Smooth muscle antibody in patients with warts. Sera from fifty-four patients with warts were tested for the presence of commonly found autoantibodies. Smooth muscle antibody (SMA) was detected at a significantly higher level than in a control group of healthy blood donors matched for age and sex, and was in the IgM class. The SMA-positive sera gave a microfilamentous staining pattern also in the IgM class, on fixed HEp2 tissue culture cells. Absorption of positive sera with smooth muscle removed both SMA staining and the anti-cellular staining.


Hypochlorite-induced alterations to canine serum complement. Changes in the concentration of the components of complement produced by NaOC1 both in vitro and in vivo are recorded. C1, C4 and C7 are particularly sensitive to this oxidizing agent, although all components decrease at high concentrations of NaOC1. Following oxidation, complement componenets return rapidly to normal. Data are presented to indicate that part of this repair mechanism is due to the action of reducing agents such as ascorbic acid and part is due to the synthesis of the individual components. The unique sensitivity of complement components to oxidation make this treatment of potential value in suppressing the inflammatory response.


Renal cystic disease associated with tuberous sclerosis complex: renal failure treated by cadaveric kidney transplantation. Chronic renal failure in patients with tuberous sclerosis may be secondary to diffuse cystic disease, a lesion less common than the better known hamartomatous angiomyolipomas. Uremia, in the case of a nineteen-year old female with end-stage renal disease, was associated with severely atrophic kidneys that contained numerous collapsed and scarred cysts. No hamartomas were present. The patient survived for more than three years following cadaveric renal transplantation.


Investigations on Leydig cell function and regulation after renal transplantation. The hypothalamic-hypophyseal-Leydig cell axis was investigated in 17 male patients following renal transplantation. Plasma levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined by radioimmunoassay under basal conditions and after stimulation with chorionic gonadotrophin (HCG) and hypothalamic releasing hormone (LH/FSH-RH) respectively. The investigations were carried out one to five years after renal transplantation. It was demonstrated, that primary dysfunction of Leydig cells may occur after renal transplantation. In some cases however normal Leydig cell function with adequate testosterone secretion may return. It remains uncertain, whether the Leydig cell dysfunction is a result of preexisting toxic uremic damage or whether it is due to immunosuppressive therapy with prednisone and azathioprine.


Fetal haemoglobin in homozygous sickle cell disease. Synthesis of fetal haemoglobin is prolonged in homozygous sickle cell disease. Its intracellular distribution is irregular and red cells containing high levels of Hb F enjoy greater protection from sickling and subsequent destruction. This relationship is reflected in a number of associations between Hb F level and the haematological and clinical parameters of the disease. High fetal haemoglobin levels are associated with more normal red cell survival, more normal oxygen affinity, and more normal red cell characteristics whereas clinically they are associated with less evidence of vessel obstruction, persistence of splenomegaly, more normal skeletal development and body habitus, and a generally more benign clinical course. Attempts to prolong Hb F synthesis might therefore be expected to lead to amelioration of the clinical features of the disease. The factors leading to persistence of Hb F synthesis is SS disease are largely unknown although they appear to be operative as early as the first three months of life.


Immune haemolytic disease: the autoimmune haemolytic anaemias. The autoimmune haemolytic anaemias are common syndromes, with protean clinical features reflecting a variety of significant associated diseases. A diagnosis of this state should alert the clinician to the possibility of an aberrant immune mechanism. Years may elapse between development of the haemolytic process and the eventurl emergence of the entire disease pattern. The haemolytic anaemia should be considered as the easily diagnosed part of a complex, multisystem disease resulting from malfunction of the immune apparatus. Therapy can be exceedingly difficult. The following outline is suggested as a general approach: 1. Start prednisone 60 mg daily. If a therapeutic response occurs, continue this dosage until the haematocrit reaches 30 per cent. A slow but progressive reduction should then be initiated. 2. If prednisone dosages greater than 15 mg daily are required to maintain the remission, treat as a therapeutic failure. 3. If no response occurs after one week of prednisone, start azathioprine 2.0 to 2.5 mg/kg. 4. If no response is apparent after two additional weeks (three weeks of prednisone), progressively reduce and eventually discontinue prednisone. 5. If no response occurs after a total of four weeks of azathioprine, one of two alternative therapies should be started: (a) perform splenectomy, or (b) increase azathioprine by 25 mg daily, every one to two weeks, until either a response occurs or reduced bone marrow function is observed. 6. If azathioprine and splenectomy both fail, experimental therapies such as antithymocyte antiserum or thymectomy should be considered. 7. Transfusions are to be used only as temporary paliation in life-threatening neurological or cardiovascular complications.


Monitoring of patients with head injuries. A practical protocol for evaluating and monitoring head injured patients has been presented. It has been stressed that monitoring is an ongoing process which begins with the initial evaluation and continues throughout the patient's hospital stay. The level of monitoring and thus the parameters to be monitored are determined on an individualized basis according to the patient's clinical status and his level of stupor and coma. It has been suggested that for mild head injuries, adequate monitoring includes periodic evaluation of the neurological status and vital signs; but the more severely injured patients require extensive and frequent monitoring of a large number of clinical and physiological parameters. Among the many parameters, the continuous monitoring of ICP and the respiratory system are perhaps the most useful indicators of the patient's condition. Several methods for continuous ICP monitoring which are readily adaptable to most neurosurgical practices have been discussed. These include the intraventricular catheter, subarachnoid screw, and the closed Rickham reservoir connected to a ventricular catheter. In our institution, the Rickham reservoir has been used to monitor ICP and at the time of this report, satisfactory ICP recordings have been obtained in 27 of 30 head injury patients. Although this method requires a small surgical procedure, we believe that the decreased incidence of infection, the rapid access to ventricular fluid, and its potential for long term monitoring justify its use. Suggestions for monitoring other physiological parameters have also been presented. Particular emphasis has been placed on the management of infants and children with head injuries. The clinical entity of chronic subdural hematoma in infants and children has been used to illustrate the value of ICP monitoring as a guide to further treatment. Finally, we have briefly discussed the place of computers in day to day patient care, research, and monitoring.


Volume and pressure in the craniospinal axis. Raised intracranial pressure is common in neurosurgical practice, but the clinical effects are variable. The factors which initiate intracranial hypertension are now fairly well established; the extent of the increase of intracranial pressure produced by any combination of these factors is a function of the volume-pressure status of the patient at that particular time and may be expressed in terms of brain clastance. The effects of raised intracranial pressure on the function of the brain are mediated through both changes in cerebral blood flow and brain shift or herniation. Understanding of these principles helps in selection of effective therapy for raised intracranial pressure. Ideal clinical management of raised intracranial pressure should be directed toward the identification of those situations in which intracranial pressure may become increased and should attempt to prevent intracranial hypertension before it actually occurs.


Phenobarbital plasma levels in neonates. This pilot study demonstrated marked variation in neonatal phenobarbital utilization. In order to rapidly achieve therapeutic levels, it is suggested that a loading dose of 8 to 10 mg per kg be administered for 2 days followed by reduction of dosage to a maintenance level of 5 to 6 mg per kg with frequent monitoring of plasma phenobarbital concentrations. The optimal plasma concentration of phenobarbital for control of neonatal seizures or withdrawal syndromes appeared to be between 15 to 30 mug per ml.


Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn. Digoxin rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Virtually nothing is known about the effects of transplacentally administered digoxin on the fetus. Toxicity has been reported in the fetus of a woman ingesting a huge overdose of digitoxin; the same result would be anticipated with digoxin poisoning. Serum levels in pregnant women receiving the standard dose of 0.25 mg tend to be subnormal and certain patients may require a small increase in dose during the last trimester. While the full-term neonate appears to tolerate relatively high doses and the resultant high serum levels, there is no compelling evidence that such doses are necessary or even useful. Since toxicity can and does occur in neonates, especially during administration of loading (digitalizing) doses, it is recommended that maintenance doses of 0.01 mg per kg per day be used routinely. If the full inotropic effect is needed immediately, a loading dose of 0.03 mg per kg may be employed. Maintenance therapy is then begun on the following day. Without a loading dose cumulation occurs for about 3 days; after 5 or so days, serum levels will equal those found after use of a loading dose followed by maintenance therapy. Results of a single study suggest that the daily dose should be divided and given every 12 hours. After about 1 week of therapy, the serum level should be determined and the dose modified to maintain a serum level of 1 to 2 ng per ml. If the therapeutic effect is less than desired, a cautions increase in dose to as high as 0.02 mg per kg per day or to that dose which produces serum levels up to 3 ng per ml can be tried. Certain infants appear to tolerate serum levels of 3.5 to 4 ng per ml but such infants must be closely monitored. There are no data which indicate that a greater inotropic response will occur at these high serum levels, though this point has not been definitively investigated, and is the highest priority question for research. The intramuscular route should be researved for the unusual situation. Vomiting should be considered an early sign of toxicity and may act as a "safety valve." When adminstered in solution (as in the elixir or solution for intravenous use), oral digoxin is rapidly absorbed an an inotropic response is found within minutes, reaching a peak within hours, so that little is gained by parenteral administration. If an inotropic effect is urgently needed, intravenous administration of ouabain will give an immediate response.


Protein metabolism during pregnancy.

Protein metabolism during pregnancy. Protein metabolism is altered during pregnancy to allow for an increased rate of tissue synthesis. These adjustments seem to be mediated primarily by hormonal changes. The observed nitrogen, and therefore protein, retention is in the order of 1.1 gm N per day during the last half of pregnancy. The theoretical gain of nitrogen in fetal and maternal accessory tissues is about 0.8 gm per day during the same period. Animal data and a few human studies suggest that the difference may be accounted for by maternal gain of fat-free tissue. The rate of nitrogen retention appears to increase by a factor of 3 from early to late pregnancy. The current NRC protein recommendation for pregnancy is 30 gm additional protein or 1.3 gm per kg pregnant body weight. This allowance takes into consideration the low efficiency of protein utilization in the practical diets consumed by most pregnant women. The recommendation is made assuming that energy needs have been met. Within reasonable limits increased energy intakes will improve protein utilization. Some clinical surveys have noted a relationship between prenatal diet and infant size at birth, infant health in early life, pregnancy complications, and fertility rate; others have failed to find these associations. Supplements of food given to pregnant women in an attempt to improve outcome are associated with significant improvement in poorly nourished women but less impact in more well nourished women. When healthy pregnant women eat to appetite, the protein and energy intakes seem to be comparable to the current NRC recommendations.


Vitamin passage across the placenta.

Vitamin passage across the placenta. A pregnant woman who has adequate nutrition available in the form of a standard diet will provide the vitamins required by the fetus for normal development. Active transport of the water-soluble vitamins plus easy oral absorption after birth insure nutritional sufficiency at any gestational age. The fat-soluble vitamins which have a much slower transfer rate as the result of facilitated diffusion do not achieve the same degree of storage in the developing fetus. Thus, the premature infant who has decreased stores and who may have impaired oral absorption initially may become deficient in a fat-soluble vitamin (A, D, E, K) during the first 4 to 6 weeks of life. Oral or possibly parenteral supplementation following birth, however, would seem more appropriate than subtoxic doses administered to the mother prenatally.


Nutrition for the low birth weight infant. Satisfactory nutrition of the low birth weight infant concerns the nurse, obstetrician, pediatrician, and nutritionist. It may be that at present the most satisfactory feeding for the low birth weight infants is human milk. Such factors as protein quantity and quality, fat quantity and quality, immune factors, and osmolar factors may be uniquely suitable for the human infant regardless of his weight. Because of present limitations in the availability of fresh human milk, infant formulas have been adopted with reasonable success in the nutriture of the low birth weight infant. Those formulas which most nearly simulate human milk are most widely used. Broad outlines for the composition of these formulas have been given. Regardless of the availability and ease of administration of either human milk or formula, it is unlikely that any form of external nutriture can equal the advantages provided by intrauterine growth. Until better methods are devised for prolonging intrauterine growth, presently available feeding regimens should be considered experimental and in a state of flux.


Nutritional management of infants with inborn metabolic errors. Inborn errors of metabolism can dramatically manifest themselves in the new born period or remain completely undetected. Awareness on the part of the physician, with every attempt being made to arrive at an early diagnosis, is the basis for a favorable outcome. Many approaches to therapy are possible but the most frequently used is that of substrate restriction in the form of dietary control. Frequent monitoring of growth as well as of plasma biochemical analysis can result in adequate nutritional status as well as in normal development.


Infant nutrition.

Infant nutrition. Although most physicians agree that human milk is superior to artificial feeding, the latter is far more popular in well developed countries. There are various reasons for the decrease in breast feeding but a major factor has been the introduction of a variety of simple, safe milk and milk-substitute formulas. The healthy full-term infant will thrive on any of a number of properly prepared formulas as well as human milk. Mothers should be encouraged to breast feed by the obstetrician and pediatrician, but should not be made to feel guilty if they do not. Regardless of the method used for feeding, proper instruction is mandatory. A practical approach to the management of breast feeding is presented, as is a guide to artificial feeding. A brief review of the full-term infant's nutritional requirements is given together with a comparison of human milk, cow's milk, and commercially prepared feeding products. The availability and use of the specialized formulas is also included.


Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis. Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after 10-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7alpha-hydroxy-5,11-diketotetranoprostane-1,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.


Nefopam and morphine in man.

Nefopam and morphine in man. A new analgesic, nefopam, is chemically distinct and pharmacologically unrelated to any presently known analgesic. A comparison was made of morphine and nefopam in 74 patients who required parenteral analgesia for moderate to severe postoperative and somatic pain, using a single administration, 2-dose level, double-blind design. A significant dose-response curve was obtained with nefopam and with morphine, and there was no significant deviation from parallelism. The time-effect curves for the 2 drugs were similar. The estimated relative potency of nefopam to morphine indicates that 20 mg of nefopam HCl is the approximate analgesic equal of 12 mg of morphine SO4. There were no adverse effects with nefopam and one adverse reaction to morphine.


Butorphanol and pentazocine in patients with severe postoperative pain. Either butorphanol tartrate (1, 2, or 4 mg) or pentazocine (30 or 60 mg) was given intramuscularly (5 dose groups) to 262 patients, who were scheduled for major operations, if they had severe pain after full awakening in the recovery room, postoperatively under double-blind conditions. There were at least 50 patients in each of the five dosage groups. Pain intensity and relief were scored numerically for each treated patient at 1/2 1, 2, 3 and 4 hr, while under direct surveillance, and the patients were seen again for follow-ups during the first 24 hr postoperatively. Appreciable pain relief developed within 30 min at all dose levels, with a peak analgesic effect apparent at about 1 hr. Satisfactory relief persisted for 4 hr in the majority of patients in each group. With the lowest dose of butorphanol tartrate (1 mg), which gave good pain relief for only 2 to 4 hr, approximately 60% of the patients had to be remedicated within 4 hr. Vital signs were not appreciably affected, but the patients who received the high dose of analgesics (butorphanol tartrate 4 mg or pentazocine lactate 60 mg) were often quite drowsy. The incidence of other side effects was negligible. The relative potency assay showed that butorphanol was approximately 20 times as potent as pentazocine for up to 4 hr.


Oral benzquinamide in the treatment of nausea and vomiting. The clinical antiemetic effect of bezquinamide by oral route at a dosage of 100 mg 3 times daily was evaluated by a controlled double-blind method in 183 studies of patients treated with 5-fluorouracil. The incidence of nausea and vomiting in benzquinamide-treated patients was equal to that in placebo-treated patients and significantly higher than that in patients treated with prochlorperazine, 10 mg 3 times daily. Sedation was the only significant side effect observed, and this occurred at essentially equal rates in benzquinamide- and prochlorperazine-treated patients.


A comparison of fenfluramine and amphetamine in man. dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally in random sequence at weekly intervals using a double-blind crossover design. Fenfluramine had little effect on blood pressure and temperature, but caused a marked dilation of pupils, whereas amphetamine was a potent vasopressor and a weak mydriatic. While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.


Duration of hydralazine action in hypertension. The effect on blood pressure of giving hydralazine orally, 300 mg per day divided into 2, 3, and 4 doses, was studied in 4 hypertensive patients. There was no significant difference in average mean arterial pressure for the 3 regimens. Fluctuations of mean arterial pressure with time were not significantly different for the regimens as indicated by coefficient of variation. The mean coefficient of variation for the 2 days prior to initiation of hydralazine dosing was 4.0% +/- 0.3 (SEM) and for the 3 dosing regimens ranged from 4.1% to 4.8%. Heart rate was used as an index of vasodilator-induced increase in sympathetic tone and therefore as a measure of possible side effects. Fluctuations in heart rate were small and were not associated with symptoms. After discontinuation of hydralazine, the time for blood pressure to return halfway between initial placebo value and end treatment value varied from 30 to 140 hr. A tracer dose of hydralazine 14C. HCl was administered intravenously to the patients. The urinary excretion of 14C showed a multiexponential pattern of elimination with a previously undescribed prolonged terminal phase. Under the conditions of the present study, a daily dose of 300 mg of hydralazine was as effective and free of side effects given in 2 as in 4 divided doses.


Occurrence, transport, and storage of octopamine in human thrombocytes. 3H-octopamine was found to be accumulated in human platelets, achieving a maximum concentration gradient of 30:1. Its accumulation was partially inhibited by reserpine, imipramine, serotonin, ouabain, dinitrophenol, and iodoacetate. When octopamine was added to platelet preparations, it led to a decrease of both endogenous and 14C-serotonin. To determine whether octopamine accumulates in human platelets in vivo, preparations from 6 patients receiving monoamine oxidase inhibitors and 17 control subjects were assayed enzymatically for octopamine. Octopamine was detectable in all of the drug-treated patients, averaging 0.45 +/- 0.06 ng/mg protein, while only 4 of the 17 control subjects had detectable (greater than 0.05 ng/mg protein) platelet octopamine. Although much lower than platelet serotonin levels, these octopamine levels are in the range of those reported for platelet norepinephrine and epinephrine.


Clinical trials of drugs from the viewpoint of the academic investigator (a satire). Dr. Lasagna was unable to attend the workshop in person, and therefore delivered his remarks by videotape, in the assumed role of the newest "Secretary of Human Experimentation" at the Department of Health, Education, and Welfare addressing a public television audience. There is no difficulty in sensing the serious truths underlying the satire in his address.


Panel 2: phase II investigations.

Panel 2: phase II investigations. At the end of Phase II, a decision must be made as to whether or not the drug should be developed as a therapeutic agent. Such a decision may be based on many criteria in addition to the scientific data derived from the Phase II study. At this point, expert judgment is needed. One should like to assume that if the decision is made to proceed with the increasingly expensive and laborious process of further development, the drug will, barring some completely unforeseen misadventure, ultimately find its way into clinical therapeutics. Phase II studies, therefore, are the most crucial stage in the course of drug development. Planning of these studies requires great care and investigators of the highest caliber should be used for their conduct. The escalating costs of new drug development are resulting in an undesirable imbalance of efforts in the direction of studies characterized more by easily defined end points than by therapeutic needs. Industry, academia, and the FDA must all be concerned with facilitationg studies in areas of most-needed therapeutic advances.


Imaging studies in renal failure. Emphasis of selection and sequencing in the clinical evaluation. The focus of this review will be on the current role of imaging studies in the clinical evaluation of patients with acute and chronic renal failure. We will stress the application of these studies in specific clinical settings in an effort to indicate the current value, and also to suggest fruitful areas for future clinical investigation. It is clear that imaging studies are an essential component in the evaluation of acute and chronic renal failure. Physicians who manage such patients must choose appropriately from a variety of available studies to obtain a maximal information with the least risk to their patients. This selection is influenced by local conditions, the most important among these being the experience and technical skill of those involved. Attention to detail is particularly important and it is critical that the studies be done at the appropriate time in the evaluation. There will be emphasis on the evolving role of imaging studies in evaluating these patients.


Occult traumatic lesions of the cervical vertebrae. The numerous general and special techniques for examination of the cervical spine, with particular reference to the demonstration of occult traumatic lesions will be presented and evaluated. The advantages and limitations of each technique will be presented. Optimal procedures will be suggested for the examination of the acutely injured patient, with injuries of unknown severity, as well as for the longer term followups and minor injuries. The mechanisms of the production of cervical spine traumatic lesions and the long term abnormalities to be anticipated will be related, together with the types of radiographic findings associated with them. These will be presented in the context of the anatomy, function and dynamic physiology of the cervical spine. The dynamic interrelationship between segments of the cervical spine and the cervical spine as a whole, as well as the interrelation of the cervical spine with the skull and the remainder of the spine will be considered. The clinical data available in the literature will be collected and correlated with the radiographic findings. The results will be used to evaluate the clinical significance of these occult traumatic lesions, and the efficacy of therapy.


Clinical evaluation of two daily doses of naproxen and indomethacin: result of a double-blind crossover trail. A double-blind crossover clinical trial is reported on the effects of naproxen in two doses, 500 mg. and 750 mg. daily, and 100 mg. indomethacin daily in 23 patients with classical rheumatoid arthritis, each drug being given for 1 week. The results show that there was little to choose between the drugs and that there was clinical equivalence between the two doses of naproxen. Radioactive pertechnetate (99mTc) joint uptakes were depressed by both naproxen and indomethacin, indicating anti-inflammatory effect.


A double-blind trial of methocarbamol versus placebo in painful muscle spasm. A double-blind trial of methocarbamol versus placebo was carried out in 59 matched pairs of patients suffering from painful muscle spasm. Methocarbamol (1500 mg. q.d.s.) was found to be effective in approximately 60% of patients compared with 30% of patients receiving placebo (p less than 0.01). Side-effects were of almost equal incidence in the two groups.


A preparatory technique for examination of imperfect fungi by scanning electron microscopy. Thin 12 mm diameter coverslips, coated with nutrient agar, were inoculated with a fungus, incubated, and sequentially examined with the light microscope and then the scanning electron microscope (SEM), thus providing the valuable capability of correlation of results obtained from these two microscopic analyses. A sandwich of two coverslips was prepared for light-microscopic observations, and then separated and the agar-coated coverslip on which the fungus had grown was passed through fixative solutions, critical point dried, metal-coated and examined in the SEM. The technique was designed primarily for studies of conidiogenesis in rapidly growing human pathogenic imperfect fungi.


The possibility of latent centromeres and a proposed nomenclature system for total chromosome and whole arm translocations. Translocations involving entire chromosomes or whole chromosome arms may not necessarily require deletion of a centromere. Conceivably, in the process of centromeric or telomeric fusion or of fusion of a centromere with a telomere, centromeric inactivation may occur, thus preserving both centromeres--one functional, the other latent--in the resultant translocation chromosome. If such latent centromeres exist and, in addition, are capable of being reactivated, it would explain how additional functional centromeres are acquired in the reverse process of chromosomal fission or fragmentation. A system of nomenclature is proposed for identifying the origin and nature of these chromosomal rearrangements.


Potent combinations of beta-lactam antibiotics using the beta-lactamase inhibition principle. Several penicillins known to be stable to enterobacterial beta-lactamases were tested in combination with beta-lactamase-sensitive penicillins and cephalosporins in a turbidimetric system. Nafcillin was found to be the best beta-lactamase inhibitor amongst agents presently available commercially, but the related, new semi-synthetic penicillin BRL 1437 (2-isopropoxy-1-naphthylpenicillin) was consistently found to be superior. Using 103 ampicillin-resistant coliform bacilli and antibiotic levels achievable in urine, cephalothin or cephaloridine alone achieved long-term suppression of growth (greater than 20 h) of 16 and 13% of strains, respectively, while the additional presence of BRL 1437 suppressed growth for longer than 20 h of 81% of the remaining strains. Even where 'success' was not achieved according to these stringent criteria, regrowth was significantly delayed by the presence of BRL 1437. Suppression of growth for longer than 20 h by BRL 1437 plus cephalothin was achieved with all of the 46 Escherichia coli strains tested. Antibiotic combinations were also studied in an in vitro model which stimulates the hydrokinetic features of the urinary bladder. Suppression of the growth of two highly resistant E. coli strains was achieved in this system, for therapeutically acceptable periods of time, with combinations of cephalothin or cephaloridine with BRL 1437, but not nafcillin.


Adjuvant immunotherapy for malignant brain tumors in infants and children. Immune deficiency of immunocompetent cells or of humoral factors are essential causes of tumor growth. The authors have investigated the transfer of immunocompetent cells - allogeneic bone marrow cell transfusion and white blood cell intracranial infusion - for the treatment of 11 malignant gliomas in infants and children as an adjuvant to surgery, radiation and/or chemotherapy. Ten cases, from 3 months to 11 years, received bone marrow cell transfusion. Two medulloblastomas and 3 pontine gliomas are dead. Five cases are alive and well 37-65 months following surgery. Among these two posterior fossa neoplasms, a medulloblastoma and a glioblastoma have survived 46 and 65 months, respectively. One cerebral glioblastoma received allogeneic white blood cells infused locally into the tumor bed: it recurred 1 year following surgery, chemotherapy, and immunotherapy. Cytolysis of the tumor cells by sensitized lymphoid cells were demonstrated in this case. The role of immunotherapy should be limited at the present time to adjuvant therapy until its effect on tumor growth is statistically confirmed. The results so far are promising, and improvement of the immunological approach in treating malignant brain tumors is under way.


Manifestations and management of Arnold-Chiari malformation in patients with myelomeningocele. As a result of the authors' experience they advocate posterior fossa decompression in patients with myelomeningocele at the first sign of compression of bratn stem or the cervical cord or both. If decompression is not undertaken at once the impaired gag and cough reflexes place the child at risk. He may develop pneumonia. If decompression is delayed too long full neurological recovery will not occur. The removal of bone and the opening of dura must be carried down to the bottom of the tonsillar tip, sometimes as low as C7. The most dramatic improvement occurs in infants whose symptoms are life threatening. Less dramatic but just as real is the improvement in older children. Although investigations such as myelography and ventriculography will show the malformation, they are not essential. The associated visible malformations and the clinical condition are the most reliable means of making the diagnosis. Delaying the decompression risks the life of the infant and threatens the quality of life for the older child.


[Hyperacute kidney graft rejection with and without demonstration of antibodies]. Hyperacute rejection was studied in presensitized recipients of renal homografts and pig-to-dog heterografts. In these experiments antidonor antibodies can be observed but their participation in the rejection process cannot be assessed quantitatively. The importance of antibodies lies in their capacity to activate the complement system, which in turn destroys the graft. Intrarenal complement activation was also demonstrated in two clinical cases of hyperacute rejection, in one of which activation was by the alternate pathway.


[Aspergillus infection in skin transplantation and its therapy]. In a 10 years old girl sustaining a corrosive injury of the lower leg from sulphuric acid, in the region of a skin transplantation colonization with Aspergillus fumigatus (Fresenium) and Aspergillus niger (van Tieghem) took place. This infection endangered the attempt of transplantation and the saving of the foot. Treatment by medication with nystatin (moronal) and canesten (clotrimazol) were ineffective. Pimaricin (pimafucin, natamycin) quickly erradicated the mycotic infection and secured an undisturbed progress for the transplantation. Additionally the epidemiology of infections by Aspergillus is briefly discussed.


The assessment of thiothixene in chronic schizophrenia. A double-blind controlled trial. The results are reported of a double-blind controlled trial of a recently introduced major tranquilizer thiothixene (Navane, Pfizer) against chlorpromazine in 24 chronic schizophrenics in the Royal Edinburgh Hospital, Edinburgh, Scotland. Additionally, a limited experiment in withdrawal of routine tranquilizers in these patients (one month) was carried out prior to the trial. Changes in manifest psychosis (symptoms) and social disability were assessed by the use of the Lorr scale (IMPS) and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE) at suitable intervals. The results indicated that thiothixene conferred no advantage over chlorpromazine in symptom relief or social improvement. Serial measures showed no significant change in these patients as a group when on active drugs as opposed to placebo, or with the course of time. 12.5% of patients relapsed during the placebo period: these patients were younger than the non-relapsers and had received larger daily doses of phenothiazines prior to the trial.


[Contaminated infusions as cause of nosocomial Serratia marcescens septicaemia in children (author's transl)]. At the University Children's Clinic at Munich 25 cases of Serratia marescens septicaemia (mainly bacteriocin types 18 and 44) occurred within one year, predominantly in newborns and infants. Almost all of the children were seriously ill from an underlying illness or had been operated on. Two thirds had received antibiotics before the septicaemia occurred but they were ineffective. Of a total of nine antibiotics tested against 51 Serratia marcescens strains, nalidixic acid (99% sensitivity) and amikacin (100%) proved the most effective. Main source of the septicaemia were contaminated infusions, from which in as many as 35% of cases microorganisms, usually Serratia marcescens, had been isolated. Intensive hygienic measures at once terminated this "sepsis wave".


Stimulation of LH release and ovulation in the rat by cutaneous application of luteinizing hormone-releasing hormone (LH-RH) in dimethyl sulfoxide (DMSO). The efficacy of cutaneously applied luteinizing hormone releasing hormone (LH-RH)  in stimulating LH release in the chronically ovariectomized, estrogen/progesterone-blocked rat and ovulation in the chlorpromazine-blocked, proestrous rat was investigated. Following the cutaneous application of 25 or 100 mug of LH-RH in 100% dimethyl sulfoxide (DMSO), serum LH rose to a peak at 1 hr, then declined toward basal levels in the ensuing 3 to 4 hr. LH-RH applied cutaneously in either 100% DMSO or 0.9% NaCl was also capable of inducing ovulation in the chlorpromazine-blocked, proestrous rat; however, LH-RH in 0.9% NaCl did not yield a linear log-dose-response relationship, therefore a valid ED50 potency ratio for DMSO/0.9% NaCl could not be estimated. Nonetheless, 0.9% NaCl was a considerably less effective cutaneous vehicle than DMSO. Cutaneous application of LH-RH in DMSO in doses of 100, 50, 25, 10, 5, 2.5 and 1 mug induced ovulation in 100%, 100%, 90%, 73%, 30%, 10% and 0% of the rats, respectively. When the percent ovulation response was transformed to probits and plotted against the logarithm of the LH-RH dose an approximately linear log dose-response was obtained; the same relationship also held true for ovulation induction following sc LH-RH administration. In turn, the ED50's of these two parallel dose-response curves yielded a potency ratio estimate (sc/cutaneous) of 0.025, suggesting that 2.5% of the cutaneously applied LH-RH dose was absorbed through the skin in a biologically active form. These data indicate that DMSO privdes a convenient cutaneous vehicle for the administration of LH-RH.


Anti-insulin serum coupled to Sepharose 4B as a tool for the investigation of insulin biosynthesis in the B-cells of obese hyperglycemic mice. The biosynthetic activity of the B-cells of obese hyperglycemic mice (obob) was measured by the incorporation of [3H]leucine into proteins in collagenase-isolated pancreatic islets. To quantitate the incorporation into proinsulin and insulin, an immune binding method was used. For this purpose, anti-insulin serum was coupled to cyanogen bromide-activated SepharoseR 4B. This turned out to be a specific and versatile technique for the measurement of newly synthesized proinsulin and insulin in the B-cells. The B-cells of obob mice appear to be well adapted to a high rate of hormone biosynthesis, since at 16.7 mM glucose 44% of [3H]leucine incorporated into TCA-precipitable proteins was bound to the insulin antibodies coupled to Sepharose 4B. The insulin biosynthetic rate was stimulated 9 times at 16.7 mM glucose, during a 3-h incubation, compared with the basal insulin biosynthesis rate.


Blockage of estrogen-induced release of luteinizing hormone by reserpine and potentiation of synthetic gonadotropin-releasing hormone-induced release of luteinizing hormone by estrogen in the ovariectomized ewe. These experiments tested the effects of reserpine on estrogen-induced LH release and the effects of estrogen on gonadotropin-releasing hormone-induced LH release in ovariectomized ewes. Injection of 50, 200, or 500 mug of estradiol benzoate (EB) into progesterone-treated ewes, or of 50 mug of EB into non-treated ewes induced a large surge in serum LH levels approximately 15 h later. Injection of 5 mg/ewe of reserpine 6 h prior to the EB, blocked the LH surge. Reserpine reduced, but did not block the release of LH induced by injection of 20 mug or 40 mug of synthetic gonadotropin-releasing hormone (GnRH). Injection of graded doses (5, 10, or 20 mug) of GnRH into progesterone-treated ewes that had been treated with reserpine, induced increases in serum LH levels that were proportional to the logarithm of the dose. In the final series of experiments both progesterone-treated and non-treated ewes were injected with reserpine and then with either EB or oil. Fifteen hours after receiving EB or oil they were injected with either GnRH or the diluent. GnRH elevated serum LH levels significantly higher in ewes given EB than in those given oil. LH levels in ewes given oil and diluent were not elevated. These data suggest that reserpine blocked EB-induced LH release by an action on the central nervous system and that EB acted directly on the anterior pituitary to increase the response to GnRH.


Modulation of the enzymic activity of chicken pepsin by the covalent modification of its single -- SH group. The single cysteinyl residue of chicken pepsin was modified with a wide spectrum of reagents to produce mixed disulfides or alkylated derivatives. All these derivatives showed enhanced catalytic activity towards the synthetic peptide Z-Ala-Ala-Phe-OPrP, where OPrP is the 3-(4-pyridyl)-propyl-1-oxy group. The overall catalytic constant kcat/Km for these derivatives was 4 -- 25-fold larger than that of the native enzyme. The activity of the enzyme towards denatured hemoglobin was slightly decreased (10--45%) by these modifications. When the mixed disulfide derivatives were treated with excess mercaptan, the sulfhydryl group was regenerated and activity reverted to that of the native enzyme. The --SH group of chicken pepsin reacted preferentially with reagents containing an aromatic group. The reaction was found to depend on the ionization of a single group, presumably the --SH itself, with a pKa = 7.5. The rate of reaction of the fully deprotonated species with various disulfides was 100--1000-fold smaller than that of the --SH group of glutathione. It is suggested that the groups attached covalently to  the sulfhydryl also interact with other amino acid side chains in the protein thereby affecting the active center of chicken pepsin.


Initiation specificity of the poly(cytidylic acid)-dependent Qbeta replicase activity. The initiation specificity of RNA synthesis catalysed by the poly(C)-dependent Qbeta replicase activity was investigated with various synthetic ribopolymers as template. It was found that the initiation efficiency of a series of oligo(C) with various chain lengths is proportional to the template size. Synthetic riboheteropolymers containing cytidylic acid were accepted as templates only if they contained at their 3' end a cytidylic acid sequence of more than 5 nucleotides. Such an oligocytidylate sequence served also as an initiator sequence for copying the non-cytidylic-acid-containing part of the heterotemplate. RNA synthesis always began with the incorporation of GTP, even if the 3'-terminating nucleotide of the template was not cytidylic acid.


Solution conformation of virginiamycins (staphylomycins). The 1H (at 300 MHz) and 13C nuclear magnetic resonance spectra of virginiamycins S and S4 and vernamycin Balpha have been unravelled and analyzed. Together with model building and theoretical considerations, this allows the detailed description of their solution conformations. The depside bond can rotate and gives to the backbone some conformational mobility. The orientation of the depsicarbonyl bond depends on the surrounding. Apparent discrepancies between the different methods that are applicable for the disclosure of the nature of peptide H-bonding, have found a rational explanation.


On the dissociation and association of Escherichia coli ribosomes. The dissociation and association behaviour of 70-S ribosomes of Escherichia coli has been studied. It has been shown that the dissociation-association reaction can be both a real dynamic equilibrium and a non-equilibrium reaction, dependent upon the ionic conditions of the solvent. At relatively high ionic strength (I = 0.15 M or more) the dissociation-association reaction is an equilibrium reaction, whereas at lower ionic strength (I = 0.1 M or less) there is no dynamic equilibrium between 70-S ribosomes and its subunits. In the latter case a hysteresis in the dissociation-association reaction is observed. Whether there is a dynamic equilibrium or not can be demonstrated by a single centrifugation experiment, using the analytical ultracentrifuge.


Ultrastructural organization and biochemical characterization of chromatin - RNA - protein complexes isolated from mammalian cell nuclei. Extranucleolar elements were isolated from mammalian cell nuclei and characterized by correlative biochemical-ultrastructural studies. These complex structures were shown to retain a supra-particle arrangement closely resembling the organization in situ of definite nuclear areas. In particular the morphological RNA - protein species, namely perichromatin fibrils and granules, were detected in association with characteristic regions of chromatin. By autoradiographic experiments, we were able to show that perichromatin fibrils represent the morphological state of newly formed heterogeneous nuclear RNA (hnRNA). Chromatin - RNA - protein complexes were further fractionated by means of a treatment dissociating the chromatin component. A minor part of DNA, possibly involved in the biosynthesis and the processing of hnRNA, remains linked to the resulting RNA - protein network.


Phage Qbeta replicase: cell-free synthesis of the phage-specific subunit and its assembly with host subunits to form active enzyme. Cell-free translation of Qbeta RNA and subsequent partial purification of the enzyme resulted in replicase activity. From 0.5 to 1.5% of all R chains synthesised were found in the 7-S replicase complex. The presence in the 7-S complex of the host subunits of authentic replicase, i (= S1) and EF-Ts, was shown by the effect of antisera directed against ribosomal protein S1 and EF-Ts, respectively. Furthermore, the presence of EF-Ts was demonstrated by thermal denaturation of in vitro replicase made by a cell extract from an Escherichia coli mutant with a thermolabile EF-Ts. In vitro replicase did not assemble spontaneously during protein synthesis but was formed upon subsequent purification. Assembly could be induced by ammonium sulphate precipitation (60% saturation) alone. It is concluded that the functional phage-coded subunit synthesised in vitro recognises i and the EF-Tu - EF-Ts complex among a mixture of host proteins.


The use of primed synthesis by DNA polymerase I to study an intercistronic sequence of phiX-174 DNA. A decadeoxynucleotide complementary to ten nucleotides in the major ribosome-protected fragment of phiX-174 plus-strand DNA has been chemically synthesized and used as a primer for DNA polymerase I on phiX-174 plus-strand DNA as template. The sequence of the first 40 nucleotides incorporated onto the decadeoxynucleotide has been determined. This sequence extends further the sequence of the intercistronic region preceding gene G and shows the presence of another termination codon. The sequence was determined by using manganese as the activating cation for DNA polymerase I which allows ribonucleotides to be incorporated as well as deoxyribonucleotides. The ribo-substituted product was then cleaved specifically at the ribonucleotide residues to generate a series of overlapping ribo-terminated fragments whose sequences were sufficient to determine the complete sequence of the first 40 nucleotides. No evidence for misincorporation by DNA polymerase I in the presence of manganese was detected.


The importance of Escherichia coli ribosomal proteins L1, L11 and L16 for the association of ribosomal subunits and the formation of the 70-S initiation complex. 50-S subunits were washed with LiCl solutions of different concentrations. After washing with 1 M LiCl solution the particles lost their ability to attach either to 30-S subunits or to the AUG - 30-S subunit - fMet-tRNAfMet complex or to a poly(U) - 30-S subunit - Phe-tRNAPhe complex. Those proteins which were removed by LiCl were fractionated on a Sephadex G-100 column. Of the fractionated proteins only the combinations L1 and L11 or L1 and L16 were essential for the association of 50-S 1.0 cores (particles prepared by washing 50-S subunits in 1.0 M LiCl) with 30-S subunits. These three proteins were also required for the formation of a stable complex between 50-S 1.0 cores, mRNA, 30-S subunits and aminoacyl-tRNA.


Interaction between arginase and L-ornithine carbamoyltransferase in Saccharomyces cerevisiae. The regulatory sites of arginase. The inhibition of ornithine carbamoyltransferase by arginase in Saccharomyces cerevisiae, which is under the control or arginine and ornithine, involves a regulatory site for arginine on the arginase distinct from its catalytic site. This regulatory site is responsible for the reinforcement effect of arginine on the inhibition of ornithine carbamoyltransferase by arginase. The binding site of ornithine carbamoyltransferase on arginase is also shown by our analysis.


Envelope-bound N-acetylmuramyl-L-alanine amidase of Escherichia coli K 12. Purification and properties of the enzyme. N-Acetylmuramyl-L-alanine amidase activity was detected in Escherichia coli K 12 by usine N-acetylmuramyl-L-alanyl-gamma-D-glutamyl-(L)-meso-[3H]diaminopimelic acid as a radioactive substrate. This activity cleaves the amide bond between the residues of N-acetylmuramyl acid and L-alanine. It was readily obtained in a soluble form either by mechanical disruption of the cells or by spheroplast formation. In the latter case the release of most of the activity into the sucrose medium seems to indicate that it is either periplasmic or associated with the outer membrane of the envelope of E. coli K 12. The enzyme was purified to near homogeneity. A molecular weight of 39 000 was determined by gel filtration and confirmed by polyacrylamide gel electrophoresis. Further characterisation of this N-acetylmuramyl-L-alanine amidase activity was carried out by investigating several of its properties.


The isolation of two different lipopolysaccharide fractions from various Proteus mirabilis strains. Four distinct Proteus mirabilis strains were extracted by the phenol/water procedure. After ultracentrifugation of the dialyzed water phase, the pelleted lipopolysaccharide was purified and analyzed. The sugar composition of this lipopolysaccharide fraction I was similar for all four strains, containing only small amounts of strain-specific constituents. A second lipopolysaccharide fraction was isolated from the supernatant above (termed L1 fraction) after removal of nucleic acids. DEAE-cellulose chromatography indicated that this material is not a polysaccharide but rather a water-soluble lipopolysaccharide containing strain-specific constituents such as uronic acids, amino acids, amino sugars, neutral sugars, ethanolamine and phosphate, depending on the strain from which lipopolysaccharide II was isolated.


Identification of ribitol phosphate as a constituent of the lipopolysaccharide from Proteus mirabilis, Strain D52. A polyol was released from the lipopolysaccharide of Proteus mirabilis, strain D52, during alkaline hydrolysis and its phosphate ester was isolated after acid hydrolysis. This polyol has been identified as ribitol by comparison of the free polyol, its phosphate ester and its anhydro derivative formed after acid treatment with authentic xylitol, D- and L-arabitol, ribitol and their corresponding derivatives on paper and gas-liquid chromatography.


Function of the duct-ligated canine pancreatic allograft. Heterotopic transplantation of a duct-ligated canine pancreas was performed in 20 previously pancreatectomized, non-related recipient dogs. A technical procedure was elaborated for this grafting. It was found that early, fatal postoperative bleeding in the recipient could be avoided when the interval between pancreatectomy and transplantation was reduced from 7 to 2-4 days. The early endocrine function was studied in 15 surviving animals by determination of blood glucose and serum insulin during fasting and during glucose load. 24 h after transplantation the blood glucose values were normal and 4-8 days after transplantation the glucose tolerance was within normal limits. The serum insulin was on a supranormal level, also during glucose load. The early endocrine capacity of the transplanted duct-ligated pancreas after transplantation was found to be satisfactory, restoring the blood glucose in the pancreatectomized recipients to normal levels.


The psychiatric aspects of cardiac intensive therapy: a review. The post cardiotomy state is typically delirious and although organic factors are important it is multi-determined. Cerebral ischaemia has been implicated in the development of psychological disorder after resuscitation but longer term neurotic disorders also occur. Affective disturbances, particularly depression, are associated with the coronary care experience. The following conditions are directly related to an increased incidence of psychological disorder: age, loss of sleep, sensory deprivation, stressful experiences, pre-operative morbidity (both physical and mental), the severity of both surgical trauma and the post-operative medical state. For both the staff who administer intensive therapy and the patient who receives it there are unique psychological hazards, the management of which depends largely on mutual understanding and support.


Behaviour of the duct-ligated canine pancreas during hypothermic albumin perfusion. The behaviour of eight duct-ligated canine pancreata was studied during 23 hours of continuous, hypothermic perfusion, with an albumin electrolyte solution. The organs developed a considerable oedema during perfusion. This did not seem to influence on the vascular resistance of the organs. A continuous insulin release, a moderate increase in LDH concentration and only small changes in the electrolyte concentrations were observed in the perfusate, indicating only a moderate degree of cellular damage.


Twenty-four-hour preservation of the duct-ligated canine pancreatic allograft. Twenty previously pancreatectomized dogs received a duct-ligated pancreatic allograft; 16 of the grafts were preserved for 24 h, 9 with continuous hypothermic albumin perfusion, 7 with simple hypothermic storage; 4 glands were transplanted immediately and served as controls. The outcome of preservation was assessed by studying the early endocrine function of the glands. Excluding five early failures due to bleeding, all grafts showed endocrine activity after transplantation and the glucose values were on a normal level. An initial hyperglucemia caused by pancreatectomy disappeared within 24h. In the two groups with 24h preservation, no differences in graft function were found. In the control group, there was a hypoglucemic tendency the first days after transplantation and a prolonged hyperinsulinemia during glucose load. It could be concluded that duct-ligated, isolated canine pancreas well tolerated 24h of preservation both by continuous hypothermic albumin perfusion and by simple hypothermic storage in an extracellular type of fluid.


An improved method for the quantitative analysis of M-mode echocardiograms. A computer-assisted system is described which speeds and extends the quantitative interpretation of M-mode echocardiographic recordings. The system consists of a digitizing tablet, minicomputer, TV monitor and a hard copy device. M-mode echocardiograms are placed on the digitizing surface and traced using the digitizing pen. The entered signal includes the endocardial surfaces of the anterior and posterior left ventricular wall for at least one cycle, and two Q waves from a simultaneously recorded ECG to identify end diastole and heart rate. End systole is determined automatically as corresponding to the minimum LV dimension. Results of analysis include continuous plots of estimated volume and circumferential fiber shortening rate (CFSR) vs time. Determinations of special interest are also displayed: enddiastolic volume (EDV) and endsystolic volume (ESV), ejection fraction, cardiac output, mean and peak CFSR. M-mode echocardiograms obtained from 25 normal volunteers are used to evaluate the system. The standard error of the estimate of the computer-assisted system is comparable to the error between observers, furthermore the computer system adds no significant systematic or random error. Comparison between M-mode estimated volumes and angiographically determined values has been described previously and Sy - x here is significantly greater. The main advantages of this system are: 1. a continuous plot of estimated LV volume and CFSR is provided; 2. beat-to-beat analyses are facilitated; 3. the automatic determination of end systole removes possible errors in judgement made previously; 4. it is time saving when one considers the amount of data obtained. With these advantages and the generally satisfactory performance in the clinical trials, this system appears to have extended the clinical quantitative capabilities of M-mode echocardiograms.


Plasma catecholamines and blood substrate concentrations: studies in insulin induced hypoglycaemia and after adrenaline infusions. Plasma adrenaline-blood glucose interrelationships in insulin-induced hypoglycaemia in man have been studied using a sensitive double-isotope derivative method for adrenaline estimation. Plasma adrenaline reached a peak of 1.24 ng/ml at 45 minutes after insulin while blood glucose reached a nadir of 22 mg/100 ml at 30 minutes. There was a strong correlation both between the rise in adrenaline and the degree of hypoglycaemia and between the rise in adrenaline and the post-hypoglycaemic rise in glucose. Plasma noradrenaline rose from 0.29 to 0.59 ng/ml, the rise correlating with the rise in adrenaline. Changes in pulse rate preceded and were unrelated to changes in plasma catecholamines. Fuel mobilisation in response to adrenaline infusion (6 mug/min. for 20 min.) in normoglycaemic man was also studied. Plasma adrenaline concentration rose from a mean of 0.02 ng/ml to 0.71 ng/ml while plasma noradrenaline concentration was unchanged. Blood glucose rose from 71 to 98 mg/100 ml while plasma insulin decreased from 11 to 8 muU/ml. Blood lactate rose by 0.85 mM while pyruvate concentration remained unchanged. Blood glycerol concentration rose twofold and ketone body concentration threefold but there was little change in the concentrations of the glucogenic amino acids, alanine, glutamate and glutamine. Both the 3-hydroxybutyrate/acetoacetate ratio and the lactate/pyruvate ratio rose implying a more reduced intracellular state due presumably to increased hepatic fatty acid oxidation. It is concluded that adrenaline enhances the recycling of lactate and spares glucose through the mobilitsation of lipids but that amino acids are little affected.


Insulin metabolism, insulin sensitivity and hormonal responses to insulin infusion in patients taking oral contraceptive steroids. The metabolism of unlabelled human monocomponent insulin was studied in a group of six patients being treated with combined oestrogen-progestogen oral contraceptives (OC) and compared with a group of ten normal subjects. The parameters of insulin metabolism were determined by a priming dose-continuous infusion technique which enabled measurements of metabolic clearance rate (MCR) of insulin to be made at four separate steady state hormone concentrations spanning the physiological range. In normal subjects MCR was greatest at low insulin concentrations, falling from 24.7 ml/kg/min. at 16 muU/ml to 11.4 ml/kg/min. at a mean concentration of 280 muU/ml. In the OC group, MCR averaged 20.5 ml/kg/min. and did not change with increasing plasma insulin concentration. The plasma half-disappearance time (T 1/2) was longer than normal in the OC group (5.6 vs. 4.4 min., p less than 0.05) despite a higher MCR. The prolonged T 1/2 indicated that the apparent distribution space was increased in those on OC (166.6 vs. 82.7 mg/kg., p less than 0.0025). The results are interpreted as indicating increased capillary permeability to insulin and increased peripheral degradation. The fact that MCR did not fall in the OC group with increasing plasma insulin concentrations whereas it did in normal subjects, suggested that OC leads to the loss of saturable component of insulin degradation that is present in normal subjects. Insulin sensitivity (as judged by induced hypoglycaemia) was reduced in the OC group while growth hormone responses were within the normal range. Plasma cortisol was increased in those taking OC but the response to insulin induced hyperglycaemia was less marked than normal. The results indicate a significant alteration in insulin metabolism in these subjects, which may contribute to the impairment of carbohydrate tolerance seen in some women taking combined OC.


A stereotaxic headholder for visual neurophysiology. A stereotaxic headholder is presented that offers the following advantages: 1. It is especially suitable for visual neurophysiology, because the eye and surrounding orbit are not affected by bars or clamps. 2. It is easy to handle, because the ear bars are mounted on movable slides above the main frame. 3. It is versatile and can be used without additional adapters for different species of animals.


Synaptosomal uptake and levels of serotonin in rat brain areas after p-chloroamphetamine or B-9 lesions. In contrast to the pronounced fall in 5HT levels and synaptosomal uptake caused by p-chloroamphetamine, bilateral lesions of the B-9 cell group caused minimal regional changes, except for 35% decreases in the metathalamus-thalamus. We conclude therefore that the prolonged biochemical effects of p-chloroamphetamine are not due to a selective cytotoxic action on B-9 cells; and that a lateral 5HT pathway, possibly from the B-9 cell group, projects to the metathalamus-thalamus.


[Correlation of the bioelectrical activity and energy metabolism in various parts of the dog brain in the process of ontogeny under ether anesthetic conditions]. Experiments conducted on 50 puppies of 2-days, 2-weeks and a month old evidenced that the maturing of the central nervous system in puppies was accompanied by a progressive growth of the bioelectric activity and of the energy exchange forse. With advancing age of the animals the inhibitory action of ether on the oxygen uptake by the tissues of the visual, auditory cortical zones and of the medial thalamus along with the biocurrents in these structures were on a decline. At the same time, as the post-natal development of the animals went on, the processes of oxidative phosphorylation in the cortical segments were disturbed greater than at the 2-week age. In 2-day old animals it did not change substantially by comparison with controls.


[Experimental and clinical study of d, 1-oxyphedrin]. Comparative pharmacological and toxicological studies were carried out on animals covering the preparation d,1-oxyphedrine (myophedrine), put out in the GDR, as against the drug 1-oxyphedrine. The activity of both drugs showed no material difference. Clinical trials demonstrated good tolerance of the drug both by healthy persons and patients with its intravenous administration twice a day in amounts of 1 mg, or by mouth--3 times a day in amounts of 8--16 mg. In outpatients with anginal pains after sustained myocardial infarction and also in institutionally treated patients with myocardial infarction the activity of d,1-oxyphedrine proved to be not inferior to that of 1-oxyphedrine.


Nutritional application and implication of 1,3-butanediol. Research in the United States on synthetic sources of dietary calories was initiated in 1958 to develop high nutrient density food for extended manned space travel. Of many known compounds screened, 1,3-butanediol was the most promising. Small amounts in ester form with fatty acids exist in nature, and tests indicate a low acute oral and chronic toxicity similar to that of propylene glycol or glycerol. Multi-generation reproduction, teratological, and mutagen studies have revealed nothing detrimental. Following an adaptation period, 1,3-butanediol furnishes approximately 6 kcal/g if fed at levels not exceeding 20% in the diet of rats. Higher levels result in an impairment in growth and food utilization. In young animals, body fat stores appear to be lessened, as is resistance to the stress of extreme cold. However, dogs fed 20% 1,3-butanediol can maintain sustained muscular work on treadmills, but larger amounts can result in incoordination due to a narcotic effect common to glycols. Little research has been conducted on the behavioral effects of large doses. At present, 1,3-butanediol is used mainly as a solvent for food flavors. If the unpleasant taste problem can be overcome and if given FDA approval, 1,3-butanediol may have an increased role in our food supply as a functional food additive, preservative, and source of calories for man and animals.


Studies on sperm antigenicity. 2. In vivo and in vitro cellular reactivity in guinea pigs sensitized to homologous and heterologous spermatozoal autoantigens. In vitro delayed type hypersensitivity was demonstrated with peritoneal exudate cells from guinea pigs of the Rockefeller and Hartley strains, immunized with different preparations of the guinea pig male reproductive tract (RMT) emulsified in complete Freund's adjuvant-H37Ra. The RMT preparations were purified guinea pig spermatozoal autoantigens S, P, and T; whole guinea pig spermatozoa, and extract from epididymal tissue. The cellular sensitivity in vivo was demonstrated by injecting the proper antigen into the skin of the tested animals and in vitro by the macrophage inhibition technique. Peritoneal exudate cells from guinea pigs sensitized with whole guinea pig spermatozoa cells were inhibited in vitro by the specific antigen, epididymal extract, and autoantigen-T. Autoantigen-S was found to be a weak immunogen. However, the migration of peritoneal exudate cells from guinea pigs sensitized with large amounts of antigen-S was inhibited by whole spermatozoa in vitro. This cross-reactivity revealed the possibility that the immunogenicity of purified autoantigen-S might be connected to its molecular size. According to the immunizing dose of the antigens, testicular lesions of either the aspermatogenic or orchitis type were found in the testes of sensitized guinea pigs. Lesions in the testes of the guinea pigs were not detectable by cross-immunization with heterologous human or rat spermatozoa, although some degree of in vitro cross-reactivity was detected by skin test studies.


Immunologic studies of male infertility. Infertile men with azo- or oligospermia of unknown cause were investigated for evidence of testicular autoimmunity. Testicular germinal cell antibodies were found in 14% of the patients, compared with 5% of normal men, and 21% had spermatozoal antibodies, compared with 5% of the normal subjects. One-third had positive macrophage inhibitory factor tests, compared with 5% of normal subjects. However, of autoantibodies against thyroid, stomach, and nuclear material, only the prevalence of thyroid cytoplasmic antibodies was significantly greater than in normal subjects; serum IgG, IgM, and IgA levels were normal in all cases tested. Furthermore, there was no excess of lymphoid tissue on biopsy and no evidence of antibody deposition in the testicular tissue. The evidence for autoimmunity is less impressive than that for leprous orchitis, which has been proposed as a model for testicular organ-specific autoimmunity. Nevertheless, it is possible that certain germinal cell or spermatozoal antibodies may be directed against factors necessary for orderly spermatogenesis. If so, they may play a role in some cases of maturation arrest and shedding defects.


Inhibitory activity of four analogs of luteinizing hormone-releasing hormone in vivo. Four analogs of luteinizing hormone-releasing hormone (LH-RH), [des-His2,D-Ala6]-LH-RH, [des-His2,D-Ala6, des-Gly-NH2(10)1-LH-RH ethylamide, [des-His2,D-Leu6]-LH-RH, and [D-Phe2,D-Leu6]-LH-RH, at 300-fold molar ratios (analog/LH-RH) led to an almost complete inhibition of LH response to LH-RH in anesthetized 4-day cycling rats on the afternoon of proestrus. At a 75-fold molar ratio, [des-His2,D-Ala6]-LH-RH still inhibited the LH-RH-induced LH release by 50%. The ethylamide substitution at the COOH terminus of [des-His2,D-Ala6]-LH-RH did not significantly improve the inhibitory activity of the molecule.


Gonadotropin-releasing activity of two highly active and long-acting analogs of luteinizing hormone-releasing hormone after subcutaneous, intravaginal, and oral administration. The gonadotropin-releasing activities of two synthetic analogs of luteinizing hormone-releasing hormone (LH-RH), D-Ala6-des-Gly10-LH-RH ethylamide and D-Leu6-des-Gly10-LH-RH ethylamide were evaluated in immature female rats after subcutaneous, intravaginal, and oral administration. Maximal peaks of serum LH and follicle-stimulating hormone (FSH) levels after administration of both analogs by any of the three routes were obtained at 2 hours. Therefore, serum gonadotropin levels declined slowly, so that at 6 hours LH levels had returned to base line values, whereas FSH levels remained elevated for up to 10 hours. The integrated serum gaondotropin levels after LH-RH and both analogs over a 10-hour period indicated that D-Leu6-des-Gly10-LH-RH EA and D-Ala6-des-Gly10-LH-RH EA released more LH and FSH than did the LH-RH decapeptide. The intense and long-acting properties of these analogs in releasing LH and FSH suggest the possibility that they may be more useful therapeutically than LH-RH.


Immune capacity of mice tolerating a weakly incompatible skin allograft. I. Tolerance induction by neonatal skin graft in adult recipients or by neonatal inoculation of adult cells. An analysis was made of the so-called "tolergenic" effect of neonatal skin grafts which tend to survive longer than control adult grafts and confer this tendency also on simultaneously transplanted adult grafts of the same genotype. When the time interval between the neonatal and adult grafts varied from zero to 150 days, it could be demonstrated that neonatal skin grafts are capable of inducing second-set response comparable to that induced by adult grafts provided that the adult graft is not given simultaneously but only following 20 days or later. Signs of immune erises (i.e. various degrees of a round-cell infiltration) were, however, detected histologically even with shorter intervals of time. The involvement of some non-specific components in the early postgrafting period was indicated by a similar effect of sera from recipients of syngeneic grafts and MSA-incompatible grafts on the survival of grafts across the male-specific antigen barrier. Only long surviving allografts tend to specifically reduce the recipient's immune responsiveness. The possible mechanisms of the specific and non-specific components in the effect of neonatal skin grafts and the factor of time are discussed.


[Effect of sodium salicylate on the cerebral blood circulation (an experimental and clinical study)]. The effect of sodium salicylate (100 mg/kg intravenously) on the circulation rate of the cerebral blood flow, total arterial pressure, oxygen tension in the cerebral tissue (by the polarographic method) and on the pressure in the brain venous vessels was studied on anesthetized cats with controlled respiration. In rheumatic patients the action of the drug (10 ml of a 10% solution, intravenously) on the rheoencephalographic findings and the total arterial pressure was investigated. Sodium salicylate was shown to raise the tonicity of the intra- and extracranial vessels, to lower the amplitude of the pulse fluctuations and to highten the total arterial pressure. The cerebral circulation depends upon changes in the tonicity of the cerebral vessels and on the total arterial pressure, i. e. with a significant rise of the latter it increases in spite of a greater vascular resistance. Changes in the blood flow are followed by corresponding variations in the PO2 of the brain tissue. No significant changes of the pressure in the venous system of the brain could be established.


Cyclophosphamide-induced immunological tolerance: recovery leads to a memory state. Tolerance to SRBC has been induced in adult mice by the aid of cyclophosphamide, and the duration of the tolerant state has been tested by a second injection of antigen at different times thereafter. As evidenced by 19S and 7S PFC 4 days after challenge, tolerance in this model is of relatively short duration and leads spontaneously to a memory state.


[LH and FSH responses to synthetic LH-RH in various estradiol levels of anovulatory women (author's transl)]. Synthetic LH releasing hormone (LH-RH) is effective in increasing both serum LH and FSH in humans. Therefore, LH-RH is used to clarify the function of the hypothalamic pituitary ovarian axis in adult women. Variations in response to synthetic LH-RH during different phases of the menstrual cycle are known. These variations may be due to changes in the ovarian secretion of sex streoid hormones during the menstrual cycle. In the present study, effects of serum estradiol (Ed) on pituitary gonadotropin response to synthetic LH-RH were studied in 55 subjects without ovulation. Serum levels of LH, FSH and Ed were determined before and at 30 min after intramuscular administration of 100 mug LH-RH. LH and FSH levels in the serum were measured by the double antibody method of radioimmunoassay. Ed levels were determined by the radioimmunoassay method of T. Makino, using the antiserum against Ed-6-oxime-BSA donated by Dr. T. Makino and applied to the microcolumn of sephadex LH 20. Preliminary evidence about Ed levels during the normal menstrual cycle and in anovulatory women suggested that an Ed level under 30 pg/ml indicates the presence of a small amount of Ed. Therefore, 55 patients were divided into 2 groups; the low Ed group that showed low basal Ed levels (under 30 pg/ml) and the Ed normal group that showed normal basal Ed levels (over 30 pg/ml). Pituitary gonadotropin responses to synthetic LH-RH were studied in these two groups. No statistical difference was shown between the two groups studied for basal LH level and FSH level. After LH-RH injection in the Ed normal group, serum LH level was significantly higher and serum FSH level was significantly lower than that in the low Ed group. Then, in order to clarify the difference in two groups, the ratio of LH to FSH (LH/FSH) before and after administration of LH-RH was examined. The ratio in the Ed normal group was significantly higher than one in the low Ed group before and after administration of LH-RH. Moreover, the percentage increase of the ratio was significantly larger in the Ed normal group than that in the low Ed group. A positive correlation (r=0.4228, p less than 0.01) was found between LH/FSH following administration of LH-RH and circulating the Ed level. These results suggest that the response of pituitary gonadotropins to LH-RH is changed by serum Ed and that serum Ed causes a differential release of LH and FSH in response to LH-RH. The data seem to demonstrate that LH-RH and serum Ed show a complex interplay in releasing LH and FSH.


[A study on the regulatory mechanism of hypothalamo-hypophyseo-ovarian system in estrous cycles of rats: Changes in responsiveness of the anterior pituitary gland to synthetic LH-RH (author's transl)]. It is generally accepted that the sexual cycle in mammals is accomplished by the systematic coupling of components of the hypothalamo-hypophyseo-gonadal system. However, how these components are related to each other to develop the sexual cyclicity has not yet been clearly established. A gonadotropin releasing factor (GnRF), which has been extracted and purified from porcine hypothalamus and whose molecular structure was determined in 1971, has been synthesized in many laboratories. The synthetic GnRF, named LRF or LH-RH, has gonadotropin releasing activity for many species of mammals, including humans. The debut of the synthetic LRF has given us a pure material and a direct means of stimulating, relatively easily, the gonadotroph cells in the anterior pituitary glands. In the present study, variations in the gonadotropin releasing activity of the pituitary gland in relation to synthetic LRF was investigated throughout the sexual cycle of rats. The relationship between pituitary sensitivity and levels of steroid hormones in the blood is discussed.


Antidiabetic action of somatostatin--assessed by the artificial pancreas. By means of a glucose-controlled insulin- and glucose-infusion system (GCIGIS) we examined the effect of somatostatin on insulin and glucose requirements following meals or oral glucose loads in juvenile diabetics. In six of seven patients the insulin requirement with somatostatin was remarkably reduced to between 38 per cent and 79 per cent of that of otherwise identical control experiments. No reduction could be found in the seventh case, fed only 575 kcal. In all cases we observed an increase in dextrose demanded from the GCIGIS ranging between 28 per cent and 192 per cent of the control amounts. In addition, a lowering and smoothing of postprandial blood glucose curves caused by somatostatin application was a general finding. It seems to us most likely that the well-known suppression of the secretion of growth hormone and glucagon, both insulin antagonists, is responsible for the antidiabetic action of somatostatin.


Observations on patients with neural-tube defects in a metropolitan hospital clinic: an epidemiological history. A survey of the population of the Spina Bifida Service (107 patients) of Georgetown University Hospital, Washington, D.C., and of a control population in the same hospital revealed that, although situated in an ethnically heterogeneous area, Service patients with a history of neural-tube defects in siblings or family significantly more often had ancestors on both sides from the British Isles than did either isolated cases or the controls. In addition, of 107 families reviewed, nine had more than one affected child, nine had a positive family history for neural-tube defects, and nine of the patients and seven of an estimated total of 220 siblings had an unrelated major birth-defect. These incidences are among the highest published so far. Contrary to other surveys, there was no deficiency of twinning among the sibships, nor of males among the Spina Bifida Service patients. These observations indicate the desirability of studying each population of patients with neural-tube defects in order to provide more realistic counseling and so that clues may be gathered as to the genetic mechanisms and environmental factors which led to the production of such defects.


Toxic encephalopathy and acute brain-swelling in children. Problems in the diagnosis and management of children who present with an acute encephalopathic illness are examined. The aetiology, pathogenesis, pathology and clinical features of acute toxic encephalopathies are discussed, together with the differential diagnosis of those encephalopathies which are not induced by toxicity. Guidance is given on measures for the reduction of raised intracranial pressure and the management of defects of homeostasis. It is essential that facilities for intensive monitoring of these children be available during the acute phase of illness in order to reduce the number surviving with sequelae of mental and physical handicap.


Foetal-associated material: its expression in long-term cultured human skin. Using immunofluorescence and electron microscopy, we have demonstrated the presence of "foetal substances" (antigens) in skin kept in tissue culture medium for periods of time ranging from 9 days-18 weeks. This is a specific reaction demonstrated with an anti-human foetal serum raised in New Zealand white rabbits. It is suggested that the expression of foetal substances by cells in the skin under these abnormal conditions might lead to the masking or modification of the normal histo-compatible antigens, enabling such skins to survive transplantation without rejection.


Organ culture of foetal rat pancreas. Effects of parabiotic culture with foetal adrenal glands. The differentiation and growth of the foetal rat pancreas (20 days postcoitum) was studied in parabiotic organ culture with foetal adrenal tissue. In such co-cultures, characteristic pancreatic morphology was preserved and further acinar cell differentiation was fostered. Acinar cells contiunued to represent about 65% of the total explant volume following short-term incubation. The selective islet cell proliferation, previously observed in control pancreatic explants cultured alone, did not occur when adrenals were co-cultured. In addition, the amylase content of the incubation media and of the explanted pancreatic tissue remained high with adrenal co-culture, while the insulin content of the media and of the explanted tissue was markedly suppressed when compared to control pancreatic explants cultured alone. The effects of the adrenal in maintaining the differentiated acinar component of the pancreas and suppressing media insulin concentration diminished over extended incubation. The addition of adrenals to culture of foetal pancreatic explants after 6 days of control culture (at a time when differentiated acinar cells were not identifiable in the explant) did not result in redifferentiation of the acinar component, but did markedly depress media insulin content. Removal of adrenals after 4 days of co-culture resulted in an immediate rise in media insulin concentration and a rapid decline in pancreatic acinar mass. An adrenal-exocrine pancreatic axis is proposed and it is suggested that foetal adrenal secretions may play an important role in the development of the exocrine pancreas in vivo as well as in vitro.


[The Caceres-USPHS (version HP-3) computer program. Evaluation of automatic analysis of 40,000 ECG (author's transl)]. The main features of Caceres-USPHS (version HP-3) program for automatic analysis of the ECG are reviewed. Our experience at the Ospedale Regionale di Udine has now reached a total of 40,000 tracings analyzed by such a program and with an HP 1530-A computer system. In a detailed study of 1,000 consecutive computer-analyzed tracings reviewed by three experienced cardiologists, 534 were normal and 466 abnormal. A high degree of specificity was detected in the normal group (only 1.5% of false negatives) while the sensivity was rather low. In the abnormal group there were 18.1% of false positives and while the agreement was 100% in complete bundle branch block and some types of infarction, it was 56% in atrial fibrillation and 47% in incomplete right bundle branch block. Program errors were more common in measurements and pattern recognition; they were unusual in the program logic (0.3%). A significant improvement over comparable data obtained one year previously was attributed to a better quality control in data recording and to increase physician acceptance of the program diagnostic criteria. On the current and past figures of accuracy, it is concluded that the version HP-3 of Caceres-USPHS program represents a step forward in computer-derived ECG interpretation. However more progress is still needed for a larger and more profitable clinical application of this ECG computer program.


A new user-oriented electrocardiographic program. A new program for electrocardiographic processing will become available in 1975, "tuned", as part of a system, to take advantage of newer computer and data acquisition hardware at the same time as past experience on other programs has been carefully retained. User flexibility is a key feature along with safe methodology. The program is undergoing modification as part of a data pool user plan.


Experiences with different computerprograms for the ECG-analysis. As the use of computers for ECG-analysis has left the stage of laboratory investigation, and different systems are offered by industrial firms with high grade promises concerning their reliability, it seemed about time to perform an evaluation of the programs available. Each ECG of 252 adult patients was recorded in one session from adhesive electrodes within 10 minutes on the magnetic tapes of the data-acquisition-units of four different manufacturers. The computer-analysis of each of these ECGs was done by six programs of Pordy (Mt. Sinai-Hospital, New York), Caceres, Smith (Mayo Clinic, Rochester), Arvedson, Riedl with modified criteria of the USPHS and Riedl with criteria of the Minnesota-code. Besides this each ECG was also analysed in the conventional way by each of the three cardiologists involved in this study. The results of the computers' and the physicians' analysis concerning rhythm, extrasystoles, infarctions and ST-T-segment-variations are demonstrated and discussed.


[The use of computers in the exercise of electrocardiography (author's transl)]. The use of computers in the exercise of electrocardiography is considered. The problems related to this use concern the choice of leads, the filtration of the signal, the recognition of characteristic segments of ECG, the calculation of various indexes and their statistical evaluation for diagnostic purposes. The authors use a bipolar derivation filtered by averaging and digital filters. The characteristic points of ECG are recognized by the analysis of the curvature. The Tchebycheff coefficients of the S-T tract are evaluated; they appeared to be a very good means for judging positive and negative cases.


Antitumor activity of polysaccharides from Serratia marcescens. A lipopolysaccharide (serratigen) and a polysaccharide (serratimannan) were isolated from Serratia marcescens, red strain No. 51. They were different from any other polysaccharides previously reported. The antitumor activity of these polysaccharides was determined. Serratimannan showed 63% tumor inhibition and serratigen 38%, at a dose of 150 mg/kg, against solid tumor of sarcoma-180 using ICR mice. The fraction obtained by removal of proteins from the crude extract by the Sevag method showed a high antitumor activity against solid tumor of sarcoma-180 using Swiss albino mice, but did not show so high an activity using ICR mice. In total packed cell volume method, these polysaccharides exhibited a high rate of antitumor activity against ascites tumor of sarcoma-180.


Immunotherapy of human malignant melanoma with oil-attached BCG cell-wall skeleton. A first case of malignant melanoma treated with oil-attached BCG cell-wall skeleton (BCG-CWS) is reported. The patient, a 70-year-old farmer, with metastatic malignant melanoma was treated intralesionally with oil-attached BCG-CWS or was given intradermally with oil-attached BCG-CWS together with irradiated autologous and allogeneic tumor cells. Four months after the start of the immunotherapy with oil-attached BCG-CWS, Primary tumor and metastatic inguinal lymph nodes regressed markedly without any significant complications. Lymphocytosis in the peripheral blood was usually observed after injection of oil-attached BCG-CWS.


Immunofluorescent staining of gastric mucosal glycoprotein in gastric carcinoma of dogs and rats induced by N-methyl-N'-nitro-N-nitrosoguanidine. Immunohistological studies, using the fluorescein isothiocyanate-labeled antibody against gastric mucosal glycoprotein, were made during the development of gastric cancer, induced in dogs and rats by oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In an early stage, the regenerative glands were lined by fluorescent mucus cells. Carcinoma cells of orderly glandular structure, produced in dogs, were devoid of fluorescence. Carcinoma cells of less differentiation, produced in rats during further advanced stage, were well fluorescent. The immunofluorescent profiles of such experimentally induced gastric carcinoma were found to be the same as those of human gastric adenocarcinoma.


Effect of Nocardia and Mycobacterium cell-wall skeleton on autochthonous tumor grafts. Cell-wall skeleton of Nocardia rubra and of Mycobacterium bovis BCG in the oil-attached form, when injected mixes with autografts of spontaneous mammary adenocarcinoma or of methylcholanthrene-induced sarcoma of mice, suppresses the growth of tumor autografts to a demonstrate extent. The BCG whole cell wall showed no effect. The local destruction of tumor autografts did not induce recognizable systemic immunity to the respective tumors. These findings are commended upon from immunological and chemical points of view.


[Iron treatment by effervescent tablets (author's transl)]. In a randomized double-blind study the new effervescent iron tablet Loesferron was tested in 57 postpartum patients. Hgb and red blood count rose significantly with this treatment. It was found that on effervescent tablet daily was sufficient for a satisfactory result of the treatment. No side effects were noted to this well tasting iron beverage. The reason is probably the prior dilution of the iron compound which delivers lower local iron potentials to the gastric mucosa.


[Foreign body granulation in the breast after injection of a polyvinylpyrrolidone containing preparation. A case report (author's transl)]. A case is reported of a patient who developed large foreign body granulations in the breast and in the epigastric area after injection of a polyvinylpyrrolidone containing medication (Depot-Impletol).


Double-blind evaluation of naftidrofuryl in treating elderly confused hospitalised patients. In a double-blind comparison between naftidrofuryl and placebo, naftidrofuryl-treated patients improved significantly on scales completed by the nurse, occupational therapist and physician. No improvement was found for placbo-treated patients. When the response to each treatment was compared, naftidrofuryl was found to be significantly better than placebo on both nurse and physician assessment. There was considerable variation between assessors which suggests that they were measuring different aspects of the patients' condition. There was also considerable variation in patient response, some improved on naftidrofuryl and some deteriorated; some improved on placebo and some deteriorated. However, overall it would seem that patients admitted to hospital with confusional states benefit from treatment with naftidrofuryl.


Immune function and survival in a long-lived mouse strain subjected to undernutrition. Functional immune changes were monitored in populations of the long-lived C57BL/6J strain of mice which were subjected to dietary restriction from time of weaning or subjected to such restriction both before and after weaning, along with the appropriate control populations. Responses to T and B cell mitogens (PHA, Con-A, pokeweed, bacterial lipopolysaccharide, and PPD), to injected sheep red blood cells, and measurement of skin allograft rejection rates were followed. Early in life, restricted mice appear immunosuppressed, as judged by all these parameters. Skin allograft rejection remained suppressed until relatively late in life. Other responses tended to reverse from the earlier pattern; by mid-life restricted mice responded better than controls. Dietary restriction profoundly affects the immune system. Mice on such regimes display anatomic and certain immune functional changes which suggest that the immune system may mature less rapidly and stay "younger" longer than in the controls. Furthermore, dietary restriction results in prolongation of life span.


Reticulin antibodies in patients with coeliac disease and their relatives. The sera of 69 index coeliac patients, 121 of their first-degree relatives, and 104 controls were screened for the presence of reticulin antibodies. Among the untreated coeliac patients 75% of adults and 93% of children had reticulin antibody in their serum. Reticulin antibody was not present in any adequately treated coeliac patient. Of the first-degree relatives, 21 were reticulin antibody positive; 17 of these were biopsied and 12 were shown to have coeliac disease. Sixty-five of the coeliac relatives who did not have reticulin antibodies in their sera were biopsied and two had coeliac disease. Of the 68 relatives and 63 controls with normal biopsies, five of the relatives and four of the controls were reticulin antibody positive.


Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy. Early changes in coagulation were found in patients following a paracetamol overdose. Low levels of clotting factors II, V and VII were present within 24 hours of the overdose. As the levels of factor II correlated with plasma fibrinogen values at this time, it is possible that they were consumed in the process of intravascular coagulation, although this was not supported by the presence of raised titres of fibrin degradation products. The prothrombin time ratio was greater than 2-2 within 30 hours of ingestion of the overdose in all patients who eventually died, whereas it was less than this in those developing only moderate liver damage. The administration of fresh frozen plasma to patients did appear to reduce the maximum abnormality of the prothrombin time ratio, which was significantly less three days after the overdose in the group receiving fresh frozen plasma. However, the coagulation disturbance was of short duration, and the prothrombin time ratio had also returned to normal within one week of the overdose in the control patients, and the administration of fresh frozen plasma did not appear to reduce the morbidity or mortality in the treated patients.


The use of fresh frozen plasma or a concentrate of factor IX as replacement therapy before liver biopsy. Thirty patients with various types of chronic liver disease and a prothrombin time prolonged for four or more seconds who required needle liver biopsy for diagnostic purposes were given either fresh frozen plasma or a concentrate of clotting factors as a prophylactic measure. The prothrombin time returned to within normal limits in seven of the 15 patients given the concentrate and in three of those receiving fresh frozen plasma. Levels of factors II, IX, and X showed increases of about 30% following concentrate administration; corresponding rises in the group given fresh frozen plasma were less. This was because of the smaller quantity of clotting factors administered with fresh frozen plasma and the increase in factor II and IX activity/kg body weight/unit of clotting factor injected was greater when fresh frozen plasma was used. In neither group was there clinical evidence of bleeding, but it was of interest that most of the clotting factor levels, except in factor II, before biopsy were above those normally required for haemostasis. No evidence of disseminated intravascular coagulation was found with the concentrate injection, and the most worrying finding was the appearance of HBAg some months later in three patients, two from the concentrate group and one from those given fresh frozen plasma. However, the conversion of these patients to HBAg positive may be unrelated to the clotting factor replacement therapy.


Function of the anal sphincters in spinal man. Eight patients with traumatic transverse lesions of the spinal cord and eight healthy controls were examined with respect to the function of the anal sphincters. Continuous recordings of anal pressure and electromyograms from the striated sphincter muscles were obtained during gradual rectal distension by means of an air-filled balloon. The patients were more prone than the controls to display a cessation of all electrical activity from the striated muscles in response to rectal distension and they also exhibited a less pronounced inflation reflex. It is concluded that upon rectal distension in normal man the striated muscles are stimulated by a cerebral centre at an unconscious level as well as by a low centre of the spinal cord. The former accounts for an augmented inflation reflex and maintained or increased electrical activity when rectal distension is substantial. The smooth internal sphincter was found to be independent of cerebral influence at rest as well as during rectal distension.


Aspiration biopsy of carcinoma of the pancreas. Peroperative pancreatic aspiration biopsies were performed on 21 patients with pancreatic lesions using a standard 20-ml disposable syringe and a 21-gauge needle. No complications were recorded which could be attributed to this procedure. A further 10 aspiration biopsies were carried out on postmortem specimens in an attempt to determine the accuracy of this method in the diagnosis of carcinoma of the pancreas. It is concluded that peroperative pancreatic needle biopsy is a safe procedure which is easily performed without special instruments. In can be of enormous value to the surgeon in planning the treatment of patients with pancreatic lesions. In cases where there is an operable mass in the pancreas it offers a simple and quick method of determining the presence of malignant cells and thus definitive surgery may be performed with confidence. For the inoperable cases it offers a method of histological confirmation of the operative findings.