Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog. The effects of digoxin on monovalent cation active transport were determined in cardiac tissue obtained from dogs given inotropic, toxic, or lethal doses of digoxin. In hemodynamically monitored dogs, active uptake of the K+ analogue Rb+ was determined in vitro in a control myocardial biopsy, and then in serial biopsies from the same dog after the infusion of [3H]digoxin in doses sufficient to cause a sustained positive inotropic effect in the absence of toxicity, and finally after additional doses to induce overt toxicity. Nontoxic digoxin doses producing a mean increase of 20% in left ventricular (LV) dP/dt significantly reduced Rb+ active transport by 25% below control values. At the onset of digoxin-induced arrhythmias, maximal LV dP/dt was 53% above control whereas active Rb+ transport was reduced by 60% below baseline values (P less than 0.001). Control dogs given vehicle alone showed no significant change in contractility or in monovalent cation active transport. In another group of dogs given a lethal dose of digoxin, Rb+ active transport was reduced 59% below control levels at the onset of overt toxicity and was further reduced 80% below control at the time of onset of a fatal rhythm disturbance. When dogs were given high affinity digoxin-specific IgG or Fab fragments at the onset of overt toxicity, toxicity was rapidly reversed, and monovalent cation active transport increased to 51% of control at the time of restoration of sinus rhythm. Twenty-four hours after antibody reversal of arrhythmias, monovalent cation transport values approximated normal control levels. These data provide quantitative estimates of the extent of inhibition of monovalent cation transport by digoxin at inotropic, toxic, and lethal endpoints. Similar degrees of transport inhibition were present at the time of onset of digoxin-induced arrhythmias and at the time or arrhythmia reversal by digoxin-specific antibodies.


Release of active and inactive renin by the porcine kidney. We studied the relative rates of release of active and inactive renin by the kidney in anesthetized pigs. Renin concentration was determined in arterial and renal venous plasma as follows: (1) before and after stimulation of renin release with isoproterenol or furosemide, (2) after suppression of renin release by extracellular fluid volume expansion, and (3) after administration of propranolol or indomethacin. Inactive renin was activated by dialysis of plasma at pH 3.3 for 24 hours. Renin concentration was estimated by radioimmunoassay determination of angiotensin I after a 3-hour incubation with excess homologous renin substrate. Following isoproterenol, the release of active renin increased from 8 +/- 4 (SEM) to 58 +/- 34 ng/min, and inactive renin increased from 53 +/- 33 to 321 +/- 136 ng/min. Similarly, furosemide stimulated the release of both active and inactive renin. Both forms of renin were suppressed by propranolol or indomethacin. Although changes in renin release following volume expansion were not statistically significant, the direction of change for both forms of renin was similar. Following logarithmic conversion of the rate of release, the plot of active vs. inactive renin formed a straight line. Values for active renin as a percentage of the total renin in simultaneously drawn arterial and renal venous plasma samples were not different. Thus, under the conditions of these experiments, release of active and inactive renin appears to be controlled by similar mechanisms. Both stimulation and suppression of renin release result in parallel changes in release of the two forms. Data on relative amounts of active renin in arterial and renal venous plasma suggest that there is no systemic conversion of the two forms.


Biochemical and morphological correlates of acute experimental myocardial ischemia in the dog. IV. Energy mechanisms during very early ischemia. Tissue energy metabolism was examined in posterior (ischemic) and anterior ("control") regions of canine ventricles after 5 and 10 minutes of left circumflex coronary artery occlusion. When compared to identical regions of normal hearts, the following changes were found: (1) decreases in glycogen and phosphorylase activity in the anterior and posterior regions, (2) depressed state 3 rates of oxygen consumption of isolated mitochondria in both anterior and posterior regions, (3) shifts in optimum substrate concentrations for palmityl-CoA (+ carnitine) oxidation by mitochondria in the anterior and posterior regions, and (4) decreases in the apparent zero order and first order rates of mitochondrial palmitylcarnitine production. These changes correlated with a marked decrease in developed tension in the posterior regions. Depression in tension development in the posterior regions of the heart still was present after 30--60 minutes of reperfusion following a 10-minute period of occlusion. Glycogen content in the reperfused areas was significantly decreased after 60 minutes of reperfusion when compared to normal areas and to control hearts perfused for 70 minutes. After reperfusion, mitochondrial function appeared to return toward "normal." However, the slow restoration of contraction of the ischemic area suggests that cellular mechanisms operative in vivo to restore pump function still might be abnormal.


Choline uptake into renal phospholipids following renal ischemia in rats. Renal phospholipid metabolism was studied after ischemia was induced by occlusion of the left renal artery in the rat. There was no change in the rate of cellular [14C]choline uptake after 25 or 60 minutes of ischemia. However, [14C]choline incorporation into phospholipid was two to three times greater in slices from the ischemic kidney than in slices from the contralateral control kidney. The increase occurred after 25 minutes of ischemia plus 15 minutes of reflow, and after 60 minutes of ischemia with or without reflow. When [14C]choline was injected into rats after a 60-minute period of renal ischemia, the rate of incorporation into phospholipid in the ischemic kidney was almost twice that of the control kidney. These results were similar to those of the in vitro experiments. Since virtually all of the cellular phospholipids of the kidney are present in cellular membranes, renal ischemia affects membrane metabolism. The mean distribution ratio of alpha-aminoisobutyric acid in slices of kidneys ischemic for 60 minutes was similar to that of control slices: 4.11 +/- 0.2 (SEM) vs. 4.30 +/- 0.30. The normal uptake of alpha-aminoisobutyric acid indicates that the increased incorporation of choline is associated with functional integrity of the membrane.


The effect of brief vagal stimulation on the isolated rabbit sinus node. We developed an isolated rabbit atrial preparation which responds consistently and reproducibly to brief, submaximal stimulation of the autonomic nerves contained in it. In 6 of 11 preparations in the presence of propranolol (1 mg/liter), the time course of changes in the atrial rate following 120 msec vagal stimulation was bimodal. The maximal slowing occurred at 0.64 +/- 0.16 second, and the peak secondary slowing occurred at 2.3 +/- 1.0 seconds. An acceleratory component occurred between the first and second peaks between 0.8 and 1.6 seconds. The total time course of vagal effect lasted for 5.0 +/- 2.0 seconds. These changes in rate could not be explained by shifts in the location of the primary pacemaker. The acceleratory component was due to a 4.7 +/- 2.0 (SD) mV depolarization of the maximum diastolic membrane potential of the primary pacemaker of the sinus node which lasted for 1.8 +/- 0.3 seconds. Following vagal stimulation, there was an increase of 0.2 mM in the activity of potassium in the extracellular space recorded with a potassium-sensitive electrode; this peaked between 1.4 and 2.5 seconds and cleared with an exponential time course. The halftimes for recovery ranged between 2.8 and 4.6 seconds. The initial peak slowing of the bimodal time course and the acceleratory component therefore appear to be direct effects of acetylcholine. The secondary slowing occurs after acetylcholine presumably has been inactivated and occurs coincidently with the accumulation of potassium in the extracellular space.


Acetylstrophanthidin-induced reflex inhibition of canine renal sympathetic nerve activity mediated by cardiac receptors with vagal afferents. The present experiments were performed to determine whether digitalis-induced augmentation of cardiac receptor discharge could induce reflex reductions in renal sympathetic nerve activity. Intracoronary injection or epicardial application of acetylstrophanthidin (AS) in chloraloseanesthetized dogs caused large decreases in renal sympathetic nerve activity which were accompanied by modest decreases in heart rate and arterial pressure. Vagotomy prevented these reflex responses. Cholinergic blockade with atropine markedly attenuated the heart rate responses to AS but had little effect on the arterial pressure or renal nerve activity responses. Epicardial application of lidocaine blocked cardiac vagal afferents and the reflex responses to intracoronary AS. In sinoaortic denervated dogs, the relationships between doses of AS and mean arterial pressure, heart rate, and renal nerve activity responses were linear. Decreases in renal nerve activity were evoked by doses of AS which did not reflexly change heart rate or arterial pressure. These data show that AS can evoke reflex bradycardia, hypotension, and withdrawal of renal sympathetic nerve activity solely by augmenting the inhibitory influence of cardiac receptors with vagal afferents. This reflex effect may contribute to the changes in renal function and thus to the diuresis that occurs when heart failure is treated with digitalis.


Contractures and increase in internal longitudianl resistance of cow ventricular muscle induced by hypoxia. This study was performed to determine whether hypoxia in glucose-free solutions can increase the electrical resistance of intercellular junctions in ventricular muscle. Internal longitudinal resistance (Ri), mechanical tension, and transmembrane action potentials were measured simultaneously in cow ventricular trabeculae. The mean control value of Ri was 265 +/- 38 omegacm (mean +/- SE) at 34 degrees C. After 1 hour of hypoxia in glucose-free Tyrode's solution, it had increased by 300 +/- 41% (n = 11, P less than 0.001). The rise in Ri was closely related to the increase in resting tension (contracture). These effects were more pronounced during a second exposure to hypoxia and were potentiated by application of epinephrine, by increasing extracellular calcium concentration, and by increasing frequency of stimulation. Addition of glucose (50 mM) provided some protection against hypoxia. It is inferred that the increase in Ri is entirely due to the increase in the resistance of intercellular junctions (electrical uncoupling). Intracellular calcium may be responsible for both the contracture and the uncoupling.


A possible role for elastin ligands in the proteolytic degradation of arterial elastic lamellae in the rabbit. Thoracic aortae of normal rabbits were perfused with pancreatic elastase in vitro at 37 degrees C and 70 mm Hg pressure in the presence or absence of elastin ligands previously shown to stimulate or inhibit the enzymatic degradation of elastin. Perfusion with elastase results in an average of 3.6 lamellae degraded, whereas addition of sodium linoleate before and during the perfusion with elastase increases this value to 7.9 (P less than 0.001). Conversely, perfusion with the cationic detergent, dodecyltrimethylammonium chloride, completely prevents the degradation of elastic lamellae by elastase. These effects do not reflect alterations of the intrinsic catalytic activity of elastase, but apparently indicate the formation of complexes between the elastin ligands and arterial elastic lamellae, as is consistent with prior studies indicating such interactions between fatty acids or detergents and purified elastin. These studies suggest that agents such as fatty acids may significantly alter the metabolic susceptibility of elastin in vivo and possibly contribute to the degradation of elastic lamellae seen in arteries with advanced atherosclerosis.


Effects of hypothermia on propranolol kinetics. Propranolol may be uniquely useful in cardiac surgical procedures, since beta adrenergic blockade can prevent the hypokalemia and associated arrhythmias which result from systemic hypothermia. To determine the effects of hypothermic cardiopulmonary bypass (HCPB) on the in vivo handling of propranolol, serial drug plasma concentrations (Cp) were measured during HCPB in 12 patients who had been treated chronically with propranolol prior to surgery. Although no further propranolol was given during the procedure, Cp values (corrected for plasma volume dilution) were higher during hypothermia than in the preoperative period, falling to or below control levels after rewarming. Due to the variables inherent in patient surgery, meaningful kinetic analysis could not be carried out. Therefore, intravenous propranolol (1 mg/kg) was given twice to each of 5 dogs, first after anesthesia only, then after anesthesia and systemic cooling to 26 degrees in a water bath Cp values measured serially over 2 hr after drug administration were consistently higher during hypothermia. Compared with the paired normothermic control studies, hypothermia markedly reduced the apparent volume of distribution (6.78 +/- 1.65 vs 2.08 +/- 0.58 L/kg; p less than 0.001) and the total body clearance of propranolol (64.4 +/- 11.0 vs 32.3 +/- 7.2 ml/kg/min; p less than 0.005). These data show that hypothermia substantially alters the pharmacokinetics of propranolol, resulting in plasma drug levels higher than those predicted from kinetic patterns derived under normothermic conditions.


Altered drug binding due to the use of indwelling heparinized cannulas (heparin lock) for sampling. The effect of the use of the so-called heparin lock for blood sampling on the binding of propranolol has been studied and a cumulative dose-response curve to heparin constructed. The use of this method of blood sampling introduced considerable artifactual changes into the measurement of propranolol's plasma binding. The free fraction rose from 9.9% to 13.4% after only 50 U of heparin was used to flush the cannula. The increase in the free fraction of propranolol showed excellent correlation with the increase in free fatty acid levels (p less than 0.001, r = 0.996). The importance of ensuring that sampling techniques do not introduce artifactual changes in pharmacokinetic studies is emphasized.


Isosorbide dinitrate in acute and chronic heart failure. The hemodynamic effects of sublingual isosorbide dinitrate (ISD) were studied in 12 patients with congestive heart failure (CHF) of many causes. The duration of CHF in the chronic group varied from 3 to 62 months (mean, 29.5). Hemodynamic parameters were obtained serially before and 10, 20, 30, 45, 60, and 120 min after a 5 to 15 mg dose of ISD sublingually. The hemodynamic effects were pronounced at 45 min and returned to control levels in 120 min. Heart rate did not change. Hemodynamic parameters that changed after ISD were mean arterial pressure (-7%, p less than 0.05), mean pulmonary artery pressure (-17%, p less than 0.05), and mean pulmonary capillary wedge pressure (-29%, p less than 0.005). Mean cardiac index (+3%, p = NS) and mean stroke work index rose (+9.4%, P X NS); mean total systemic resistance fell (-10%,  p = NS). Thus the duration of hemodynamic effects of ISD is less than 2 hr and sublingual ISD induces beneficial reduction of pulmonary capillary wedge pressure in patients with acute and chronic CHF without increasing cardiac index and stroke work index.


Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin. The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.


Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin. The purpose of this investigation was to determine whether the anti-inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.


Kinetics of gallium nitrate, a new anticancer agent. Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half-life (t1/2) of 0.5 to 1.8 hr (mean 1.0) and a terminal t1/2 of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 72% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.


Fantasy in psychiatric patients: exploring a myth. Through six interrelated studies the author examines the common conception that daydreams and fantasy are important factors in the onset and maintenance of severe psychopathology, particularly hallucinatory psychosis. Results of the studies failed to support the idea that psychotic patients have particularly frequent or vivid daydream activity, and indicate instead that psychotic patients tend to inhibit aspects of normal fantasy. Hallucinatory schizophrenics, in particular, were blocked in their emotional-interpersonal imagery. In a study of depressed patients, a negative fantasy style was found to be associated with clinical depression. Sleep disorder was similarly associated with a negative fantasy style.


A single-bedtime-dose self-medication system. A medication system in use at the Florida Mental Health Institute is based on the unit-dose procedure and weekly reviews of patients' medications. The program is aimed at reducing the use of polypharmacy and of concentrates and stabilizing patients on a single daily bedtime dose of medication. Once patients are stabilized on a single dose, they are trained by the nurses and through a drug group to manage their medications independently after discharge. The system has produced savings of up to 90 per cent of medication costs per patient and is gaining acceptance in other mental health facilities in the state. The authors believe it has the potential for even greater therapeutic and financial benefits by reducing the recidivism that occurs when discharged patients discontinue their drugs.


Antiparkinsonian drug abuse: eight case reports. Although abuse of antiparkinsonian drugs has rarely been reported in this country, there is evidence that it is more widespread than has generally been believed. The author reports eight cases in which abuse of the drugs was suspected. He emphasizes the need for increased awareness among physicians of the potential for abuse of antiparkinsonian agents and greater caution in prescribing them.


Patients without communities: whose responsibility? The authors conducted a study at an urban state hospital to determine if a patient's place of residence--within or outside the hospital's service district--was reflected in the admission rates or the quality of care received. No differences between in-district and out-of-district patients could be found on any parameter studied. The authors believe the results support the unique role of the state hospital as a facility that accepts its mandate as a referral of last resort.


Privacy commission report contains serious flaws. Few will argue that confidentiality of the patient medical record is a real concern, particularly at a time when demands for information from the medical record are numerous and constantly increasing. However, the recommendations of the Privacy Protection Study Commission, if implemented, could cause severe problems for hospitals. The author discusses those recommendations and why they cause concern.


Cost containment pressures make suppliers partners in productivity. As demands for cost containment, productivity, and efficiency continue to be made of health care providers, more and more questions are being asked about the cost benefits and appropriateness of health care products and supplies. And, as hospitals continue to make their purchasing decisions in a regulated economy, it is likely that their decisions will alter the sales, marketing, and service responsibilities of hospital suppliers. In an effort to educate hospital suppliers to what lies ahead, Hospitals and Trustee magazines recently held the first National Symposium on the Hospital Market, the details of which are presented here.


Management information system ensures maintenance coordination. The computer-based management information system implemented at Massachusetts General Hospital has proved to be an effective system for ensuring better coordination of maintenance activities in the hospital's maintenance department. The system provides accurate, up-to-date information that managers can use to make decisions concerning allocation of manpower, employee performance, and utilization of resources.


Consortium upgrades 12 hospitals' infection control programs. A consortium's infection control nurse and physician epidemiologists boost the member hospitals' infection control efforts through onsite rounds, establishment of group standards, reports on each hospitals' performance, ongoing education, medicolegal assistance, monitoring of use of isolation evaluation of infection control products, and other activities.


Investment in mailroom services produces better communications. A survey of mailroom practices at Providence Medical Center, Seattle, revealed inadequate working conditions and a lack of supervision. This article explains how careful planning and management enabled the mailroom to control copying costs and to improve services to patients, physicians, and hospital staff.


Preparation systems have significant effect on costs. The analysis of food service costs in this article provides an overview of the potential for cost containment of alternative food service systems for facilities ranging in capacity from 100 to 550 beds. This work was conducted mainly with U.S. Army hospital facilities in mind; however, the methodology and overall results are general and apply to any hospital that wishes to design an economical food service.


Nurse mentor system cuts costs, boosts quality of patient care. A new approach to patient care, which combines the mentor concept used in industry and the team concept used in traditional health care delivery systems, is helping to solve one hospital's problems of a chronic regional shortage of registered nurses, regularly rising costs, lack of recognition for individual interpersonal and clinical expertise, and the lack of an ongoing staff development program. The nurse mentor at Children's Hospital of San Francisco acts as a patient advocate and also counsels, teaches, coaches, supports, promotes, and inspires the members of her primary nursing team.


Creative management engineers foster communication, change. Today's hospitals need creative management engineers to bring about innovative change, to foster a participative climate, and to strengthen training systems. However, management engineers need to work with hospital administrators who understand the field and who can expand their expectations beyond the traditional areas normally thought of as being within the purview of management engineering.


Management engineering unit serves two-hospital system. The multihospital structure at the Albert Einstein Medical Center in Philadelphia forces the management engineering department to concentrate an increasing amount of its time on management effectiveness activities. Although the center's structure creates some internal time-management problems for the department, its staff members believe that the drawbacks are small when they are compared with the fact that their activities can, and do, have a positive effect on more than one institution.


Special project consultants can aid hospital engineers. Hospital engineers occasionally need consultants to study overall operations, suggest improvements, and develop cost-cutting programs. Day-to-day operations often keep in-plant engineers too busy to undertake these kinds of special projects. But given the crucial need for hospitals to cut energy consumption and costs, these special studies need to be done. The right consultant can do the job.


Referral-outreach program links community clinics and hospital. In the San Diego area, a special program has established a linkage system between a major medical center and community clinics that provide primary care to persons in generally low-income, medically underserved neighborhoods. This system ensures continuity of care for the clinic patients through referrals to the medical center and follow-up back at the clinics and through provision of special services by the medical center's physicians onsite at the clinics.


Variable budgeting in the pharmacy.

Variable budgeting in the pharmacy. Because the operation of the pharmacy department is critical to the successful financial management of any hospital, pharmacists need to develop systematic budgeting systems that truly reflect costs. The variable budgeting techniques proposed by this author can reflect fluctuations in the cost of drugs.


Basic cost analysis can improve in-service education. When the director of a hospital's in-service education department analyzed basic cost data regarding his staff, he discovered an unnecessarily wide range of costs per student hour. The analysis changed his conception of the ideal educator, and he subsequently reorganized his department. The process he used is detailed herein.


Vertically linked organizations hold challenges and opportunities. As more and more hospitals integrate their services with other health care facilities, the need to explore the challenges and opportunities associated with such arrangements grows proportionately. This study of vertically integrated health care organizations places special emphasis on the internal relationships associated with such factors as structure and control, team building, and developing new initiatives.


Industrywide management plan can affect quality, cost of care. Physicians, hospital administrators and trustees, other health care service managers, Blue Cross-Blue Shield plans, HSAs, government, and business corporations can participate in management of the health care system as a whole in order to ensure the delivery of high-quality care and to control health care costs. This participation can include many activities, such as education about management problems and methods, use of shared services and management improvement programs, implementation of incentive reimbursement, and promotion of hospitals' interaction at the local level.


Hospitals' future depends upon long-range planning. In order for hospitals to shape their own future, it is necessary for them to take the initiative in establishing a solid and continual planning process. Strategic planning should take into consideration the external environment and the internal responses to that environment. The New Jersey Hospital Association, which has developed such a plan, offers information to other associations and their members who are considering a similar undertaking.


New York study shows regulatory costs unreasonably high. Concerned about the high and rising costs of compliance with regulations imposed by all sources, the Hospital Association of New York State (HANYS) undertook a study to determine the precise nature of those costs. The study shows both that the costs are high and that regulatory influence is pervasive. HANYS recommends that all concerned with the regulatory process, regulators and regulated alike, take a new, hard look at regulations.


Nursing comes of age in South Korea--with an American Maryknoller's help. Maryknoll Sister Patricia Conroy devoted 20 years to the nursing profession in South Korea. Through her work with the Maryknoll Junior College of Nursing in Busan and with the Korean Nurses Association she was instrumental in changing the traditional, Western-oriented nursing curriculum to a course of study more suited to South Korea's present community health needs.


Clergy health day: ministering to the ministers. Mercy Hospital, Port Huron, MI, held a Clergy Health Day for ministers from the community. The program, which included components on physical, mental/emotional, and spiritual health of the clergy, was judged helpful by both participants and those persons in the hospital responsible for the program.


Residential care as an alternative to abortion. St. Joseph Hospital, Chicago, through its Gehring Hall program, is offering unwed mothers an alternative to abortion. Gehring Hall provides accepted residents a stable, homelike living situation, comprehensive medical care, job opportunities, and counseling. St. Joseph's administration hopes the early experiences of Gehring Hall will inspire other health care facilities that adhere to Catholic teachings to serve unwed mothers, who have little other recourse in the public sector.


Sensitized supervisors--a key to preserving nonunion status. Properly selected, trained, sensitive supervisory personnel are the private, nonprofit hospital's first line of defense against attempts by unions to organize employees. Successful front line supervisors administer rules fairly, transmit information accurately, and strive for good human relations.


What hospital employees value most.

What hospital employees value most. Do employees want a high salary, job security, lots of leisure time, chances for pomotion, or satisfying tasks? A study in a 487-bed hospital of employee attitudes toward work revealed that what employees value most about their work depends, in large measure, on the kind of jobs they have.


Characterization of a mutant mouse lymphoma cell with deficient transport of purine and pyrimidine nucleosides. A clone (AE1) of cells resistant to adenosine cytotoxicity was isolated from a mutagenized population of mouse T-lymphoma (S49) cells. These adenosine-resistant cells cannot transport adenosine or any other purine or pyrimidine nucleoside tested, but their transport of purine bases is intact. The AE1 cells also have an impaired ability to salvage thymidine. Kinetic analyses of the uptake of purine and pyrimidine nucleosides further substantiate the evidence that the facilitated transport of purine and pyrimidine nucleosides in S49 cells is mediated by the same carrier. Growth rate and transport studies indicate that the lack of expression of the nucleoside transport in AE1 cells is recessive in intraspecies cell-cell hybrids.


Incorporation of exogenous heme into hepatic cytochrome P-450 in vivo. Parenteral administration of [3H]heme to allylisopropylacetamide-treated rats resulted in the formation of a radiolabeled allylisopropylacetamide-porphyrin adduct in the liver, which was isolated and purified. Since formation of this adduct requires the heme moiety of a functional cytochrome P-450 species, our findings indicate that exogenously supplied heme had been incorporated into the hepatic microsomal hemoprotein. Moreover, they suggest that exogenously supplied heme readily gains access to an "unassigned" heme pool, which provides heme for cytochrome P-450 formation.


Serine proteinases and their inhibitors in Phycomyces blakesleeanus. Three serine proteinases of Phycomyces blakesleeanus were isolated and characterized. The molecular weights were determined to be 18,000, 22,000, and 60,000. The proteinases were solubilized by detergent or salt treatment. Two soluble proteins that specifically inhibit these proteinases were also isolated and characterized. Both these proteins formed 1:1 complexes with the serine proteinases. A molecular weight of 10,000 was estimated for both inhibitors. They were found to be present in excess in the cells. An acid proteinase of Phycomyces was able to take the inhibitor off a serine proteinase.inhibitor complex. This proteinase was partially purified. The proteinases and inhibitors of three mutant strains were partially purified and compared with a standard strain. These mutants exhibit abnormal growth responses of the sporangiophore to light. Mutant specific changes of the proteinases and their inhibitors were detected, but a connection to the behavioral responses could not be demonstrated.


Concomitant induction of phenylalanine ammonia-lyase and flavanone synthase mRNAs in irradiated plant cells. Irradiation of previously dark-grown cell suspension cultures from parsley (Petroselinum hortense Hoffm.) with ultraviolet light caused large, concomitant increases in mRNA activities for two characteristic enzymes of phenylpropanoid metabolism, phenylalanine ammonia-lyase, and flavanone synthase. The rates of enzyme synthesis both in vitro in a reticulocyte lysate and in vivo were quantitated by direct immunoprecipitation of the labeled enzyme subunits. Following a period of about 2 h, during which possible changes were below the limits of detectability, the two mRNA activities increased rapidly in irradiated cells for serveral hours. Phenylalanine ammonia-lyase mRNA reached a peak in activity a few hours earlier than flavanone synthase mRNA. The apparent half-lives of the enzyme activities were about 7 to 10 h for phenylalanine ammonia-lyase and 5 to 7 h for flavanone synthase. These data were used to calculate the expected, light-induced changes in enzyme activity from the measured changes in mRNA activity. The results for both enzymes were in agreement with experimental data, indicating that the light-induced changes in enzyme activity can be explained by changes in the respective mRNA activity. Some data concerning changes in the degree of polyadenylation of the mRNAs and the inhibitory effects of 7-methylguanosine 5'-phosphate are presented.


Phosphylation and protein kinase activity of platelet tubulin. Platelet tubulin isolated by two successive cycles of polymerization-depolymerization was shown to contain protein kinase activity. The phosphorylating activity measured by incorporation of [32P]phosphate from [gamma-32P]ATP was cAMP-independent and behaved with respect to substrate specificity, cation requirement, and maximum incorporation of phosphate similarly to tubulin of brain. Contrary to tubulin from that source, however, platelet tubulin itself, not one of its co-purifying proteins appeared to be the source of the protein kinase activity. This was suggested by assays of tubulin freed from its associated proteins by chromatography on DEAE-Sephadex and on immunosorbent columns containing monospecific antibody to human platelet tubulin. Further corroboration was obtained from experiments in which tubulin was applied to casein affinity columns. No separation of protein kinase from colchicine binding activity could be obtained. Gel filtration showed that all of the in vitro phosphorylated tubulin was aggregated. Tryptic peptide patterns of 32P-labeled alpha- and beta-tubulin subunits were analyzed by ion exchange chromatography. Multiple peptides in both tubulin subunits were identified as acceptors of [32P]phosphate. In vivo phosphorylated tubulin was demonstrated to contain an average of 5 phosphoserine residues/monomer.


The role of tyrosine in the association of proteins and nucleic acids. Specific recognition of single-stranded nucleic acids by tyrosine-containing peptides. Oligopeptides containing tyrosyl, lysyl, and alanyl residues bind to polynucleotides and nucleic acids as shown by proton magnetic resonance, fluorescence spectroscopy, and difference absorption spectroscopy. Proton magnetic resonance data indicate that stacking of tyrosyl residues with nucleic acid bases takes place only in single-stranded structures (such as poly(A) or denatured DNA). Stacking interactions lead to a quenching of tyrosine fluorescence. However, the tyrosyl fluorescence of the peptides is quenched in their complexes with both single-stranded and double-stranded nucleic acids. A comparison of the behavior of homologous peptides containing Tyr, methoxytyrosine, and Phe leads to the conclusion that hydrogen bonding of tyrosine with bases or phosphates is not involved in the investigated complexes. An energy transfer mechanism from tyrosine to nucleic acid bases is proposed to account for fluorescence quenching in oligopeptide complexes with double-stranded DNAs. Due to the specificity of its stacking interaction for single-stranded nucleic acid structures, tyrosine might be involved through such interactions in the selective recognition of single strands by proteins.


Proteolysis of prothrombin by thrombin. Determination of kinetic parameters, and demonstration and characterization of an unusual inhibition by Ca2+ ions. A discontinuous assay to measure the proteolysis of tritiated prothrombin to fragment 1 and prethrombin 1 by thrombin has been devised, based empirically on extracting the radiolabeled fragment 1 into 4% p-toluenesulfonic acid. The assay is shown to be valid for the measurement of the initial rate of reaction in simple mixtures and has been used to determine the Michaelis-Menten parameters. The Km, 127 microgram of prothrombin per ml, and the kcat, 6.9 s(-1), indicate that, in the absence of other controls, attack of thrombin on prothrombin would be overwhelming during coagulation in plasma and that the prothrombin concentration would be rate-limiting. However, Ca2+ ions at concentrations around 1 mM reduce the rate of proteolysis by at least 20-fold. This inhibition is rapidly reversible by the addition of chelating agents. Measurement of initial rates at Ca2+ concentrations up to 1.5 mM shows that the inhibition is multisite and perhaps involves cooperative binding of the metal ions. The effect of Ca2+ on the kinetic parameters has also been investigated. kcat could not be measured because thrombin could not be saturated with prothrombin under conditions amenable to assay, but the Km is increased, showing that the inhibition by Ca2+ is at least partially competitive. An independent qualitative demonstration that Ca2+ is inhibitory in the reaction of native prothrombin with thrombin has been obtained by measurement of intrinsic fluorescence.


A raphe dendrite bundle in the rabbit medulla. A Golgi-Cox, histofluorescence, and electron microscopic examination of the serotonergic raphe nuclei of the rabbit medulla has revealed a large, vertically-oriented midline dendrite bundle extending from the floor of the fourth ventricle to the ventral boundary of nucleus raphe pallidus. The bundle was confined to the medulla, and averaged 150-200 micrometer in width in the adult. This dendrite bundle received contributions from four major sources: (1) Dendrites of midline and paramedian neurons of nucleus raphe obscurus; (2) Dendrites of midline and paramedian neurons of nucleus raphe pallidus; (3) Shafts from tanycytes located on the midline floor of the fourth ventricle; and (4) Dendrites from neurons of the medullary reticular formation. Perikarya and dendrites of serotonergic raphe neurons frequently abutted tanycyte shafts, midline bhood vessels, and perikarya and dendrites of other raphe neurons. The tanycyte shafts extended from the floor of the fourth ventricle into the bundle, and often ran the entire length of the bundle, where they intertwined themselves among neurons and dendrites of the medullary raphe nuclei. This study suggests that neurons of the medullary raphe may be influenced by communication channels including dendro-dendritic contacts within the midline bundle, fourth ventricular cerebrospinal fluid-borne influences through tanycyte shafts, blood-borne influences through the direct neuronal-vascular relationship in the raphe, and traditionally described axonal contacts impinging upon raphe neurons. We suggest that the raphe neurons might act as both neurons and endocrine-neural transducer cells.


The development of the septal region in the rat. II. Morphogenesis in normal and x-irradiated embryos. Morphogenesis of the septal region was examined in normal rat embryos from embryonic day (E) 10 to E22. The greater part of the septal region is postulated to form from two separate anlagen which can be clearly distinguished in the telencephalon by E13 and E14. One lies in the anterior ventromedial wall and presumably forms the nucleus of the diagonal band, medial, lateral, and triangular septal nuclei. The other lies in the posterior ventrolateral ridge and presumably forms the bed nuclei of the stria terminalis and the anterior commissure. On E15, the early differentiating cells in these anlagen fuse in the same region where the anterior commissure will cross on E17. With later embryonic development, differentiating cells of the strial bed nucleus accumulate rostral and caudal to the fused area. The same pattern is found in the medial and triangular septal nuclei and in the nucleus of the diagonal band. The differentiating cells of the lateral septal nucleus accumulate dorsal and lateral to medial and triangular septal nuclei. On E16 and E17, a prominent subependymal zone develops in the anterior septal region and presumably gives rise to the nucleus accumbens. A quantitative analysis was made of three cell zones (neuroepithelium, subependymal zone, differentiating cell zone) at coronal levels through the developing nucleus accumbens and the nucleus of the diagonal band (anterior level) and the medial and lateral septal nuclei (middle and posterior levels). At all levels, the area of the neuroepithelium continually declines, that of the differentiating cell zone continually increases, and that of the subependymal zone shows a rise and decline. On a proportional basis, both the neuroepithelium and subependymal zone occupy significantly more area anteriorly than posteriorly, while the differentiating cell zone shows the reverse gradient. To accurately locate regions of primitive mitotic and migratory cells within the zones at each level, the number of cells surviving a single exposure to 200 R X-rays in embryonic brains (E15-E22) were compared with controls. Each zone responded differently to X-ray insult. The radiosensitivity of the neuroepithelium decreases significantly after E19; the subependymal zone is highly radiosensitive throughout; the differentiating cell zone is radioresistant throughout. The significance of these findings is discussed in the light of the autoradiographic determination of the time of formation of septal neurons (Bayer, '79).


The morphology of local non-spiking interneurones in the metathoracic ganglion of the locust. The morphology is described of a number of non-spiking interneurones in the metathoracic ganglion of the locust that control motor neurones innervating muscles in the coxa and femur of a hind leg. The non-spiking interneurones are penetrated with microelectrodes, physiologically characterized, injected with cobalt, and the stain subsequently intensified with silver. The interneurones have diverse shapes but all are local, intraganglionic interneurones. Their cell bodies are 10-20 micrometer in diameter and lie in either the ventral or dorsal layers of cell bodies that form a cortex around the ganglion. The branches of the interneurones are profuse and overlap those of the motor neurones that they affect. On interneurone may have branches in both the most ventral and the most dorsal areas of the neuropile. Most interneurones have branches only in one half of the ganglion, but one interneurone has extensive and asymmetrical regions of branches in both halves of the ganglion (fig. 4). Similar physiological effects can be mediated by interneurones with distinct morphologies. For example, the single slow extensor motor neurone is excited by six distinct morphological types of interneurones (figs. 10-13). It is suggested that as many as 65% of the neurones within a ganglion may be local interneurones, many of which in turn may be non-spiking.


Organization of trigeminothalamic tracts and other thalamic afferent systems of the brainstem in the rat: presence of gelatinosa neurons with thalamic connections. Thalamic projections from trigeminal and certain other nuclei of the brainstem of the rat have been investigated using the technique of retrograde transport of horseradish peroxidase (HRP). The pattern of trigeminothalamic projections is very specifically related to the individual subnuclei of the complex. The Main Sensory Nucleus (MSN) provides profuse cross connections to the ventrobasal thalamus (VB); these arise exclusively from medium and small-sized neurons, but never from the large cells. In addition to these crossed connections, a small ipsilateral dorsal trigeminothalamic tract arises from the dorsal third of the most rostral part of the MSN; this is the only ipsilateral connection to VB found in the trigeminal complex. Subnucleus Oralis has no projections to the thalamus; it is suggested that it may be concerned primarily with reflex activation of the facial nucleus, with which it is co-extensive in the rostro-caudal axis. Subnucleus Interpolaris has a well-defined crossed projection of moderate size which arises from the large, medium and some of the small neurons. Subnucleus Caudalis has a sparse output to the thalamus and differs in its projections from rostral to caudal. At the most rostral level, all layers (marginal, transitional gelatinosa and magnocellularis) contain neurons which project to the thalamus; particularly conspicuous in this respect are the marginal neurons, most of which are strongly labelled. The presence of gelatinosa neurons projecting to the thalamus emphasizes a point made in earlier reports, that these neurons do not form an homogeneous population. At caudal levels, the marginal neurons are the major source of thalamic projections, while connections to the thalamus form deeper lying neurons are infrequent. With a single exception, the medullary reticular nuclei contained no neurons with thalamic connections; a small number of reticulo-thalamic neurons were found in the ventral pontine area. Marked labelling of the medial cuneate nucleus and moderate labelling of the gracilis and lateral cuneate nuclei occurred contralaterally to the injection site. A small numebr of medial cuneate and gracile neurons project to the ipsilateral thalamus. Projections from the solitary nucleus were always ipsialteral. The boundaries of individual subnuclei of the lateral sensory trigeminal complex in the rat have been redefined on the basis of cytological criteria; these are in good accord with the corresponding thalamic projection patterns.


Unmyelinated axons in the trigeminal motor root of human and cat. The fiber composition of the human and cat trigeminal "motor roots" were studied utilizing the electron microscope. Twelve to twenty percent of fibers in the human trigeminal motor root are unmyelinated whereas 9-15% are unmyelinated in the cat. The only previous examination of the fiber composition of the peripheral trigeminal motor nerve utilized the light microscope and indicated that less than 5% of fibers were unmyelinated in cat. No study of the fiber composition of the motor nerve root is available. The present results are similar to those recently obtained by others for spinal ventral roots. The function of unmyelinated fibers in the trigeminal "motor root" is unknown, however indirect evidence, both laboratory and clinical, suggests a potential sensory function for them. The findings question seriously the concept that the functional separation of the nervous system into motor and sensory systems has anatomical correlates in the spinal and cranial nerve roots. The results relate directly to our conceptualization of the nervous system and also to the design of methods for the treatment of intractable pain.


Properties of neurons in cat's dorsal lateral geniculate nucleus: a comparison between medial interlaminar and laminated parts of the nucleus. We studied the receptive field properties of 460 cells in the cat's dorsal lateral geniculate nucleus (LGNd), 108 cells were located in the medial interlaminar nucleus (MIN) and 352 in the laminated part of the LGNd. In both the MIN and laminated parts of the LGNd, relay cells belonging to all three functional classes (W, X and Y) have been identified. Of cells in the laminated LGNd, about 32.5% were Y cells, about 54.5% were X cells and about 8.5% were W cells. By contrast, in the MIN, about 84% were Y cells, only about 4.5% being X cells and about 7.5%, W cells. In the laminated LGNd, Y cells represented 25% of cells with receptive fields near the area centralis (0-3 degrees eccentricity group) and about 42% in the group of cells with the most peripherally located receptive fields (20-40 degrees eccentricity group). A similar but much weaker trend was observed in the MIN. In the laminated LGNd but not in the MIN the receptive field center sizes increased with increasing eccentricity of receptive field position. At any eccentricity, receptive field centers of MIN Y cells tended to be larger than those of Y cells in the laminated LGNd. Response latency ranges to orthodromic and antidromic stimulation were the same for cells located in the laminated LGNd and those in the MIN. However, the mean response latency to stimulation of the optic chiasm was significantly shorter for Y cells in MIN than for Y cells in the laminated LGNd. Our results suggest that the most numerous cells observed histologically in the MIN, class 1 cells of Guillery ('66) are morphological equivalents of Y cells.


A preganglionic autonomic nucleus in the dorsal gray commissure of the lumbar spinal cord of the rat. The distribution in the spinal cord of the rat of preganglionic neurons sending fibers into the hypogastric nerve was determined with the retrograde transport of horseradish peroxidase (HRP). Labeled cells were present in the intermediate gray matter of spinal segments L1-L2. The majority (81%) of HRP-filled cells formed a continuous column along the midline in the dorsal gray commissure. This cell column was termed the dorsal commissural nucleus (DCN). The remainder of HRP-labeled cells were present bilaterally in the middle and lateral regions of the intermediate gray; the majority of the latter cells were located along the lateral border of the intermediate gray. The present finding of a midline preganglionic autonomic cell column in the spinal cord of a mammal is contrary to previous reports, in which sympathetic preganglionic neurons have been localized primarily in the lateral intermediate gray. The DCN may be species-specific and related to the system of short adrenergic neurons present in the pelvis.


Quantitative analysis of nerve fibre densities in the cochlea of the house mouse (Mus musculus). Transverse sections of the cochlear nerve, silver-stained surface preparations of the cochlea, and silver- and osmium-stained tangential sections of the cochlea of the house mouse were made to determine the number and density of nerve fibres entering the organ of Corti and their distribution to inner and outer hair cells along the cochlear spiral. A number of 12,578 +/- 819 fibres was counted within the cochlear nerve, which is almost equal to the total number of 12,350 +/- 810 fibres entering the organ of Corti. The 12,350 fibres divide into 9,780 (= 79%) fibres running to the inner hair cells, 703 (= 6%) basilar (afferent) fibres and 1,867 (= 15%) upper tunnel radial (efferent) fibres innervating the outer hair cells. About 93% of all afferent fibres are connected to the inner hair cells, and only 7% innervate outer hair cells. The density of fibres running to the inner hair cells varies considerably and has a significant (p less than 0.01) absolute and relative maximum 3.7 mm and 2.9 mm from the apex respectively (total length: 6.84 mm) and decreases toward apex and base. The density of afferent fibres running to the outer hair cells shows a slow increase up to 2 mm from the apex, and remains on a constant low level (5.5 fibres per 40 micrometer) down to the base. The density of efferent fibres running to the outer hair cells increases linearly up to about 2 mm from the apex, remains rather constant (10 fibres per 40 micrometer) from 2 mm to 4 mm, and then decreases toward the base. Generally, the outer hair cells show a convergent innervation pattern, the inner hair cells a divergent one. The significance of the present measurements is discussed in relation to respecitve results from other mammals and in relation to auditory thresholds.


The development of the septal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. Neurogenesis in the rat septal region was examined with 3H-thymidine autoradiography. The rats in the prenatal groups were the offspring of pregnant females given two injections of 3H-thymidine on consecutive days in an overlapping series: embryonic day (E) 13 + E14, E14 + E15,. . . E21 + E22. The rats in the postnatal groups were injected in a nonoverlapping series: the day of birth and postnatal day (P) 1, P2 + P3, P3 + P4. On 60 days of age, the percentage of labelled cells and the proportion of cells added during each day of formation were determined at several anatomical levels within the midline nuclear group (nucleus of the diagonal band, medial and triangular septal nuclei), the lateral septal nucleus, and the ventrolateral nuclear group (nucleus accumbens, bed nuclei of the stria terminalis and the anterior commissure). The neurons within each nuclear group form in significantly different waves, those of the midline group forming between E13-E17, the lateral septal nucleus between E15-E19, the bed nuclei of the stria terminalis and anterior commissure between E14-E18, the nucleus accumbens between E17-P2. All nuclei and nuclear groups show characteristic gradients of formation. Both the midline nuclear group and the bed nucleus of the stria terminalis (including the commissural bed nucleus) have their earliest forming neurons lying near the crossing of the anterior commissure; younger nuerons are located both rostrally and caudally with the youngest neurons lying in the most rostral extension of the diagonal band nucleus and the strial bed nucleus. The lateral septal nucleus forms along a strong mediolateral gradient throughout its length after neurogenesis is almost complete in the midline nuclear group. Throughout the length of the nucleus accumbens, the oldest neurons are located ventrally while progressively younger cells are found dorsally beneath the inferior horn of the lateral ventricle.


Requests for as-needed medications by asthmatic patients. Relationships to prescribed oral corticosteroid regimens and length of hospitalization. In a previous study, patient-coping styles, indexed by panic-fear symptomatology, were found to be associated with specific patterns of requesting as-needed (PRN) medications and treatments: Patients who tend to emphasize their symptoms (high panic-fear) requested PRNs frequently, even on days when their pulmonary function levels were essentially normal, while those who tend to minimize their symptoms (low panic-fear) requested PRNs infrequently, even on days when their pulmonary function levels were subnormal. In the present study, we found that patients who requested PRNs frequently spent more days in the hospital than those who requested PRNs only rarely. Intensive medication regimens (i.e., daily corticosteroids or alternate-day corticosteroids supplemented with TAO, cromolyn, or aerosolized steroids) were more often prescribed for patients requesting PRNs frequently than for those requesting PRNs rarely. These differences in patient management were attributable neither to differences in pulmonary function nor directly to differences in panic-fear rating. Thus, patient-coping styles can influence the treatment prescribed, and optimal management requires that individual patient-coping styles be considered in planning a regimen.


Large airway constriction in allergic rhinitis: response to inhalation of helium-oxygen. Pulmonary function results were compared in 15 allergic rhinitis and 30 normal subjects. Airways resistance (RAW) was higher (p less than 0.01) and specific conductance (SGAW) and lower (p less than 0.01) in the rhinitis group. Maximal expiratory flow (VeMax), lung volumes, and results of tests measuring airways closure, distribution of ventilation, diffusing capacity, volume of isoflow, and density-dependence of VeMax at 50% of vital capacity (deltaVeMax50) did not differ significantly between the two groups. Following inhalation of isoproterenol, RAW decreased and SGAW and VeMax increased significantly in both groups. On the other hand, delta-VeMax50 decreased significantly in the rhinitis group (p less than 0.01) and increased significantly in the control group (p less than 0.05). In addition to comparing pulmonary function in rhinitis patients and control subjects, physiologic measurements were also made on two separate occasions in the rhinitis subjects (minimal or no symptoms; very symptomatic). Although rhinitis symptomatology varied considerably (p less than 0.001), pulmonary function results were not significantly different. Hence we conclude that: (1) Rhinitis subjects have large airway constriction which does not vary with season or symptoms. (2) As in normal control subjects, airflow limitation occurs in the large airways of rhinitis subjects. (3) The predominant site of isoproterenol-associated bronchodilatation differs between allergic rhinitis and normal subjects.


Multiple nevoid basal-cell carcinoma syndrome (Gorlin's syndrome): possible confusion with metastatic medulloblastoma. Case report. The authors report a diagnostic dilemma involving a child who, 8 years previously, had total excision of a medulloblastoma. On x-ray studies, lytic lesions of the skull were seen. The differential diagnosis and some of the clinical and pathological aspects of the nevoid basal-cell carcinoma syndrome versus metastases are discussed.


Computerized tomography and pathological correlation in cystic meningiomas. Report of two cases. Meningiomas have been reported to have associated areas of surrounding low density on computerized tomography (CT). These low-density areas may represent edema, widened subarachnoid spaces, loculated cerebrospinal fluid, demyelination, or adjacent tumor. Two cases are presented in which this adjacent area of low density represented a tumor cyst. Recognition is important as the CT appearance of these lesions may simulate a metastatic tumor.


Recurrent subependymal giant-cell astrocytoma in the absence of tuberous sclerosis. Case report. A case is described of a subependymal giant-cell astrocytoma that occurred as a mural nodule within a cyst in the parietal lobe. The tumor recurred twice over a period of 47 years despite two extensive surgical resections. Neither the patient nor any of his children suffered tuberous sclerosis, a disease with which this type of astrocytoma is associated.


Computerized tomographic demonstration of rotational atlanto-axial fixation. Case report. The authors report a case of rotational fixation of the atlanto-axial joint in which the diagnosis was not reached by conventional radiographic techniques. The clinical impression of rotational fixation was ultimately confirmed by computerized tomography. This new diagnostic modality can be very helpful in arriving at a very difficult diagnosis.


Pressor response resulting from experimental contusion injury to the spinal cord. Experimental contusion paraplegic injury to the posterior spinal cord in cats results in a sudden increase of systemic blood pressure to between 200 and 250 mm Hg, and an increase in pulse pressure and a slowing of pulse rate. This initial hypertensive phase lasts approximately 3 to 4 minutes, and then is followed by a hypotensive phase. This pressor response is mediated by the alpha adrenergic receptor sites of the peripheral sympathetic nervous system and can be blocked by intravenous phenoxybenzamine, an alpha adrenergic blocking agent. The hypotensive phase is the result of an overall reduction in alpha adrenergic vascular tone and can be reversed by the infusion of metaraminol or intravenous fluids. The alterations in blood pressure that follow impact injury are most likely related to alterations of peripheral arteriolar resistance and venous return of blood to the heart.


The contrast-enhanced CT scan in the diagnosis of isodense subdural hematoma. The authors review 29 cases of surgically-proven isodense subdural hematomas examined by non-contrast and contrast-enhanced computerized tomography scans. Three types of isodense collections were noted: homogeneous isodense collections, mixed-density collections, and gravitational layering within subdural collections. Contrast enhancement within the cerebral cortex, cortical vessels, and subdural membranes led to the correct diagnosis in each case. Contrast-enhanced scans are essential for the evaluation of isodense subdural hematomas.


Combined neurilemmoma and angioma. Tumor of ectomesenchyme and a source of bleeding. Eight cases are described of intracranial and peripheral neoplasms composed of mixed neurilemmoma and hemangioma. It is proposed that ectomesenchyme can differentiate into neurilemmoma and angioma. The latter may be related to recently described angiogenetic factors, or to developmental factors as in rare cases of arterial angiomas. The angiomatous part may be common, but has often been overlooked. The presence of abnormal vessels, whether in kind or in number, helps explain various biological features of neurilemmoma. These vessels frequently bleed within the tumor, which results in the characteristic hemosiderin-laden macrophages. Bleeding may also occur into the cerebrospinal fluid (CSF) to create xanthochromia. The frequent increase in CSF protein in cases of neurilemmoma is attributed to transudation of serum from abnormal vessels. Less commonly, bleeding may be sufficient to cause subarachnoid hemorrhage. The dense collagen usually associated with these angiomas accounts for the relative infrequence of major hemorrhages.


Thermoregulatory sweating in palmar hyperhidrosis before and after upper thoracic sympathectomy. To assess thermoregulatory sweating in palmar hyperhidrosis, the authors determined the responses of three groups of normal, hyperhidrotic, and denervated subjects to a variety of ambient temperatures (TA's), 22 degrees, 28 degrees, and 41 degrees C. The normal group had no hyperhidrosis, with intact T2-3 ganglia, the hyperhidrotic group had palm hyperhidrosis with intact T2-3 ganglia, and the denervated group had hyperhydrosis treated with T2-3 ganglionectomy. Both groups of hyperhidrotic and denervated subjects maintained oral and mean skin temperatures within normal limits displayed by the normal group over a wide range of TA's tested. The local sweating rate (LSR) of both the palms and the soles of the feet in the hyperhidrotic group was decreased to a minimal level by either the T2-3 ganglionectomy or the subcutaneous administration of atropine sulfate. Furthermore, the denervated group had a significantly lower LSR of both the forehead and the upper chest regions, but showed a higher LSR or both the ventral thigh and the lateral lumbar regions at a TA of 41 degrees C when compared to the LSR of either the normal or the unoperated hyperhidrotic group. The data demonstrate that the surgical removal of both the T-2 and the T-3 ganglia, although producing no alterations in the thermal balance, does produce abnormalities in quantitative distribution of thermoregulatory sweating in man.


Bacteriology and therapy of lung abscess in children. The bacteriology and clinical findings of ten pediatric patients with lung abscess are presented. Bacteriologic data were based on percutaneous transtracheal aspiration obtained before initiation of antimicrobial therapy. Anaerobic bacteria were present in all ten patients; in nine they were mixed with aerobic bacteria. The most frequent isolates were Peptostreptococcus (8), Peptococcus (5), Bacteroides melaninogenicus (6), and Bacteroides fragilis (3). The aerobic isolates most frequently recovered were alpha-hemolytic streptococci (5), group A beta-hemolytic streptococci (4), and Escherichia coli and Klebsiella pneumoniae (4 each). Virtually all abscesses were located in dependent pulmonary segments. Antimicrobial therapy was guided by the bacteriologic findings and was successful in all instances.


Postextubation atelectasis: a retrospective review and a prospective controlled study. To determine the role of chest physiotherapy in the prevention of postextubation atelectasis in neonates intubated for greater than 24 hours, a retrospective survey compared the incidence of this complication in a newborn intensive care unit prior to and following the institution of a routine of chest physiotherapy. Eight of 23 infants extubated developed atelectasis in the "pre-physio" period, whereas only one collapse occurred in 20 infants treated with a routine of physiotherapy at extubation (P less than 0.025). Subsequently a prospective controlled trial compared the use of a routine of physiotherapy at extubation with no physiotherapy. Eight of 21 infants not receiving physiotherapy developed postextubation atelectasis and none of 21 infants receiving physiotherapy developed atelectasis (P less than 0.01). Seventy-six percent of the collapses involved the right upper lobe. A vigorous program of chest physiotherapy, including postural drainage emphasizing the positions of the right upper lobe and chest vibrations, will significantly reduce the incidence of postextubation atelectasis.


Variations in inspiratory:expiratory ratio and airway pressure wave form during mechanical ventilation: the significance of mean airway pressure. Twelve neonates with severe lung disease were studied while mechanically ventilated with volume pre-set infant ventilators, using different I:E ratios and different airway pressure waves. While FIO2 tidal volume, respiratory rate, and PEEP remained constant, I:E ratios were increased, first by reducing inspiratory flow rate, which produced a triangular pressure wave, and then by using an inspiratory time hold mechanism, which produced an inspiratory plateau or squared pressure wave. Peak inspiratory pressure, mean airway pressure, PaO2, PaCO2, pH, and blood pressure were measured and compared for each I:E ratio and pressure wave combination. In all patients, increases in oxygenation appeared to be directly related to increases in MAP. Optimum oxygenation and ventilation occurred with the I:E ratio and pressure wave combination that produced the highest MAP. Because MAP changes with any alteration in PEEP, I:E ratio, or airway pressure wave, it is a clinically useful composite measure of all pressures transmitted to the airways by a mechanical ventilator.


Impaired autoregulation of cerebral blood flow in the distressed newborn infant. Cerebral blood flow was measured, using the 133Xe clearance technique, a few hours after birth in 19 infants with varying degrees of respiratory distress syndrome. Ten of these infants had had asphyxia at birth. The least affected infants with normotension (systolic blood pressure 60 to 65 mm Hg) had CBF values of about 40 ml/100 gm/minute. Hypotensive infants with asphyxia at birth or RDS or both had values for CBF of about 20 ml/100 gm/minute, or less. CBF was strongly correlated with the arterial blood pressure, showing a linear relationship that was identical in infants with asphyxia at birth and infants with RDS only. CBF varied considerably with spontaneous variations in blood pressure, suggesting that autoregulation was lacking. This finding may explain why distressed premature infants are prone to develop massive capillary bleeding in the germinal layer with penetration to the ventricles.


Assessment of patent ductus arteriosus shunting using diastolic pressure analysis. Ductal shunting significantly affected the time necessary for aortic diastolic pressure to fall to one-half an initially selected value (t1/2). Fourteen premature infants with clinical evidence of left-to-right ductal shunting had a mean t1/2 of 277 msec (range 133 to 383 msec) compared with a mean t1/2 of 455 msec (range 332 to 567 msec) in 14 neonates with no clinical evidence of ductal shunting (P less than 0.01). Seven older infants with ductal shunting confirmed at cardiac catheterization had a mean t1/2 of 360 msec (range 240 to 392 msec). Infant catheterization data and animal studies are suggestive of an inverse relationship between the magnitude of shunt and the t1/2. The t1/2 determined by diastolic pressure analysis is a useful method for serial evaluation of ductus arteriosus shunting.


Polymorphonuclear leukocyte dysfunction in children with recurrent otitis media. Depressed PMN chemotactic responsiveness was observed in 17.5% of 97 patients studied, depressed PMN bactericidal activity in 23.3% of 30 patients, and depressed PMN chemiluminescence activity in 15.8% of 19 patients. Depressed chemotactic


Predictability of peak serum gentamicin concentration with dosage based on body surface area. We examined gentamicin dosage based on body surface area (60 mg/m2 intravenously every eight hours) as a means of attaining therapeutic but nontoxic serum concentrations in 58 patients ranging in age from 0.7 to 73 years. All but one patient had peak serum levels between 3.4 and 8.0 microgram/ml. The mean serum gentamicin half-life was shorter in patients less than 10 years of age (76 minutes) than in patients aged 10 to 50 years (116 minutes) and in patients aged 50 to 63 years (184 minutes) (all significant at P less than 0.01). We conclude that gentamicin dosage based on body surface area produces uniform peak serum gentamicin concentrations in both children and adults, and that the safety and efficacy of a shorter dosage interval for children deserves investigation.


High-dose propranolol therapy in the management of supraventricular tachycardia. Five patients, age 3 weeks to 11 years, presented with supraventricular tachycardia that remained uncontrolled following adequate digitalization. Four of these patients underwent invasive electrophysiologic studies to determine the mechanism of the arrhythmias. Of these four patients, three had concealed Wolff-Parkinson-White syndrome, and one patient had evidence of dual A-V nodal pathways. Propranolol was added to the medical treatment and was administered orally in doses ranging from 7 to 14 mg/kg/day (average 9 mg/kg/day). All five children remain free of their tachycardia except for one patient who occasionally has supraventricular tachycardia with febrile illnesses. No adverse reactions to these high doses of propranolol were encountered.


Abnormal neutrophil maturation in a neutrophil defect with morphologic abnormality and impaired function. Neutrophils from a patient with recurrent pyogenic infections since infancy were found to have morphologic abnormalities and impaired functions. The neutrophils had an abnormal nuclear shape, no or few secondary granules, and no alkaline phosphatase activity. Primary granules were normal in number and structure, and were positive for peroxidase. Immature granulocytes were structurally normal. The neutrophils were impaired in chemotaxis and bactericidal capacity. The patient's marrow cells formed increased numbers of granulocytic colonies of small size in culture. Her peripheral leukocytes produced elevated levels of CSA and adherent marrow cells did not inhibit colony formation. These data indicate an intrinsic neutrophil defect which allows normal proliferation of precursor cells, but results in abnormal morphogenesis and impaired function as the cells mature.


Percentile curves for hemoglobin and red cell volume in infancy and childhood. Percentile curves were calculated for hemoglobin and mean corpuscular volume in children between 0.5 and 16 years of age. The curves were derived from several populations of non-indigent white children who lived near sea level. Subjects were excluded from the reference population if they had laboratory evidence of iron deficiency, thalassemia minor, and/or hemoglobinopathy. The final reference populations included 9,946 children for the derivation of the hemoglobin curves and 2,314 for the MCV curves. The percentile curves should be particularly applicable to the diagnosis and screening of iron deficiency and thalassemia minor.


Preatherosclerotic aortic lesions in cystic fibrosis. Patients with cystic fibrosis have fat malabsorption, providing an experimental model for evaluation of the hypothesis that a low-fat intake may prevent atherosclerosis. We studied the frequency and extent of aortic precursor lesions (fatty streaks, early fibromusculoelastic lesions, late fibromusculoelastic lesions) found at autopsy in this disease as well as in other patients with debilitating disorders but with no apparent impairment of fat absorption. Fatty streaks were less common in the cystic fibrosis group, as were the late fibromusculoelastic lesions. There was no significant difference in the frequency, length, or thickness of the early fibromusculoelastic lesions. The findings suggest that fat may be responsible for progression but not initiation of the fibromusculoelastic precursor lesions, and support the concept that early restriction of dietary fat may prevent, delay, or otherwise modify atherosclerosis in the adult.


Reduced serum 25-hydroxyvitamin D concentration and disordered mineral metabolism in patients with cystic fibrosis. Vitamin D and mineral metabolism were studied in 21 adolescents and young adults with cystic fibrosis and the results were compared to those in 21 matched controls. All CF patients had been maintained on standard multivitamin supplements in combination with pancreatic enzyme replacement. Despite this supplementation, relative to control subjects the CF patients had a 36% reduction in serum 25-hydroxyvitamin D concentration, a slight but significant reduction in serum calcium concentration, evidence of calcium malabsorption with secondary hyperparathyroidism, and a 14% decrease in bone mass measured by the photon absorption technique. Currently accepted modes of pancreatic enzyme replacement and vitamin D supplementation are often inadequate to maintain normal mineral homeostasis in CF patients; additional measurements may be required to reduce the risk of clinically significant osteopenia concomitant with prolonged survival in CF.


Helmet treatment for plagiocephaly and congenital muscular torticollis. Plagiocephaly usually originates in late fetal life through aberrant constraint of the fetal head and is often associated with sternocleidomastoid torticollis. In some patients the obligue head shape may become a permanent, cosmetic disability. Individually fitted plastic helmets, similar in style to football helmets, have been successfully used to remold the deformed heads of four infants. Each helmet is designed to fit snugly against the prominent aspects of the infants' cranium and to be loose fitting where the head is shallow. As the brain grows, the head is molded to fit the helmet and thus acquires a more usual shape. The treatment has been safe and effective. When torticollis is persistent after the initiation of treatment, rubber straps can be fixed to the outside of the helmet and attached to the side rails of the crib. While the infant sleeps, the straps can be tightened to stretch the shortened sternocleidomastoid muscle.


Fatal neonatal nemaline myopathy with multiple congenital anomalies. The clinical course and autopsy findings in a patient with fatal neonatal nemaline myopathy are described. A hypotonic infant required mechanical ventilatory support immediately following delivery and developed progressive congestive heart failure. He had mild facial dysmorphism, a high-arched palate, clinodactyly, short first metacarpals, abnormal dermatoglyphics, simian creases, and bilateral talipes varus. Light and electron microscopic study of a muscle biopsy was diagnostic of nemaline myopathy. Autopsy revealed a papillary muscle anomaly, myocardial scarring, and hepatic fibrosis. The severe clinical impairment in this infant and the unusual associated anomalies are compared with other examples of nemaline myopathy. Nemaline myopathy is a cause of respiratory insufficiency in the neonatal period.


Familial syndrome of mental retardation, short stature, contractures of the hands, and genital anomalies. Two teen-age XY brothers with mental retardation, short stature, obesity, genital abnormalities, and contractures of their hands are described. They have generalized osteoporosis and a history of frequent fractures. Their endocrinologic evaluation was normal except for mild glucose intolerance and delayed, but normal puberty. Although these brothers are similar to individuals with Prader-Willi syndrome, their unusual hand contractures, clinically significant osteoporosis, and lack of hypotonia indicate that they represent a different entity.


X-linked hypogonadism, gynecomastia, mental retardation, short stature, and obesity--a new syndrome. Five male members in four generations of the same family had hypogonadism, gynecomastia, mental retardation, obesity, and short stature. The X-linked mode of inheritance, the distinctive facies, the normal size of the hands and feet, and the true gynecomastia are the main characteristics. Endocrine evaluation and histologic studies of the testes suggest partial hypogonadotropic hypogonadism. This disorder represents a new syndrome distinct from others previously described.


Prenatal administration of betamethasone for prevention of respiratory distress syndrome. The outcome of 114 infants of birth weight 750 to 1,750 gm who received prenatal betamethasone therapy was compared retrospectively to that of 138 infants delivered to untreated women. The incidence of respiratory distress syndrome in all treated infants was 37.7% compared with 50.7% (P = 0.05) in untreated infants. There was no apparent benefit of therapy among infants delivering less than 48 hours after the first dose and among infants less than 750 gm birth weight. Among infants delivering two to ten days after therapy, RDS 25.0 vs 50.7%) and mortality (8.9 vs 22.5%) were significantly reduced. Among surviving infants with RDS, fewer infants in the two to ten-day treated group required oxygen at FIO2 greater than 0.5 for more than 24 hours. Our findings confirm previous reports that prenatal glucocorticoid treatment reduces the incidence of RDS and mortality in premature infants. In addition, they indicate that therapy is more effective when delivery is delayed at least two days, that very small premature infants do not benefit from treatment, and that RDS may be less severe after prenatal exposure to betamethasone.


Absence of povidone-iodine-induced mutagenicity in mice and hamsters. Povidone-iodine USP was tested for mutagenicity in mice by the dominant lethal assay or micronucleus test and in Chinese hamsters by the bone marrow test. None of the three tests revealed any evidence of mutagenic effect.


GLC determination of butylated hydroxyanisole in human plasma and urine. A highly sensitive and specific GLC method was developed for the analysis of butylated hydroxyanisole, a commonly used antioxidant. Concentrations below 100 ng/ml could be detected in human plasma and urine. Preliminary pharmacokinetic studies demonstrated that, upon administration of 100 mg po, butylated hydroxyanisole was quickly absorbed and removed from the plasma with a high degree of intersubject variability.


Quantitative determination of chlorthalidone in pharmaceutical dosage forms by high-pressure liquid chromatography. A reliable and selective high-pressure liquid chromatographic procedure for the quantitative determination of chlorthalidone in pharmaceutical dosage forms is described. A comparison of this stability-indicating procedure with the USP spectrophotometric assay is presented for chlorthalidone tablets and chlorhalidone tablets containing reserpine.


Anticonvulsant activity of alkyl-substituted N-benzylcyanoacetamides. Thirteen new derivatives of 2-alkyl- and 2,2-dialkyl-N-benzylcyanoacetamide, a cyano analog of beclamide, were synthesized and tested for anticonvulsant activity. The unsubstituted compound was more active and more toxic than the derivatives. No activity was observed when the alkyl substituents in the symmetrically disubstituted derivatives contained a total of six or more carbon atoms or when benzyl was a substituent. The monosubstituted compounds were more toxic than the disubstituted compounds.


Direct spectorphotometric assay of quaternary ammonium compounds using bromthymol blue. Benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate were assayed quantitatively by a direct spectrophotometric method with bromthymol blue buffered at pH 7.5. The method shows good results at concentrations of 0--300 microgram/ml and in the presence of epinephrine bitartrate, phenylephrine hydrochloride, pilocarpine hydrochloride, and polyvinyl alcohol.


Enantiomeric purity of naproxen by liquid chromatographic analysis of its diastereomeric octyl esters. A sensitive and specific analytical method was developed to determine the enantiomeric purity of naproxen. A simple derivatization of naproxen with (S)-(+)-2-octanol proceeded quantitatively and gave a mixture of diastereomeric esters displaying baseline separation on liquid chromatography. The ratio of these esters was the same as the ratio of enantiomers present in naproxen samples assayed. Reproducibility of the method was excellent.


Stability of E-type prostaglandins in triacetin. A drug delivery system for E-type prostaglandins is described. In this system, consisting of drug dissolved in triacetin and filled into soft gelatin capsules, normally unstable prostaglandins show excellent stability at room temperature.


Fluorinated phenytoin anticonvulsant analogs. Six ring-fluorinated phenytoin analogs were synthesized, and their anticonvulsant activity in the maximal electroshock seizure and subcutaneous pentylenetetrazol assays was determined. 5-(4-Fluorophenyl)-5-phenylhydantoin, 5-(3-fluorophenyl)-5-phenylhydantoin, and 5,5-bis(4-fluorophenyl)hydantoin were active in the maximal electroshock seizure assay. The compounds were much less potent than phenytoin but showed an extremely long duration of action.


Applications of paired ion high-pressure liquid chromatography: quantitative determination of potassium guaiacolsulfonate and other ingredients in cough syrups. A method for the quantitative determination of potassium guaiacolsulfonate and phenylephrine hydrochloride in commercial dosage forms was developed. The method is based on paired ion high-pressure liquid chromatography with tetrabutylammonium as the counterion. The method not only separates potassium guaiacolsulfonate from phenylephrine hydrochloride but also from some other ingredients: chlorpheniramine maleate, sodium benzoate, colors, and flavors. Furthermore, two isomers of potassium guaiacolsulfonate, potassium salts of 4- and 5-guaiacolsulfonic acid, also separate from each other. The method was tried on five different commercial dosage forms (all with different colors) with excellent results on three. In the other two samples, which also contained codeine, three may have been a stability problem.


Effect of nonsteroidal anti-inflammatory and other pharmacological agents on tuberculin reaction. Nonsteroidal anti-inflammatory and other pharmacological agents were tested in the efferent arc of the tuberculin skin reaction in the guinea pig. A low but significant inhibition was produced by the acidic anti-inflammatory agents, including the arylalkanoic acids, the anthranilic acids, indomethacin, and phenylbutazone. Some nonacidic anti-inflammatory agents also were inhibitory; benzydamine caused a high inhibition. Except for methotrexate, the antineoplastic--antimetabolite agents were not potent inhibitors. Inhibition without toxicity was produced by the coumarin anticoagulants, the diuretics, chloroquine, tilorone, and the following immunoregulators: antithymocyte gamma-globulin, cyclophosphamide, and penicillamine. Levamisole, colchicine, heparin, and niridazole were inhibitory but produced lethality either at or above the effective dose.


Molecular connectivity analyses of structure influencing chromatographic retention indexes. The molecular connectivity indexes of various aliphatic alcohols, ketones, ethers, and esters were used to describe structural features influencing chromatographic retention indexes. Good correlations were obtained within chemical classes for a particular stationary phase.


Determination of water in aluminum chlorohydrate and effervescent tablets by Karl Fischer Analysis. A procedure was developed for the quantitative determination of loosely bound water in aluminum chlorohydrate and the water content in denture cleanser effervescent tablets. The basic method involves extracting the water from the sample into dioxane followed by titration of the dioxane in methanol with Karl Fischer Reagent. Matrix Ingredients did not interfere.


South American plants II: taspine isolation and anti-inflammatory activity. Croton lechleri L. (Euphorbiaceae), a plant from the Upper Amazon Valley of Peru, yielded the alkaloid taspine. The anti-inflammatory activity of taspine hydrochloride was studied using the carrageenan-induced pedal edema method, the cotton pellet-induced granuloma method, and the adjuvant polyarthritis model.


Fluorescence assay of hydroxynaphthaoquinones. Three procedures for fluorescence assay of hydroxynaphthoquinones are reported. The first procedure, based on prior sodium dithionite reduction and determination of the fluorophore in butyl acetate, is applicable to all of the hydroxynaphthoquinones investigated (detection limit: +/- 0.020 microgram of quinone/g of butyl acetate). The second method, specific for 5-hydroxy-1,4-naphthoquinones (juglone series), involves warm reduction with stannous chloride in an acid medium and determination of the fluorophore in chloroform (detection limit: +/- 0.020 microgram of quinone/g of chloroform). The third method, based on the reaction of Guilbault and Kramer, is applicable to 5-hydroxy- and 5,8-dihydroxy-1,4-naphthoquinones having both free quinonoid positions (detection limit: +/- 0.020 microgram of juglone/g of dimethyl sulfoxide and 0.070 microgram of p-naphthazarin/g of dimethyl sulfoxide). The nature of fluorophores also was investigated.


Development of an estriol-releasing intrauterine device. Estriol-releasing intrauterine devices were developed for experimental use in animals and humans. The devices consist of a reservior containing the steroid surrounded by a rate-limiting polyurethane membrane. After an initial transient, the drug is released from the device at a constant rate for 1 year or more; devices with a much longer release period can be fabricated readily. A constant release rate is achieved by maintaining solid drug in the reservoir and good physical contact between the drug and the inside wall of the device. The methods used to fabricate the devices are described along with release rate and stability data.


Pharmacokinetics of morphine and its surrogates II: methods of separation of stabilized heroin and its metabolites from hydrolyzing biological fluids and applications to protein binding and red blood cell partition studies. The inhibition of the spontaneous hydrolysis of heroin in fresh dog plasma on blood (t1/2 = 8 min) is effected by 10 mg of sodium fluoride/ml (t1/2 = 40 min) and 35 microgram of tetraethyl pyrophosphate/ml (t1/2 = 415 min). Tetraethyl pyrophosphate is the inhibitor of choice and gives the same stability for heroin as in phosphate buffer. Aged plasma loses its enzymatic efficiency. Heroin in cerebrospinal fluid hydrolyzes at rates similar to those in buffer. Modified extraction procedures developed for enzyme-inhibited plasma at pH 4.5 have high extraction efficiencies (86--100%) and permit isolation of undergraded heroin from its metabolites. Separations of heroin and metabolites from enzyme-inhibited plasma were effected by described high-pressure liquid chromatographic systems and from TLC with elution of pertinent developed spots. Efficiencies of these TLC recoveries were 81 +/- 1% for heroin and 82 +/- 1% for morphine. Contrary to the literature, heroin has significant protein binding where 40% of that not bound to an ultrafiltration membrane is bound to dog plasma proteins. The apparent partition coefficient is 1.4 +/- 0.2 between red blood cells and plasma water, and it is 0.8 +/- 0.1 between red blood cells and dog plasma.


Liquid chromatography in pharmaceutical analysis XI: determination of muscle relaxant--analgesic mixture using reversed-phase and ion-pair techniques. High pressure liquid chromatography using reversed-phase and/or ion-pair techniques was used to optimize resolution of aspirin-containing muscle relaxant mixtures as well as other therapeutic agents commonly found in muscle relaxant-analgesic mixtures. The compounds were chromatographed on an octadecylsilane column using methanol--water solvent systems, some of which contained tetrabutylammonium cation as counterion. Mixtures of methocarbamol--aspirin and chlorzoxazone--acetaminophen were selected to demonstrate separation and quantification. The methocarbamol--aspirin mixture was chromatographed with methanol--water (40:60, pH 6.8) containing 0.01 M tetrabutylammonium cation at a flow rate of 2.0 ml/min. The chlorzoxazone--acetaminophen mixture was chromatographed with methanol--water (50:50) at a 2.0 ml/min flow rate. The separation and quantitation of each mixture were achieved in approximately 8 min with accuracy in the 2--3% range.


Formation of a thio analog of noracronine. Acronine was heated with tetraphosphorus decasulfide in benzene to give a mixture of products, the major component (A) being identified tentatively as an unstable product derived from four molecules of noracronine with one molecule of tetraphosphorus decasulfide. Treatment of Compound A with various solvents and heat converted it into a maroon solid (B), which was shown to be 7-thionoracronine.


Molecular connectivity study of halocarbon anesthetics. The structure--activity relationships of 45 halogenated hydrocarbons using molecular connectivity were studied. A very good correlation was obtained between the anesthetic activity and the molecular connectivity term o chi v in addition to the polar hydrogen factor, QH. The equation reported accounts for the quantifies the known structure--activity observations on general anesthetics. The results are discussed briefly with reference to the mechanisms of action of general anesthetics.


Quantitative GLC determination of oxycodone in human plasma. A GLC assay was developed for the determination of oxycodone levels in human plasma using a nitrogen-specific detector. The assay was developed for use in bioavailability studies of therapeutic doses of oxycodone. After ingestion of a commerical tablet containing 4.5 mg of oxycodone hydrochloride and 0.38 mg of oxycodone terephthalate by six volunteers, the mean peak oxycodone concentration in plasma was 18.4 ng/ml at 1 hr.


Interaction of the antimalarial alpha-dibutylaminomethyl-2,6-bis(trifluoromethylphenyl)-4-pyridinemethanol with human serum albumin. Binding of the antimalarial alpha-dibutylaminomethyl-2,6-bis(trifluoromethylphenyl)-4-pyridinemethanol with human serum albumin was studied using difference spectroscopy, fluorescence quenching, and equilibrium dialysis. Results indicated that the number of high affinity binding sites of the drug on protein is 0.45, with the total number of binding sites being 3.3--4.0. The binding constants were in the range of 0.57--4.00 x 10(6) M-1. The drug was bound more strongly to a nonionic detergent than to either a cationic or anionic detergent. Interpretation of these data and fluorescence quenching results indicated that the drug is possibly bound to a hydrophobic site on human serum albumin.


Reliability of Arrhenius Equation in predicting vitamin A stability in multivitamin tablets. Shelflife predictions of vitamin A stability in multivitamin tablets were calculated based on data obtained from the analyses of six multivitamin tablet preparations by the classical Arrhenius treatment. This approach gave excessive variation in the predictions. The same data were treated by a modified Arrhenius method, which reduced the variation. Long-term room temperature data show that incorrect slopes were predicted in three of the six sets of data with the modified approach. The data indicate that erroneous predictions can result when applying the Arrhenius treatment to accelerated data and that this approach should be used with extreme caution in establishing the expiration date of a multivitamin tablet product, especially where the limiting ingredient for expiration dating is a preprocessed raw material and not a single-entity chemical.


Effect of sulfisoxazole on pharmacokinetics of free and plasma protein-bound bilirubin in experimental unconjugated hyperbilirubinemia. The effect of sulfisoxazole on the time course of free (unbound) bilirubin concentrations in plasma was studied. Normal adult rats were made hyperbilirubinemic by continuous intravenous infusion of bilirubin. Sulfisoxazole was administered by either rapid intravenous injection or slow intravenous infusion, and the plasma concentrations of free and total (free plus bound) unconjugated bilirubin were determined as a function of time. Rapid injection of sulfisoxazole caused a rapid and pronounced decrease of total bilirubin concentrations in plasma but had only a transient effect on the concentration of free bilirubin. Slow infusion of sulfisoxazole caused a gradual and eventually pronounced decrease of total bilirubin concentrations in plasma but had no apparent effect on the concentration of free bilirubin at any time. These results are consistent with recently developed pharmacokinetic theory according to which the plasma clearance of total bilirubin should increase upon administration of a displacing agent while the plasma clearance of free bilirubin should remain unchanged. Bilirubin-induced encephalopathy caused by sulfisoxazole or other displacing agents may be due to very transient elevations of free bilirubin concentrations in plasma of infants with elevated plasma concentrations of total bilirubin and the consequent redistribution of the pigment to extravascular sites, including the brain.


Carbon-13 magnetic resonance spectroscopy of drugs III: penicillins. The natural abundance 13C-NMR spectra of a series of penicillins (penicillin V methyl ester, penicillin V, penicillin G, methicillin, oxacillin, cloxacillin, and dicloxacillin) were studied. The chemical shifts were assigned using the pulse Fourier transform technique with the aid of long-range carbon-13 hydrogen coupling. The previous assignments of pencillin V methyl ester were revised.


First-pass effect after rectal administration of thiazinamium methylsulfate. The absorption and metabolism of the quaternary ammonium compound thiazinamium methylsulfate were studied in humans using plasma concentration data and urinary excretion measurements. After giving a dose of 150 mg in suppositories, the relative bioavailability was 5.8 +/- 3.2 (SD) % of the dose, comparable to the values obtained following oral administration. The degree of first-pass effect observed after rectal administration was comparable with that after oral administration.


Determination of submicrogram quantities of clonidine in biological fluids. A sensitive and specific GLC method using electron-capture detection was developed for clonidine in plasma and urine. Di-perfluoroacyl derivatives of both clonidine and the 4-methyl analog of clonidine (used as an internal standard) were formed, and an extraction process was developed for the removal of excess derivatization reagent and endogenous biological compounds; the assay permitted quantification of 25 pg of clonidine/ml in a 4-ml plasma sample. The assay was used to elucidate the time course of plasma concentrations in a normotensive subject following oral administration of 50, 100, and 200 microgram of clonidine hydrochloride and also to determine unchanged drug excreted in the urine.