Mechanics of ventilation with positive end-expiratory pressure. The effect of graded increments in positive end-expiratory pressure (PEEP) on arterial oxygen partial pressure (PaO2) and shunt fraction (Qs/QT), oxygen delivery, and respiratory mechanics and work required to ventilate 8 critically ill patients is reported. The work required to ventilate the patients increases markedly with the application and progressive increase in the level of PEEP. However, improvement in lung mechanics lowers the net work of ventilating the lungs. At 20 cm H2O PEEP, the mean value for the work of ventilation in this group of patients is twice the mean value without PEEP. The increase in work of ventilation with PEEP is critical in the use of PEEP when patients are breathing spontaneously with or without intermittent mandatory ventilation.


Gross and microscopical blood supply of the trachea. Twenty-one human tracheal specimens were perfused and dissected, 10 with conventional techniques and 11 with clearing and microdissection techniques. The lateral pedicles of the trachea and esophagus induct vessels from the inferior thyroid, subclavian, supreme intercostal, internal thoracic, innominate, and superior and middle bronchial arteries. These vessels are interconnected along the lateral surface of the trachea by an important longitudinal vascular anstomosis. From the 2 lateral longitudinal anastomoses the lateral and anterior tracheal walls receive their blood supply through transverse segmental vessels that run in the soft tissues between the cartilages. These transverse vessels interconnect the longitudinal anastomoses across the midline and feed the submucosal capillary network that arborizes richly beneath the endotracheal mucosa. The tracheal cartilages receive nourishment from the capillary bed applied to their internal surface. The esophageal arteries and their subdivisions that supply the posterior membranous wall of the trachea contribute almost nothing to the circulation of the cartilaginous walls.


Clinical spectrum of infantile lobar emphysema. Infantile lobar emphysema in an uncommon disease affecting newborns and infants with varying degrees of respiratory distress, evidence of lobar overaeration, mediastinal shift, and herniation. Congenital malformations of the bronchi and alveoli and extrinsic compression by vessels and cysts account for less than 50% of these cases. All segments of the upper and middle lobe may be involved, but the major overexpansion occurs in the anterior segment. Respiratory distress may be absent, mild, or severe, and the condition may be acutely progressive, acutely reverisble, chronic, or recurrent. This symptom complex is the result of multiple factors requiring investigation prior to definitive operation.


Levo-bunolol and propranolol: further evaluation of oral beta-blocking activity in conscious dogs. The oral beta-adrenoceptor blocking activity of bunolol, propanolol, and their levo-isomers was compared against isoproterenol- and treadmill exercise-induced tachycardias in normal conscious dogs. Relative potencies against isoproterenol were (ascending order): propranolol=1, levo-propranolol=2, bunolol=40, and levo-bunolol=102. Large oral doses of levo-bunolol and propranolol suppressed exercise tachycardia by only 18% (range 10 to 22%). Compared to the isoproterenol response, the tachycardia associated with severe exercise in the healthy trained dog was largely resistant to beta-receptor blockade showing factors other than beta-receptor stimulation to be involved. Differences in duration of beta-blockade were observed at equiactive doses of levo-bunolol and propranolol. The isoproterenol response had returned to greater than 50% of control by 12 hr after propranolol but was less than 10% of control at 12 hr after levo-bunolol. The time to 50% recovery of the exercise tachycardia was 24 hr after levo-bunolol and 6 to 9 hr after propranolol. The results show oral levo-bunolol to be considerably more potent and to have a longer duration of action than propranolol in inhibiting both isoproterenol and exercise-induced tachycardias in conscious dogs.


Development of a lesion resembling diabetic nephropathy in a renal homograft. One month following a cadaver renal transplant for obstructive uropathy, a 27-year-old man developed diabetes mellitus. Two years later, marked proteinuria and decreased renal function were detected. Eight months later, a second decline in function occurred. Light microscopy of graft biopsy specimens obtained after each decline in renal function showed increased mesangial cells and matrix, thickening of Bowman capsule, and tubular atrophy with basement membrane thickening. Vascular changes, interstitial infiltrate, and fibrosis were not prominent. Electron microscopic studies of the second biopsy specimen confirmed the light microscopic changes; subepithelial dense deposits were also detected. Immunofluorescent studies of both biopsy specimens demonstrated linear staining of glomerular and tubular basement membranes and Bowman capsule for IgG and albumin. Antikidney antibodies were not detected in the patient's serum. These observations suggest development of the diffuse form of diabetic nephropathy in a renal homograft following steroid-induced diabetes mellitus.


Potassium homeostasis in chronic diabetes mellitus. Potassium homeostasis was evaluated in 13 patients with diabetes mellitus. In eight, plasma renin activity was low; plasma aldosterone concentration was decreased in all; seven had a history of spontaneous hyperkalemia. After administration of glucose orally, there were paradoxical increases in serum potassium levels in seven patients. After potassium loading, maximal values and increments of serum potassium were higher and fractional potassium excretion was lower in the diabetic than in the control subjects, although the differences were not statistically significant. Abnormalities of potassium homeostasis in diabetes are probably related to insulin and mineralocorticoid deficiency. Diabetic patients with hypoaldosteronism have the potential for severe hyperkalemia should renal or extrarenal mechanisms for potassium homeostasis be challenged by severe acidosis be challenged by severe acidosis, diminished renal function, marked hyperglycemia, or administration of potassium salts or potassium-sparing diuretics.


Relationship of plasma renin activity and aldosterone levels with hemodynamic functions in essential hypertension. Correlates of plasma renin activity and plasma aldosterone levels with hemodynamic functions were studied in 47 male patients with untreated, permanent essential hypertension. All subjects had a normal creatinine clearance and received a diet of 110 mEq/day of sodium. Supine plasma renin activity was directly correlated with cardiac index (P less than.01) and cardiopulmonary blood volume (P=.01). Percentage changes in plasma renin activity and total peripheral resistance in response to upright position were positively correlated (P less than.001). Supine plasma aldosterone level was directly correlated with stroke index (P less than .001) and negatively correlated with hear rate (P less than .05). No significant correlation of aldosterone level was observed with the other measurements, including plasma renin activity. The study points to the neural sympathetic control of plasma renin activity in essential hypertension and suggests the existence of some interrelationships between aldosterone level and cardiac performance.


[Incorporation of glycine and serine in sideramines of the ferrichrome type with fungi of the genus Aspergillus in vivo and in vitro (author's transl)]. A 1.6-11.8% incorporation of labelled glycine and serine into ferrichrome, ferricrocin and ferrichrysin has been achieved with four strains of Aspergillus in vivo. Cell-free extracts of Aspergillus fumigatus and A. quadricinctus capable of cyclohexa-peptide biosynthesis have been prepared.


Isothermic variation of the specific growth rate of Saccharomyces cerevisiae in batch culture. The specific growth rate (mu) of a respiration-deficient mutant of Saccharomyces cerevisiae growing under defined experimental conditions in batch culture (mineral medium plus glucose and vitamins at 25 degrees C) varied from experiment to experiment over a wide range (0.10-0.24 h-1) and showed a normal distribution. Neither the age of the culture, the history of the inoculum, nor experimental error accounted wholly for the variability of mu. The variation was positively correlated with the specific rate of glucose transfer and negatively with the specific rate of production of non-fermentative CO2. The yield decreased with mu implying higher maintenance requirements in batch culture (4.7 mmoles g-1 h-1) than in continuous culture (0.8 mmoles g-1 h-1). It was concluded that the strain is capable of establishing any one of several steady states of growth under the same experimental conditions, each steady state displaying some build in inertia with respect to change. The variations of the specific rates of glucose transfer and non-fermentative CO2 production, and of the yield appeared to be consequences rather than causes of the variation of mu. The ultimate causes of the variation of mu remained unidentified.


First-rank symptoms of schizophrenia in Schneider-oriented German centers. First-rank symptoms of schizophrenia, such as thought insertion, thought broadcasting, "made" volition, and delusional perception, were introduced for purposes of diagnosis into a German university clinic. Such "Schneiderian" criteria were evaluated in 210 case records. Ratings employed formal definitions. Of 210 records examined, 69 (33%) of the schizophrenic patients had first-rank symptoms. The frequency of finding such symptoms in a group of schizophrenics is compared to other reports. There are considerable differences in frequency of individual symptoms as well as total number of such symptoms across centers, but the use of precisely agreed on definitions of first-rank symptoms may lead to better agreement.


[Oncogenic virus induction by halogenated pyrimidines (author's transl)]. Oncongenic DNA and RNA Viruses are integrated into the cell genome of vertebrates. Physical, chemical and biological agents, among them the halogenated pyrimidines ododeoxyuridine (IdU) and bromodeoxyuridine (BdU) cause the induction of these viruses in cells of many species. In this review the action of IdU and BdU in certain cell differentiation systems chondrogenesis, myogenesis and others) and on activation of oncogenic viruses, first of all of type C-RNA viruses, is described and some possible mechanisms of induction are discussed.


Cell-mediated immunity in experimental syphilis in rabbits. The development of cell-mediated immunity was studied in rabbits: a) experimentally injected with T. pallidum, and b) artificially immunized with nonviable T. pallidum. The macrophage migration inhibition test (MMI test) using ultrasonicate of T. pallidum as antigen was employed to demonstrate this type of immunologic response. Lymphocytes of syphilitic rabbits were found to exert a pronounced inhibitory effect upon macrophage migration as early as one month after infection; between the fourth and sixth month, a transient decrease of this capacity occurred, followed by a slow but steady increase during the next two years, i.e. until the end of the observation period. In rabbits in which the infection had been controlled by penicillin treatment in the fifth month, no increase but gradual diminution of this capacity was observed. In the group of rabbits artificially immunized with nonviable T. pallidum, the MMI response appeared very shortly after commencement of the immunization and persisted for about nine months after completion of the immunization procedure. Only a crude correlation could be established between levels of the MMI response of the immunized animals and their resistance to infection with T. pallidum.


Characterization of lymphocyte E rosette inhibitory factor in sera from tuberculous patients. Rosette inhibitory factor (RIF) in serum of patients suffering from active pulmonary tuberculosis, after in vitro contact with lymphocytes from healthy subjects, inhibits spontaneous rosette formation of these lymphocytes with sheep red blood cells (SRBC). RIF is not a C-reactive protein. By the use of chromatography on Sephadex G-200 and single analytic flotation, RIF was found to be contained in the beta-lipoprotein fraction. The presumable mechanism of formation of this factor and suggestions concerning its action on T cells are discussed.


Immune processes in the course of infection with dysentery bacilli. III. Protective activity of spleen cells and serum from mice immunized with killed dysentery bacilli. Killed dysentery bacilli induce immunity in mice which can be transferred to other mice with serum. Spleen cells do not transfer this immunity, in contrast to spleen cells from mice immunized with live dysentery bacilli. The results of this and previous studies 5,17 suggest that immunity in mice infected with dysentery bacilli depends on two coexisting effector mechanisms--cell-mediated and humoral immunity. Live bacilli induce both, however killed bacilli stimulated humoral immunity and protect mice equally effectively against lethal infection with dysentery bacilli.


Partial characterization of a factor present in normal human and animal serum which stimulate E rosette formation by lymphocytes from tuberculous patients. The influence of sera from healthy human beings on ability of lymphocytes from patients with active pulmonary tuberculosis to form rosettes with SRBC was studied. Lymphocytes incubated for 2 hours with sera from healthy subjects recovered ability to form rosettes spontaneously with SRBC. The factor responsible for stimulation of the lymphocytes is contaned in the albumin fraction. Sera from mice, rabbits, guinea pigs and fetal calf serum had a similar effect to that of sera from healthy human beings. The character of this factor and the mechanism of its action are discussed. The stimulating factor is accompanied by an inhibitor.


Heterologous reactivity of in vitro cultured mouse cells with natural human serum antibodies. Studies employing the cytotoxic and immunofluorescence tests revealed presence of natural human serum antibodies in the serum of various human donors, which reacted with normal and pathologic mouse cells cultivated in vitro. This reactivity was due to presence on the cell surface of heterologous HMAg antigen incorporated into the cell membrane from calf serum. Immunofluorescence studies demonstrated localization of this antigen on the cell surface. Absorption of human sera with calf serum or with lyophilized cow's milk abolished or markedly weakened the ability of these sera to react with cultured mouse cells.


John and William Hunter on aneurysms.

John and William Hunter on aneurysms. John and William Hunter made important contributions to vascular surgery that have prevailed until today. Their studies of aneurysm formation, pathology, and treatment laid the foundation for many modern surgical concepts. In the Great Wind mill School of Anatomy, and subsequently at St George's Hospital, London, the Hunters defined true and false aneurysms. William Hunter, in addition, was the first to describe the arteriovenous aneurysm or fistula. Later, John Hunter developed a successful operation for popliteal aneurysm based on his meticulous laboratory investigations. These Scots showed a unique experimental and clinical genius rarely present in late 18th-century medicine.


Renal transplantation in Lindau-von Hippel Disease. Renal cell carcinoma may develop in up to 25% of patients with Lindau-von Hippel disease who survive the earlier manifestations of this disease, and this neoplasm may frequently be bilateral. With early detection of such lesions, operative cure of renal cell carcinoma is more likely in these patients. However, some patients may need to undergo bilateral nephrectomy for cure. Such a patient may benefit from cadaver renal transplant in spite of the increased risk of cancer in immunosuppressed patients. We present such a case in a patient with Lindau-von Hippel disease.


Salmonella abscess. A potential nosocomial hazard. Abscess formation by Salmonella species is an uncommon but significant manifestation of salmonellosis. These localized infections can serve as sources for hospital outbreaks. Appropriate isolation measures and management require early recognition. Three patients with Salmonella abscess were admitted to hospital with a diagnosis other than Salmonella infection. In two, admitted with diagnoses of cholelithiasis and acute appendicitis, respectively, postoperative Salmonella infections developed. A third was diagnosed as having traumatic epididymitis, but was found to have Salmonella orchitis. Appropriate antibiotic therapy was effective in two of the three instances; the other resolved spontaneously. There were no recognized nosocomial infections related to these patients, in spite of delayed diagnosis and treatment. Proper routine wound care plus handwashing after patient contact can minimize the spread of these organisms from unsuspected infections.


Rapid application of skin grafts.

Rapid application of skin grafts. We describe the use of modern surgical staplers and clips to permit the rapid application of skin grafts over large and complex defects. This saves anesthesia time, permitting more extensive surgery. "Skin tunnels" are virtually eliminated.


A simple stereotactic method to isolate and remove foreign bodies. For the past several years, a simple technique using an image intensifier has been employed to isolate and remove foreign bodies from the extremities. Five consecutive cases were recorded to demonstrate its accuracy and simplicity. After the foreign body was identified by an x-ray film, the wound was infiltrated with local anesthesia and the foreign body was "located" by two venipuncture needles placed with the aid of an image intensifier. A small incision was then made between the needles to locate the foreign body at their tips. In this manner, foreign bodies have been consistently removed successfully in the emergency room in a relatively short period of time.


Acupuncture analgesia and anesthesia.

Acupuncture analgesia and anesthesia. After the war of liberation, Mao Tse Tung encouraged an integration of Western and traditional Chinese medicine. Several schools of therapeutic acupuncture have defined different points of puncture, originally assumed to be on an empiric basis but now rationalized as areas where nerve endings congregate. Results of therapeutic acupuncture in China cannog be evaluated because of inadequate record keeping. At the University of Washington Pain Clinic, immediate results (two to three days) are good but never lasting, nor do they decrease concomitant medication. For anesthesia, acupuncture acts to produce only hypalgesia in most patients, although some experience total analgesia. Patient selection and mental preparation are careful. Hence, the method is used in much less than 10% of the operations in China, and in these the analgesia is satisfactory by Western standards in only approximately 30%. Concepts as to the mode of action of acupuncture analgesia range from an attitudinal change towards sensory input to the release of a neurohumoral analgesic substances.


Immune responses in the treatment of advanced carcinoma of the breast. Effects of adrenalectomy. We set out to answer the question, "Is the effect of adrenalectomy associated with or mediated through the immune response?" Eleven patients were studied preoperatively and postoperatively by in vitro immunologic tests. The assay system used included absolute T cell counts, phytohemagglutinin (PHA) blastogenesis, leukocyte adherence inhibition (LAI) after contact with 3M potassium chloride breast antigens, and blocking as measured in the blastogenesis and LAI assays. Good correlation was found between favorable clinical response to adrenalectomy and a rise in the number of absolute T cells, an increase in LAI positivity, and a decrease in blocking as measured by LAI blocking assay, but no correlation was seen in PHA blastogenesis assays. The association of clinical objective responses and improved immune responses is of significance.


Inhibition of beta-glucuronidase by chlorinated hydroquinones and benzoquinones. An earlier study of the metabolism of pentachlorophenol has shown that a metabolite, tetrachloro-p-hydroquinone, possessed pronounced inhibitory action on the activity of beta-glucuronidase from bacterial origin. Several other chlorinated hydroquinones and benzoquinones have now been studied with regard to their ability to inhibit beta-glucuronidase of various origin in vitro and in vivo. All the studied chlorinated hydroquinones and benzoquinones were found to be potent inhibitors of beta-glucuronidase of bacterial origin. D-glucaric acid-1.4-lactone was included for comparison and was found to be less active than the other studied compounds. The inhibition was found to be competitive in nature. No inhibitory effect of the benzo- and hydroquinones studied in vitro or in vivo could be demonstrated on beta-glucuronidase from livers. The result calls for precaution when using bacterial beta-glucuronidase to split urinary conjugates of glucuronic acid.


[Immunofluorescent demonstration of the 3d component of complement in alveolar pyorrhea]. Biopsy material of the gingiva obtained from 15 patients with alveolar pyorrhea and 5 persons comprising a control group at the age of 20 to 40 years were investigated by direct immunofluorescent method with the use of labeled fluorescein-isothiocyanatoms of rabbit antisera against IgG and C3 (the third component of compliment) of man, as well as histologically. Clinically, the degree of severity of the lesion was determined by the Russell's index (1956): 0--healthy persons (25%), 1--moderate gingivitis (5%), 2--gingivitis (10%), 6--parodontitis (55%), 8--severe parodontitis (5%). Histologically, mild, moderate, and severe forms of alveolar pyorrhea were singled out. The mild degree of lesion was noted in 30%, moderate--in 15%, and severe--in 45% of patients. The mild form corresponded to 0, 1, and 2, and the severe form--to 6 and 8 according to the Russell's index. In all observations, control including, the presence of IgG in cells of the connective tissue and inside the epithelium was noted. Positive reaction to C3 was observed only in diseased persons, being most pronounced in severe forms of histopathological changes and maximal clinical manifestations.


[State of humoral and cellular immunity in experimental amyloidosis]. On a model of caseine amyloidosis in 52 rabbits it was shown that in the preamyloid phase the humoral immunity was stimulated, but as soon as the first deposits of amyloid appeared, it was inhibited. The cellular immunity was inhibited starting from the 20th day of the experiment. On the 40th day of the experiment the cellular immunity was found to be less inhibited in the animals with initial deposits of amyloid as compared with the animals with no amyloidosis; on the 60--80th day in progressing of amyloidosis differences in the degree of inhibition of the cellular immunity were obliterated. The degree of fixation of IgG in amyloid was directly dependent on its content in the blood serum and on the "age" of amyloid.


[Morphologic demonstration of adsorption of Sonne shigellae onto intestinal epithelium]. Electron-microscopy studies of the process of absorption of Shigella sonnei on the epithelium of the intestine villi of Syrian hamstes were carried out. In the study there were used 20 animals and 8 stains of Shigellae isolated from patients with acute dysentery. It was shown that in inoculating into an isolated loop of the intestine adhesion of Shigellae to the surface of border cells was accompanied by rearrangement of glycocalyx with subsequent destruction of microvilli in the zone of adsorption. Simultaneously, lysis of adsorbed bacteria occurred. An assumption is put forward that penetration of Shigellae into the epithelium is a multistaged process which is realised in the phase of adsorption not by one bacterium but by the whole pepulation with the help of soluable substances producing a toxic effect.


Baclofen, a new antispastic drug. A controlled, multicenter trial in patients with multiple sclerosis. A double-blind, five-week, multicenter trial was conducted to compare the effect of baclofen, a unique amino acid derivative, with that of placebo in the treatment of 106 patients with spasticity secondary to multiple sclerosis. A spasticity assessment method that included a neurological examination, physicians' clinical impressions of changes during treatment, and a patient's self-evaluation was used to determine efficacy. This method showed baclofen (70 to 80 mg daily maximum, titrated) is effective relative to placebo in relieving symptoms of spasticity, such as flexor spasms, pain and stiffness, resistance to passive joint movements, and tendon stretch reflexes. Patient self-evaluation results also showed a significant reduction in clonus. Side effects were generally mild and transient.


[Arthrodesis of the wrist with the use of bone graft and stable plate osteosynthesis. Results in 27 patients (author's transl)]. 36 arthrodesis of the wrist have been controlled. The operative technique could be divided into two groups. On the first group a stable osteosynthesis and cortico-cancellous bone graft have been used. The second group has been treated by other internal rigid fixation. 13 patients of the first and 14 of the second group have been followed up. It was possible to obtain an arthrodesis by all methods. The stable kind of arthrodesis makes the  handposition secure, the postoperative immobilization in cast much shorter and avoids the danger of pseudarthrosis.


Effect of inflammatory mediators on nasal mucosa. A technique used for study of permeability and vasodilation in the middle ear has been adapted to study the response of nasal mucosa to common inflammatory mediators involved in the natural production of allergic or infectious rhinitis. All of the mediators tested (histamine, prostaglandin E1, bradykinin, the C3a fraction of complement, Escherichia coli endotoxin, and lysozyme) were found to increase nasal permeability to the isotopic tracer 99mTc as the pertechnetate ion. Histamine increased the permeability of nasal mucosa to technetium-labeled plasma protein. Results indicate that the nasal mucosa is approximately ten times as permeable to the pertechnetate ion as middle ear mucosa. Nasal mucosa was also noted to be permeable to protein, even in the absence of inflammatory mediator, in contrast to prior studies of middle ear mucosa that showed little or no permeability in the absence of inflammatory mediator. In almost all cases, a corresponding change in vasodilation accompanied permeability changes.


Proplast in the middle ear and oval window of cats. Poly(tetrafluoroethylene) carbon fiber implant material (Proplast), an all-plastic material, was evaluated for use in otologic surgery. Response to the implant was studied in the middle ear and vestibule of 14 cats by placing the Proplast in the oval window after stapedectomy. After a one year follow-up, it appears that Proplast was tolerated well, causing no inflammatory reaction in either the vestibule or cochlea, or in the middle ear cavity. Fibrous tissue ingrowth was found throughout the implant, and a fibrous tissue membrane covered both the vestibular and the tympanic surfaces of the Proplast. Being well tolerated by both middle ear and inner ear tissues, this porous, all-plastic material offers several otologic applications.


[Experimental research to carry out a contralateral anastomosis of the arteria carotis (author's transl)]. The contribution is presenting a procedure for reconstruction of cerebral blood flow after resection of the A. carotis communis and the A. carotis externa in animal experiments. The preparation in human corps will demonstrate the possibilities on anatomical points. The surgical intervention is based on the fact that we can tie up the A. carotis externa on both sides without disadvantage. On the healthy side, without formation of metastasis, we prepare the A. carotis externa from the bifurcation up to the region of the Mm. pterygoidei. There we will tie up the vessel. The vessel can be transplanted to the contralateral side via a retropharyngeal "tunnel". On this side we dissect the big vessels of the neck. There the suture will be applied to the transplanted A. carotis externa and to the stump of the A. carotis interna by end-to-end or end-to-side anastomosis. The results are documentated by angiographies and local pressure measurements during the operation.


[Nystagmus analysis by computer (author's transl)]. Automatic quantitative nystagmus analysis by means of a digital computer primarily gives a lot of data. Analysis then means reducing this amount of numerical data to a few relevant results. Because the diagnostic importance is not known yet for all available nystagmus parameters, this implies the risk of losing essential informations. Therefore, limitations of the number of parameters as well as of the duration of the investigated intervals by the method of analysis have to be avoided. This then allows studying the diagnostic value of new parameters (e.g. of the fast components) or the time course of reaction intensity. From this point of view a method of quantitative nystagmus analysis is described.


Foetal breathing.

Foetal breathing. This article looks at the current thinking about foetal breathing. Initially, animal studies are discussed and factors affecting foetal breathing defined. These studies are then correlated with preliminary human foetal studies, leading to the possible role that breathing movements may play in defining hypoxaemia in the foetus a risk.


The treatment of flail chest injury.

The treatment of flail chest injury. Flail chest injuries are traditionally managed by long-term artificial ventilation, which in itself is hazardous and expensive. A more conservative therapeutic regime is described, and the results of this regime are compared with those following the previous traditional regime used in the Respiratory Unit, Royal Brisbane Hospital. The place of artificial ventilation in relation to spontaneous ventilation is redefined in the context of this new regime.


Pseudotumours due to oil palm thorn injury. Three cases are reported in which pseudotumours developed in the hand following injury by oil palm thorns. In one patient there was a periosteal reaction of the proximal phalanx adjoining the site of injury. The lesions were excised, and the embedded oil palm thorn was identified in all three. The clinical and pathological features of the lesions and problems in their diagnosis are described. In every case the local tissue reaction was out of proportion to the size of the foreign body, raising the possibility that a toxic substance might have been released by the thorn.


Loudness balance procedures for the measurement of recruitment. COLES and PRIEDE have recommended that in the alternate binaural loudness balance test use of the normal ear as the reference standard be now abandoned in favour of the worse ear. Their data are critically reviewed and shown to be subject to cumulative errors of methodology and interpretation.


The repair of large oral fistulae.

The repair of large oral fistulae. Reports of three cases of large oral fistula following tumour excision are presented. The repairs utilized deltopectoral, forehead, and scalp flaps. Technical points discussed include the de-epithelialization of folded flaps, the preservation of vermilion, the placement of immediate fascial slings and the use of island flaps.


The separation of oligonucleotides of baker's-yeast value transfer ribonucleic acid 2b by high-voltage electrophoresis on DEAE-paper and by thin-layer chromatography. A modified procedure for the separation of oligoribonucleotides is described that is based on the combination of t.l.c. on cellulose and electrophoresis on DEAE-paper at 4000 V on a cooling plate. The technique is relatively rapid and allows the analysis of larger quantities than is possible by electrophoresis on cellulose acetate.


Activation of selenate by adenosine 5'-triphosphate sulphurylase from Saccharomyces cerevisiae. In the presence of ATP and Mg2+, ATP sulphurylase from Saccharomyces cerevisiae catalysed the conversion of selenate into a compound with the electrophoretic and acid-lability properties of adenosine 5'-sulphatophosphate. Structural characterization, involving extensive purification of adenosine 5'-selenophosphate, proved impossible. However, we showed ATP-, Mg2+- and ATP sulphurylase-dependent, and inorganic pyrophosphatase-stimulated, production of elemental selenium from selenate in the presence of GSH (reduced glutathione). Since selenate was not reduced by GSH, this reaction proved that ATP sulphurylase had formed an active selenate. The enzyme catalysed formation of elemental selenium had the same kinetics and GSH-dependency as the non-enzymic reduction of selenite to elemental selenium by GSH. In the presence of inorganic pyrophosphatase, 2 mol of Pi was released for each mol of 'active selenate' formed. This was shown by a spectrophotometric assay for elemental selenium. The observed reactivity with thiols and the instability of the enzymic product were those predicted for selenium anhydrides. By analogy with the chemistry of sulphur, the product of the thiolytic cleavage of a selenium anhydride would be converted into selenite. The selenite would then be reduced by the thiol to elemental selenium. We conclude that ATP sulphurylase can catalyse the formation of adenosine 5'-selenophosphate. The anhydride can be reduced by thiols in a manner similar to the reduction of selenite. These results probably explain the ability of mammals, lacking a sulphate reductase system, to incorporate selenium from selenate into seleno-amino acids.


Sites and specificity of the reaction of bipyridylium compounds with anaerobic respiratory enzymes of Escherichia coli. Effects of permeability barriers imposed by the cytoplasmic membrane. The ability of the oxidized and singly reduced species of several bipyridylium cations to cross the cytoplasmic membrane of Escherichia coli was studied to locate the sites of reaction of the dyes with anaerobic respiratory enzymes. Benzyl Viologen radical crossed the membrane rapidly, whereas the oxidized species did not. The oxidized or radical species of Methyl Viologen, Morfamquat or Diquat did not rapidly cross the membrane. It was also shown that the dithionite anion does not cross the cytoplasmic membrane of E. coli. Diquat radical donates electrons to the nitrate reductase pathway at the periplasmic aspect of the membrane, whereas Benzyl Viologen radical reacted directly with nitrate reductase itself (EC 1.7.99.4) at the cytoplasmic aspect of the membrane. Thus the pathway of electron transfer in the nitrate reductase pathway is transmembranous. Formate hydrogenlyase (EC 1.2.1.2) and an uncharacterized nitrite reductase activity react with bipyridylium dyes at the periplasmic aspect of the membrane. Fumarate reductase (succinate dehydrogenase; EC 1.3.99.1) reacts with bipyridylium radicals, and formate dehydrogenase (cytochrome) (EC 1.2.2.1) with ferricyanide, at the cytoplasmic aspect of the membrane. The differing charge and membrane permeation of oxidized and radical species of bipyridylium dyes greatly complicate their use as potentiometric mediators in suspensions of cells or membrane vesicles.


Some factors affecting the production, by cultured baby-hamster kidney cells, of BHK glycoprotein I which cross-reacts immunologically with Tamm-Horsfall glycoprotein. Cultured baby-hamster kidney cells (BHK-21/C13), which are adapted to grow in suspension (strain 2P), roduce a glycoprotein, termed BHK glycoprotein I, which cross-reacts immunologically with hamster urinary (Tamm-Horsfall glycoprotein. BHK glycoprotein I was isolated in an electrophoretically (sodium dodecyl sulphate/polyacrylamide gel) homogeneous form by application of affinity chromatography to the medium in which cells had been cultured. Insolubilized anti-(Tamm-Horsfall glycoprotein immunoglobulin G) was used as the adsorbent. The amount of BHK glycoprotein I associated with the cultured cells was found by both radioimmunoassay and immunofluorescence to be related to the amount of Ca2+ in the medium and to the particular stage of the cell cycle. 5'-Nucleotidase was also shed by the cells into the culture medium in amounts related to the stage of the cell cycle. The turnover of hamster Tamm-Horsfall glycoprotein in vivo appeared to be considerably more rapid than can be accounted for by cell turnover. Hamster Tamm-Horsfall glycoprotein was shown to be ineffective in inhibiting agglutination of chicken erythrocytes caused by influenza virus.


A comparison of the effects of phytohaemagglutinin and of calcium ionophore A23187 on the metabolism of glycerolipids in small lymphocytes. 1. The effects of phytohaemagglutinin and of a Ca2+ ionophore (A23187) on glycerolipid metabolism in lymphocytes from pig lymph nodes were compared (a) by studying the incorporation of [32P]Pi and [3H]glycerol, and (b) by following the redistribution of [3H]glycerol among the lipids caused by these agents in pulse-chase experiments. 2. Phytohaemagglutinin only stimulated 32P incorporation into phosphatidylinositol and, to a slight extent, phosphatidate. Removal of most of the extracellular Ca2+ somewhat decreased this response. 3. Ionophore A23187 stimulated the labelling of phosphatidate and phosphatidylinositol with 32P to a much greater extent than did phytohaemagglutinin: the increase in phosphatidate labelling, but not that of phosphatidylinositol, was almost abolished by the removal of extracellular Ca2+. 4. The combined effects of phytohaemagglutinin and ionophore appeared to be additive, rather than synergistic. 5. Treatment with ionophore A23187 somewhat decreased the total incorporation of [3H]glycerol into glycerolipids, possibly because it lowered cell ATP content. In these experiments di- and tri-acylglycerol behaved anomalously, triacylglycerol labelling being suppressed completely, whereas that of diacylglycerol was enhanced. The pulse-chase results revealed that triacylglycerol was converted into diacylglycerol in the ionophore-treated cells, and the availability of this diacylglycerol probably led to the enhanced labelling of phosphatidate and phosphatidylinositol in the these cells. 6. Thus an increase in intracellular Ca2+ concentration appeared to have three effects on glycerolipid metabolism: (a) slight inhibition of some metabolic step preceding phosphatidate synthesis, (b) inhibition of diacylglycerol acyltransferase and (c) activation of a triacylglycerol lipase. 7. In contrast, it seems likely that the only effect of phytohaemagglutinin is to stimulate phosphatidylinositol breakdown. 8. Pig polymorphonuclear leucocytes treated with ionophore A23187 showed metabolic changes that were similar to those demonstrated with lymphocytes. 9. A possible similarity is suggested between Ca2+-stimulated triacylglycerol lipase in lymphocytes and polymorphonuclear leucocytes and previous observations of enhanced triacylglycerol metabolism in stimulated cells whose metabolic functions involve membrane fusion.


Adenosine and the regulation of insulin secretion by isolated rat islets of Langerhans. The effect of adenosine in insulin secretion and adenylate cyclase activity of rat islets of Langerhans was investigated. Adenosine inhibited insulin secretion stimulated by glucose, glucagon, prostaglandin E2, tolbutamine and theophylline. Adenosine decreased basal adenylate cyclase activity of the islets as well as that stimulated by glucagon prostaglandin E2 and GTP, although fluoride-stimulated activity was not affected. Neither insulin secretion nor adenylate cyclase activity of the islets was affected by adenine, AMP or ADP. The inhibitory effect of adenosine on adenylate cyclase activity was not altered by either phenoxybenzamine (alpha-adrenergic blocker) or propranolol (beta-adrenergic blocker), suggesting that the effect is not mediated through the adrenergic receptors of the islet cells. These results suggest that the intracellular concentration of adenosine in the beta-cell may play a role in regulating insulin secretion and that this effect may be mediated via alterations in the activity of adenylate cyclase in the beta-cell.


The stimulus-secretion coupling of glucose-induced insulin release. Insulin release due to glycogenolysis in glucose-deprived islets. 1. When pancreatic islets are preincubated for 20h in the presence of glucose (83.3mM) and thereafter transferred to a glucose-free medium, theophylline (1.4mM) provokes a dramatic stimulation of insulin release. This phenomenon does not occur when the islets are preincubated for either 20h at low glucose concentration (5.6mM) or only 30 min at the high glucose concentration (83.3mM). 2. The insulinotropic action of theophylline cannot be attributed to contamination of the islets with exogenous glucose and is not suppressed by mannoheptulose. 3. The secretory response to theophylline is an immediate phenomenon, but disappears after 60min of exposure to the drug. 4. The release of insulin evoked by theophylline is abolished in calcium-depleted media containing EGTA. Theophylline enhances the net uptake of 45Ca by the islets. 5. Glycogen accumulates in the islets during the preincubation period, as judged by both ultrastructural and biochemical criteria. Theophylline significantly increases the rate of glycogenolysis during the final incubation in the glucose-free medium. 6. The theophylline-induced increase in glycogenolysis coincides with a higher rate of both lactate output and oxidation of endogenous 14C-labelled substrates. 7. These data suggest that stimulation of glycolysis from endogenous stores of glycogen is sufficient to provoke insulin release even in glucose-deprived islets, as if the binding of extracellular glucose to hypothetical plasma-membrane glucoreceptors is not an essential feature of the stimulus-secretion coupling process.


The effects of antioxidants on the metabolism and mutagenicity of benzo[a]pyrene in vitro. Antioxidants inhibit the rat liver microsomal mixed-function-oxidase-catalysed hydroxylation of benzo[a]pyrene. These antioxidants also decrease the formation of mutagenic products from benzo[a]pyrene as judged by the Ames bacterial-mutagenicity assay [B.N. Ames, J. McCann & E. Yamazaki (1975) Mutat. Res. 31, 347-364]. It is suggested that antioxidants exert their protective effect against cancer by inhibiting the formation of carcinogenic metabolites.


Interlaboratory variability of valproic acid determinations. 19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The interlaboratory variability between the results was very high. Only 4 out of 13 laboratories had 6--12% of their results within the 95% confidence limit for each sample. The precision of repeated determinations was fairly good. 6 out of 10 participating laboratories had a coefficient of variation of less then 5%. The reproducibility and the agreement between the different procedures for quantitative analysis of dipropylacetate is similar to that reported for other major antiepileptic drugs.


[On the mechanism of action of valproid acid]. In mice, the influence of valproic acid (di-n-propylacetate, DPA) on central level of gamma-aminobutyric acid (GABA) as well as the activity of the enzymes regulating GABA metabolism, glutamate decarboxylase (GAD) and GABA-alpha-oxoglutarate aminotransferase (GABA-T) were studied. It was shown that the elevation of GABA by DPA was accompanied by an activation of GAD. GABA-T was inhibited only by toxic doses or high concentrations of DPA in vivo and in vitro, and so was GAD. DPA proved able to antagonize the biochemical alterations induced by convulsant doses of isoniazid, i.e., decreases in the level of GABA and the activity of GAD. These results point to a role of the transmitter pool of GABA regulated by GAD in the anticonvulsant effect of DPA.


Preliminary observations on valproic acid kinetics in patients with epilepsy. A rapid gas chromatographic method for determination of sodium valproic acid (di-n-propylacetate, DPA) is described. A new sample can be injected every third min, and the reproducibility, in terms of the coefficient of variation, is better than 3%. The method has been used to study clinical pharmacokinetics of DPA in patients with epilepsy during long-term treatment. A poor correlation between daily dose (mg/kg) of DPA and steady state serum levels, attained within few days, was observed. A fixed sampling time in the individual patient, preferably before ingestion of the morning dose, is of great importance for DPA due to extended fluctuations of the serum levels during the day. Most patients had DPA serum levels in the order of 50 microng/ml. No constant relationship was found between increase of the dose and the corresponding increase of the serum levels. Interactions of clinical importance was observed between DPA and other antiepileptic drugs, as addition of DPA resulted in elevated serum levels of diphenylhydantoin and phenobarbital. Carbamazepine levels were unaltered. After withdrawal of DPA the half-life was about 14 h in adult patients. DPA levels in CSF were in the order of 10% of the corresponding serum levels.


Pharmacokinetic studies with valproic acid in man. A specific gaschromatographic assay for the simultaneous determination of valproic acid (dipropylacetate, DPA) and ethosuximide was developed. In 13 epileptic patients only treated with DPA a significant correlation(r = 0.88; p less than 0.01) between the minimal steady state plasma level of DPA and its dose (mg/kg body weight) was found. Plasma protein binding experiments in 3 healthy volunteers revealed a relatively strong binding of approximately 95%. The pharmacokinetics of DPA was evaluated after a single oral solution of 600 mg in 2 healthy subjects. Absorption was rapid with maximum plasma levels of approximately 70 microng/ml within 1--3 h. DPA was eliminated with a half-life of 7.9 and 10 h. Assuming 100% absorption a total plasma clearance of 10--13 ml/min and an apparent distribution volume of 0.13--0.16 l/kg were calculated. The urinary excretion of unchanged DPA is neglegible (1% of dose). It is suggested that the great fluctuations of the plasma concentrations within a dosing interval may be minimized by special galenic formulations.


[On the enteral absorption of valproic acid (author's transl)]. The absorption of valproic acid (dipropylacetic acid, DPA)--administered by capsules (free valproic acid) and dragees (valproate sodium)--has been studied. Regarding their bioavailability, both forms of administration examined are equivalent, which means that they are representing therapeutical alternatives.


Massive digoxin ingestion. Report of a case and review of currently available therapies. Recent reports of treatment of massive digoxin overdosage have emphasized the success of medical therapy. This report describes a fatal outcome to this problem despite aggressive medical management, including pervenous cardiac pacing and draws attention to deficiencies in current treatment of a serious problem.


Haemodynamic effects of salbutamol and nitroprusside after cardiac surgery. The haemodynamic effects of a continuous intravenous infusion of salbutamol (15 to 30 microgram/min) and nitroprusside (50 to 100 microgram/min) were compared in 9 patients after cardiac surgical operations. The mean falls in left atrial pressure and systemic vascular resistance were similar with the two drugs but salbutamol caused a greater increase in heart rate, maximum acceleration of aortic blood flow, and maximum rate of change of left ventricular power. Because these differences would cause greater myocardial oxygen consumption with salbutamol and because the infusion of salbutamol is less easily controlled, nitroprusside is the preferred drug after cardiac operations.


Diflunisal: efficacy in postoperative pain. 1. Seven hundred and forty patients complaining of pain after oral or orthopaedic surgery or episiotomy were studied in five single dose or short-term double-blind, controlled, randomized studies comparing efficacy and safety of diflunisal with that of acetylsalicylic acid, glafenin or placebo. 2. Diflunisal was found to be effective in relieving postoperative pain in 75-85% of patients. A twice day dosage schedule seems to be clinically adequate, 375 mg twice daily proving to be equally effective as glafenin 200 mg three times daily. No serious drug-related clinical or laboratory adverse experiences were encountered in any of the five studies.


The effect of temperature on concanavalin A-mediated agglutination of cells with rigid receptors. The agglutination of a yeast, Candida albicans, by concanavalin A has been described. The agglutination was cell-number dependent. Prolonged incubation (60 min) was needed to reach maximum agglutination at 37 degrees C. The rate but not the extent of agglutination was temperature dependent. The dimeric forms of concanavalin A, obtained either at low pH or after succinylation, agglutinated the yeast cells as well as the tetramer. Temperature changes affected the agglutination of yeast cells by dimers and by tetramers to the same extent.


Functional symmetry of the beta-galactoside carrier in Escherichia coli. Cytoplasmic membrane vesicles with either normal or inverted orientation were prepared from Escherichia coli. The lactose transport activity of these vesicle preparations was compared. The parameters measured were net efflux, counterflux, and K+/valinomycin-induced active uptake of lactose. With membrane vesicles derived from both wild-type and cytochrome-deficient strains the right-side-out and inverted membrane preparations showed similar rates of lactose flux in all assays. According to these criteria, the activity of the beta-galactoside transport protein is inherently symmetrical. One major difference was observed between the native and inverted vesicle preparations: the inverted vesicles had approximately twice the specific activity of native vesicles in the counterflux and K+/valinomycin-induced uptake assays. This difference can be largely ascribed to the presence in the normal vesicle preparation of vesicles with a high passive permeability to lactose. Such vesicles are apparently absent from the inverted vesicle preparations.


The effect of A23187 upon calcium metabolism in the human lymphocyte. Treatment of human peripheral lymphocytes with mitogenic concentrations of the divalent cation ionophore A23187 led to an initial marked increase in the uptake of calcium by these cells, but the amount of accumulated calcium retained decreased with time so that after 8-12 h of culture, the calcium content of treated cells was only 1.5-2.0-fold higher than that of control cells. Three possible explanations for the biphasic nature of ionophore-induced calcium uptake were considered: (1) the ionophore underwent chemical or metabolic inactivation upon prolonged incubation; (2) massive accumulation of calcium caused irreversible uncoupling of mitochondria in these cells with consequent loss of accumulated calcium; or (3) with time there was a redistribution of ionophore within the cell, and sufficient ionophore was taken up by internal, most likely mitochondrial, membranes to cause an efflux of calcium from internal stores. By developing a bioassay for ionophore and examining the time-dependent effects of ionophore in the presence and absence of calcium, it was concluded that the third explanation was the most likely. The general implications of these results are discussed.


A new method for the isolation of renal basement membranes. A method is described for the isolation of basement membranes from rabbit renal cortex in which the detergent N-lauroyl sarcosine is used as the disruptive agent. The isolated membranes have been compared with membranes prepared using ultrasonication and they were comparable both in terms of purity and gross chemical composition. Glomerular and tubular basement membranes were isolated by first separating glomeruli from tubules by density gradient centrifugation followed by detergent treatment of the separated tissues. The detergent method has the advantage that the basement membranes retained their native structure to a large degree, whereas sonicated membranes were severely fragmented. Collagen fibres were a significant contaminant in both preparations and were revealed more clearly by negative staining than by examination of thin sections. Studies with the detergent-treated membrane revealed that a few proteins, which seemed to be membrane components, were extracted with 1 M NaCl and that these proteins were lost from the basement membranes during sonication used in the conventional isolation procedure.


Manganese(II) as a paramagnetic probe of the tertiary structure of transfer RNA. The effect of manganese on both the low field (10--15 ppm) and the high field (o--3 ppm) NMR spectra of unfractionated tRNA and yeast tRNAPhe has been investigated. Trace amounts of Mn2+ cause selective broadening of resonances which are assigned to specific tertiary interactions. The order in which resonances broaden is the same as the order in which they are stabilized by the addition of magnesium, namely s4U8 - A14, U33 and A58 - T54. From this we conclude that three of the strong binding sites probably are the same for both Mn2+ and Mg2+, and that these sites are located close to the tertiary interactions which are stabilized by the strongly bound metals. The broadening data, taken in conjunction with published X-ray data on yeast tRNAPhe, permit us to suggest some plausible locations for the strong binding sites.


Isoleucyl-tRNA synthetase inactivation and the extent of aminoacylation of tRNAIle from Escherichia coli. A difference in isoleucine acceptance between normal and sulfur-deficient tRNA from Escherichia coli C6 (rel-, met-, cys-) was eliminated when more isoleucyl-tRNA synthetase was added at the reaction plateau. Enzymatic deacylation was similar for both tRNAs. These results suggest that enzyme inactivation caused a premature reaction plateau which was not predicted by the rates of acylation and deacylation.


Inhibition of DNA polymerase-alpha and -beta of calf thymus by 1-beta-D-arabinofuranosylcytosine-5'-triphosphate. 1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (araCTP), an active form of a inhibitor of DNA replication, 1-beta-D-arabinofuranosylcytosine (araC) was tested for its inhibitory action on the DNA polymerase-alpha and -beta (EC 2.7.7.7) purified from calf thymus. The reaction of DNA polymerase-alpha was shown to be more sensitive to the inhibition by araCTP than that of DNA polymerase-beta. The mode of the inhibition by araCTP was competitive to dCTP in the reaction catalysed by either DNA polymerase-alpha or -beta. The Ki value of DNA polymerase-beta for araCTP was 32 micron; eight times higher than that of DNA polymerase-alpha (4 micron) for this inhibition.


A comparison of the differential DNA melting profiles with the CsCl density profiles of DNA from Escherichia coli, cow, mouse, rat and chicken. Moderate resolution thermal denaturation profiles are presented for the purified DNAs from Escherichia coli, cow, mouse, rat and chicken. All show multiple thermal transitions indicative of large blocks of DNA with very similar base composition. The eucaryotes all have much more of this kind of DNA than does E. coli. The satellite DNAs of cow and mouse are clearly visible and it is likely that the other transitions represent additional families of repeated DNA.


Polyamine levels in Escherichia coli during nutritional shiftup and exponential growth. At different exponential growth rates obtained either by varying the carbon source of the culture medium or limiting glucose uptake, intracellular levels of putrescine and spermidine were measured. Over a ten-fold increase in growth rate an approximately three-fold increase in putrescine level and a 3.5-fold increase in spermidine level per cell absorbance were observed. Conditions favoring an abrupt alteration in growth rate, such as occur following nutritional shiftup of Escherichia coli, resulted in a significant increase in the intracellular level of putrescine and virtually no change in the spermidine level. Because of the magnitude and the timing of the change in polyamine levels, the hypothesis that polyamines are (the components) responsible for inducing the rapid increase in the rate of RNA synthesis following nutritional shiftup is rejected.


Nitrogenase of Klebsiella pneumoniae. Water proton NMR relaxation studies on the binding of divalent metal ions and nucleotides to the iron protein. Interactions between the iron protein, Kp2, of nitrogenase manganese ions, magnesium ions, and the nucleotides ATP or ADP, have been studied in aqueous solution by monitoring the water proton NMR relaxation rate enhancement caused by Mn2+. Binding of Mn2+ to a molecule of Kp2 occurs at four sites, indistinguishable within experimental error, having a Kd = 350 +/- 50 micron. The Mn2+ - Kp2 complex has a low characteristic enhancement (epsilonb = 6 +/- 0.5). All four sites can alternatively bind Mg2+, not necessarily with the same dissociation constant, but with a mean Kd = 1.7 +/- 0.3 mM. Ternary complexes with the configuration EMS or (formula: see text) are formed between Kp2, Mn2+ and nucleotide (ATP or ADP). The ternary complexes with Mg2+ in place of Mn2+ probably have the latter configuration. A novel treatment of enhancement data (a 'high metal' approximation) is given.


The characterization of type I and type III collagens from human peripheral nerve. The normal chemical features of peripheral nerve collagens were determined on postmortem, histologically normal adult human femoral nerve. 1. Genetically distinct type I, [alpha1(I)2]alpha2, and type III, [alpha1(III)]3, were isolated by differential salt precipitation and the component subunit chains, alphal(I), alpha2 and alphal(III) were obtained by ion-exchange chromatography and gel filtration. 2. The molecular weight of alphal(I) and alpha2 of type I collagen was 95 000 and that for type III was 280 000. Reduction of type III with dithiothreitol yielded expected alpha1(III) chains of 95 000 molecular weight. 3. The amino acid composition of the three collagen chains, alpha1(I), alpha2, and alpha1(III), was the same as previously reported values for the corresponding chains from human skin except for slightly elevated hydroxylysine content. 4. Peripheral nerve collagen was found to contain 81% type I collagen and 19% type III. These results indicate that peripheral nerve collagen characteristics closely simulate that of human skin and differ from that of human aorta and other parenchymal organs. These data will permit a chemical analysis for possible abnormalities of peripheral nerve collagen in various neurogenic disorders.


Purification of protein A, an outer membrane component missing in Escherichia coli K-12 ompA mutants. Outer membrane materials prepared from an Escherichia coli ompA (tolG) strain do not contain one of the major outer membrane proteins found in ompA+ strains. This protein has been purified in high yield from detergent-solubilized cell envelope material prepared from an ompA+ strain by preparative electrophoresis in polyacrylamide gels containing sodium dodecyl sulfate. The purified protein is homogeneous in three electrophoretic systems, contains 2 mol of reducing sugar/mol of peptide and has alanine as the N-terminal amino acid. The amino acid composition is nearly identical to outer membrane protein II or B purified by others from incompletely solubilized cell envelope material. Thus, the fraction of outer membrane protein II or B that is difficult to solubilize is identical with the more readily solubilized fraction.


Stereoselectivity and stereospecificity of the alpha,beta-dihydroxyacid dehydratase from Salmonella typhimurium. 1. In addition to the known 2R,3R- and 2R, 3S-2,3-dihydroxy-3-methylpentanoic acids (DHI), the 1S,3S- and sS,DR-isomers were prepared. 2S-2,3-Dihydroxy-3-methylbutanoic acid (DHV) was also prepared in addition to the known 2R-isomer. 2. The six dihydroxy acids were examined for their ability to promote the growth of isoleucine-valine (ilv)-requiring strains of Salmonella typhimurium and to serve as substrates for the alpha,beta-dihydroxyacid dehydratase of the same organism. 3. Only 2R,3R-2,3-dihydroxy-3-methylpentanoic and 2R-2,3-dihydroxy-3-methylbutanoic acids supported growth of the ilv strains of S. typhimurium. 4. alpha,beta-Dihydroxyacid dehydratase utilized the three isomers with the 2R-configuration as substrates but not those with the 2S-configuration. 5. In an additional growth study that utilized the 3R- and 3S-isomers of 3-methyl-2-oxopentanoic acid, the alpha-keto acid analogue of isoleucine, only the 3S-isomer supported growth. 6. It is concluded that the mechanism of action of the dehydratase is stereospecific in that the proton that is attached to C-3 of the substrate occupies the same steriochemical position as the departing hydroxyl group (Fig. 6).


[Primary structure of the casein macropeptide of kappa casein of buffalo]. The complete amino acid sequence of Italian water buffalo (Bubalus arnee) caseinomacropeptide, the C-terminal fragment released from kappa-casein by chymosin, has been determined. It contains 64 amino acid residues including one phosphoserine and differs from its bovine (Bos taurus) B counterpart by 10 amino acid substitutions. The sequence of the last 11 amino acid residues of para-kappa-casein is also reported. In relation to the Ala148/Asp substitution which is responsible for the different electrophoretic behaviour of bovine kappa-caseins B and A, water buffalo kappa-casein is homologous to the bovine variant B. It is suggested that a variant Thr136-Ala148 might be the wild type of the Bos genus.


Oxidative phosphorylation in intact chl-r mutants of Escherichia coli K 12. The efficiency of oxidative phosphorylation was estimated in intact resting cells of Escherichia coli K 12, strain PA 601 (chl-s) and its chl-r mutants, all of them grown anaerobically in the presence of nitrate. The oxidation of endogenous NADH in intact chl-s cells was accompanied by the formation of ATP whatever the terminal electron acceptor, oxygen or nitrate, so that it was possible to conclude that the energy conservation sites are operating with either of the two acceptors in cells grown anaerobically in the presence of nitrate. For chl-r mutants oxidation of endogenous NADH correlated with ATP-production was found only with oxygen as electron acceptor. It is concluded that the energy-conservation sites are preserved in these mutants, the nitrate respiratory chain of which is altered. This assumption is corroborated by the effects of uncouplers of oxidative phosphorylation on ATP-synthesis.


Metabolic and EEG changes during transcendental meditation: an explanation. Two experiments were conducted to measure the oxygen uptake (Experiment II) and the carbon dioxide production (Experiment I) during transcendental meditation. A control group of non-meditators and a few meditators listening to music was used for both experiments. In Experiment I, a controlled group of fasting meditators was also included. A drop in oxygen consumption and carbon dioxide production, found by previous authors during transcendental meditation, was confirmed. It was, however, possible to show that these drops were physiologically of small significance, and were of the magnitude to be expected from muscle relaxation. EEG recordings were taken during Experiment II in the meditating group. The EEG results showed transcendental meditation to be a method of holding the mediator's level of consciousness at stage 'onset' sleep. No evidence could be found to suggest that meditation produced a hypometabolic state beyond that produced by muscle relaxation and there was no evidence that the EEG changes were different from those observed in stage 'onset' sleep. No support was found for the idea that transcendental meditation is a fourth stage of consciousness.


Biofeedback-aided relaxation and meditation in the management of hypertension. Based on clinical, epidemiological, and experimental work, a possible pathogenesis of essential hypertension is outlined. In the light of this possible pathogenesis, a behavioral treatment program is suggested which centers on the regular use of systematic training. Several controlled studies are described in which experimental patients given such training show clinically significant and lasting reductions in systolic and diastolic pressure. Following training, experimental patients also show quicker recovery of blood pressures to baseline levels after exposure to standardized laboratory stressors. Probable long-term benefits of relaxation training are suggested. Such benefits, however, can only be maintained if the patient regularly practices relaxation and integrates this into his everyday activities. How to motivated symptomless hypertensives to accept this requirement is discussed in the light of the writer's personal experience.


An NMR approach to tRNA tertiary structure in solution. Atomic coordinates of E. Coli tRNA1Val have been generated from the X-ray crystal structure of Yeast tRNAPhe by base substitution followed by idealization...


Association kinetics with coupled diffusion. An extension to coiled-chain macromolecules applied to the lac repressor-operator system. The association of a molecule onto a specified binding site on a large chain-like macromolecule is described in the "sliding" model, where the molecule is allowed to move along the chain in a one-dimensional diffusion which is coupled to the three-dimensional diffusion in solution. The present work extends a previous one by treating the chains more generally as coiled instead of straight. The model is applied to the lac repressor-operator association. A general expression for the rate of unspecific attachment to a chain-like macromolecule is also derived.


Models of membranes of cerebral cells as substrates for information storage. The past decade has seen a growing understanding of functional capacities and structural organization of cell membranes. Studies in immunology, endocrinology and neurobiology have led to some unifying concepts about processes of transduction at the membrane surface, and the coupling of surface events to the interior of the cell. My interest in these problems has been directed in no small measure by interactions with Lars Onsager. His kindly tutelage and rigorous criticism have been a source of endless encouragement to those who sought the full measure of his wisdom in the difficult area of the energetics of membrane excitation. Onsager's unflagging interest in mechanisms of ion transportation led him to earnest consideration of a variety of non-classical models of conduction in proteins, always tempered by his deep insight essential aspects of physical chemistry. My discussions with him at the MIT Neuroscience Research Program were a regular stimulus to the experiments which our groups have undertaken in search of answers to questions raised by the models presented here. Above all, Lars Onsager was a kindly, gentle man. In this personal example, he will be as sadly missed as for his broad and imaginative approach to critical questions in the physical and biological sciences.


Considerations in predicting phenotypic modifications in amino acid profiles of total cell protein of microorganisms. A mathematical model is presented that describes the concentration of an amino acid in total cell protein as a function of its concentration in individual cell proteins or in sets of cell proteins. The resulting equation makes it possible to calculate how the makeup of cell proteins must change to obtain a specified alteration in the content of an amino acid in the total cell protein. It is recognized that protein species or sets of proteins that are distinguished by being richer or poorer in a key amino acid than the overall protein must undergo considerable variations in content. The necessary extent of these shifts suggests that the amino acid composition of total cell protein is not likely to be affected significantly by variations in the cultivation conditions.


[Origin of hematopoietic cells in a syngenous and semisyngenous focus of heterotopic hematopoiesis]. Heterotopic hemopoiesis foci were produced by the bone marrow of C57BL/6 or (CBA X C57BL)F1 mice grafted under the renal capsule of (CBAT6T6XC57BL)F1 mice, bearing the chromosomal translocation. The cytogenetic analysis of the hemopoietic cells in the foci 20 to 120 days after the transplantation showed that in 40% of the transplants only the recipient's hemopoietic cells proliferated, whereas the rest were mosaic and contained on the average less than 20% of donor's cells both in the syngeneic and in the semisyngeneic systems. These characteristics remained stable for at least 4 months. The data obtained suggest a single inflow of not less than 10 effective hemopoietic stem cells per graft. The clone stability indicated that during the steady-state hemopoiesis the cell exchange between various regions of the hemopoietic system was not great, if any.


[Interaction of the isolated DNA of lambda phage with spheroplasts of E. coli treated with sturine]. The method of centrifugation in sucrose density gradient (30-55%) of the spheroplast membrane preparations treated and untreated with sturine and infected with phage lambda DNA demonstrated that sturine, treatment increased the phage lambda DNA absorption three-fold. About 50% of the lambda DNA molecules adsorbed by spheroplasts are bound with the cytoplasmic membrane of spheroplasts treated with sturine; 50% of the lambda DNA molecules are bound with the cell wall membrane on the sturine-untreated spheroplasts. The data obtained allow to conclude that the stimulating effect of sturine in E. coli spheroplasts transfection by lambda DNA is connected with redistribution of phage DNA absorbed on spheroplasts from the cell wall to the cytoplasmic membrane facilitating the penetration of DNA and its fastening on the membrane.


[Barrier-fixing function in germ-free animals]. The state of barrier-fixative function was studied in germfree and conventional guinea pigs and rats. Under conditions of conventional animals contamination with E. coli 055 (in doses of 500 million and 10 milliard microbial bodies for subcutaneous and oral inoculation, respectively) only an early transitory bacteremia developed at the early postinfection periods. As to bacteriemia in gnotobiotes, it increased progressively leading to the animal death in the course of 2 to 3 days. A decreased fixative and bactericidal capacity of the regional lymphatic apparatus and deep structures of the mononuclear-phagocytic system was revealed in germfree animals. An experimental confirmation of the participance of antibodies in the manifestation of the barrier-fixative function to E. coli was obtained. These studies demonstrated an important role of the microbial factor in the formation of the macroorganism barrier-fixative function.


[Pharmacokinetics of ftorafur-2-14C in rats with Walker carcinosarcoma]. The pharmacokinetics of phthorafur-2-14C (Ph) was investigated after its intravenous injection to rats with Walker carcinosarcoma. The blood plasma level of Ph-2-14C and its metabolites proved to decrease in to a three-phase process. The content of the agent in the tissues decreased in the following sequence: the kidney, small intestine, tumour, stomach, muscle, heart, liver, lungs, spleen, brain and fat. The tumour was observed to contain Ph-2-14C and endogenous metabolite 5-phthoruracil-2-14C. Excretion of the agent continued for 48 hrs, 52.2% of the administered dose being eliminated via the urinary tract, 30% as 14CO2, and 0.8% in feces.


Low molecular weight intracellular iron transport compounds. Evidence is presented for the existence of an intracellular pool of low molecular weight iron compounds which acts as an intermediate between extracellular iron and a wide variety of intracellular processes. It is in equilibrium with storage iron and iron enzymes and is of major importance in iron toxicity and chelation therapy.


Determination of continuing medical education needs of clinicians from a literature search study, Part I. The study. Continuing medical education is an area of current concern to health sciences librarians. A comprehensive study of literature searches requested by physicians and by fourth-year medical students serving their five-week preceptorship with a rural physician was conducted: (1) to determine if there is any pattern to the requests received so that areas of study for continuing medical education can be ascertained; and (2) to determine whether there is any appreciable difference in nature and complexity between those searches requested by clinicians and those requested by medical student preceptees. Literature search requests were examined in terms of individual MeSH subjects, subcategories, and categories for each subject covered in every search. This analysis has demonstrated that assessing the clinical problems of practicing physicians may be one method of determining needed continuing medical education topics.


Determination of continuing medical education needs of clinicians from a literature search study. Part II. Questionnaire results. Part II of this study of the needs of clinicians for continuing medical education (CME) examines the results of a questionnaire sent of Oklahoma physicians to determine if they would request formal CME courses in the same subject areas in which they had previously requested in formation from librarians. The degree of correlation between literature search requests and responses to the questionnaire confirms that the analysis of library information requests may be one approach to determining CME needs.


[Control of pulmonary ventilation during muscular exercise (author's transl)]. The ventilatory changes as function of time or power depend on the type of exercise. However, in any case, two kinds of factors are involved in these changes : fast, neurogenic, factors and other factors, slower, which are thought to be humoral. Neurogenic stimuli arise from the periphery and from the central nervous system. Peripheral stimuli are induced by the repetitive changes of muscle length and by the motion of articulations. Ventilatory output is also increased by stimuli coming from motor centers. These two kinds of factors induce a ventilatory increase at the start of exercise ("accrochage ventilatoire"). Both chemical and physical stimuli act as humoral factors. The arterial PO2 is scarcely reduced even during maximal exercise, but the increased blood level of norepinephrine may account for the enhanced sensitivity of the centers to the oxygen drive. The sensitivity of the respiratory centers to PaCO2 is not increased. The pH is lowered and can reach 7.15 during very intense exercise. tthis acidity may account for the increased ventillatoy output under these circumstances. The increased body temperature may partly explain the progressive increase of ventilatory output during long lasting exercise, but it does not change the alveolar ventilation. It thus appears that the exercise ventilatory behaviour meets the metabolic, acid-base balance and thermolytic requirements.


Malaria field studies in a high-incidence coastal area of El Salvador, C.A. A three-year investigation was made of the incidence patterns and characteristics of malaria in a small high-incidence coastal area of El Salvador with a resident population of about 6,000 persons and a migrant population of 3,000 to 4,000 others. It found a significant increase in the incidence of Plasmodium falciparum cases during the three-year period, combined with relative stability in the annual number of Plasmodium vivax cases. A close correlation was observed between the seasonal occurence of P. falciparum cases in 1973 and vector densities, and between vector densities and aerial application of agricultural insecticides. Cases of P. vivax appeared about twice as common in the 5 to 14 year age group as in older or younger groups, and cases of P. falciparum seemed only about one-third as frequent in the 0 to 4 year group as in older groups. The attack rate in 1973 was somewhat higher in males than in females. There appeared to be a decrease in parasite densities with age, as well as a direct correlation between parasite densities and the degree of disability (symptoms and "in bed" time) reported by patients.


[Kidney biopsy from the viewpoint of a clinician]. Technique, indications, contraindications and complications of percutaneous biopsy of the kidney and the renal transplant are reviewed. In Basle, after introducing fluoroscopic control, 347 consecutive percutaneous biopsies were followed by two serious complications only: persistent bleeding led to partial nephrectomy of the lower pole in one case and nephrectomy in a second case where spontaneous hemorrhage had occurred at the upper pole (temporally but not causally related to the biopsy of the lower pole). A further 110 biopsies of renal transplants done also with fluoroscopic control resulted in no complication whatsoever.


[Application of modern methods to clinical autopsy]. Among the numerous modern methods at the disposal of pathologists, four techniques and their applications are demonstrated: 1. An enzymatic stain for macroscopic diagnosis of early myocardial infarcts. 2. Immuno-histochemistry in juvenile diabetes. 3. Electron microscopy in pulmonary hypertension in relationship with the intake of slimming pills. 4. X-ray micro-analysis in the the diagnosis of asbestosis. These various techniques are of great interest but can only be performed on fresh necropsy specimens taken early after death.


[Pathology and clinical medicine. An introduction]. In the introduction the author presents a review of themes connected with the autopsy and some problems of pathology which are not discussed in further detail during the course of the symposium. Thus, the signification and influence of religious, metaphysical, legal, socioeconomical and certain technical factors of the autopsy practice are briefly described, followed by a synopsis of the situation of the pathologist facing the demands of medicine, science, education, and administration. As a conclusion, follows a survey of the history and the activities of the Neuchâtel Institute of pathological anatomy.


Marital stability following the birth of a child with spina bifida. The matrimonial stability of 142 families where a child with neural tube malformation (mostly spina bifida) was born between 1964 and 1966, including 56 families with a surviving spina bifida child, was examined in January 1976. The divorce rate for families with a surviving child was found to be nine times higher than that for the local population and three times higher than for families experiencing bereavement of their spina bifida child. Marriages which followed a pre-nuptial conception resulting in a spina bifida child were particularly vulnerable and had a divorce or separation risk of 50 per cent. All the divorced fathers had remarried, but only one of the mothers. It is concluded that a handicapped child adds greatly to the strain on a marriage, especially when this has not been cemented before the arrival of a child. This strain is diminished by the child's early death.


The possible roles of histamine, 5-hydroxytryptamine and prostaglandin F2alpha as mediators of the acute pulmonary effects of endotoxin. 1 In an attempt to investigate the possible role of released vasoactive substances in mediating the pulmonary pressor responses to E. coli endotoxin, cats were pretreated with histamine, 5-hydroxytryptamine (5-HT) or prostaglandin antagonists, with a histamine depleting agent (compound 48/80) or with an inhibitor of prostaglandin synthetase (sodium meclofenamate).2 The administration of endotoxin (2 mg/kg) resulted in a rapidly developing pulmonary hypertension (pressure twice normal after 2-3 min), increases in right atrial and intratracheal pressures, systemic hypotension and bradycardia. These effects were unaffected by methysergide in a dose sufficient to prevent the effects of intravenously administered 5-HT.3 Endotoxin responses were also unaffected by a combination of mepyramine and burimamide in doses sufficient to reduce markedly the effects of intravenously-administered histamine. In cats pretreated (chronically or acutely) with compound 48/80, endotoxin induced a transient pulmonary pressor response which was not maintained.4 The pulmonary and systemic responses to endotoxin were prevented by the prior administration of the prostaglandin antagonist, polyphloretin phosphate and by pretreatment with the prostaglandin synthetase inhibitor, sodium meclofenamate.5 It is concluded that a pulmonary vasoconstrictor prostaglandin is involved in the acute response to endotoxin in the cat.


An outcome study of group psychotherapy. In 1975 a long-term follow-up was undertaken on patients collected as in-patients, treated and studied in 1962-64 (Bovill, 1972). Treatment was by didactic group psychotherapy and relaxation. Treatment was for a mean of six months and of 30 sessions, treatment remained available on demand for a mean of two years after discharge from attendance. In 1975 30 treated patients and 24 control patients were traced out of the original 36 in each group. The criterion of success was, as before, the inverse of days spent re-hospitalized. The success ratio fell from 7: 1 in 1962-64 to 2 1/2: 1 in 1965-74 and to 2: 1 in the single year 1974. This fall was expected in view of the known spontaneous recovery rate operating on the controls.


Effects of naloxone on pethidine-induced neonatal depression. Part I--Intravenous naloxone. Infants whose mothers had had pethidine during labour were given either naloxone 40 microgram or isotonic saline administered intravenously double-blind within one minute of birth. Peak alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a specific sound stimulus were measured regularly up to 48 hours after birth. Alveolar carbon dioxide tension was significantly lower and alveolar ventilation significantly higher half an hour after birth in the naloxone-treated group than in the saline-treated group, but these differences between the groups were not significant at any other time, and there were no significant differences in sucking frequency or pressure, milk consumption, or habituation to the auditory stimulus.


Ontogeny of neurophysin in the rat pituitary gland. An electron microscope immunohistochemical study. The ontogenic development of neurophysin has not been investigated so far. To study this problem, electron microscopic immunohistochemistry was performed on ultrathin sections of the posterior pituitary of foetal and newborn rats. A concomitant appearance of secretory granules and neurophysin was first noted in the posterior pituitary of 18-day foetus. Neurophysin was detected only in the secretory granules, all of which were labelled. The number of granules (75-110 nm in diameter) as well as the intensity of the reaction for neurophysin increased as the foetus became older. In the newborn rat, the secretory granules were more numerous and showed a strong neurophysin positive reaction. The results support the hypothesis that neurophysin is an essential component for the formation of the secretory granules in the hypothalamo-neurophypophysial system.


The maintenance and identification of mouse cerebellar granule cells in monolayer culture. Methods are described for maintaining postnatal mouse cerebellar cells in monolayer culture, and for identifying granule cells in such cultures. Cells from cerebella of 7-day-old mice are dissociated with trypsin and DNAse, then plated at 1-1.5 X 10(6) cells/35 mm dish in a high-potassium modification of Hams F12 medium plus 10% fetal calf serum. Under these conditions, cells grow either singly or in small clumps, and develop complex meshes of single fibers and fiber bundles over a period of several days. Granule cells are identified by a combination of several criteria including their size, shape and relative proportion of the total cell population as determined by phase contrast and scanning electron microscopy; nuclear morphology, demonstrated by transmission electron microscopy, and failure to take up [3H]gamma-aminobutyric acid (GABA) in the presence of several other cell types which do, shown by autoradiography.


In vitro behavior of granule cells from Staggerer and Weaver mutants of mice. The survival, in monolayer culture, of cerebellar granule cells from the cerebellar mutants Staggerer and Weaver was studied to examine whether the observed in vivo granule cell degeneration is intrinsic or environmentally induced. Granule cells in vitro can be identified by means of a combination of criteria including their size, shape, nuclear morphology, relative proportion of the total cell population, and failure to take up gamma-aminobutyric acid (GABA) in the presence of several other cell types which do. Cultures from both Staggerer and Weaver cerebella had surviving granule cells for at least 3 weeks in vitro. Therefore, since the mice used as the source of the cells were 7 days of age, the degeneration observed in vivo cannot be a case of irreversibly programmed cell death determined before postnatal day 7. While the behavior of Weaver granule cells is essentially the same as littermate controls, cells from Staggerer cerebella both clump less and survive considerably longer than those from wild-type. The role of intrinsic granule cell differences vs. primary changes in some other cell type is discussed.


N-terminal amino acid sequences of acid proteases: acid proteases from Penicillium roqueforti and Rhizopus chinensis and alignment with penicillopepsin and mammalian proteases. The amino-terminal sequence (33 residues) of the acid protease from Penicillium roqueforti has been determined with an automated sequencer. The amino-terminal sequence of Rhizopus pepsin (published by Sepulveda, P., Jackson, K. W. & Tang, J. (1975) Biochem. Biophys. Res. Commun. 63, 1106-1112) has been extended from 27 residues to 39 residues. Also, it was found that two forms of Rhizopus pepsin differ in position 15, where Rhizopus pepsin I has an isoleucine and Rhizopus pepsin II a valine residue. The new sequences have been aligned with the amino-terminal sequences of penicillopepsin (EC 3.4.23.7), pig pepsin (EC 3.4.23.1), calf chymosin (EC 3.4.23.4), human pepsin (EC 3.4.23.2), human gastricsin (EC 3.4.23.3), and cow pepsin (EC 3.4.23.1). Residues 31-35 (numbering based on pig pepsin, Tang, J., Sepulveda, P., Marciniszyn, Jr., J., Chen, K.S.C., Huang, W.-Y. , Tao, N., Liu, D. & Lanier, P. (1973) Proc. Natl. Acad. Sci. U.S.A. 70, 3437-3739) are identical in all enzymes. This section contains one of the two aspartic acids (Asp-32) implicated in the active site. The similarity of the sequences provides strong evidence for the homology of these acid proteases.


The effect of proflavine on pyruvate kinase I of Escherichia coli B. Proflavine (PF) inhibited glucose use in sensitive but not resistant Escherichia coli B. Glucose transport (as measured by alpha-methylglucoside accumulation) was only partly inhibited by PF concentration that completely blocked glucose use. Fructose 1,6-diphosphate-(FDP)-regulated pyruvate kinase (PK1) (EC 2.7.1.40), the only glycolytic enzyme affected by PF, was completely inhibited by a dye concentration of 0.8 mM. The inhibition curve for PF was sigmoidal, suggesting that PF was acting as an allosteric inhibitor. PF increased the K 1/2 for phosphoenolpyruvate (PEP) and lowered the V; however, it had no effect on the Hill number for PEP. PF inhibition was partially reversed by FDP but not by cyclic AMP, AMP, ATP, fuctose 6-phosphate, or dithiothreitol. Studies with a variety of acridines indicated that those substituted at the 3-position are the most effective inhibitors and also that hydrophobic interactions may be involved in PF inhibition of PK I. PK I for E. coli B/Pr was also strongly inhibited by PF, indicating that PF resistance does not lie at the level of this enzyme. Ribose-5-phosphate-regulated pyruvate kinase (EC 2.7.1.40) was much less sensitive that PK I to the inhibitory effects of PF. A role for PF as a molecular probe for PK I has been proposed.


[Comparative value of 2 technics of corneal preservation for rabbit corneal grafts]. The author compares corneal cryo-preservation in liquid nitrogen with corneal preservation using McCarey-Kaufman solution. Corneal grafts were performed on 38 rabbits which were then studied histologically at different intervals after surgery. The clinical results were similar: 45.5% clear grafts 1-2 months after surgery in the first group (cryo-preservation) and 50% clear grafts 1-3 months after surgery in the second group (preservation with the McCarey-Kaufman solution). The histological results indicated that in both groups, enough donor endothelial cells survive to keep the corneal graft clear; however there were many important endothelial changes in the first group and only a few in the second group.


The relationship between oxygen extraction and extravascular mean transit time in the canine heart. A significant relationship was observed between myocardial oxygen extraction and the extravascular mean time transit time. This relationship implies that oxygen extraction by the myocardium is a time-dependent process, and emphasizes the critical link between blood flow and myocardial oxygen consumption.


Serological reactivity of chemical fractions of Mycoplasma bovis. Crude chemical fractions, homogenates, and whole cells of Mycoplasma bovis were tested for serological reactivity using agar gel diffusion, ring precipitation, indirect hemagglutination, inhibition of growth inhibition (IGI), and complement-fixation (CF) tests. Only the IGI and the CF tests gave sensitive and reproducible serological information. Preliminary studies indicated lipids to be the serologically reactive components of M. bovis.


Alternatives to hexachlorophene bathing of newborn infants. In controlled trials newborn infants were bathed with Lactacyd, pHisoHex, Hibitane, Lanohex or tap water. Bacteriologic samples were taken from three sites (groin, axilla and cord) immediately after birth, following an initial bath with one of the test agents, and on day 3 or 5 after a water bath. Initial bathing with all agents, including water, reduced the concentration of bacteria on the skin to a similar extent. However, comparisons of bacterial flora at birth versus those on days 3 and 5 indicated differences in the actions of the various agents on pathogenic and nonpathogenic organisms. Lactacyd and Hibitane appeared to be suitable alternatives to hexachlorophene in the control of pathogenic bacteria on the skin of newborns. However, their absorption and toxicity in the newborn are unknown and, unless use of a skin disinfectant is warranted, routine bathing of newborns with tap water appears to be satisfactory.


VM 26 and VP 16-213: a comparative analysis. VM 26 and VP 16-213 are epipodophyllotoxin analogs. This paper presents a comparative analysis of their experimental and clinical features but fails to disclose any significant difference between these drugs. Similar studies with other classes of compounds might help to define some rationale for the development of analogous cytotoxic agents.


Chemical carcinogenesis.

Chemical carcinogenesis. The field of chemical carcinogenesis is reviewed, with emphasis on three aspects: 1) environmental chemicals are a major cause of human cancer; 2) most chemical carcinogens require metabolic activation by mixed-function oxidases to electrophilic metabolites that form strong covalent chemical bonds with cellular macromolecules and thereby initiate the carcinogenic process; and 3) several systems are available in which normal cells can be transformed by chemical carcinogens into malignant cancer cells. Much has been learned about the cellular mechanisms of chemical carcinogenesis using these systems. They also have considerable potential to be used as prescreens for environmental carcinogens.


Molecular biology of the response of cells to radiation and to radiomimetic chemicals. Radiation and radiomimetic chemicals can be both carcinostatic and also carcinogenic and mutagenic. In all cases the critical reaction is with the cellular DNA in which both ionizing radiation and radiomimetic chemicals produce a variety of adducts and changes. Human cells respond to these lesions in several ways. Some adducts are ignored. Other are recognized as different by the excision repair mechanism and are cut out of the DNA. Other adducts may be by-passed by special post-replication repair mechanisms so that viable daughter cells still containing altered DNA are produced. Unrepaired lesions may lead to chromosome aberrations and cell death. Since only viable cells can produce tumors, post replication repair is critical to the initial events in carcinogenesis. Lesions which are converted to DNA strand breaks, on the other hand, lead to cell death. Knowledge of the changes produced in DNA and understanding of the different cellular responses possible should permit prediction of the relative tumorigenic and tumoristatic properties of compounds.


Advances in diagnostic radiology: problems and prospects. The advances in diagnostic radiology are summarized under the headings of new techniques, new procedures and new programs. The most dramatic progress has occurred in the field of imaging technology, where computerized tomography (CT) has revolutionized the approach to brain imaging. Less obvious and secure is the position of body CT imaging, partly a result of technological deficiencies but also, as a result of imaging potential. Improved image amplification and angiographic techniques have made possible interventional radiographic procedures that hold great promise for the future. Radiologists with an interest in diagnostic oncology must play a dominant role in helping guide these new advances and direct the more appropriate application of conventional radiographic techniques in the diagnosis and followup of neoplastic diseases.


The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA). Certain D-arabinosyl nucleosides, notably arabinosyl cytosine (araC) and arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell of virus-induced DNA polymerases, competing with dCTP and dATP respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the aranucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g., against herpes virus in herpetic kiratitis.


Pharmacokinetics: selectivity of action related to physicochemical properties and kinetic patterns of anticancer drugs. Since the therapeutic index of drugs used for the treatment of cancer is small, optimal use depends on whatever advantage can be gained by achieving an effective concentration at the critical site in the cancer cell for a period of time sufficient to kill that cell while minimizing the action on normal cells or allowing their recovery. Advances in 1) methodology for measurement of minute amounts of drugs in tissues and body fluids, 2) better understanding of cell cycle kinetics and 3) development of kinetic models and computer simulation of compartmental drug distribution now aid better choice of dosage, mode of administration and treatment schedules. Limitations on the entry of amethopterin (Methotrexate) into cells and body compartments is compared with another folate antagonist, metroprine (DDMP), having the same mode of action, yet able to penetrate into brain. CSF and amethopterin-resistant cells because of greater lipid solubility. Pharmacokinetic considerations related to the limited effectiveness of present drugs for the treatment of brain tumors lead to the concept of "compartmental chemotherapy" based on selective drug contact with tumor combined with selective protection of tissues of limiting toxicity.


Multiple basis of combination chemotherapy. In combination chemotherapy, the type of drug interactions can be divided into three broad categories: 1) combinations based on cooperative effects of active drugs; 2) combinations in which the effectiveness of an active drug is increased by the concurrent administration of an inactive agent; and 3) combination of an active drug with an agent capable of selectively reversing the toxicity of the first drug. Many concepts have been proposed to explain the synergistic interaction between two active drugs at the level of the target cell. These include multiple inhibition of a single enzyme, enhanced activation, decreased inactivation, increased drug uptake, sequential blockade, concurrent inhibition, complimentary inhibition, and concerted inhibition. The therapeutic advantage of combination chemotherapy may reside in the whole organism, reflecting increased bioavailability of drug, reduced dose-limiting toxicity or reduced impairment of host defenses; it may reside in the tumor cells, reflecting the multiple molecular mechanisms of interaction mentioned above. Examples discussed include among others methotrexate plus citrovorum factor, thymidine or allopurinol, araC plus tetrahydrouridine and 3-deazauridine plus testosterone.