A dosage response curve for the one rad range: adult risks from diagnostic radiation. Most exposure to low-level ionizing radiation, both diagnostic x-rays and nuclear radiation, occur in the range between 100 milirads and 10 rads--the "one rad range". In the past, the estimates of hazards in this range have been obtained by linear extrapolation from data on persons who were exposed to much higher dosages, generally in the centirad range used in radiotherapy of non-malignant disease. This article presents the first dosage response curve for the one rad range ever to be developed directly from data on men exposed to ordinary diagnostic radiation. The findings are based on approximately 220 men with non-lymphatic leukemia and more than 270 random-sample controls from the Tri-State Survey. The new findings suggest that the estimates previously obtained by extrapolation from high dosage levels to low dose levels underestimate the actual hazards by an order of magnitude. The new dosage response curves indicate that linear extrapolation fails because it disregards the subgroups in the general population that are particularly vulnerable to x-ray. There are immediate implications concerning the use of medical x-rays in screening or for routine purposes. The past risk-benefit calculations are based on extrapolative estimates and require drastic revision. Uses of x-ray which were previously marginal are now clearly counterindicated.


Farm tractor fatalities: the failure of voluntary safety standards. There are no governmental standards for operator protection which require compliance by farm tractor manufacturers. To see how the Wisconsin farming population fares under voluntary safety standards, death certificate data were used to determine rates of tractor-associated fatal injuries. The injury deathrate associated with tractors on farms increased from 10.9 per 100,000 male farm residents during 1961-1965 to 13.6/100,000 during 1971-1975 (p less than .05). Deaths associated with overturning tractors were most common; with death rates of 6/100,000 male farm residents for 1961-1975. The rise in tractor-associated death rates shows that voluntary safety standards are not protecting the farm population. Rollover protective structures (ROPS) are designed to protect operators when tractors overturn but under voluntary safety standards these ROPS are sold only as optional accessory devices. Current Occupational Safety and Health Administration regulations which require ROPS for employees operating tractors do not protect self-employed farmers and their families. It is recommended that the government require all tractors sold to be equipped with ROPS as is currently the case in England and Sweden.


Body contact swimming rescues--what are the risks? A survey of 482 lifeguards and Water Safety Instructors revealed that at least one-half had performed body contact swimming rescues (BCRs). Over two-thirds of these BCRs occurred when the lifesaver was relatively inexperienced in actual water rescues of any kind although virtually all rescuers had received formal lifesaving training. The victim tried to grasp the rescuer in 26 per cent of the BCRs which took place in swimming pools and 39 per cent of those occurring in lakes. Most of these attempts were made during the approach and were predominantly from the front, around the rescuer's head and neck or wrists and arms. Since the majority of victims were younger and smaller than their rescuers and got into difficulty less than 3 m from safety, only a small proportion of the grasps were perceived as endangering the lifesaver. Consequently, the victim was often permitted to retain the hold while being rescued. Grasps which were reported to be threatening tended to be applied by individuals of equal or larger physical size than the rescuer and usually occurred at distances exceeding 3 m from safety.


[The dose-effect-ratio of isobaric bupivacaine in spinal analgesia (author's transl)]. Isobaric bupivacaine 0.5% with adrenaline 1:200,000 was used for spinal anaesthesia. The influence of dose (mg) and volume (ml) on segmental spread and duration of spinal block was investigated. Bupivacaine 10 or 15 mg was injected in 2 or 3 ml of solution. The segmental spread and duration of analgesic block was tested at certain time intervals. The results showed that: 1. an increase in dose is not followed by a larger segmental spread or longer duration of analgesic block, 2. the increase of the volume injected is followed by an increase in segmental spread of analgesic block. This is independent of the concentration of the local anaesthetic, 3. the segmental regression of analgesic block starts in the cephalad segments. Therefore, higher spread of analgesic block provides prolonged analgesia in the lower segments. The results of this investigation are controversal in relation to the reports in the literature of the last two decades. The increase in dosage of the local anaesthetic did not increase the segmental spread and duration of analgesia. Only the volume injected is responsible for an increase in segmental spread of analgesia. Of course the concentration of the local anaesthetic injected has to be at least the minimal concentration necessary to result in a sensory nerve block.


[Loss of resistance in axillary plexus blockade]. The results of the "loss of resistance" method for identification of the perivascular space are demonstrated. The axillary plexus with its accompanying structures is embeded in the perivascular space. 20 pressure readings were performed with a special transducer. A statistically significant pressure loss was demonstrated after passing the vascular and nerve sheath. The distinct pressure differences during the tissue penetration are recognized with the finger guiding the syringe, similar to the technique used for peridural anaesthesia. We thus believe that we can offer an exact method for blocking the axillary plexus with maximum safety which does not rely on the cooperation of the patient.


[The effect of local anaesthetics on uterine blood flow and O2-consumption in non-pregnant sheep (author's transl)]. 11 non-pregnant sheep were prepared for chronic studies with an electromagnetic flow transducer placed around one uterine artery and with catheters in both uterine veins, aorta and inferior vena cava. The 4 local anaesthetics bupivacaine, etidocaine, lignocaine and chloroprocaine were infused intravenously on consecutive days in a randomized manner. During the infusions of all 4 local anaesthetics, uterine blood flow decreased due to an increase of uterine vascular resistance. The uterine arteriovenous O2-difference increased, while the uterine O2-consumption decreased without development of an acidosis of the uterus. The same changes were observed in 8 animals, to which oestrone had been administered intravenously prior to the infusions of local anaesthetics. Local anaesthetics had the same effects in the non-pregnant and pregnant uterus. A direct vasoconstrictive mechanism on the uterine vessels as well as a depressing effect on metabolism is discussed for the local anaesthetics.


Effect of diazepam on emergence from ketamine anaesthesia. A double-blind study. The series comprises 109 healthy females aged 14-49 years (mean age 28 years) hospitalized for legal abortion or diagnostic curettage. The patients were premedicated with morphine-scopolamine 0.4-0.7 ml i.m. (morphine 20 mg/ml, scopolamine 0.6 mg/ml) and atropine 0.01 mg/kg i.v. Ketamine 1.5 mg/kg was administered i.v. and immediately thereafter 2 ml of a coded solution i.v. consisting either of diazepam 10 mg or its solvent only. Supplementary doses of ketamine 0.2-0.4 mg/kg were administered when needed. Diazepam reduced the incidence of unpleasant dreams and experiences to a significant degree (p less than 0.01) according to the postanaesthetic interviews of the patients. Nausea occurred in the diazepam group in 2 per cent and in the placebo group in 17 per cent (p less than 0.01). In respect to the differences in opinion presented in literature the authors consider the time of administration of diazepam at induction to be of decisive importance and find prophylactic prevention of dreams justified as it cannot be predicted which of the patients will have unpleasant or even terrifying dreams. Dreams and/or experiences or their memories must be prevented at the stage at which the effect of ketamine commences. The authors do not, however, recommend ketamine anaesthesia for young adults, even when supplemented with diazepam. On the other hand, the authors consider the positive observations made during the study to be applicable to all other ketamine anaesthesias.


[Interactions between nitrous oxide and central depressants]. The combined effects on mice of N2O and various central depressants were investigated. A loss of the righting reflex was taken as the criterion for the drug effects. Essential differences could be demonstrated in the type of interaction: diazepam, flunitrazepam, and medazepam have a supra-additive effect in combination with N2O; the solvent of diazepam and an experimental product, Ro 21-3981 (8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4]-benzodiazepine maleate) a simply additive one. However, the interactions between N2O and barbiturates (pentobarbitone and phenobarbitone), and N2O and ethanol were found to be infra-additive. The results of this and previous investigations indicate that additive or supra-additive interactions can only be expected in those cases in which at most one of the two active ingredients in addition to its depressive effect also exhibits an excitatory component.


Oral oxazepam as a premedicant in minor surgery. The clinical effects of oral oxazepam and placebo as premedicants were tested in a double-blind study in 40 gynaecological patients. The gas chromatographically measured concentrations of the active, unconjugated forms of oxazepam in the plasma were correlated with the clinical effects of oxazepam, assessed both subjectively and objectively. The insertion of an intravenous cannula was significantly more difficult (p less than 0.001) in the placebo premedicated group. However, there was no significant difference between the two groups in the cutaneous temperature of the left forefinger. Of the eleven parameters tested there was a significant difference between the oxazepam and placebo group in the quality of sleep on the night before operation (p less than 0.05) and in the degree of preoperative sedation (p less than 0.01). The combined results of the eleven parameters of the oxazepam group also differed positively significantly from the placebo group (p less than 0.01). There was no obvious relationship between the plasma concentration and clinical effect of oxazepam.


[Determination of intrapulmonary shunt in acute lung failure and during therapy by means of extracorporeal oxygenation (author's transl)]. The reasons for the especial importance of acute lung failure within the framework of intensive medicine are elaborated. In most cases acute lung failure can be successfully treated by timely ventilation and support for the heart-function. If conventional therapy fails, extracorporeal long-term oxygenation by means of a membrane oxygenator can be a successful technique, provided that a very critical indication is available. The magnitude of the intrapulmonary right-left shunt S is an important parameter for the assessment of the extent of acute lung failure and its prognosis, and also in the establishment of the indication for the use of extracorporeal oxygenation and the therapeutic process. The derivation of simple extended shunt equations for any form of extracorporeal oxygenation is possible on the basis of measurements of blood-flow and oxygen transport. This represents an important contribution to the mathematical description of a therapeutic technique.


Testosterone and UVL-B stimulation of epidermal melanocytes in rat scrotal skin. The effects of UVL-B and/or testosterone replacemnt therapy are compared in normal and castrated rats in order to determine whether testosterone is required for UVL-B (290-315 nm) stimulation of melanogenesis in the testosterone-dependent epidermal melanocyte system of the scrotal skin of black Long Evans rats. Testosterone is not a prerequisite for UVL-B stimulation of melanocytes as in both castrates and normal animals the melanocytes respond to UVL-B by increases in size, length and number of dendrites (dendriticness), and tyrosinase activity (intensity of Dopa reaction). Addition of testosterone to castrates does enhance the effects of UVL-B. However, UVL-B with or without testosterone cannot maintain normal melanogenesis in rats irradiated immediately after castration nor can it restore normal melanogenesis following long term castration. Bth the amount of UVL nergy/exposure and the number of exposures are important variables in stimulation of the epidermal melanocytes. Administration of a dose of UVL-B to castrates in a single exposure is ineffective, while the same overall dose spread over several exposures increases the size and dendriticness of melanocytes. Testosterone and UVL-B act synergistically in affecting melanogenesis although neither singly nor in combination are they able to fully restore normal melanogenesis.


Pharmacokinetics of 3H-fentanyl in the dog anesthetized with enflurane. Fentanyl is often used as an anesthetic supplement for short procedures because it has a rapid onset and brief duration of action. However, persistence of ventilatory depression several hours following the last dose has been seen. The authors studied the pharmacokinetics of fentanyl in the dog to find an explanation for the occasionally prolonged duration of action. 3H-fentanyl citrate, 10 or 100 microgram/kg, was injected intravenously in dogs anesthetized with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl and for total 3H radioactivity. Kinetic indices were derived by nonlinear least-squares analysis of log concentration (ng/ml) vs. time relationships. Initially, the elimination of fentanyl from plasma was very rapid, and 98 per cent of the amount administered was removed from plasma in the first 5 min after an intravenous injection. However, the terminal elimination phase was prolonged (t1/2 = 199 +/- 17 min). The apparent volume of distribution was large (9.81/kg) and independent of dose. Repetitive doses produced an accumulation of fentanyl. 3H-labelled metabolites of fentanyl were present in the earliest samples of plasma, and accounted for the major portion of the total 3H radioactivity in both plasma and urine. Urine collected for six hours contained 36 per cent of the total 3H radioactivity administered, but only 4 per cent of fentanyl administered was excreted as unchanged fentanyl. The authors conclude that most of a single dose of fentanyl is rapidly eliminated from the body by biotransformation and leads to accumulation of the drug when administered in very large or repeated doses. Under these circumstances the slow release of drug from tissues results in persistent plasma levels of fentanyl and a prolonged duration of action.


Volatile metabolites and decomposition products of halothane in man. The presence of two volatile halothane metabolites, 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl) and 2-chloro-1,1-difluoroethylene (CF2CHCl), and a metabolite-decomposition product, 2-bromo-2-chloro-1,1-difluoroethylene (CF2CBrCl), were identified by gas chromatography-mass spectrometry in exhaled gases of 16 patients anesthetized with halothane in nonrebreathing, semiclosed and totally closed anesthesia circuits. No significant differences in concentrations of CF3CH2Cl and CF2CHCl were found relative to the anesthesia circuits used. CF2CBrCl could not be identified in the expired gases of patients anesthetized with a nonrebreathing circuit (Bain), but was present in gases recovered from both semiclosed and totally closed circuits. Under totally closed-circuit rebreathing conditions, the concentration of CF2CBrCl increased to 4-5 ppm, indicating significant breakdown of halothane by the soda lime. Possible pathways for formation of the two metabolites and the metabolite-decomposition product are presented, as well as clinical implications of these findings.


Towards an understanding of chronic pain mechanisms: the use of psychologic tests and a refined differential spinal block. Forty patients with chronic pain below the waist level were evaluated in a multidisciplinary pain clinic using a refined differential spinal block (DSB) technique. The refinements consisted of verbal instructions to prevent biasing the patients, coupled with a thorough evaluation of verbal and physiologic responses to the block. When demographic and psychologic data were assessed according to pain mechanisms, a pattern of patient groups emerged along a chronic pain continuum. Stress, anxiety, depression, and hysteria, as well as the neurophysiologic and demographic factors, modified the responses to the block. Long-term follow-up of these patients, including repeat DSB procedures and confirmatory anatomic blocks of sympathetic and somatic nerves, validated these impressions. The findings indicate a link between pain mechanisms and psychosocial factors that may directly influence responses to DSB.


Mucociliary clearance in the canine lung during and after general anesthesia. Central and peripheral pulmonary mucociliary clearance was assessed by tantalum bronchography and serial chest roentgenograms in dogs. Thiopental, 25 mg/kg, did not change clearance from awake values. Halothane 1.2 MAC, for six hours, delayed both central and peripheral clearance by at least three hours. After halothane or diethyl ether, 1.2 MAC, for two hours, recovery of mucociliary clearance was delayed for approximately three and a half hours


Cerebral energy levels during trimethaphan-induced hypotension in the rat: effects of light versus deep halothane anesthesia. Hypotension may be expected to produce less perturbation of metabolism in the brain when cerebral metabolic rate is lowered by deep anesthesia. Male Wistar rats having unilateral carotidartery ligation were exposed to mean arterial pressure (MAP) of 40 torr for 22 min by an intravenous infusion of trimethaphan during anesthesia with halothane, 0.6 or 2 per cent, in oxygen. Cortical tissue metabolite levels on the side of the ligated carotid artery were more abnormal in rats receiving halothane, 0.6 per cent, than in those receiving halothane, 2 per cent. Values at halothane, 0.6 per cent, were adenosine triphosphate (ATP), 1.71 +/- 0.05 (+/-SEM) mumol/g, phosphocreatine (PCr) 1.97 +/- 0.07 mumol/g. and lactate 16.5 +/- 5.1 mumol/g; corresponding values at halothane, 2 per cent, were ATP 2.27 +/- 0.02, PCr 4.02 +/- 0.23, and lactate 4.75 +/- 0.9 mumol/g. ATP and PCr values were significiantly lower (P less than 0.05) and the lactate value was significantly higher with halothane, 0.6 per cent, than with halothane 2 per cent. Cerebral oxygen consumption decreased 47 per cent in rats anesthetized with halothane, 2 per cent. Preservation of cortical metabolite levels in deeply anesthetized animals suggests a protective effect of cerebral metabolic depression.


Halothane mimics oxygen in oxygen microelectrodes. The effects of halothane and enflurane on the polarographic measurement of oxygen with five platinum and three gold microelectrodes were examined. Oxygen microelectrodes were calibrated in saline solution equilibrated with either nitrogen (N2) or air, then either halothane, 1.0 per cent, or enflurane, 2.0 per cent, was added to the gas mixture. For each electrode, polarographic curves were determined during exposure to five equilibrating gas mixtures: N2, air, N2 plus halothane, air plus halothane, and N2 plus enflurane. Halothane variably increased the current produced (and therefore the estimated oxygen tension) at all polarizing voltages in saline solution equilibrated with either N2 or air. The effect was present in both conical platinum electrodes and recessed-tip gold electrodes and was not prevented by membrane coatings of polystyrol, Rhoplex or collodion. Enflurane did not alter the polarographic measurement of oxygen. It is concluded that tissue oxygen tension measurements, made with these microelectrodes and membranes, may be unreliable in the presence of halothane.


Chrysosporium species as fungal air pollutants. Air filters utilized in monitoring industrial air pollutants were analyzed for the presence of airborne fungi. The genera of fungi isolated were essentially those isolated in other areas of the United States; however, Chrysosporium species, unreported in previous airborne surveys, were found in significant numbers. Thirty-six genera of fungi were recovered over a one-year period. Aspergillus and Chrysosporium were isolated most frequently from the filter samples examined.


Arterial oxygen saturation by non-invasive oximetry technique: an office test for determining jeopardy of status asthmaticus. A newly developed technique in ear oximetry which can be performed in a doctor's office may obviate the need of sending an asthmatic patient to the hospital for arterial gas blood studies and may be a means of ear marking impending status asthmaticus and respiratory failure.


Food allergy in children with hyperactivity, learning disabilities and/or minimal brain dysfunction. Ninety hyperactive children, 22 children with learning disability and eight emotional-inattentive children were tested for allergy to 43 food extracts using the in vitro radioallergosorbent test (RAST). Fifty-two percent of all children exhibited allergy to one or more of the foods tested. Within the hyperactive group a statistically significant association was found between the number of allergies and teachers' (Conners) scores of hyperactivity. This association was statistically significant only in those hyperactive children who also had learning disability and minimal brain dysfunction. A statistically weak association was also found between a small number of children clinically diagnosable as hyperactive and the number of allergies or total allergy scores. A causal relationship between food allergy and a small subgroup of children with a primary diagnosis of hyperactivity is suspected.


Peripheral airways obstruction in patients with rhinitis. Nine young lifetime nonsmoking patients with symptoms of rhinitis but without any history of asthma or wheezing and nine age-matched healthy lifetime nonsmoking control subjects were studied with respect to subdivisions of lung volume, forced vital capacity, forced expiratory volume (1.0 sec), and flow-volume curves breathing air, and also breathing a mixture of 80% helium--20% oxygen (He-O2) from which were obtained airflows at 50% VC (Vmax50), the percentage increase in Vmax50 breathing He-O2 as compared to air (deltaVmax50) and the point where He-O2 and airflow-volume curves became identical (Visov). No significant differences between the two groups in age, subdivisions of lung volume or forced expiratory airflow rates were recorded. However, deltaVmax50 was significantly lower in the patients (16.4 +/- 12.0) compared to the controls (47.7 +/- 16.4) (p less than .001) and Visov was higher in the patients (28.4 +/- 14.9) as compared to the controls (14.4 +/- 7.6) (p less than .01). After bronchodilator therapy Vmax50 increased in the control subjects (p less than .005) but not in the patients and deltaVmax 50 decreased in the control group but was unchanged in the rhinitis patients. These results suggest that patients with rhinitis who have normal airflow rates may have peripheral airways obstruction not readily reversible with bronchodilators.


Bronchial asthma and pathological processes in the nasopharynx. I. Clinical analysis during remission and attack. In 54 patients with bronchial asthma and a control group of 15 subjects laryngological, bacteriological and cytological examinations of the nasopharynx were performed. This region was found to be inflamed in 38% of the patients with asthma; in a group of asthmatic patients hypersensitive to aspirin, the percentage rose to 87%. In the asthmatic patients, as compared with the control group, there was a diminished neutrophilic exudate, a marked epithelial desquamation reaction and an abundant lymphocyticosinophilic exudate in a considerable percentage of cases.


New allergenic pollens of Delhi State, India, and their clinical significance. Antigenic extracts of 26 new pollen types were assessed on 175 patients with respiratory allergy for their allergenicity, using the intradermal test. A total of 4,550 intradermal tests were performed in addition to 1,040 skin tests performed on 40 non-allergic healthy individuals as a control. Fisher's Extract Probability Test was used to determine the statistical significance of the allergenicity, expressed in percentages of markedly positive skin reactions (2+ and above). Only 13 of the 26 pollen types investigated proved to be statistically significant as possessing allergenicity. The relative sensitivity of different diagnostic tests was also assessed. Markedly positive reactions evaluated by Passive Transfer (P-K), conjunctival and bronchial challenge tests were found to be equally significant. The P-K and bronchial challenge tests gave significant correlation with markedly positive intradermal tests.


Two pediatric allergists' sojourn in the People's Republic of China. One cannot visit modern day mainland China without being impressed with the apparent vastness of the population which seems ever on the move. While manifestations of allergic disease among Chinese children resemble those seen in western countries, some factors peculiar to China, such as life style, diet, housing and absence of household pets, influence age of onset and geographic distribution of some allergic syndromes in Chinese children.


Production of antibody against T-2 toxin. Antibody against T-2 toxin was obtained after immunization of rabbits with bovine serum albumin-T-2 hemisuccinate conjugate. The antibody had greatest binding efficiency for T-2 toxin, less efficiency for HT-2, and least for T-2 triol. Cross-reaction of antibody with neosolaniol, T-2 tetraol, and 8-acetyl-neosolaniol was very weak. Diacetoxyscirpenol, trichodermin, vomitoxin, and verrucarin A essentially gave no cross-reaction with the antibody. The sensitivity of the binding assay for T-2 toxin detection was in the range of 1 to 20 ng per assay. Detailed methods for the preparation of the conjugate and the production of immune serum and methods for antibody determination are described.


Moniliformin, a metabolite of Fusarium moniliforme NRRL 6322: purification and toxicity. Fusarium moniliforme NRRL 6322 produced about 600 mg of recoverable moniliformin, a mycotoxic metabolite, per kg of corn grit medium. The moniliformin was extracted from the grits with methanol, purified by preparative thin-layer chromatography, and crystallized from ether. The 50% lethal dose for chicken embryos was 2.8 microgram per egg. For 1-day-old chicks dosed with moniliformin by crop intubation and for female and male mice injected intraperitoneally, the 50% lethal doses were 5.4, 20.9, and 29.1 mg per kg of body weight, respectively. The toxin did not cause a reaction on mouse skin.


Decreased glycogen mobilization during ochratoxicosis in broiler chickens. Graded doses of pure ochratoxin A (0, 0.5, 1.0, 2.0, 4.0, and 8.0 microgram of toxin per g of feed) were incorporated into a commercial diet which was fed to chickens from hatching to 3 weeks of age, at which time the experiments were terminated. Liver glycogen levels were elevated significantly (P less than 0.05) by 4.0 and 8.0 microgram/g but not lower doses. Glucagon stimulation of glycogen mobilization was inhibited at the same concentrations. Histopathological examination revealed cytoplasmic but not nuclear deposits of glycogen in cells at the periphery of liver lobes. These data demonstrated that ochratoxin inhibited glycogenolysis. Impaired ability to generate glucose from glycogen could account for the increased susceptibility to cold stress previously reported to occur in ochratoxicosis. Based on present and prior observations, it seems possible that ochratoxin induces a syndrome which mimics the glycogen storage disease of type X which is caused by a deficiency in the cyclic AMP-dependent enzyme of the glycogenolytic enzymatic cascade.


Low-intensity microwave radiation and the virulence of Agrobacterium tumefaciens strain B6. When virulent cells of Agrobacterium tumefaciens strain B6 were exposed to low-level microwave radiation at a frequency of 10,000 MHz and an intensity of 0.58 mW/cm2 for 30 to 120 min, a 30 to 60% decrease in their ability to produce tumors on potato and turnip disks was observed. This microwave exposure did not affect the viability of these bacteria or their ability to attach to a tumor-binding site nor did it induce thermal shock. This loss of virulence was reversible within 12 h.


Isolation and characterization of large treponemes from the bovine rumen. Ten strains of strictly anaerobic spiral organisms were isolated in pure culture from a 10(-7) dilution of bovine rumen contents. Three strains were studied in detail. These strains morphologically resembled previously isolated and described rumen treponemes except the new isolates were larger, 0.7 micrometer wide and 12 to 25 micrometer long. They rapidly fermented pectin and, less readily, L-arabinose, inulin, and sucrose. Acetic and formic acid were the main fermentation products from pectin; small amounts of succinic acid were also formed.


Patterns of cell division, DNA base compositions, and fine structures of some radiation-resistant vegetative bacteria found in food. Representative highly radiation-resistant Moraxella-Acinetobacter (M-A), Pseudomonas radiora, Micrococcus radiodurans, and Micrococcus radiophilus exhibited a wide variety of division systems and cell wall characteristics. However, the most resistant M-A possessed unusually thick cell walls, indicating a possible role of the cell wall in radiation resistance in the M-A. Thick septation was present in most of the bacteria studied, but was absent in P. radiora, thus excluding this as a necessity for high resistance. Reliable determination of the number of division planes of the M-A for use as a taxonomic criterion was achieved by the direct observation of dividing cells. The highly resistant M-A were found to divide in multiple planes and had base compositions of 54.0 to 57.5%, unlike typical Moraxella and/or Acinetobacter species. The taxonomic position of most highly resistant bacteria remains unclear.


Effect of two organophosphorus insecticides on the phosphate-dissolving soil bacteria. Dimethoate and malathion added to soil at 10 and 100 microgram/g caused an initial stimulation of CO2 production. Total counts of bacterial propagules were increased. All insecticide applications increased bacteria producing  phospholipases from week 1 until week 4 after the application; bacteria then returned to the original levels.


Tremorgenic toxins produced by soil fungi. Penitrem A or an unknown tremorgenic toxin, "X," was produced by 10 of 60 fungal isolates obtained from a pasture involved in an outbreak in cattle and sheep resembling migram and ryegrass staggers. Tremorgenic properties of extracts containing penitrem A or toxin X were confirmed by bioassay.


Selective antibacterial action of 2-mercaptoethanol on propionibacteria in skin cultures. 2-Mercaptoethanol applied to the surface of agar medium had a selective antibacterial effect on Propionibacterium acnes and Propionibacterium granulosum without interfering with the growth of Peptococcus saccharolyticus or staphylococci in anaerobic cultures of skin or in pure cultures. In aerobic broth culture, 2-mercaptoethanol inhibited aerobes and stimulated anaerobes, consistent with its action as a reducing agent.


Membrane filtration of food suspensions. Factors affecting the membrane filtration of food suspensions were studied for 58 foods and 13 membrane filters. Lot number within a brand, pore size (0.45 or 0.8 micrometer), and time elapsed before filtration had little effect on filterability. Brand of membrane filter, flow direction, pressure differential, age (microbiological quality) of the food, duration of the blending process, temperature, and concentration of food in the suspension had significant and often predictable effects. Preparation of suspensions by Stomacher (relative to rotary blender) addition of surfactant (particularly at elevated temperature) and prior incubation with proteases sometimes had dramatic effects of filterability. In contrast to popular opinion, foods can be membrane filtered in quantities pertinent to the maximums used in conventional plating procedures. Removal of growth inhibitors and food debris is possible by using membrane filters. Lowering of the limits of detection of microorganisms by concentration on membrane filters can be considered feasible for many foods. The data are particularly relevant to the use of hydrophobic grid-membrane filters (which are capable of enumerating up to 9 X 10(4) organisms per filter) in instrumented methods of food microbiological analysis.


Accelerated mineralization of two organophosphate insecticides in the rhizosphere. Numerous xenobiotic compounds, including the organophosphate insecticides O, O-diethyl-O-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate (diazinon) and O, O-diethyl-O-p-nitrophenyl phosphorothioate (parathion), appear to be degraded in the soil environment by an initial cometabolic attack. Comparing the mineralization rates of radiolabeled diazinon and parathion in root-free and in rhizosphere soil, we tested our hypothesis that, because of the presence of root exudates, the rhizosphere is an especially favorable environment for such co-metabolic transformations. The insecticides were added individually at 5 mug/g to sealed flasks containing either soil permeated by the root system of a bush bean plant or identical soil without roots. Periodically, the flask atmospheres were flushed through traps and the evolved (14)CO(2) was quantitated. Bush bean plant roots without associated rhizosphere microorganisms failed to produce a significant amount of (14)CO(2). During 1 month of incubation, rhizosphere flasks mineralized 12.9 and 17.9% of the added diazinon and parathion radiocarbon, respectively, compared to 5.0 and 7.8% by the soil without roots. The mineralization of parathion but not of diazinon was stimulated in a similar manner when soil without roots was repeatedly irrigated with a root exudate produced in aseptic solution culture. Viable counts of microorganisms on soil extract agar were not significantly altered by root permeation or by root exudate treatment of the soil, leaving population selection and/or enhanced cometabolic activity as the most plausible interpretations for the observed stimulatory effects. Rhizosphere interactions may substantially shorten the predicted half-lives of some xenobiotic compounds in soil.


Production of surface-active lipids by Corynebacterium lepus. Corynebacterium lepus was grown in 20-liter batch fermentations with kerosene as the sole carbon source. Critical micelle concentration measurements indicated the production of appreciable quantities of biosurfactants. This surface activity of the culture medium was due to lipids, which were extracted and identified. Samples of C. lepus whole broth were taken during a fermentation and monitored for surface tension, amount of surfactant present, and lipid content. The changes in the surfactant measured correlated with concentration changes of several surface-active lipids. An early dramatic increase in surfactant concentration was attributed to the production of a mixture of corynomycolic acids (beta-hydroxy alpha-branched fatty acids). Surface activity at the end of the fermentation was due to a lipopeptide containing corynomycolic acids plus small amounts of several phospholipids and neutral lipids which were identified by thin-layer chromatography.


Preferential binding of radiolabeled zearalenone to a protein fraction of Fusarium roseum graminearum. Zearalenone [6-(10-hydroxy-6-oxo-trans-1-undecenyl)beta-resorcyclic acid lactone] is a hormone produced by Fusarium spp. which regulates the sexual stage in F. roseum. 3H- and 14C-labeled zearalenone were found to bind preferentially to one of two peaks containing uncharacterized proteins obtained from the cytosol of young mycelium and resolved by gel column chromatography. The proteins were partially purified by successive resolution on Sephadex G-100, Sephadex G-200, and BioGel P-300. Free zearalenone (37%) was reisolated from the purified proteins after resolution by thin-layer chromatography or partitioning with ethyl acetate.


Cutaneous histologic features in Ehlers-Danlos syndrome: study of 21 patients. Skin biopsy specimens from 21 patients with Ehlers-Danlos syndrome (EDS) were compared with controls. With two exceptions, the appearance of the dermal collagen and elastic tissue as seen in the two groups was indistinguishable. One example of type 4 EDS contained a dermis composed of fibers that resembled actinically damaged elastic tissue. The single example of type 6 EDS contained particularly thin collagen fibers. The dermal thickness of specimens of EDS was similar to that of controls, although the abnormal-appearing specimen of type 4 EDS was also abnormally thin. Since the other two biopsy specimens of type 4 appeared to be within the range of normal, there may be heterogeneity in this form of EDS.


Relapsing polychondritis: unusual neurological findings and therapeutic efficacy of dapsone. Relapsing polychondritis is a rare disease of undetermined cause. The most frequently seen symptom is redness and swelling of the cartilaginous ear, followed by cartilage inflammation elsewhere in the body. Our five cases had neurologic symptoms that posed diagnostic difficulties. Because vasculitis is not uncommon in relapsing polychondritis, it was difficult to determine whether these neurologic symptoms were attributable to relapsing polychondritis or to other unrelated causes. In our cases, specific neurologic complaints were caused by a concomitant but unrelated disease, rather than by relapsing polychondritis. We add five additional documented cases to the medical literature and confirm the therapeutic efficacy of dapsone in the treatment of this unusual disease.


Photochemotherapy for mycosis fungoides: a clinical and histological study. Nine patients with stages 2 or 3 mycosis fungoides (MF) and one with Sézary's syndrome were treated with oral methoxsalen and long-wave ultraviolet light. Previous therapy had either failed or achieved only partial control. Satisfactory clinical control was achieved in all but one case. Histological improvement was seen in all cases, but complete clearance of lymphoid infiltrate was noted mainly in epidermal and papillary dermal infiltrates. Lower dermal infiltrate remained largely unchanged. The case of Sézary's syndrome was inadequately controlled with systemic prednisone and cyclophosphamide, but addition of photochemotherapy improved the erythema and pruritus. This shows that photochemotherapy may have a place in MF treatment both alone and perhaps in conjunction with other treatments. An early relapse occurred on stopping photochemotherapy in four cases, but one patient has had three months' full remission.


Systemic lupus erythematosus: association with psoralen--ultraviolet-A treatment of psoriasis. Systemic lupus erythematosus (SLE) developed in as 23-year-old woman with psoriasis during treatment with psoralen-ultraviolet-A (PUVA). The connective tissue disease was characterized by an erythematous rash, hair loss, nephritis, splenomegaly, seizures, and coma. Serum antinuclear antibodies were present in high titer, and hypocomplementemia developed. Antibodies to native or ultraviolet-irradiated DNA were not demonstrated. While the association of psoriasis and lupus may have been fortuitous, the temporal relationships suggest that PUVA treatment in this case may have been of pathogenetic importance in the development of the connective tissue disease.


Hereditary C2 deficiency associated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies. Selective congenital deficiency in the second component of complement has been described in association with lupus erythematosus (LE) and other connective tissue disorders. We identified a 59-year-old woman with a 13-year history of cutaneous LE and no detectable serum C2. The patient's photosensitivity, large polycyclic erosive cutaneous lesions, lack of renal disease, paucity of serological findings, and high incidence of bacterial infection is consistent with previously described patients with this association. Uniquely, the patient demonstrated secondary infection with Staphylococcus aureus and Trichophyton rubrum in the skin lesions themselves. Immunologic studies disclosed depression in both humoral and cellular immunity. Moderation in her clinical disease and immunologic measurements has been observed after treatment with levamisole hydrochloride. Immunogenetic studies of the patient's four-generation kindred was consistent with an autosomal recessive inheritance of C2 deficiency genetically linked to HLA, segregating with the B18 allele. Mixed lymphocyte culture determinations reinforce evidence for linkage between the HLA-D locus and the trait for C2 deficiency.


Prolidase deficiency: its dermatological manifestations and some additional biochemical studies. Prolidase deficiency occurred in a 13-year-old girl. Determinations were made of prolidase and prolinase activities in cultured fibroblasts, and thin layer chromatographic studies of skin prolidase were performed. The patient had chronic, recurrent ulcers on the legs and feet, diffuse telangiectasia, shallow scar-like atrophic lesions on the face and arms, soft and thin abdominal skin, and premature gray hairs. Prolidase in the patient's skin fibroblasts was absent. Greatly reduced prolidase activity was demonstrated in the patient's skin. A review of hitherto reported cases of this disease showed such skin manifestations as (1) skin ulceration or skin fragility with scar formation, (2) purpuric lesions, (3) telangiectasia and/or photosensitivity, and (4) thickening of the skin with lymphedema.


Systemic lupus erythematosus and dermatitis herpetiformis: concurrence with Marfan's syndrome. There is increasing evidence that, as in systemic lupus erythematosus (SLE), deposition of immune complexes plays a role in the pathogenesis of dermatitis herpetiformis (DH). Dermatitis herpetiformis and SLE were diagnosed in a 15-year-old girl with Marfan's syndrome who died of cardiac tamponade secondary to cystic medial necrosis of the ascending aorta. The concurrence of these diseases suggests that predisposition to immune-mediated disorders may be associated with the expression of multiple clinical entities.


Kawasaki's disease appearing as erythema multiforme. In 1967, Kawasaki reported an acute, febrile, mucocutaneous condition accompanied by swelling of cervical lymph nodes that affected infants and young children in Japan. He called it mucocutaneous lymph node syndrome. We report here a case of Kawasaki's disease with characteristic findings that demonstrated a typical erythema multiforme rash. With the increased number of reported cases of Kawasaki's disease in the United States, it becomes increasingly important to differentiate the exanthem of Kawasaki's disease from early erythema multiforme.


Laser surgery for blue rubber bleb nevus. A 21-year-old man has had extensive cutaneous and visceral manifestations of the blue rubber bleb nevus syndrome since birth. Surgical therapy with the carbon dioxide laser was successful in removing 225 skin hemangiomas without recurrences or complications such as hemorrhage and infection. The cosmetic and follow-up results have been excellent.


Cutaneous metastatic carcinoma and elephantiasis symptomatica. An elderly man had elephantiasis of a lower extremity that was partially covered with verrucose papules, but also had sharply delineated islands of normal-appearing skin. Biopsy showed cutaneous metastases to be responsible, at least in part, for the clinical appearance. Patients with elephantiasis with "skipped areas" should be suspected of having cutaneous metastatic malignant neoplasms.


Localized eosinophilic fasciitis.

Localized eosinophilic fasciitis. Two patients developed an erythematous, rock-hard induration of their forearms after strenuous physical activity. Peripheral eosinophilia was noted in one patient, but hypergammaglobulinemia was absent. Systemic corticosteroid treatment resulted in remarkable involution of the process in one patient, while the other experienced spontaneous involution. The histologic changes were those of eosinophilic fasciitis.


Intractable hypoglycemia in a patient with renal failure. A patient with chronic renal failure developed intractable hypoglycemia after 2 1/2 years of dialysis. Metabolic studies did not suggest that malnutrition, substrate limitation, hormone deficiency, or insulin excess were responsible for the low blood glucose level. Impaired gluconeogenesis may have been an important factor, but studies in this patient suggest that enhanced glucose utilization may also play a role in the pathogenesis of hypoglycemia in renal failure.


Hypothermia, a grave prognostic sign in hepatic coma. Hypothermia is a grave prognostic finding in hepatic coma. Occasionally, it is found in patients whose conditions are stabilized clinically or are improving. When hypothermia occurs, the patients usually die within 24 to 48 hours. All of the patients described herein who eventually improved sufficiently to be discharged from the hospital achieved normal temperatures.


Mucocutaneous lymph node syndrome in a young adult. Mucocutaneous lymph node syndrome (MLNS) is an acute febrile illness of unknown cause first described in Japan but more recently reported in the United States. The mean age in confirmed cases was 3.8 years (range, 3 months to 13 years), and the mortality is 1% to 2% when associated with coronary artery thrombosis and aneurysm. We describe the first case of MLNS in a young adult, with the additional clinical finding of associated arthritis.


Dissecting aortic aneurysm manifesting as acute pericarditis. Two patients with coarctation of the aorta initially had acute idiopathic pericarditis with anterior pleuritic chest pain as the chief complaint. A pericardial friction rub was present in both patients. Both patients died suddenly. At autopsy, they were found to have a dissecting aneurysm of the ascending aorta with extension into the pericardial space; acute pericardial tamponade was the cause of death. We recommend that when a patient with coarctation of the aorta is admitted with pericarditis, aortic dissection should be considered and appropriate diagnostic procedures undertaken. In all young patients with acute pericarditis there should be careful palpation of the femoral pulses and review of the chest x-ray film for rib notching.


Cysticercotic cyst involving the pleura. An unusual case of an abnormal chest roentgenogram. We describe a case of human cysticercosis appearing as an abnormal chest roentgenogram. The patient had a long history of ingestion of undercooked pork. The diagnosis was entertained only after surgical resection, but the history obtained from this patient gave an important clue toward a parasitic infestation.


Atrial myxoma with multiple myeloma.

Atrial myxoma with multiple myeloma. A male patient was observed for seven years, from the onset of neurologic symptoms to removal of a left atrial myxoma. Mild broad-based elevation of the serum gamma-globulin level with a normal bone marrow aspirate was seen early in the course of disease. The broad-based gamma-globulin level increased, and at the time of surgical removal of the tumor, the patient was found to have a monoclonal increase of K light chain IgG with 60% infiltration of the bone with immature plasma  cells. The findings are consistent with the view that continuous immunologic stimulation by products of the atrial tumor resulted in malignant transformation of immunocytes with resulting IgG multiple myeloma.


Isolated high serum triiodothyronine levels. Clinical relevance after sodium iodide I 131 therapy. Ten of 25 thyrotoxic patients treated with sodium iodine I 131 had thyroid function test results that indicated a high triiodothyronine (T3) level, with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) levels, within 15 months of treatment. This pattern was usually transitional and lasted a variable time, eventually leading to euthyroidism, hyperthyroidism, or hypothyroidism. It is concluded that an isolated elevation of T3 levels after radioactive iodine therapy can be associated with any clinical pattern of thyroid function and has no clear prognostic value. No specific treatment is needed for this abnormality.


Baker's cysts and true thrombophlebitis. Report of two cases and review of the literature. We describe two patients who had knee pain and were found to have the unusual combination of a Baker's cyst and true thrombophlebitis. Since Baker's cysts can dissect along the gastrocnemius, they can cause leg pain and simulate thrombophlebitis, but they do not require anticoagulation therapy. Most of the literature implies that the two syndromes are mutually exclusive; however, our cases lend support to the fact that a dissecting popliteal cyst does not rule out the possibility of thrombophlebitis. Venography should be performed if there is any doubt as to the diagnosis.


Macrocytosis, mild anemia, and delay in the diagnosis of pernicious anemia. Various factors led to delays of several months to several years in the diagnosis of pernicious anemia in 11 patients, occasionally with serious consequences. These cases illustrate that earlier diagnosis is possible with closer attention to abnormal results of common tests. Macrocytosis, detected by high mean corpuscular volume, often preceded anemia but was not investigated, especially when anemia was only slight. Several cases demonstrated that vitamin B12 deficiency may initially produce only a mild macrocytic anemia, which is maintained for a long period before a rapid worsening supervenes; the reason for the latter acceleration of anemia is unknown. Most serious was the evidence that mild anemias are often ignored. Stricter attention to the established limits of normal hemoglobin values is required. These aspects of physician performance have implication for the recognition of all anemias.


Detection and treatment of occupational lead nephropathy. Reduced glomerular filtration rates (GFR less than 90 ml/min/1.73 sq m) were found in 21 of 57 lead workers in whom excessive body lead burdens had been shown by the urinary excretion of more than 1,000 microgram of lead per day during an edetate disodium calcium lead-mobilization test. In 12 patients, renal biopsies confirmed the diagnosis of occupational lead nephropathy and further excluded other possible causes of kidney disease. Glomerular and tubular immunoglobulin deposition in seven of eight biopsy specimens examined by immunofluorescent microscopy raises the possibility that an autoimmune response may contribute to the interstitial nephritis of occupational lead nephropathy. The GFR increased 20% or more in four of eight patients treated with 1 g of edetate disodium calcium three times weekly for from six to 50 months, further confirming the diagnosis of lead nephropathy and indicating a favorable response to prolonged chelation therapy.


Diagnostic accuracy of gray scale ultrasongraphy for the jaundiced patient. A report of 275 cases. This study of cholestatic jaundice suggests that gray scale ultrasonography should precede invasive techniques or surgery. The failure of ultrasound to demonstrate dilated ducts suggests intrahepatic cholestasis. Display of liver parenchyma by ultrasound provided the correct diagnosis of diffuse liver disease in 61% of the cases. Observation of a dilated biliary tree allowed differentiation between intrahepatic and extrahepatic obstruction, with an accuracy of 96.4%. One false positive (0.7%) occurred, and most false negatives were due to gallstones producing intermittent obstruction owing to a ball-valve effect. Observations of normal biliary canaliculi suggest that physiological distention of intrahepatic biliary vessels does not occur. Long-standing obstruction of biliary tree may result in permanent distention despite surgical relief, predisposing the patient to recurrent ascending cholangitis. This stresses the need for early diagnosis and prompt relief of extrahepatic biliary obstruction.


Pleural fluid lysozyme in human disease. Lysozyme content was measured in the plasma and pleural fluid of 110 patients with pleural effusions of various causes. The concentration of pleural fluid lysozyme was significantly higher (P less than .001) in patients with tuberculous pleurisy than in those with primary pulmonary carcinoma, metastatic carcinoma of the lung, connective tissue disease, nonspecific pleurisy, or congestive heart failure. Tuberculous patients also had a significantly higher (P less than .001) pleural fluid-to-plasma lysozyme ratio than did the other patients. Plasma lysozyme activity did not differ significantly among the various patient groups. Lysozyme was identified immunohistochemically in epithelioid cell granulomas in tuberculosis, in activated macrophages in lymph nodes adjacent to tuberculous lesions, and in granulocytes in pleural empyema. No lysozyme was detected in neoplastic cells in pulmonary carcinoma. The results show that the determination of pleural fluid lysozyme is a simple, fast method for obtaining corroborative information in the differential diagnosis of tuberculous pleurisy.


Staphylococcus aureus bacteriuria.

Staphylococcus aureus bacteriuria. One hundred twenty-seven episodes of Staphylococcus aureus bacteriuria were reviewed retrospectively in two hospitals to establish the rate of occurrence, clinical importance, and associated predisposing factors. Staphylococcus aureus was an infrequent urinary isolate, and accounted for only about 1% of all positive urine cultures. Although almost all cases in a Veterans Hospital occurred in elderly men, episodes in a community hospital were observed in women and children as well. Patients usually had pyuria (71%) but only 39% had urinary symptoms of fever. Among predisposing factors, serious underlying diseases were uncommon, but urinary tract manipulations or abnormalities were present in nearly two thirds of patients. Fifty-five percent of cases were nosocomial, and 73% of these were associated with urinary catheterization or other invasive urinary tract procedures. Most patients (61%) were not treated for their bacteriuria, and there was a secondary bacteremia rate of 5.5% in the Veterans Hospital. Although infrequently encountered, the presence of S aureus in urine should be treated with at least as much concern as more frequently encountered bacteria.


Plasma norepinephrine response to standing in patients with pheochromocytoma or medullary carcinoma of the thyroid. We determined the effect of a lying/standing test on 22 patients with medullary carcinoma of the thyroid (MCT), seven patients with pheochromocytoma (six of whom also had MCT), six healthy first-degree family members of patients with MCT, and nine normal subjects who did not have a family history of MCT. The purpose of the study was to determine if the patients with MCT had an altered noradrenergic response to standing and to determine if this test would be useful in screening MCT patients for the presence of pheochromocytoma. All of the patients with MCT, as well as all of the healthy family members, had normal urinary excretion of catecholamines and their metabolites. Plasma norepinephrine (NE) concentrations, plasma cortisol levels, and blood pressure (BP) were determined during the lying/standing test. The plasma NE concentration showed the expected increase with a change in posture; the plasma cortisol concentration did not change. There was no significant difference in the plasma NE, plasma cortisol, and BP response in the four study groups. Only one of the seven patients with pheochromocytoma had a hypertensive episode in response to standing. We conclude that there is probably a normal noradrenergic response to standing in patients with MCT, and the standing/lying test, as performed in this study, is of limited value in screening for the presence of pheochromocytoma.


Vasopressin-resistant nephrogenic diabetes insipidus. A result of amphotericin B therapy. Polyuria and polydipsia developed in two cases during amphotericin B therapy for deep mycoses. Neither patient could concentrate his urine in response to water deprivation or exogenous vasopressin. Other causes of vasopressin-resistant nephrogenic diabetes insipidus were not present. Three months after amphotericin B therapy had been discontinued, concentrating ability improved toward normal. A third patient was further observed and demonstrated normal diluting capacity but impaired free-water reabsorption, suggesting a distal tubular defect consistent with nephrogenic diabetes insipidus. Four months after discontinuing therapy, renal concentrating ability was normal. Amphotericin B can induce a reversible form of nephrogenic diabetes insipidus.


Pitfalls in the laboratory diagnosis of atypical hyperthyroidism. When hyperthyroidism results from active thyroidal secretion, both serum hormonal levels and the radioactive iodine uptake (RAI) are elevated. Discordant results (increased serum hormone levels and a low RAI) are found either in the usual forms of hyperthyroidism when large quantities of iodide are ingested, or in atypical forms of hyperthyroidism, including spontaneously resolving hyperthyroidism of subacute thyroiditis, thyrotoxicosis factitia, toxic struma ovarii, and functioning metastatic thyroid cancer. Two patients are described who exemplify pitfalls in the interpretation of thyroid function test results in atypical hyperthyroidism. The following guidelines are helpful in avoiding these pitfalls: (1) An RAI should be performed in all thyrotoxic patients to confirm the presence of thyroidal hypersecretion, rather than atypical hyperthyroidism. (2) A positive response to thyroid-stimulating hormone stimulation is an important finding differentiating the other atypical forms of hyperthyroidism listed from subacute thyroiditis.


Short and long sleep and sleeping pills. Is increased mortality associated? Prospective epidemiologic data of the American Cancer Society disclosed that reported usual sleep durations among groups who complained of insomnia and sleeping pill use "often" overlapped with those of groups who had no complaints. Reports of insomnia were not consistently associated with increased mortality when several factors were controlled; however, men who reported usually sleeping less than four hours were 2.80 times as likely to have died within six years as men who reported 7.0 to 7.9 hours of sleep. The ratio for women was 1.48. Men and women who reported sleeping ten hours or more had about 1.8 times the mortality of those who reported 7.0 to 7.9 hours of sleep. Those who reported using sleeping pills "often" had 1.5 times the mortality of those who "never" used sleeping pills. These results do not prove that mortality could be reduced by altering sleep durations or by reducing hypnotic prescribing. Rather, studies are needed to determine the causes of these mortality risk factors.


Crossing the border into borderline personality and borderline schizophrenia. The development of criteria. Although there is a large psychiatric literature on various "borderline" conditions, there has been no agreement as to the definition of the concept. A review of the literature reviewed two major uses of the term: Borderline Schizophrenia and Borderline Personality. Two item sets were developed to provide diagnostic criteria for the two concepts. High sensitivity and specificity were demonstrated for both item sets using data describing 808 borderline and 808 control patients. These criteria will be used in the forthcoming DSM-III classification for the categories of Borderline Personality Disorder and Schizotypal Personality Disorder.


Prognostic implications of six alternative definitions of schizophrenia. The ability of six different operational definitions of schizophrenia to identify prospectively patients whose eventual prognosis would be poor was studied using data from a six-year follow-up of a series of 134 patients with functional psychoses. All six definitions were more successful at predicting a poor symptomatic outcome than a poor social outcome. Spitzer's Research Diagnostic Criteria, Carpenter's flexible criteria, and Langfeldt's criteria predicted a poor outcome as well as the original clinical diagnoses and were considerably better than the New Haven criteria, Schneider's first rank symptoms, or the computer program Catego.


Unipolar depression: is it divisible into autonomous subtypes? Depression spectrum disease has been defined as an illness in which a first-degree family member has alcoholism and/or antisocial personality. Pure depressive disease may be considered as the remainder of the depressive illnesses or more rigorously as depression in a person who has a family history of depression but no alcoholism. Evidence is presented that the course of the illness is different in the two groups. Depression spectrum disease is more variable, with more personality problems and interpersonal conflict. Preliminary data indicate that depression spectrum disease may be linked to such genetic markers as C3 or alpha-haptoglobin.


Suicide and alcoholism. Interpersonal loss confirmed as a predictor. We earlier reported that nearly one third of a consecutive series of 31 alcoholics who committed suicide had experienced loss of a close interpersonal relationship within six weeks or less of their death. In a replication study of 50 additional unselected alcoholic suicides, we found that 26% had experienced such loss within six weeks. As before, the distribution of such events was strikingly and significantly skewed toward the final weeks of the subject's life. This powerful confirmation gives added significance to such loss as a predictor of suicide among alcoholics.


Electroencephalographic similarities between chronic alcoholics and chronic, nonparanoid schizophrenics. We compared the EEG power spectral density patterns for chronic, nonparanoid schizophrenics and age-matched chronic alcoholic and control subjects. Bilateral precentral (F-T) and postcentral (C-O) derivations were used in the analysis. The nonparanoid schizophrenics and alcoholics showed increased low-frequency activity (0 to 6 Hz) in all derivations in comparison to the control subjects. Chronic alcoholics were found to have increased high-frequency activity primarily in the precentral derivations. Nonparanoid schizophrenics showed increased power in the high-frequency bands predominantly in the left precentral derivation. We discuss the implications of patterns of differences concerning the issue of nonspecificity of the EEG in psychiatry.


Use of calcitonin in psychotic agitation or mania. Synthetic salmon calcitonin was administered subcutaneously to 12 inpatients with several primary psychotic diagnoses. Increases in serum total calcium and inorganic phosphorus levels and decreases in CSF calcium level had earlier been observed during periodic psychotic agitation or mania. By contrast, calcitonin, which decreased serum calcium and phosphorus levels and increased CSF calcium level, appeared to produce transient (24-hour) increases in depression and decreases in arousal in this double-blind placebo-controlled trial. Quantitative activity monitoring confirmed the rater's impression that this agent had tranquilizing or depressant effects in such patients. When given in the evening, this polypeptide also appeared to delay sleep onset, as demonstrated both by nurses' 30-minute sleep checks and by the same longitudinal activity record. A decreased hypocalcemic response to calcitonin was noted in the agitated patients, which might explain the increases in serum calcium level described at the "switch".


Trigeminal neurotization of paralyzed facial musculature. Modification of the Lexer-Rosenthal surgical procedure. We introduce a modification of the Lexer-Rosenthal surgical technique for reinnervation of the facial muscles by trigeminal neurolization in patients with facial paralysis. Four patients with such paralysis were seen in the Cranial Nerve Research Clinic, Oakland, Calif. Three of the four patients had their paralysis surgically treated, and recovery of facial motion was compared with that in one patient, in whom spontaneous trigeminal neurotization occurred. Those patients whose facial paralysis was surgically treated had fair to excellent results, and the technique is considered superior to alternative hypoglossal or spinal accessory anastomosis.


Brain stem evoked potential findings in children with otitis media. Sixty-three children from 2 to 12 years of age were studied by means of brain stem evoked potentials (BEP) and otoscopic evaluation in a preliminary assessment of the sensitivity of BEP latency measures to middle ear abnormality. Wave I proved to be the most sensitive component; 81.25% of subjects with acute suppurative otitis media and 62.50% of subjects with secretory otitis media demonstrated latencies prolonged by more than 1 SD beyond the values observed in normal control subjects. Of the same subject groups, 86.21% and 93.31% demonstrated wave I latencies within normal limits upon retesting after the otitis had resolved. The BEP technique permitted identification of several subjects with abnormal audiometric findings despite normal otoscopy. There are implications for use of the BEP as a clinical adjunct to traditional methods of auditory assessment.


The abnormally patent eustachian tube. Alterations in psychological status resulting from polytef paste injections. Several authors have noted that patients with an abnormally patent Eustachian tube (APET) seem to be psychologically disturbed. We investigated the psychological status of these patients before and after treatment with polytef paste (Teflon) injections. Twelve women were evaluated by a series of tests designed to catalog the nature and intensity of the symptoms, the degree to which symptoms affected the patient, psychopathological trends, and an assessment by the patients of improvement. Results prior to treatment indicated that the patients' symptoms were quite disturbing and were moderately disabling; such symptoms affected concentration, and a marked decrease in the enjoyment of life was noted. After treatment, a notable decrease in APET symptoms was reported, with a parallel decline in emotional disturbances. Patients felt less depressed, anxious, and angry, and they reported that the quality of life was much improved. These findings indicate that physical symptoms can have profound effects on emotional status. In such cases, the most effective psychological treatment is control of physical symptoms rather than psychiatric referral.


A new acoustic reflex pattern.

A new acoustic reflex pattern. A new crossed-vs-uncrossed acoustic reflex pattern has been observed in four patients with retrocochlear disorder. The new reflex pattern is characterized by a unique "uni-box" configuration. Reflexes are abnormal with sound to the affected ear on crossed stimulation only. In one additional patient, a variation of the uni-box pattern was found on suprathreshold reflex amplitude measures. WE observed a large ear difference between reflex amplitude functions in the crossed condition, but not in the uncrossed condition. This observation suggests that reflex amplitude measures may be a valuable addition to threshold measures in some patients.


Pathophysiological effects of Möbius syndrome on speech and hearing. The effects of Möbius syndrome (MoS) on the functioning of the peripheral speech and hearing mechanisms has not hithertofore been described, to my knowledge. Speech and hearing function of an 8-year-old MoS speaker was studied. Data were obtained from several sources. These included: electromyography of the facial muscles, physical examination of the peripheral speech mechanism, speech and language test batteries, audiological evaluation, and acoustic analyses of the speech signal. A pathologic condition was found to exist in a number of cranial nerves and in structures in the oral cavity. This resulted in consonant and vowel misarticulations, which notably affected speech intelligibility. Middle ear dysfunction was also present. Neurological mechanisms are discussed to account for these pathologies in human communication. Strategies for speech therapy and future research in MoS are presented.


Meningitis and hearing loss in children. The hospital records for 100 cases of meningitis in which acute audiometric data has been obtained were reviewed. The incidence of sensorineural hearing loss was found to be 6%. The severity of hearing impairment varied from mild to profound and was frequently bilateral and irreversible. Two-cases showed asymmetrical involvement, and in one case, there was subsequent improvement in threshold sensitivity. Factors that influenced the incidence of neurologic sequela included severity of the initial disease process, age of the patient, and duration of symptoms before diagnosis and treatment. We discuss the pathophysiologic mechanisms that may account for such hearing loss, and we emphasize the importance of early diagnosis and intensive antimicrobial therapy. Careful neurologic evaluation is required after recovery and must include periodic sequential audiometric testing.


Thorium dioxide granuloma of the neck with resultant fatal hemorrhage. A 46-year-old man had a granuloma in the neck that was caused by extravasation of thorium dioxide (Thorotrast) by an angiographic procedure performed about 30 years previously. His chief complaints were dysphagia and dyspnea with mild hoarseness. Parital resection of the tumor was performed, but his symptoms were not ameliorated. The immediate postoperative course was unfavorable. The patient died four months after the operation from massive hemorrhages from the right common carotid artery.


Mucosal melanoma. Immunological findings in a rare case treated with BCG vaccine, autologous tumor cells, and cytarabine. A case of mucosal melanoma involved the bronchus, maxillary sinus, and small intestine. Treatment with a combination of autologous tumor cells, BCG vaccine, and cytarabine was given, and the immunological system was investigated regularly. After each treatment episode, there was a transient improvement of the cell-mediated immunity to melanoma antigens. The cutaneous delayed hypersensitivity reaction to PPD was converted to a permanently positive one. In the final stage of the disease, the number of T cells was decreased. Difficulty occurred in interpreting the immunological findings according to the clinical condition.


Peripheral facial paralysis secondary to metastatic malignant melanoma. A clinicopathologic report. We report a case of disseminated malignant melanoma in which the initial sign was an isolated peripheral facial palsy on the left side. The cause of the palsy was established five months later, with the appearance of metastatic axillary nodes. The temporal bones demonstrated tumor infiltration within the marrow spaces of the petrous apices bilaterally. The left facial nerve was also extensively involved with melanoma to the level of the geniculate ganglion.


Nonsurgical closure of nasal septal perforations. Seventy-three patients had medical-grade Silastic buttons inserted transnasally (between June 1972 and June 1976) into a perforation of the nasal septum. This nonsurgical technique was done as an office procedure on 67 of the patients with the use of topically applied 5% cocaine solution. The Silastic button has remained in place in 72.6% of the entire study group; follow-up times for this group range from six months to four years. This mechanical covering of the perforation substantially reduced crusting and epistaxis, and it improved nasal respiration in many cases.


Low-frequency hearing loss in presbycusis. A central interpretation. Elderly subjects with a central phonemically balanced (PB) and synthetic sentence identification (SSI) pattern show greater low-frequency (LF) sensitivity loss than elderly subjects with a peripheral PB-SSI pattern. This LF hearing loss is not the simple consequence of age, nor does the LF hearing loss account for depressed SSI performance. We conclude that LF sensitivity loss and a central PB-SSI pattern are both components of central aging. We discuss the implications for auditory rehabilitation of elderly subjects.


Hyperbaric oxygen. A new adjunct in the management of radiation necrosis. Radiation necrosis is a significant complication of surgery for previously irradiated head and neck malignant neoplasms. We used hyperbaric oxygen therapy (HBO) as adjunctive therapy in 52 cases of radiation necrosis. Thirty-nine cases involved the head and neck. Nineteen of 23 cases of osteoradionecrosis of the mandible remain arrested after as much as two years of follow-up. Fifteen of the 16 cases of soft-tissue radionecrosis of the head and neck were successfully managed with HBO therapy as an adjunct to surgery and antibiotics. Fibroblastic proliferation, collagen formation, and capillary budding require at least 20 to 30 mm Hg of wound Po2. This effect can be achieved in wounds that are rendered hypoxic by radiation endarteritis and ischemia with high-dose or hyperbaric oxygenation.


Hearing aids. A study of the performance capabilities of new instruments. Evidence in the literature states that minimally 50% of the hearing aids that are worn by children are malfunctioning. The result is that these hearing aids are rejected by children who probably could benefit from amplification. This study shows that a large percentage of new hearing aids malfunction according to a number of specified parameters and points out the reasons for the malfunctioning. A cross-sectional sample of 14 manufacturers' hearing aid submissions (a total of 166 new aids) were comprehensively studied by the British Columbia Research and Development Laboratory, Victoria. Sixty-five percent of the hearing aids failed the primary and secondary criteria during the initial evaluation period. Results of this study provided valuable information to manufacturers of hearing aids and also to those who fit hearing aids with regard to improvements necessary to meet reasonable standards.


Posttraumatic pseudohypertelorism. (Telecanthus). Telecanthus was evaluated in a large series of patients with midfacial trauma. Nine patients were selected for detailed analysis of cause, degree of injury, and results of surgical treatment. The evaluation suggests that fractures causing the medial canthal injury are extensive, often resulting in ocular and CNS damage. Late repairs are plagued with difficulty in identification of the ligament and mobilization of soft tissues in the medial canthal area. Satisfactory function and appearance can usually be obtained by early exploration of the injury, reduction of bone fragments, and restoration of the medial canthal ligament to its normal position.


Brain stem evoked response audiometry in newborn hearing screening. Brain stem evoked response audiometry (BERA) has been used as an auditory screening procedure in three groups of newborn infants. Group 1 consisted of 220 normal-term infants who were tested within 72 hours of birth; no hearing abnormalities were uncovered (386 ears), and their threshold responses (for clicks) lay between a 10- and 20-dB hearing level (re: adult). Group 2 consisted of 75 newborns who were treated in an intensive care unit for one to 14 weeks; four were found to have severe sensorineural hearing loss (seven ears) at the time of discharge. Group 3 consisted of a group of 325 infants, 1 year or older, who had previously been discharged from the same intensive care unit; of these infants, an additional four showed severe sensorineural hearing loss. All abnormalities that were identified by BERA were subsequently confirmed by conventional audiometric measures. The estimate of an incidence of severe hearing loss in one of 50 infants who required intensive care in the neonatal period calls for careful testing of this population.


Infratemporal fossa approach to lesions in the temporal bone and base of the skull. An infratemporal fossa approach for extensive tumors of the temporal bone, clivus, and parasellar and parasphenoid regions features permanent anterior transposition of the facial nerve, resection of the mandibular condyle, and mobilization of the zygoma and lateral orbital rim. Obliteration of the pneumatic spaces of the temporal bone with permanent occlusion of the Eustachian tube and blindsack closure of the external auditory canal avoids the danger of postoperative infection and leads to primary wound healing in the shortest time. Three cases demonstrate selective utilization of the infratemporal fossa approach. Short-term results and complications were observed in 51 patients.


Pattern analysis of auditory-evoked EEG potentials. A pattern analysis approach to the detection of auditory evoked potentials in the EEG is reported. Pattern aspects of individual post-stimulus responses have been examined first through their correlation coefficients using the suprathreshold average evoked potential as a reference pattern, and second by the ensemble distribution of phase values of Fourier spectral components, employed to characterise signal pattern. The correlation study indicated that suprathreshold stimuli act to increase the reference pattern similarity of individual records. Individual harmonic phase values are distributed approximately uniformly for unstimulated EEG, but were demonstrated to be increasingly aggregated for increasingly suprathreshold stimuli. It is proposed that a fully objective audiometric technique can be based on a phase-spectral technique.


The middle ear inertial component of bone-conduction hearing in man. The middle ear inertial component of bone-conduction hearing was studied in 8 normal-hearing young adults. The inertial component was eliminated to varying degrees by introducing various positive and negative air pressures into the ear canal. Sweep-frequency Békésy tracings were obtained from 100 through 5 000 Hz for bone-conducted pure tone stimuli while the air pressure of the test ear was varied and the nontest ear was masked. Air pressures of +/- 100, +/- 300, and +/- 500 mm H2O were utilized. Results revealed maximal shift in the mid frequencies (750 Hz) and an increase in effect with increase in pressure. A second prominent region of threshold shift emerged at 2 000 Hz for the +/- 500 mm H2O air pressure conditions. Considerable variability in the magnitude of threshold shift and in the frequency region of maximum shift was observed.


Thresholds of filtered transients.

Thresholds of filtered transients. Absolute and masked thresholds were obtained for sinusoids, one-third-octave filtered noise, one-third-octave filtered clicks, and for broadband noise and clicks as a function of repetition rate of the filtered clicks. The results indicate that if signal energy is computed for each stimulus, then similar absolute and masked thresholds can be obtained. Thresholds for repetition rate and number of clicks were similar to published results on temporal integration of tones. These results provide a direct and objective means for measuring the level of brief narrow-band stimuli and support the use of these signals as a means of probing auditory sensitivity.


Improving the reliability of testing the speech reception threshold for sentences. An accurate test for measuring the speech reception threshold (SRT) for sentences in quiet or in noise has been developed. It is shown that with ten carefully selected lists of only 13 sentences each, a high test-retest reliability can be obtained. The standard deviation of SRT measured with the different lists is approximately 1 dB.


Clinical implications in calibration requirements in bone conduction standardisation. Although international agreement has long been reached on a standard threshold for air conduction audiometry, no similar standard exists for bone conduction autiometry. It is argued that the techniques applied to the determination of the air conduction thresholds are not applicable to those for bone conduction which should instead be brought into line with ISO 1964 and not established independently. A pilot study has been carried out which shows that by adopting the new approach now advocated international agreement could be attained with the expenditure of minimal time and effort.


Hearing-aid-processed signals: a new approach. A new protocol for obtaining and utilizing hearing-aid-processed signals in hearing aid research or hearing aid selection is described. Data are presented which illustrate the extent to which this procedure may be expected to result in a signal spectrum at the subject's eardrum which is the same as the spectrum the subject would have received if the hearing aid itself had been placed on his ear (a directly-aided situation). An earlier investigation by the authors indicated that the traditional protocol for the production and utilization of hearing-aid-processed signals results in substantial discrepancies between these two spectra. The data presented were obtained using the KEMAR as the subject with a Zwislocki coupler as the KEMAR's ear canal/eardrum. The discrepancy between directly-aided and hearing-aid-processed spectra was typically +/- 2 dB for ear-level hearing aids fitted using standard, vented, or open earmolds (in open earmold fittings only the amplified component of the directly-aided spectrum is reproduced).


Effects of whitening and peak-clipping on speech intelligibility in the presence of a competing message. The purpose of this experiment was to determine the effects of peak clipping on speech intelligibility when both a target speech and a competing message were simultaneously peak-clipped. A competing message composed of 5 talkers was electrically mixed with CNC discrimination words. This composite signal was presented to normally hearing subjects in three ways: unmodified, whitened, and whitened and peak-clipped. Discrimination functions were obtained for the CNC material by varying the signal-to-competition ratio. Under these conditions, essentially identical discrimination functions were yielded by the unmodified and whitened speech, whereas substantially reduced discrimination scores were obtained with the whitened/clipped speech. These results would suggest that speech intelligibility is reduced by whitening and peak clipping when more than one talker is present. This is true even though earlier studies have shown that whitening and peak clipping do not reduce speech intelligibility when only a single talker is present. Such a finding has implications for wearable amplification.


Time-compressed speech discrimination, reading readiness and the effect of clinical method. Time-compressed speech discrimination was examined on kindergarten-age children grouped according to scores on the Lindamood Auditory Comprehension Test (LAC). In experiment 1, 34 children were equally divided into two groups based upon the LAC, and administered the Word Intelligibility by Picture Identification Test (WIPI) at 0, 30 and 60% time compression. In experiment 2, 32 children were similary grouped and administered the WIPI at 0 and 60% time compression with 60% always administered first. Significant main effects for time compression and test group were found. The effects of clinical method and clinical implications are discussed.


Bioavailability of chlorpropamide.

Bioavailability of chlorpropamide. 1. The serum profiles of chlorpropamide obtained following single doses of two tablet preparations and from a suspension formulation have been compared in healthy volunteers. The amounts of chlorpropamide absorbed from the three formulations were similar but the drug was absorbed more rapidly from the suspension than from either tablet formulation. There was a small but therapeutically insignificant difference in the rate of absorption of the drug from the two tablets. 2. Changes in blood glucose concentrations were found to be related to the drug serum profile characteristics of the formulations.


Mesterolone: thrombosis during treatment, and a study of its prothrombotic effects. 1. We describe a patient who developed deep vein thrombosis after commencing treatment with the synthetic androgen, mesterolone (Pro-Viron). 2. To investigate the potential thrombogenic action of this drug, a 21 day course of mesterolone (100 mg/day) was given to nine healthy male volunteers. 3. No significant change after treatment occurred in any of the blood tests performed (clotting times, Factor VIII coagulant activity, Factor VIII related antigen, antithrombin III activity, fibrinogen, fibrinogen-fibrin degradation products, plasminogen, euglobulin lysis time, urokinase sensitivity, platelet count, haematocrit, whole blood viscosity and plasma viscosity). 4. We conclude that in a conventional dose taken for 3 weeks mesterolone does not produce a consistent measurable prothrombotic state, nor does it enhance fibrinolysis.


Prolactin responses to cimetidine.

Prolactin responses to cimetidine. 1  An intravenous injection of cimetidine 400 mg to four healthy male subjects resulted in high blood concentrations of cimetidine and a rapid three-fold increase in serum prolactin. 2  This effect was prevented by pretreatment with bromocriptine. 3  No increase in prolactin followed a single oral dose of cimetidine 800 mg administered to a different group of healthy male subjects. The mean peak blood concentration of cimetidine was less than 20% of that achieved with 400 mg i.v. 4  Only isolated reports have been received of gynaecomastia or galactorrhoea occurring during cimetidine treatment. In three of seven cases studied there was associated hyperprolactinaemia. This may be an idiosyncratic response at the lower blood concentration of cimetidine associated with oral therapeutic dose regimens.


The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine--studies in patients with peptic ulcer disease. 1 The absorption of a single oral dose of cimetidine taken on a fasting stomach or together with a meal was studied in 28 patients before and during 12 weeks treatment with cimetidine. 2  No significant changes in bioavailability were seen during treatment measured as the area under the blood concentration curve (AUC). 3  AUC after a single dose of 400 mg cimetidine was 2.05 times the area after a 200 mg dose. 4  There was a good correlation between AUC and the dose of cimetidine given corrected for body weight (r=0.89). 5  There was no difference in bioavailability if 200 mg cimetidine was taken on a fasting stomach or together with a beef steak meal. 6. During fasting conditions there was a peak in blood concentration at about one hour followed by a second unexplained peak during the third to fifth hour after dose administration. 7  With food the initial rise in blood concentrations was slower and there was only one peak occurring about 2 h after dose administration.


Impaired theophylline clearance in patients with cor pulmonale. 1  The relationship between serum theophylline concentration and daily dose was studied in 45 patients receiving aminophylline orally and in 36 patients receiving it by constant intravenous infusion. 2  Patients were categorized as uncomplicated chronic obstructive pulmonary disease (COPD) or COPD with cor pulmonale (CP). 3  Serum theophylline concentration relative to daily theophylline dose was significantly higher in patients with COPD plus CP than in patients with COPD alone. 4  Total body clearance of theophylline estimated from data obtained during constant intravenous infusion was significantly lower in COPD plus CP than in patients with COPD alone. 5  We conclude that reduced maintenance doses of theophylline are indicated in patients with COPD when complicated with CP.


Impairment of hepatic drug metabolism in alcoholics. 1  The effects of chronic ethanol intake on the elimination kinetics of antipyrine were determined in nineteen male alcoholic subjects with comparison made to fourteen male volunteers. 2  Half-lives were longer and clearance values less in the alcoholic group. 3  Significant rank correlations were found between half-life and clearance when compared with various biochemical parameters of liver function measured in the plasma of the alcoholics. 4  These results show that a significant proportion of the alcoholics studied had impaired hepatic drug metabolizing capacity and that the activity of hepatic microsomal enzymes may be related to the extent of ethanol induced liver damage in these subjects.


The effect of ageing on the hepatic clearance of propranolol. 1. Plasma propranolol concentrations were measured in healthy old and young subjects following single oral doses of 40 mg, single i.v. infusions of 0.15 mg kg-1 and after nine 40 mg oral doses given four times daily. 2. In each of the three studies, the elderly had higher plasma propranolol concentrations than the young despite having similar apparent volumes of distribution. 3. The terminal half-life of propranolol was similar in the two groups after oral propranolol but significantly shorter in the young after intravenous dosing (P less than 0.05). 4. The bioavailability assessed from the concentration-time curves after i.v. and oral dosing was greater in the elderly (P less than 0.05). 5. The differences between peak concentrations observed in old and young subjects after single oral doses were maintained during chronic therapy and there was a correlation between the individual values obtained on multiple therapy with that after a single dose (P less than 0.05). 6. Ageing appears to affect the pharmacokinetics of propranolol in two ways. Firstly, distribution to the tissues appears to be slowed. Secondly, the increased bioavailability following oral administration suggests diminished intrinsic clearance by metabolism.


Clonidine withdrawal. Mechanism and frequency of rebound hypertension. 1. The frequency and pathophysiology of the clonidine withdrawal syndrome was studied in fourteen hypertensive patients on chronic clonidine therapy. 2. After sudden cessation of clonidine (900 microgram daily) almost all of the patients showed an excessive increase of the heart rate and blood pressure. Seven of the fourteen patients had subjective symptoms, in three severe enough to require interruption of observation by therapeutic intervention 12 to 60 h after the last dose of clonidine. After clonidine withdrawal, NAE increased to abnormally high values in correlation with the blood pressure (P less than 0.01) and heart rate (P less than 0.001), whereas PRA even decreased initially, probably secondary to the rise of the blood pressure, and only rose, although not significantly, 48 h after withdrawal. PRA was not correlated with NAE, heart rate, or blood pressure. 3. It is concluded that the clonidine withdrawal phenomenon is a frequently occurring and potentially dangerous syndrome. Overactivity of the sympathetic nervous system is mainly responsible, without the mediation of the renin angiotensin system. This also explains our experience that adrenergic beta-receptor blocking drugs do not prevent the rise in BP, although they alleviate some of the symptoms.


Metabolism of sulphadiazine in malnutrition. 1. The kinetics of sulphadiazine were studied in well-nourished and under-nourished subjects. 2. The metabolic clearance rate of a single dose of sulphadiazine given either orally or intravenously was faster in under-nourished subjects. 3. The plasma protein binding of the drug was found to be reduced in under-nourished subjects. 4. Blood concentrations (48 h and 72 h) of sulphadiazine tended to be low in the under-nourished as compared with well-nourished subjects after administration of multiple doses of the drug. 5. It is concluded that a revision in the dosage schedule may not be necessary in the treatment of under-nourished subjects with sulphadiazine, since the blood concentrations were higher than the reporte d minimum to combat infection.


Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergic drugs. 1. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson treatment. Twenty-six psychotic patients received various forms of PPZ administration as well as antiparkinson drugs. 2. Biperidine (5 mg) was administered intravenously to each of five patients, who 5 days earlier had had a single dose of PPZ-enanthate i.m. No significant alterations in plasma concentrations of PPZ were observed. 3. In fourteen patients receiving oral PPZ treatment the plasma levels of PPZ and its metabolites did not deviate significantly from controls after addition of biperidine or orphenadine given for 3 weeks in fixed oral doses. 4. The ratio between PPZ plasma concentration measured 4 and 7 h after the morning dose was not affected by concomitant antiparkinson therapy. 5. It is concluded that no clinically relevant pharmacokinetic interaction takes place between PPZ and two generally used antiparkinson drugs during steady-state conditions in psychotic patients.


Effect of acute alcohol intoxication on the metabolism and plasma kinetics of chlordiazepoxide. 1. The metabolism and plasma kinetics of chlordiazepoxide have been determined in a group of volunteers and in a group of patients with acute alcohol intoxication. 2. Using the SAAM 26 non-linear least squares fitting programme, all chlordiazepoxide plasma concentration v time data following oral administration could be analysed in terms of a one-compartment open model with metabolic conversion of chlordiazepoxide to desmethylchlordiazepoxide. 3. Acutely intoxicated patients showed a prolonged elimination of chlordiazepoxide and a reduced clearance when compared with alcohol-free volunteers. The elimination of desmethylchlordiazepoxide, on the other hand, appeared to be faster in the alcoholics. 4. Alcohol exerts significant effects on the metabolism of chlordiazepoxide in acutely intoxicated patients.


Rate of onset of hypotensive effect of oral labetalol. 1 Labetalol caused a fall in blood pressure within 2 h or oral doses of 100, 200 and 400 mg in six hypertensive patients. 2 This fall which was dose-related was maximal by 3 h and was sustained when the drug was given in doses of 100 mg 8 hourly, 200 mg 8 hourly and 400 mg 8 hourly. 3 This rapid fall in pressure when labetalol is given by mouth which contrasts to that seen on administration of pure beta-adrenoceptor blocking agents is a valuable therapeutic property.


The effects of beta-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise. 1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta-adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.


Haemodynamic and electrocardiographic effects of intravenous disopyramide (rythmodan) following acute myocardial infarction. 1 The haemodynamic and electrocardiographic effects of intravenous disopyramide were studied in fifteen patients with acute myocardial infarction. 2 Five minutes after drug injection a rise in heart rate, aortic mean and diastolic pressures and systemic vascular resistence was noted which persisted for at least 30 min. A small increase in pulmonary arterial diastolic pressure (mean = 1.5 mm Hg) occurred at 5 min only and no significant change of cardiac output was found throughout the period of the study (1 h). 3 Surface electrocardiograms revealed transient prolongation of the P-R interval and a sustained increase in the QTc interval. 4 The haemodynamic changes suggest an anticholinergic effect of the drug. There was no definite evidence of a negative inotropic effect in this study, however, these peripheral haemodynamic measurements might not have revealed a modest negative inotropic effect. 5 The electrocardiographic changes are similar to those previously reported in normals and in patients without acute myocardial infarction.


Measurement of activity of 5-HT antagonists following oral administration in man: a comparison of methysergide and BW501. 1 Oral doses of BW501 and methysergide administered to healthy volunteers inhibited the ex vivo platelet aggregation response to 5-hydroxytryptamine (5-HT). 2 Two volunteers received 100 mg BW501 and two received 10 mg BW501 and aggregation response was measured immediately pre drug and at 1,3 and 24 h post drug. After 100 mg BW501 the response to 5-HT was completely inhibited at all times studied, after 10 BW501 a response too small to measure was apparent at 24 h only. 3 In two randomised crossover studies subjects received either 2 mg BW501 (nine subjects), 2 mg methysergide (six subjects) or no drug (nine subjects) and aggregation response to 5-HT was measured immediately pre drug and at 1, 2, 3, 5, 7, 24 h post drug. 4 Methysergide (2 mg) produced complete inhibition of aggregation for 24 h after dosing; following 2 mg BW501 the aggregation response was significantly lower than on the control occasion at 1 (P less than 0.01), 2 (P less than 0.01) and 3 (P less than 0.05) h post drug. The response was inhibited by rr%, 31% and 16% at these times respectively. 5 It is suggested that this technique provides a suitable method for demonstration of activity of 5-HT antagonists after oral dosing in man.