysteine incorporation into flagellin reflects misreading of CGU/C coda, we deduce a misreading probability per codon in the range of 10(-4).


Relationship between blood pressure of spontaneously hypertensive rats and alterations in membrane properties of mesenteric arteries.

Spontaneously hypertensive rats (SHR) and two strains of normotensive rats were compared with respect to enzymatic activities and calcium accumulation of plasma membrane and endoplasmic reticulum enriched fractions from their mesenteric arteries. Increased specific activities of alkaline phosphatase, 5'-nucleotidase and Mg2+-ATPase, and increased ATP-dependent calcium accumulation were found in 5- to 6-month-old SHR as compared to both strains fo age-matched normotensive rats. Alkaline phosphatase was increased in 33-day-old "early hypertensive" and 3- to 4-month-old SHR, but 5'-nucleotidase, Mg2+-ATPase, and calcium accumulation were not. Hydralazine treatment of young SHR partially prevented the increase of both alkaline phosphatase activity and blood pressure that develops with age. The relationship between alkaline phosphatase activity and the alterations in vascular reactivity associated with hypertension remains to be determined.