Properties of monoamine oxidase (MAO) in human blood platelets, plasma, lymphocytes and granulocytes. The properties of monoamine oxidase in plasma, platelets, lymphocytes and granulocytes have been studied using cells prepared from a single small (about 20 ml) sample of blood. The three substrates, 5-hydroxytryptamine, tyramine and benzylamine, have been used to obtain a more complete picture of blood monoamine oxidase than was previously possible. Measurement of Michaelis constants, use of selective inhibitors, and activity against the three substrates distinguished three types of activity. The monoamine oxidases in platelets and lymphocytes are very similar, being most active with tyramine or benzylamine as substrate and inhibited by low concentrations of deprenil. The enzymes in plasma and granulocytes are similar in their relatively high activity against 5-hydroxytryptamine and in their inhibition by semicarbazide and cuprizone with tyramine or benzylamine as substrates. They differ in their affinities for 5-hydroxytryptamine and their activity against tyramine. The activity in platelets, plasma, lymphocytes and granulocytes has been measured in a group of 15 normal subjects using three substrates.


Serum alkaline phosphatase isoenzyme patterns in patients with chronic renal failure. 1. Using acrylamide gel electrophoresis the serum alkaline phosphatase (ALP) isoenzyme patterns of 204 patients with chronic renal failure have been examined for periods up to 18 months in length. 2. Of those with elevated serum ALP activity the bone isoenzyme was largely responsible. The presence of increasing amounts of the bone isoenzyme even if the total serum ALP activity remains within the normal reference range should also indicate bone pathology. 3. Intestinal alkaline phosphatase was the major serum alkaline phosphatase in 15% of patients on regular haemodialysis and 10% of uraemic patients not on dialysis. The overall incidence of detectable intestinal alkaline phosphatase in those with normal serum ALP activity was 36%. 4. With those patients whose serum ALP activity changed significantly during the investigation this usually reflected changes in the amount of the bone isoenzyme. Patients with abnormal amounts of the intestinal isoenzymes in their serum usually showed little variation in serum ALP activity over the period of the study.


Seasonal variations in the composition of urine from normal subjects: a longitudinal study. The volume, pH and composition of 24-h urine samples, collected by 13 healthy male adults, were followed over a period of one year. Significant and systematic variations in urine pH, calcium, phosphate, oxalate, uric acid, potassium and magnesium were observed. A significant but non-sinusoidal variation in sodium excretion was found but there were no significant changes in urinary volume, creatinine or hydroxyproline. Many of the observed changes could be attributed to variations in the pattern of food consumption throughout the year but calcium, phosphate and oxalate were exceptions in that seasonal variations in these parameters appeared to be due to the effects of sunlight (or vitamin D) rather than to the diet.


Electrophoretic patterns of serum albumins collected from different blood vessels. Rabbit sera collected from different blood vessels, e.g. vena renales, vena mesenterica, vena portae, vena hepatica and aorta, were electrophoresed in an urea-containing polyacrylamide gel. The albumin fraction was separated into 5-6 sub-bands. The profile of these sub-bands (electrophoretic pattern) of the sample from one blood vessel differed from that of another blood vessel. Especially, the electrophoretic pattern of serum collected from the renal vein 2h after deprivation of food differed from that of other blood vessels. Free fatty acid concentrations of each sample were also measured, and differences in these levels were observed in sera collected from different blood vessels. However, the fatty acid concentrations in serum from the renal vein were not low enough to permit detection of any abnormality in electrophoretic pattern in the albumin. This suggests the possibility of decreased concentration of lysolecithin in the renal vein which binds to albumin and changes the electrophoretic mobility of albumin, as do the free fatty acids.


Pyruvate kinase: diagnostic value in neuromuscular disease. Pyruvate kinase activity was examined in the sera of a group of patients with neuromuscular disease and in carriers, and compared with that of creatine kinase. The following observations were made: 1. Pyruvate kinase activity was elevated in all 14 patients with Duchenne muscular dystrophy, with very high values generally correlating inversely with age or disease duration. Elevated values of pyruvate kinase were usually, but not invariably, associated with elevated values of creatine kinase. 2. Almost all patients with other muscle diseases and those with neural atrophy had modest elevations in pyruvate kinase activity. 3. ten of 17 individuals were identified as carriers of muscle disease by using both pyruvate kinase and creatine kinase while eight and nine, respectively, were detected using either assay alone. 4. When frozen stored EDTA-plasma was used for pyruvate kinase estimation, higher levels, as compared with the corresponding sera or fresh plasma, were found in controls and carriers but not in Duchenne muscular dystrophy patients. Frozen stored EDTA-plasma should, therefore, not be used for diagnostic purposes.


Development of radioimmunoassays for the measurement of aldosterone in unprocessed plasma and simple plasma extracts. Inexpensive and rapid radioimmunoassay techniques for the measurement of aldosterone in unprocessed plasma and simple plasma extracts are described. The use of low pH (pH 5.0) and merthiolate to minimise plasma protein binding and the use of aldosterone-free plasma in the standards allows the measurement of aldosterone in 50 microliter of unprocessed plasma, which has been found useful in the diagnostic screening and classification of hyperaldosteronism. Despite quantitative recovery of added (+)-aldosterone and high specificity, the aldosterone content of unprocessed plasma is overestimated, probably by the presence of a water-soluble compound which closely resembles aldosterone. The use of a simple preliminary dichloromethane extraction procedure gives an excellent correlation with values obtained after chromatography. Values are given for chosen normal people and people with benign essential hypertension, using both assay procedures in three different physiological contexts.


A semi-automated measurement of urinary catecholamines using high-speed ion-exchange column chromatography. Semi-automated measurement of urinary catecholamines, specific for dopa, noradrenaline, adrenaline and dopamine and other metabolites has been developed. Steps included alumina extraction, separation by high-speed ion-exchange column chromatography and fluorescent development by trihydroxyindole (THI) method without interference by other fluorescent substances. Recovery, reproducibility and sensitivity were satisfactory. alpha-Methyldopa, a metabolite of alpha-methyldopa, and isoproterenol were separated completely without interfering with the measurement of noradrenaline, adrenaline and dopamine.


Production and characterization of an antiserum against pancreatic glucagon. To produce a carboxy-terminal specific antiserum against pancreatic glucagon, glucagon was coupled mainly via its amino-terminal histidine to thyroglobulin, using the amino group reactive pentandial at pH 7.0 for the conjugation procedure. After repeated immunization of rabbits, one high titer antiserum was obtained with a combining site recognizing a part of the carboxy-terminal portion of glucagon as judged from the cross-reaction curves with glucagon fragments, duck pancreatic glucagon and gut glucagon-like immunoreactive substances. There was no cross-reaction with secretin, vasoactive intestinal peptide, and gastric inhibitory peptide. In spite of strong immunoreactive similarities with the antiserum 30K (Unger) this antiserum results in determinations of a somewhat higher amount of plasma immunoreactive glucagon (IRG). The difference was found to depend on a higher content of IRG with a molecular size close to immunoglobulin IgG. A patient with agamma-globulinemia had no measurable IRG of molecular size close to that of IgG, indicating a possible competitive binding of some immunoglobulins to the antiserum.


Influence of the rebox state of glutathione upon pyruvate kinase in the intact erythrocyte. 1. In isolated erythrocytes the ratio of reduced to oxidized glutathione was modified by the addition of diazinedicarboxylic acid bis-dimethylamide (diamide). Incubation of erythrocytes, with a decreased GSH/GSSG ratio, resulted in an increase in [S]0.5 of pyruvate kinase of phosphoenolpyruvate as measured in haemolysates. We presume this increase to be due to oxidation of the enzyme. 2. The apparent affinity of pyruvate kinase for phosphoenolpyruvate returned to normal when the GSSG formed was reduced to GSH intracellularly. Oxidation of pyruvate kinase could also be reversed by incubation of haemolysates with reducing agents such as 2-mercaptoethanol or dithioerythritol. 3. Intracellular oxidation of pyruvate kinase caused no significant changes in the Hill coefficient (n) or Vmax of the enzyme. However, the heat stability of the oxidized enzyme was lower than normal. Lability increased with increasing oxidation of the enzyme. 4. The possible role of oxidation processes in pyruvate kinase deficiency is discussed. It is concluded that not only 'in vitro' but also in the intact erythrocyte, pyruvate kinase is sensitive to oxidizing agents and intracellular redox state. However, that a decreased GSH/GSSG ratio can be a single cause of acquired pyruvate kinase deficiency seems highly improbable.


Urinary amino acid excretion by patients with beta-thalassemia. Twenty-four hour urinary amino acid excretion has been studied in patients with beta-thalassemia (four adult major, two adult intermedia, and three children major). beta-Aminoisobutyric acid was found to be increased (14-fold on the average) in patients with beta-thalassemia without evidence for increase in the excretion of most other amino acids. No correlation of beta-aminoisobutyric acid excretion with the hematological status of the patient was found. Elevated taurine excretion (2-fold) was also noted in the adult patients with beta-thalassemia. Greatly increased excretion of beta-aminoisobutyric acid appears to correlate with a poor prognosis and may reflect generalized tissue catabolism rather than being a specific indicator of ineffective erythropoiesis.


Serum urate in subjects with hypercalcaemic hyperparathyroidism. A positive correlation was found between serum urate and elevated serum calcium in patients with hypercalcaemic primary hyperparathyroidism. No such correlation was detected in normocalcaemic controls, matched with respect to age and sex. Neither was such a correlation confirmed either in subjects with normalized serum calcium levels after extirpation of parathyroid adenomata, or in subjects with hypercalcaemia due to other conditions than primary hyperparathyroidism, such as various malignancies, sarcoidosis and hyperthyroidism. The positive correlation between elevated serum calcium and serum urate (within normal limits) in subjects with hypercalcaemic hyperparathyroidism is suggested in subjects with hypercalcaemic hyperparathyroidism is suggested to be a clue to the explanation of an association between hyperparathyroidism and urate retention.


The effect of bile salts on the esterolytic assay of trypsin. A bile salt mixture and pure sodium taurocholate were each shown to increase the esterolytic activity of trypsin in aqueous solution and in intestinal juice. rho-Toluene-sulphonyl-L-arginine methyl ester (TAME) was used as a substrate, and both a spectrophotometric and a potentiometric assay system were used. The maximal potentiation of the esterolytic activity of trypsin by bile salts was about 1.6 to 2.2 times the activity without bile salts (depending on the assay conditions and whether the trypsin was in aqueous solution or intestinal juice). The proteolytic activity of trypsin was decreased by the addition of bile salts. It seemed likely, therefore, that the potentiating effect of bile salts on trypsin esterolytic activity is primarily on the substrate (TAME) rather than trypsin itself. It was thought that TAME might be taken up into bile salt micelles and thus be more readily hydrolysed by trypsin, but we were unable to substantiate this hypothesis. The precision of the trypsin esterolytic assay was better when bile salts were not added. If however bile salts were to be used routinely in the trypsin assay, it would be useful to ensure that the concentration of calcium, included as activator, is sufficiently low to prevent the formation of a precipitate. This precipitate is probably a complex of calcium and bile salts.


Serum 25-hydroxyvitamin D assay. Evalution of chromatographic and non-chromatographic procedures. A competitive protein binding assay for serum 25-hydroxyvitamin D is described in which normal human serum is used as the source of binding protein. A serum sample is extracted with diethyl ether/methanol and then chromatographed using silica gel. Validation of the method is reported. Silica gel chromatography is compared with LH20 chromatography. The method is also compared with extraction techniques using diethyl ether and ethanol without subsequent chromatography. It is concluded that chromatography with either silica gel or LH20 is essential. The non-chromatographic methods investigated, in addition to giving much higher values than chromatographic methods, did not meet validation requirements with respect to accuracy and behaviour of samples on dilution.


A rapid, sensitive and specific radioimmunoassay for methotrexate. A rapid, sensitive, radioimmunoassay for methotrexate has been developed using tritiated methotrexate and an antiserum raised in rabbits against the immunogen, bovine serum albumin containing 34 methotrexate residues per protein molecule. Separation of bound and free drug was attained using donkey anti-rabbit precipitating serum. The method can accurately measure as little as 50 fmol methotrexate in capillary blood samples and is not interfered with by vast excesses of natural folates nor citrovorum rescue factor. The method can handle 30 samples per day with the results available after 6 h. This makes it suitable for monitoring serum methotrexate levels after high dose therapy when a result is required within 24 h to provide helpful information regarding impending toxicity and the need for extended citrovorum rescue factor or maintenance of urinary pH.


Study of the lipods in the skin lesions in Urbach-Wiethe disease. A patient with Urbach-Wiethe disease was studied, with special attention given to the analysis of the skin and mucosal lesions. An eosinophilia in the peripheral blood and a diabetic tendency were found. The skin papules and mucosal plaques contain abundant lipids, especially cholesterol (66 percent) and phospholipids (27 percent).


The origin of the rapidly adhering cells found in amniotic fluids from foetuses with neural tube defects. The number and morphologies of cells rapidly adhering to glass (RA cells) found in amniotic fluids from foetuses with neural tube defects is independent of soluble factors in the supernatant fluid. Cells taken directly from brain and spinal cord of normal foetuses, which are rapidly adherent in culture, show numerous similarities to those RA cells which are present in the amniotic fluids of foetuses with neural tube defects. This suggests that RA cells in amniotic fluid may be reliably used as a diagnostic marker of foetal lesions involving neural tissue, in particular spina bifida and anencephaly. Other RA cells extracted from foetal peritoneal cavity and bone marrow also have distinctive morphologies and may be useful in early antenatal diagnosis of congenital defects such as exomphalos.


Trisomy 9 syndrome.

Trisomy 9 syndrome. An infant is described with multiple congenital anomalies associated with mosaic trisomy 9. Review of the three previously reported cases of trisomy 9 shows that these patients have several common features which make trisomy 9 a clinically distinct syndrome. The frequently encountered findings are: upward-slanted eyes, small palpebral fissures, enophthalmos or microphthalmos, broad base and prominent tip of the nose, microcephaly, micrognathia, low-set malformed ears, high-arched palate, congenital heart disease, skeletal and genito-urinary anomalies, abnormal palmar creases, failure to thrive, hypotonia and retardation.


Trisomy 8 syndrome. A psychological and somatic study of a mentally non-retarded male with 46,XY/47,XY,+8 chromosome constitution. A 27-year-old, non-retarded male with trisomy 8 mosaicism (46,XY/47,XY,+8) had a short head, a short broad-bridged nose, a protruding upper lip, pterygium colli, moderate kypho-scoliosis, camptodactyly of all fingers and deep furrowing on the soles. Radiographic examination of columna showed spina bifida of L1 and fusion of L5 and S1. These findings are characteristic for the trisomy 8 syndrome. A psychological study showed a personality characterized by immaturity and lack of spontaneity and self-confidence. An intelligence test (WAIS) placed him within the normal range, but presented an uneven development of the cognitive functions with special difficulties in synthetic abilities and visual scanning. His auditive span was rather low, and his memory functions were somewhat below average.


7q deletion syndrome (7q32 leads to 7qter). Four independently ascertained children who presented with unusual facies and delayed mental and physical development were found to have a similar deletion of part of the long arm of chromosome 7 (46,XX or XY, del(7)(q32); 46,XX or XY,del(7)(pter leads to q32:)). Comparison of the findings of these four cases with one other case report of a similar deletion revealed similar dysmorphologic features in all five cases.


Phenotypic correlations in patients with ring chromosome 22. This paper reports two patients with a ring 22 chromosome which has been confirmed by Q-banding. The literature contains 19 patients with a ring G-group chromosome which has been shown by chromosome banding to be a ring 22. The most commonly reported features in affected patients have included: retardation with disproportionate verbal delay, reduced head circumference, hypotonia, unsteady gait, large ears with abnormal configuration, and epicanthic folds.  The importance of these, as well as other, less often noted findings, is discussed in relation to a possible r(22) syndrome.


High incidence of spinal muscular atrophy type I (Werdnig - Hoffmann disease) in the Karaite community in Israel. Spinal muscular atrophy (S.M.A.) type I (Infantile werdnig - Hoffmann Disease) was found in 4:1,600 (1:400) infants of the Egyptian Karaite community. This group constitutes a representative sample of the Egyptian Karaite community in Israel, which numbers at present somewhat more than 7,000. The community existed as a religious and reproductive isolate for over 10 centuries. The very high gene frequency, 0.05 for the autosomal recessive gene of S.M.A. type I, is probably the result of genetic drift.


A pharmacological investigation of synthetic substance P on the isolated guinea-pig ileum. 1. The pharmacological properties of synthetic substance P have been studied on the guinea-pig ileum and compared with those of acetylcholine and other agonists. 2. The effects of synthetic substance P in the presence of atropine, hexamethonium, mepyramine and certain of the drugs which antagonize serotonin are in close agreement with those reported for the naturally occurring peptide. 3. The spasmogenic action of substance P is not mediated by cholinergic mechanisms or release of prostaglandins, and does not appear to involve release of serotonin. The inability of tetrodotoxin to attenuate responses to substance P suggests that its spasmogenic action is not elicited through neural mechanisms. Thus, it is likely that substance P acts directly on the smooth muscle of the ileum. 4. Since substance P is present in the brain and can depolarize neurones, it may be a neurotransmitter. A screening of various centrally acting drugs, whose mechanisms of action are unclear, was undertaken to seek possible interactions with substance P. Pimozide was the most potent in depressing responses to substance P but none of the drugs caused the specific antagonism which would assist in elucidating a possible physiological role for substance P.


Cardiovascular effects of carbachol and other cholinomimetics administered into the cerebral ventricles of conscious cats. 1. The cholinomimetic substances acetylcholine, nicotine, tetramethylammonium chloride and carbachol were infused intracerebroventricularly (i.c.v.) into conscious, normotensive cats and their effects on behaviour, blood pressure and heart rate recorded. 2. Intracerebroventricular acetylcholine, nicotine and tetramethylammonium chloride each produced small, mainly stimulant, effects on the cardiovascular system which were not accompanied by any marked behavioural effects. 3. Intracerebroventricular carbachol at a dose of 30 microgram produced marked and persistent cardiovascular stimulant effects accompanied by a striking rage/fear reaction. When the dose of carbachol was reduced to 7.5 microgram the behavioural effects were no longer seen but marked cardiovascular stimulant effects remained. 4. The cardiovascular stimulant effects of i.c.v. carbachol were apparently mediated via the peripheral sympathetic system since they were abolished by peripheral adrenergic neurone blockade. 5. The blood pressure and heart rate increases produced by i.c.v. carbachol were blocked by prior i.c.v. treatment with atropine, hexamethonium, guanethidine, bethanidine or propranolol. 6. The data are consistent with an interaction between central cholinergic and catecholaminergic neural pathways involved in central regulation of blood pressure and further suggest the involvement of beta-adrenoreceptors in the responses to centrally-administered cholinomimetics.


Prevention of hepatitis B in hemodialysis patients using hepatitis B immunoglobulin. A controlled study. In a controlled study, the protection effect of hepatitis B immune globulin (HBIG) was evaluated in patients hemodialyzed for less than one month in two collaborating units. Fifteen randomly selected patients received HBIG at five to eight week intervals throughout the study, and 13 other control patients received no immunoglobulin. During a follow-up period of 14 to 30 months, none of the HBIG-treated and 12 of the control patients developed evidence of exposure to virus B hepatitis, including 10 with HBs Ag antigenemia (p is less than 0.001): five of these remained persistently antigen positive. Evidence of non-B hepatitis was found in 8 HBIG-treated and in 3 non-treated patients. Only two HBIG-treated patients developed active antibodies against hepatitis B surface antigen. Thus, HBIG seems effective in preventing hepatitis B in hemodialysis patients, provided the interval between two injections is not greater than two months. However, prolonged administration of HBIG may impair passive-active immunization to hepatitis B virus.


The kidney in tropical snakebite.

The kidney in tropical snakebite. Renal pathological changes were studied by renal biopsy in 31 patients bitten by tropical poisonous snakes which included seasnake (2 cases), cobra (11 cases), green-pit viper (8 cases) and Russell's viper (10 cases). Renal failure was present only in patients bitten by seasnake and Russell's viper. Glomerular mesangial proliferation was noted in the victims of cobra, green-pit viper and Russell's viper. There was deposition of IgM AND C3 in the glomerular mesangium with extension along the capillary walls. Fibrin deposition was seen in green-pit viper cases. By electron microscopy electron dense deposits were observed in the glomerular basement membrane-like matrix. Irregular thickening of the basement membrane was found in cobra cases. Vascular changes included arteritis of the interlobular artery with C3 deposition in the arterial walls in Russell's viper cases and thrombophlebitis in both green-pit viper's and Russell's viper's victims. Dense deposits of C3 in the arteriolar walls were noted in viper-bite and cobra-bite. Tubular necrosis was demonstrated in patients envenomated by green-pit viper and Russell's viper. Necrosis was severe in seasnake and Russell's viper poisoning, but was mild in green-pit viper cases.


Glucose tolerance tests and their insulin and growth hormone responses in hemodialysis patients: are they reproducible? The concept that carbohydrate intolerance improves after hemodialysis has been challenged. Critical to this issue is the reproducibility of GTT in a dialysis population. Thirty-nine oral or i.v. GTT were performed on ten stable hemodialysis patients at weekly intervals for three weeks. Blood glucose was determined by both oxygen consumption rate during glucose oxidation and the ferricyanide method. The coefficient of variation of blood glucose ratios (Glucose at time X/Fasting glucose) by glucose oxidase varied considerably. With the i.v. GTT the coefficients of variation at 90 and 120 minutes were 27.9 and 36.8 percent in one patient but below 15 percent at 60, 90, and 120 minutes in the other four patients. Three of the five patients who received oral GTT displayed coefficients of variation greater than 20 percent at one or more sampling times. The coefficients of variation of the growth hormone ratio (Growth hormone at time X/Fasting growth hormone) during i.v. and oral GTT ranged from 2.1 to 83.6 percent. Coefficients of variation of insulinogenic indexes ranged from 16.3 to 59.3 percent. In summary, large variations in glucose, growth hormone and insulin occur during both oral and i.v. GTT when repeated on a weekly basis in stable hemodialysis patients.


Acute renal failure secondary to acute pyelonephritis. A six year-old girl presented with acute oliguric renal failure, secondary to acute, non-obstructive pyelonephritis. Evidence for pyelonephritis as the cause of renal failure included: the evolution of typical changes on serial intravenous pyelograms, an acute interstitial inflammatory exudate on percutaneous renal biopsy, and gram-positive cocci on gram stain of the biopsy tissue. Although a specific causative organism was not conclusively identified, enterococcus was isolated from the initial catheterized urine specimen. The patient recovered from the acute illness but was left with impaired renal function, hypertension, and cortical scarring. Acute, non-obstructive pyelonephritis can produce acute renal failure in children and must be considered in the differential diagnosis of this syndrome.


Glomerulonephritis associated with hepatitis B. report of a case and review of the literature. A 45-year old developed membranoproliferative GN seven years after acute hepatitis. He was found to be a chronic carrier of HBsAg, and glomeruli contained granular deposits of immunoglobulins (Ig), complement (C) and HBsAg. Six months later, HN persisted, but HBsAg has disappeared from glomeruli; Ig and C were still present. It was concluded that GN was probably due to a hepatitis B associated antigen, but not necessarily to HBsAg.


Radioiron and erythropoiesis: methods, interpretation and clinical application. Ferrokinetic studies have fallen somewhat out of fashion and this is probably because T 1/2, PIT and percentage utilization give a poor reflection of the state of erythropoiesis. Recent advances have, however, enabled total, effective and ineffective erythropoiesis to be measured. The technique is simple but time-consuming, and analysis of the data requires access to computing facilities. Nevertheless, when bone marrow erythroid activity must be assessed these radioiron methods offer a rational approach.


The kinetics of platelet production and destruction in man. Platelets are derived from the cytoplasm of mature marrow megakaryocytes through cytoplasmic demarcation by invaginating plasma membrane and fragmentation of cytoplasmic protrusions into marrow sinusoids. Thereafter, platelets survive in the circulation for about 9 to 10 days. Platelet production is regulated to meet the demands for circulating platelets by means of humoral stimulation. Mean platelet volume, about 10 fl, remains constant over a wide range of survival times and production rates. In normal individuals platelets are produced at a rate of 35 X 10(9)/1/day (or 2.5 X 10(10) fl/kg body wt.) and reflect directly the marrow megakaryocyte cytoplasmic mass. Platelets have important roles in haemostasis, arterial thrombogenesis, wound healing and atherogenesis. Measurements of platelet survival are useful as an in vivo indicator of platelet participation in pathogenesis and pharmacological prevention of these processes. At present platelet survival is most reliably determined by in vitro radiochromium population labelling. 51Cr-platelet disappearance curves require objective unbiased analysis, preferably by non-linear gamma function least squares computer fitting procedures.


Comparison of metrizamide with other myelographic agents. Metrizamide is an attractive myelographic agent with several advantages over other available myelographic agents. Radiographic detail is generally superior to Pantopaque and gas myelography, the material need not be aspiradted and does not appear to result in long-term complicaitons. Because of its low neuro-toxicity, it may be allowed to come into contact with the spinal cord and brain, unlike other water-soluble agents. Its main disadvantages are its tendency to diffuse into the CSF when run from one portion of the spinal canal to another and the occurrence of acute toxic effects such as vomiting and, rarely, seizures.


Pulmonary embolism and its prophylaxis following the Charnley total hip replacement. The incidence of pulmonary emboli after a standardized technique of total hip replacement in a series of 7,959 hip arthroplasties operated on between 1962 and 1973 was 1.04% fatal and 7.89% non-fatal. 1,174 had no prophylaxis against embolism with a fatality rate of 2.3% and non-fatal embolism in 15.2%. Phenindione, intravenous heparin and dextran all reduced the complication rate to about 1% fatal and 8% non-fatal but none was statistically better than another. Statistically, plaquenil (hydroxychloroquine sulphate), was as good as any of the other methods used and had few complications. Analysis of the blood groups, pre and post-operative hemoglobin levels, major and revision surgery showed little relationship to the incidence of embolism. The most frequent time of onset of embolism (75%) occurred in the second and third postoperative weeks with only 10% in the first week.


Hemorrhagic neuropathy of the sciatic, femoral and obturator nerves: case report and review of the literature. A 70-year-old female developed hemorragic neuropathy, involving the sciatic, femoral and obturator nerves, secondary to infection and trauma. Function returned adequately in one year in the manner of neuropraxia. Hemorrhagic neuropathy of the proximal lower extremity has been associated with hemophilia, anticoagulation therapy, trauma, hip surgery and bleeding arteriosclerotic disease of the distal aorta and iliac vessels. The majority of cases regain function in 1 year using conservative therapy.


Early detction of avascular necrosis of the femoral head by 99m technetium diphosphonate bone scan: a preliminary report. Since roentgenographic changes characteristic of avascular necrosis of the femoral head frequently do not appear for several months after onset of symptoms, it may be difficult to diagnose this condition in its early stages and then institute therapeutic measures designed to prevent collapse of the femoral head and to enhance repair. Bone scans made after intravenous injection of 99mTc DP revealed increased activity over the femoral head in 5 patients with avascular necrosis 2 to 5 months before changes appeared on conventional roentgenograms. Although increased activity at the site of the lesion is not specific for avascular necrosis, the correct diagnosis can usually be established by taking into account other clinical, roentegenographic, and laboratory findings. Bone scanning with 99mTc DP is safe, even for high-risk patients, and relatively simple to perform.


Primary results of conservative treatment and osteotomy in coxa plana: a radiological comparison. In comparison with conservatives measures, does varus and derotation osteotomy accelerate recovery and prevent femoral deformation in Perthes Disease? In groups of 25 treated with osteotomy, and 22 treated conservatively, the primary anatomic result after reossification was judged from the radiographs by visual appraisal, and that is without introducing any measurements. The severity of the disease (the maximum epiphyseal involment) was the same in both treatment groups. The anatomic result (the shape of the femoral head after reossification) was in both groups found to be related closely to the age of patient and the severity of the disease. There was no demonstrable improvement in anatomic result in the osteotomized group. This could be explained by a similar effect of the conservative and surgical treatments or that neither was effective.


Degenerative osteoarthritis associated with osteopetrosis. A case of osteopetrosis has been described in which bilateral osteoarthritis of the hips occurred before the age of 40. As the osteoarthritis was not explicable on the bases of deformity it was considered that osteoprtrosis might be the etiological factor. Further circumstantial evidence for this causal relationship has been found in a review of the literature.


Hip instability in myelodysplasia.

Hip instability in myelodysplasia. Hip stability with reference to the ambulatory capacity of the myelodysplastic child is considered in a retrospective study. In 104 cases followed between 1950 and 1975, the patients were subdivided into 6 groups based on lowest functional neurological level as determined by hip motor power. Ninety-eight major operative procedures were performed about the hip in 50 patients. Over 50% of these operative procedures proved unsuccessful in stabilizing the involved hips. Mustard's transfer of the iliopsoas was used in a small group of patients and hip stability was attained in all cases. Sharrard's transfer was successful in only 2/3 of the cases. In all 6 groups, no difference in ambulatory capacity could be shown whether or not the patient had hip stability.


Treatment of fractures of the hip and ipsilateral femur with the Zickel device: a report of three cases. Three case reports demonstrate the successful management of patients with fractures of the hip and ipsilateral femur using the Zickel device. The hip fractures were base of the femoral neck, trochanteric and substrochanteric. The ipsilateral femur fractures consisted of 2 shaft fractures and 1 supracondylar femur fracture. These 3 cases, added to those previously reported in the literature, suggest that this form of intramedullary fixation should be considered for fractures of the hip combined with fractures of the shaft of the femur and possibly even supracondylar region.


Aseptic necrosis of the humeral trochlea: a case report. An 8-year-old boy was diagnosed as having unilateral aseptic necrosis of the humeral trochlea on the basis of: loss of elbow carrying angle and decreased range of motion, radiographic demonstration of trochlear collapse and sclerosis. Partial resolution of the radiographic changes occurred within 17 months. In the absence of marked functional impairement, the treatment is conservative clinical observation.


Fibrous replacement of the deltoid muscle: a remediable cause of abduction contracture of the shoulder in scleroderma. A 32-year-old male with progressive systemic sclerosis developed shoulder abduction contractures secondary to fibrous replacement of the central portions of his deltoid muscles. Surgical release of the fibrous bands resulted in prompt restoration of nearly full shoulder motion. One month later, however, a similar band developed in the triceps muscle. Although the association in this cases may have been coincidental, the neraly simultaneous onset of muscle fibrosis and cutaneous manifestations of progressive systemic sclerosis suggests a causal relationship.


Loosening associated with G.S.B. hinge total elbow replacement in patients with rheumatoid arthritis. Total elbow replacement utilizing the G.S.B. hinge prosthesis will improve function in patients with ankylosed or painful, unstable elbows in the early postoperative period. However, painful loosening has been the primary long-term problem and has led to the abandonment of this concept even for salvage of the destroyed rheumatoid elbow joint.


Flexor tendon ruptures in the rheumatoid hand: bilateral flexor pollicis longus rupture. In a 42-year-old male with a 15-year history of rheumatoid arthritis, bilateral rupture of the flexor pollicis longus was associated with subluxation with radial deviation of the carpus and increased angulation of the tendon in relation to the navicular. Flexor tenosynovitis in the rheumatoid hand may present as carpal tunnel syndrome or ruptured flexor tendons. The condition is associated with invasive rheumatoid granulation tissue, vasculitis, ischemic necrosis due to compartment compression, and attrition rupture due to navicular bony protuberance.


Force and motion analysis of the normal, diseased, and prosthetic ankle joint. A 2-dimensional motion and force study of the ankle joint during gait has been carried out on normal subjects and patients with ankle joint disease, before and 1 year following total ankle replacemetn. The methods employed involved the use of high-speed motion picture film, force plate and foot-switch data. The Achilles and anterior tibial tendon forces, the compressive and tangential (shear) forces across the ankle during stance phase of gait were determined, based on a quasi-static analysis. During stance phase of gait normal subjects used a mean of 24.4 degree of sagittal plane ankle motion. Patients with ankle joint disease showed reduced motion which returned to near normal values 1 year following total ankle replacement. Compressive force across the ankle joint rose to about 5 times body weight during the latter part of stance phase. Backward, or aft, shear forces or nearly full body weight were demonstrated during all but the last 20% of stance phase. Patients with ankle joint disease apparently altered their gait to markedly reduce these forces. Following total ankle replacement, shear forces returned toward more normal values, but compressive forces were not significantly changed.


Benign osteoblastoma of the calcaneous.

Benign osteoblastoma of the calcaneous. This is a case report of a 29-year-old male with a chondroblastoma of the os calcis successfully treated by almost total resection of the tuber calcanei without sacrifice insertion of the tendon achilles.


Preliminary report of total ankle arthroplasty for osteonecrosis of the talus. Osteonecrosis of the talus secondary to adrenal corticosteroids is rare. The pathophysiology of the disorder is controversial. This is a report of bilateral talar necrosis secondary to steroid medications in a 23-year-old male. Conservative methods of management of the condition are not altogether satisfactory. Bilateral ankle replacement in this case resulted in alleviation of pain and improvement of function.


Morton's metatarsalgia.

Morton's metatarsalgia. In a series of 25 patients (predominantly women) with Morton's metatarsalgia, the most likely site for a neuroma is the third cleft of the left foot. If a swelling is present or if radiographic examination shows toe divergence then the diagnosis in unlikely to be a simple digital neuroma. A review of the literature suggests that there are other causes of pain in the forefoot. Usually the pain is diffuse by when it is localized, Morton's metatarsalgia is diagnosed. However, causes other than a digital neuroma, e.g. traumatic bursitis and rheumatoid arthritis, epithelial cyst, and foreign body should be borne in mind.


Monostotic Paget's disease of the spine. Mnostotic Paget's disease in the spine often presents with an atypical clinical and radiographic picture. Paget's disease should be included in the differential diagnosis of any sclerotic lesion of the spine. Although uncommon, the disease occurs even in young adults, and may present a diagnostic problem.


Ulnar nerve palsy in Paget's disease.

Ulnar nerve palsy in Paget's disease. A 73-year-old housewife with enlargement of her distal right humerus and especially the medial epicondyle due to Paget's disease developed an ulnar nerve palsy. Transposition of her ulnar nerve anterior to her elbow completely relieved her symptoms. A similar case of ulnar nerve palsy associated with expansion of the distal humerus due to Paget's disease seems not to have been previously reported.


Fibrous contracture of muscles following intramuscular injections in adults. Periarticular fibrous muscle contractures in adults from repeated injections in the same site is predictable. The causes of joint contracture in children are many and complex, but in adults it seems certain that this phenomenon is the result of repeated injections of analgesics or other agents into 1 muscle area. Any drug if repeatedly injected locally may cause fibrosis of the muscle and subsequent joint contracture. Five cases of bilateral abduction contracture of the shoulder in adults including the first case of bilateral abduction contractures of shoulder and hip plus bilateral flexion contracture of elbow and extension contracture of a knee are reported. No underlying disease which might predispose to this fibrosis of muscles was noted. The frequency and period of injections were variable over several years. In all patients the interference in activtities of daily living were serious, but the deformities were corrected by release of the fibrous band with relief of discomfort and restoration of joint motion without recurrence. Noting the potential complication of repeated intramuscular injections in one area, this practice should be avoided whenever possible in adults, as well as in children.


Cryosurgery in the treatment of bone metastases from renal cell carcinoma. Solitary metastasis is uncommon, occurring in 1.6% to 3.2% of patients with renal cell carcinoma. Because of the potential of survival, amputation of an extremity with a metastasis is frequently advocated, particularly after successful nephrectomy. The cure rate with amputation is approximately 30%. Cryosurgery for treatment of localized and limited bony metastasis in an alternative to more radical surgery. This is a report of follow-up observation of the original series of cases as well as the addition of 4 new cases with multiple metastasis.


Low doses of 1,25-dihydroxycholecalciferol increase mature bone mass in adult normal rats. Low doses of 1,25-DHCC cause a significant increase in trabecular and cortical bone mass of the mature rat skeleton by stimulated endosteal bone formation. The increased serum contents of calcium and inorganic phosphate give rise to a moderate nephrocalcinosis. An increased bone resorption occurs upon toxic dose levels causing profound nephrocalcinosis. Similar doses of 25-HCC do not affect the mature bone.


The cellular basis of bone turnover and bone loss: a rebuttal of the osteocytic resorption--bone flow theory. There is now sufficient evidence to conclude that the osteocytic resorption--bone flow theory of bone turnove is untenable. According to this theory bone is resorbed not from the surface by osteoclasts but from within by osteocytes, towards which bone flows through tissue space away from bone forming surfaces. The need to invoke resorption by osteocytes stems from the belief that too few osteoclasts are present to account for normal bone resoption, a belief which reflects unawareness of the enormous capacity of the osteoclast and the rapidity of its advance. The belief that osteocytes resorb substantial amounts of bone rests on invalid conclusions from indirect techniques, various artifacts of specimen processing and unawareness of the microscopic characteristics of woven bone. Osteocytes enlarge their lacunae by resorbing bone only as a prelude to resorption from the surface, the osteocyte and osteoclast working together as a resorbing unit. The belief that bone can flow is incompatible both with the physical properties of bone and with a substantial body of evidence relating to Haversian remodelling; the experimental data purporting to demonstrate such flow can all be explained by conventional concepts of bone turnover.


Chondrogenesis in outgrowths of muscle tissue onto modified bone matrix in tissue culture. Connective tissue outgrowths of muscle occur in vitro onto a substratum of bone matrix gelatin (BMG) chemically modified by various inorganic and organic cations or anions. Outgrowths onto BMG denatured by lyotropic concentrations of Ca2+ or complexed by only 1 mmole/1 of Cu2+ differentiate into fibrous tissue only. Onto BMG complexed with either positively or negatively charged organic molecules, the product was also fibrous tissue. Outgrowths onto undenatured and partially recalcified MBG differentiated into cartilage. These observations substantiate the view that differentiation of cartilage in tissue culture occurs in response to the undenatured form of a bone matrix protein molecular and not an unspecific surface net electrochemical charge.


The glycosaminoglycans of human articular cartilage: concentration and distribution in different layers in the adult individual. The articular cartilage from morphologically normal femoral heads from 7 humans, aged 50-85 years, was sectioned parallel to the surface firstly at 40 micron thickness and then serially at 200 micron thickness to the cartilage-bone junction. Pooled sections from separate layers were used for analysis of the glycosaminoglycans by Cetylpyridinum chloride and ECTEOLA-cellulose microcolumns. The total concentration of glycosaminoglycans per dry weight tissue showed an increase with distance from the articular surface. The increase was shown to be due, principally, to keratan sulphate, while the levels of hyaluronic acid and chondroitin sulphate showed a proportional decrease with depth. The 40 micron thick superficial layer contained a considerably lower concentration of both keratan sulphate and chondroitin sulphate than the rest of the cartilage. These superficial layer glycosaminoglycans, and particularly chondroitin sulphate, showed a more polydisperse distribution according to molecular weight/charge density than the corresponding glycosaminoglycans of the more deeply situated layers. In view of findings on bovine articular cartilage of different age-classes reported previously, these features of the superficial layer appear to represent the normal biochemical structure.


Compact bone fatigue damage: a microscopic examination. Flexural fatigue tests of bovine bone specimens produced fracture surfaces that were transverse on the tension side and oblique on the compression side. Similar fracture patterns were produced by bending tests with a single applied loading. Microscopic examination of flexural fatigue specimens prior to complete established that fatigue fracture is caused by the progressive accumulation of diffuse structural damage. The microdamage observed on the tension side consisted primarily of separation (or debonding) at cement lines and interlamellar cement bands. Tensile cracks in interstitial bone were also observed. The major damage modes on the compression side were oblique cracking and longitudinal splitting. The fatigue fracture patterns observed for the bone specimens correspond to the types of fatigue fractures observed clinically. Compact bone fatigue fractures in areas of longitudinal tensile stresses are generally seen as transverse lesions, whereas fatigue fractures in areas of longitudinal compressive stresses are normally oblique fractures. The diffuse nature of the observed fatigue damage is consistent with the hypothesis that microdamage caused by mechanical loading may serve as a stimulus for in vivo bone remodeling.


Etiological factors in the pathogenesis of femoral trabecular fatigue fractures. Detailed histological evaluation of 72 femoral heads in terms of bone density, cartilagenous integrity and number of stress fractures in 3 different clinical groups of patients suggest that femoral trabecular fatigue fractures are largely determined by the degree of osteoporosis in all clinical states. The state of the hyaline cartilage also contibutes to the development of these fractures but only when the cartilage is degenerated to a severe degree as seen in rheumatoid arthritis. Both bone density and cartilage viability may be determining factors in the pathogenesis of trabecular stress fractures in rheumatoid hips.


The etiology of Paget's disease of bone. The etiology of Paget's disease is not known but recent studies of the ultrastructure of bone cells in pagetic lesions have raised the possibility of a viral etiology. In 41 of 41 patients evaluated in France and Los Angeles characteristic nuclear inclusions were found in osteoclasts only. These structures were similar to nuclear inclusions found in the slow virus infection of the brain, subacute sclerosing panencephalitis. Definitive identification of a virus or viral antigens in pagetic lesions awaits future studies. Other possible etiologies of Paget's disease include an inborn error of connective tissue biosynthesis, a disorder of hormone secretion, a vascular disorder, an autoimmune state, and a neoplastic transformation of bone cells.


Orthopedic management of Paget's disease of bone. The role of the orthopedic surgeon in the management of Paget's disease is in: evaluation and treatment of the cause of a patient's pain; evaluation of any deformities; treatment of fractures and tumors in affected bones. Pain due to active disease must be differentiated from nerve compression syndromes and arthritic pain because effective medical treatment is now available for pagetic bones. Spinal stenosis and sciatica are frequent in patients with Paget's desease because of vertebral body remodeling and collpase. Femoral and pelvic osseus pain may improve with treatment while an arthritic hip will remain symptomatic and require hip joint replacement. On one hand, bowed femora with inactive disease appear to be subject to an aching type of pain that does not respond well to antipagetic agents. On the other hand, for some unknown reason, tibial symptoms may respond dramatically to the same treatment. Biopsy is necessary only to exclude neoplastic transformation. Bone scans are useful to screen for distribution of the disease. The serum alkaline phosphatase and 24 hour urinary hydroxyproline determinations are the main indicators of the response of the disease to treatment.


Human calcitonin treatment of Paget's disease of bone. Human calcitonin has proven to be an effective drug in the management of Paget's disease. Bone pain decreased in a high percentage of cases and biochemical indices improved in all but a few instances. Radiologic regression of the disease often was seen after several years of treatment. The drug has been uniformly effective when administered to patients who have develped resistance to porcine or salmon calcitonin due to circulating antibodies. The incidence of side effects, mainly facial flushing and nausea, was variable and uncommonly resulted in discontinuation of treatment. Further studies are required to establish the minimum effective dose.


The X isochromosome-X syndrome [46,X,i(Xq)]. Report of three cases with review of the phenotype. It is important not to confuse the 46,X,i(Xq) syndrome with the 45,X classical Turner's syndrome. There are profound cytogenetic and clinical differences between the two syndromes, which must be borne in mind in the differential diagnosis of amenorrhea and of infertility.


Accidental bed deaths in infants due to unsafe sleeping situations. Sixteen accidental deaths of infants occcurred in Wayne County (Detroit) during 1974-1975 as a result of unsafe sleeping environments. Thirteen of these deaths resulted from different modes of asphyxia, two were due to falls, and one drowned. Differential diagnoses are pointed out. It is estimated that over 600 infants die each year in the United States due to unsafe sleeping conditions. Despite the magnitude and importance of this problem, little has been provided to the public in the form of preventive education. Federal regulations, passed in 1974, control the manufacture of new cribs but do not affect the existing unsafe cribs. Suggestions for the prevention of such fatal accidents are outlined, including a safety check list for infant beds. The cooperation of all health professions is required to educate the public of these dangers to their infants.


Pindolol availability in hypertensive patients with normal and impaired renal function. Intravenous and oral pharmacokinetics of pinlolol were studied in 18 hypertensive patients-9 with normal renal function and 9 with impaired renal function. Analysis of data showed that a linear two-compartment model was suitable to describe the pindolol kinetics. Compared with patients with normal renal function, patients with chronic renal failure exhibited: (1) unchanged transfer rate constants and distribution volumes and (2) decreased total body clearance with decreased renal clearance and unchanged nonrenal clearance. Analysis of oral data by the Loo-Riegelman method showed that the pindolol absorption kinetic was not first order. Compared with patients with normal renal function, patients with chronic renal failure exhibited decreased fraction of dose effectively absorbed and increased initial rate of absorption. The initial rate of absorption was inversely correlated with the creatinine clearance. The study disclosed evidence that absorption was modified in chronic renal failure.


Physiologic and pharmacologic influences on adrenergic regulation of renin release. Changes in hemodynamic variables and plasma renin activity (PRA) induced by short-term alteration of blood pressure and sympathetic nervous system activity were studied in normotensive and hypertensive men on high-sodium and low-sodium intake. Blood pressure and heart rate alterations caused by standard cold pressor tests, amyl nitrite inhalation, phentolamine infusion, and phenylephrine infusion were recorded. PRA was measured at time 0, 5, 15, and 30 min. No change in PRA occurred in either group following cold pressore test and amyl nitrite inhalation. Phenylephrine suppressed PRA in normal but not hypertensive subjects, and phentolamine elevated PRA in normotensive and hypertensive subjects regardless of diet. Short-term stimulation of the sympathetic nervous system does not appear to elevate PRA in man. Suppression of PRA by an alpha agonist was not observed in hypertensives and may reflect barorecptor insensitivity in this group of subjects.


Nifedipine, a new antihypertensive with rapid action. Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered siblingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176/89 and to 47/19 mm Hg by an additional 10 mg.


Digoxin in hyperthyroidism.

Digoxin in hyperthyroidism. A patient with chronic atrial fibrillation developed hyperthyroidism. Increasing doses of digoxin were required to maintain satisfactor ventricular rate control. The systemic availability of oral digoxin was decreased in this patient. The metabolism of digoxin was studied in the hyperthyroid rats. The plasma digoxin concentrations were significantly decreased in the hyperthyroid rats. A threefold increase in digoxin excretion in the bile of the hyperthyroid rats was associated with these changes in plasma digoxin concentrations. Conversely, hypothyroid rats excreted less digoxin in the bile when compared with control and hyperthyroid rats. Thus, changes in digoxin absorption and its biliary excretion result, in part, in a decreased therapeutic effect of digoxin based on dose in hyperthyroidism.


Plasma protein binding of basic drugs. I. Selective displacement from alpha 1-acid glycoprotein by tris(2-butoxyethyl) phosphate. The protein binding of a number of basic drugs has been shown to be inhibited when blood is collected in Vacutainer tubes. We found that the plasticizer tris(2-butoxyethyl) phosphate (TBEP), present in plasma collected in Vacutainers, was a potent inhibitor of alprenolol and imipramine protein binding. Its concentration in the plasma could quantitatively explain the displacement phenomenon. Alprenolol binding to a solution of a physiologic concentration (0.67 gm/L, 0.015 mM) of alpha 1-acid glycoprotein (orosomucoid) was decreased from 75% to 16% by addition of 10 microgram/ml (0.026 mM) of TBEP, while imipramine binding was decreased from 69% to 13%. Alprenolol and imipramine binding to albumin and lipoproteins was virtually unchanged by TBEP. Due to its selective effect on binding to alpha 1-acid glycoprotein, TBEP may be a useful tool for studying plasma protein binding of basic drugs.


Plasma protein binding of basic drugs. II. Importance of alpha 1-acid glycoprotein for interindividual variation. The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2-fold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of alpha 1-acid glycoprotein for alprenolol (r = -0.75, p less than 0.001) and imipramine (r = -0.78, p less than 0.001), while there was no correlation for naproxen (r - 0.24, p greater than 0.1). This confirms recent experiments which showed that isolated alpha 1-acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.


Tolerance to marijuana: heart rate and subjective "high". In a 94-day supervised study of 30 subjects smoking marijuana, with drug-free periods interspersed, mean heart rate and subjective "high" decreased over the smoking period. Light smokers had greater chronotrophic and subjective effects than heavy smokers, but both demonstrated evidence of tolerance. Cumulation and minor withdrawal effects were noted.


Acebutolol disposition after intravenous administration. The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 ml/min/kg and the mean renal clearance, 2.68 ml/min/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two-compartment model. The mean fast and slow half-lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady-state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15-min infusions were used to predict plateau blood concentrations with good accuracy during an 8-hr dosage regimen.


Uricosuric effects of niridazole.

Uricosuric effects of niridazole. Niridazole, an antischistosomal drug, caused a 44% decrease in the serum uric acid (SUA) concentration in 11 patients with schistosomiasis. The mean SUA (+/- SE) was 6.3 +/- 1.4 mg/100 ml at baseline and 3.5 +/- 1.5 mg/100 ml (p less than 0.01) on day 7 of treatment. There was a significant increase in the urinary uric acid/creatinine ratio, from 0.446 +/- 0.165 at baseline to 0.550 +/- 0.145 on day 3. There was no significant difference on day 7. The fractional clearance of uric acid rose from 7.2 +/- 6.8% to 13.9 +/- 17.3% (p less than 0.01), indicating a uricosuric effect. Oxypurine excretion was unchanged. In a separate study on 7 other patients, the SUA remained low for 4 to 7 days after the last dose. Niridazole, although not an organic acid, has uricosuric effects.


Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole. Tolbutamide half-life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n = 2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within 1 to 2 hr of a single dose of sulfaphenazole and the tolbutamide half-life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing form of cytochrome P-450 with low activity for tolbutamide hydroxylation, whereas sulfaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.


Monoacetylhydrazine as a metabolite of isoniazid in man. The potent hepatotoxin, acetylhydrazine (monoacetylhydrazine), has been identified by gas chromatography-mass spectrometry as a urinary metabolite of isoniazid in man. Using a specific gas chromatographic assay procedure for acetylhydrazine, the urinary excretion of this metabolite in volunteers given a 300-mg dose of isoniazid was found to be 1.8 +/- 0.4% and 2.5 +/- 0.5% of the dose in the rapid and slow acetylators, respectively. In the same subjects the urinary excretion of diacetylhydrazine was significantly greater in the rapid acetylators, 23.0 +/- 2.0%, than in the slow acetylators, 4.9 +/- 0.9%. The results suggests that only part of the acetylhydrazine formed as a metabolite of isoniazid is excreted in the urine as acetylhydrazine and diacetylhydrazine and that a substantial proportion of the acetylhydrazine formed is further metabolized, possibly through the microsomal enzyme pathway known to be responsible for hepatotoxicity in experimental animals.


Error dependent on renal function when monoexponential equation assumed. Serum clearances of 125I-iothalamate and 131I-o-iodohippurate. An example from the literature has been used to demonstrate errors involved in calculating drug clearance by inappropriate use of the apparent drug distribution volume Vdext. The Vdext is always an overestimate of the true volume of distribution in a multicompartment system, and the degree of overestimation in using it to calculate clearance for such a system will increase as renal function increases. Drug dosages calculated on the basis of overestimated clearance values may give rise to overdosage in normal individuals, or therapeutic failure in severely uremic patients. Problems associated with the use of an oversimplified pharmacokinetic model for clearance calculations are discussed, together with the concept of model-independent calculations.


Drug metabolism in heavy consumers of ethyl alcohol. Data are presented on the rate of removal of tolbutamide from the blood from studies in heavy drinking, unemployed, male alcoholic subjects. In such subjects tolbutamide was removed faster than it was in normal subjects and faster than in patients with cirrhosis who are not drinking. This rapid removal rate persists for 4 to 9 wk after hospitalization and is reproduced with 400 gm of pure ethanol in 2 or 3 wk but cannot be reproduced with lesser amounts of beverage alcohol taken outside of the experimental study. Similar acceleration of the clearance rates was observed for warfarin and for phenytoin but could not be demonstrated for aminopyrine.


Phenacetin metabolism: effect of hydrocarbons and cigarette smoking. The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4-benzpyrene (benzo[a]pyrene), resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the  0-dealkylation of phenacetin to N-acetyl-p-aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half-life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first-pass metabolism in the liver.


Toxicity to heavy metals and relationship to seizure thresholds. The present study was designed to provide information on the effects of lead, mercury, and nickel on lethality, body weight, and brain excitability in the adult rat. Both short- (2 days) and long-term (6 wk) drug administrations were carried out in adult male albino rats (Sprague-Dawley, Zivic-Miller). Based on the mg/kg/day of drug given over a 2-day period, the LD50 values were as follows: Pb(Ac)2, 215; Pb(NO3)2, 65.9; MMC, 11.9; HgCl2, 4.5; Ni(Ac)2, 35-40; NiSO4, 35-40. High doses of each of the metals administered acutely caused a drop in body weight but had an inconsistent effect on flurothyl-induced seizure thresholds. Pb(Ac)2, 200 mg/kg/day for 2 days, produced a statistically significant anticonvulsant effect, while 50 mg/kg Pb(NO3)2 resulted in a fall in threshold. Both NiSO4 and Ni(Ac)2, 30 mg/kg, increased seizure threshold. Neither the organic nor inorganic mercury altered thresholds. Long-term administration of Pb(Ac)2, MMC, or HgCl2 resulted in marked effects on body weight but no significant change in brain excitability.


Late problems in burns.

Late problems in burns. In summary, the commonest late physical complications of the burn injury have been reviewed and an approach to their management described. An understanding of the pathophysiology of the conditions is invaluable in planning one's approach to these problems. The techniques to control and correct chronic wound and hypertrophic scar and contractural deformities have been described. We present only a brief summary of the techniques found most reliable in the management of a large group of burned children over many years.


Surgical reconstruction for congenital auriculomandibular deformities. The patient with ear, jaw, and cephalofacial soft tissue deformity presents a challenge, the resolution of which requires a careful program of surgical reconstruction. Restoration of the concavity in the ear region caused by the underdeveloped temporal bone and the hypoplastic paratid gland should precede otoplasty to insure proper spacial positioning of the new ear on the skull. The parotid-mastoid mound may be effectively augmented with autogenous jump-flap pedicled tissue, autogenous bone grafting, microvascular free-flap tissue transfer and alloplastic implants. Cartilage of Silastic frames may be used for subsequent otoplasty. When Silastic frames are used in ear reconstruction, we strongly recommend prophylactic use of a protective fascial-periosteal "fan" flap.


The role of alanine and glutamine in steroid-induced nitrogen wasting in man. 1. Administration of dexamethasone, 8 mg/day (0-02 mmol/day), for 5 days to normal subjects produced negative nitrogen balance, due to early and sustained increases in urinary urea nitrogen excretion 2. In eight subjects ingesting 0-9--1-6 g of protein day-1 kg-1 body weight the cumulative increment in urea nitrogen excretion averaged + 12-5 g (SEM 2-8, P less than 0-01) over the 5 days of glucocorticoid administration. 3. Increases in urinary urea nitrogen excretion could be related to both plasma alanine and blood glutamine changes by using a multiple regression equation. 4. These results suggest that corticosteroids induce increased release of alanine and glutamine by peripheral tissues, which may augment urea formation and negative nitrogen balance. 5. The correlation between increments in urea nitrogen excretion and increases in plasma arginine remains unexplained.


Effects of adrenaline injection on human plasma tryptophan and non-esterified fatty acids. 1. Subcutaneous injection of adrenaline into normal male volunteer subjects caused large increases of plasma non-esterified fatty acids and free tryptophan, but plasma total tryptophan fell considerably. Therefore increases of the percentage of plasma tryptophan in the free state were more marked than absolute increases of free tryptophan. 2. Plasma tyrosine fell slightly and plasma phenylalanine and cortisol were unaffected. 3. It is suggested that catecholamine release could lead to abnormalities of tryptophan disposition in stress and psychiatric illness.


Potentiation of pressor effects of noradrenaline and potassium ions in the rat mesenteric arteries by physiological concentrations of angiotensin II: effects of prostaglandin E2 and cortisol. 1. In the perfused rat mesenteric vascular bed, the effects of angiotensin II, cortisol and prostaglandin E2 on the vascular responses to noradrenaline or potassium chloride were studied. 2. Angiotensin II in subpressor concentrations potentiated the vasoconstrictor response to noradrenaline and potassium chloride. This effect of angiotensin II was inhibited in the presence of indomethacin and prostaglandin E2. 3. Cortisol in physiological concentrations inhibited the potentiating effect of angiotensin II. 4. Prostaglandin E2 enhanced the vasoconstrictor response to noradrenaline. This effect was not abolished by cortisol. 5. These results suggest that some actions of angiotensin II and cortisol in vivo are mediated by the regulation of prostaglandin synthesis or release.


The effect of human pregnancy on the pulmonary transfer factor for carbon monoxide as measured by the single-breath method. 1. The pulmonary transfer factor for carbon monoxide was measured by the single-breath method in 21 pregnant women with no previous history of cardiac or respiratory disease. Measurements were made at monthly intervals throughout pregnancy and once post partum. 2. The transfer factor was higher in the first trimester of pregnancy than in the non-pregnant state. There was a fall in the transfer factor during pregnancy until 26 weeks gestation, after which no further decrease was observed. 3. The changes in transfer factor were not explained by alterations in haemoglobin concentration or alveolar volume. 4. Simultaneous serial estimation of plasma 17beta-oestradiol were performed in all the subjects. There was no obvious direct relation between changes in the concentration of this hormone and transfer factor measurements.


Two methods for determination of renin secretion rates in rats. 1. Renin secretion rates in normal rats were determined with two different methods: (a) the product of renal plasma flow as measured by sodium p-aminohippurate and the difference between renal and peripheral vein renin activity; (b) the product of this latter difference and the renal plasma flow as calculated from the clearance and extraction of inulin. 2. The renin secretion rates, as calculated by these two methods, were not significantly different (P greater than 0-1) and were found to be highly correlated (r = 0-943; P less than 0-001).


Inter-relationships of carbonate, phosphate, monohydrogen phosphate, calcium, magnesium and sodium in uraemic bone: comparison of dialysed and non-dialysed patients. 1. Chemical and morphological features of uraemic bone disease were studied by comparison of bone composition in 44 patients with uraemia (12 dialysed and 32 non-dialysed) and 36 control subjects. The significant changes included decreased bone mineral carbonate associated with calcium, a concomitant increase in phosphate, and an increase in magnesium. There was also an increase in osteoid and a reduction in the specific gravity of the compact bone. 2. The most marked changes in bone composition were observed in patients with uraemia of more than 1 year's duration, who had been dialysed. Bone mineral sodium concentrations were not significantly altered in any group. 3. The changes in bone mineral composition appeared to be the result of several simultaneous and/or successive mechanisms: (i) loss of fixed base, calcium carbonate; (ii) replacement of carbonate by phosphate; (iii) the addition of immature bone mineral, which contains high concentrations of phosphate and relatively low concentrations of carbonate. 4. These observations are consistent with earlier views of the bone salt as an indefinite calcium/phosphate/carbonate complex. Variations in bone composition may arise from a reciprocal relationship between phosphate and carbonate. The bone mineral analogue that best explains these variations in bone composition is octacalcium phosphate carbonate [Ca4 (PO4)2(HPO4)x(CO3)1-x,zH2O].


The effect of certain chelating compounds on the urinary excretion of copper by the rat: observations on their clinical significance. 1. A screening procedure is described to assess rapidly the clinical potential of chelating agents for the treatment of Wilson's disease. 2. Rats were used as the test animal; they were kept in metabolic cages and the urine was collected in copper-free containers. The compounds investigated were given by mouth as a standard dose of 100 mg. Copper was determined by atomic absorption spectrophotometry. 3. Basal urine copper excretion was 65-1 +/- SE 2-93 nmol/24 h (4-1 microgram +/- 0-185). After penicillamine this rose to 367-1 nmol and after trien to 305-9 nmol. 4. Certain compounds caused a reduction in the amount of copper excreted in the urine, probably by forming insoluble chelates with the metal, hence rendering it unavailable for excretion at the glomerulus.


Alterations in the activity of enzymes of haem biosynthesis in lead poisoning and acute hepatic prophyria. 1. The activities of six of the enzymes of haem biosynthesis have been assayed in peripheral blood from patients with lead poisoning, acute intermittent porphyria or hereditary coproprophyria. 2. Compared with normal subjects the lead-poisoned subjects had highly significant depression of delta-aminolaevulinate dehydratase, coproporphyrinogen oxidase and ferrochelatase. 3. Lead-poisoned subjects had highly significant elevation of delta-aminolaevulinate synthase activity. 4. delta-Aminolaevulinate synthase activity was inversely related to the haemoglobin concentration. 5. Increased delta-aminolaevulinate synthase and decreased delta-aminolaevulinate dehydratase activity are also found in acute intermittent porphyria. 6. Increased delta-aminolaevulinate synthase, normal prophobilinogen deaminase and uroporphyrinogen decarboxylase and decreased coproporphyrinogen oxidase are found in both lead poisoning  and hereditary coproporphyria. 7. These enzyme changes explain the recognized patterns of porphyrins and prophyrin precurosrs in blood and urine in these conditions.


Plasma catecholamines and the pressor response to Sar1-Ala8-angiotensin II in man. 1. The initial blood pressure response to saralasin (Sar1-Ala8-angiotensin II) infusion was examined in 15 normal subjects, eight patients with untreated essential hypertension and 65 patients established on chronic haemogialysis (including six anephric patients), and related to measurements of plasma renin activity (PRA), angiotensin II, plasma catecholamines (noradrenaline and adrenaline), blood volume and extracellular fluid volume ([35S]sulphate space or exchangeable sodium). 2. A transient rise in arterial pressure, maximum after 5-6 min, occurred in all normal subjects, patient with essential hypertension and anephric patients, and in 41 of the 59 dialysis patients with kidneys. 3. In the normal subjects, saralasin infusion resulted in a significant rise in plasma noradrenaline (mean increase 360%, P less than 0-02) without change in plasma adrenaline concentration. The change in noradrenaline was significantly related to the change in mean blood pressure (P less than 0-05) and was similar to the response to 5 min of a 40 degree head-up tilt. 4. An increase in plasma noradrenaline also occurred in dialysis patients (P less than 0-005) but the change in mean blood pressure with saralasin in this group was inversely related to PRA (P less than 0-001) and angiotensin II (P less than 0-001), directly related to blood volume (P less than 0-001), but unrelated to the change in plasma noradrenaline. 5. The pressor response to saralasin may be mediated not only by angiotensin-like action on vascular receptors but also by an action on the central or peripheral autonomic nervous system.


Leg blood flow and central circulation at various blood volumes: a peroperative study of nine patients with varicose veins. 1. In a group of nine middle-aged patients undergoing varicose vein surgery, cardiac output, right atrial, pulmonary arterial and capillary pressures, and leg blood flow were measured after induction of general anaesthesia but before operation, and also during operation before and after blood substitution. 2. Under anaesthesia, the mean pre-operative blood flows in the superficial and common femoral arteries were 160 ml/min and 280 ml/min respectively. These flows are comparable with those obtained in other studies under similar conditions but lower than values obtained in conscious subjects. During the operation the leg blood flow decreased by 24%. As cardiac output remained unchanged, the fractional leg blood flow fell. After transfusion of 900 ml of blood the leg blood flow doubled. 3. It is concluded that anaesthesia, surgical trauma and variations in blood volume greatly influence the leg blood flow and that an adequate substitution of operative blood loss is of utmost importance to achieve an optimum peripheral circulation.


Effects of phenylalanine analogues on renal tubular reabsorption of amino acids in the rat. 1. A method is described for the serial determination of renal tubular reabsorption of amino acids in the ethanol-anaesthetized rat. It utilizes intravenous radio-labelled inulins, automated amino acid analysis and forced diuresis. 2. Intravenous loading with phenylalanine and infusion of phenylalanine analogues in this preparation decrease reabsorption of endogenous amino acids in accordance with existing concepts of amino acid transport. 3. Maximal tubular reabsorption (Tmax) could not be demonstrated for phenylalanine at plasma concentration below 9 mmol/l. 4. Infusion of phenylalanine analogues into phenylalanine-loaded ('phenylketonuric') rats did not specifically inhibit tubular reabsorption of phenylalanine and it is unlikely that any of the substances tested have a potential therapeutic use in man. 5. p-Guanidino derivatives of phenylalanine, in contrast to p-amino derivatives, appear to cause a dose-related basic aminoaciduria. 6. Consideration of urinary flow rates and sodium excretion suggests that the ethanol anesthesia does not modify amino acid reabsorption through effects on sodium transport or antidiuretic hormone.


The treatment of acute intermittent porphyria with laevulose. 1. The activities of the enzymes of haem biosynthesis were studied in 23 patients with acute intermittent porphyria. The mitochondrial enzymes delta-aminolaevulinate synthase, coproporphyrinogen oxidase and ferrochelatase were measured in leucocytes and the cytosolic enzymes delta-aminolaevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase in erythrocytes. 2. Leucocyte delta-aminolaevulinate synthase activity was elevated (P less than 0-001), with marked diminution of porphobilinogen deaminase activity (P less than 0-001) and reduction in the activities of delta-aminolaevulinate dehydratase (P less than 0-01) and uroporphyrinogen decarboxylase (P less than 0-005). 3. A therapeutic regimen based on intravenous laevulose infusion was studied. In four patients in acute attack and one in remission laevulose treatment was associated with a fall in delta-aminolaevulinate synthase activity, a rise in porphobilinogen deaminase and uroporphyrinogen decarboxylase activities, and a fall in urinary prophyrin precursor excretion (P less than 0-001). These studies provide a basis for the evaluation of the use of sugars in acute intermittent porphyria.


Excretion of active metabolites of vitamin D in urine and bile of the adult rat. 1. One-year-old male rats were injected intravenously with 200 pmol of 25-hydroxy[26(27)-methyl-3H]cholecalciferol per 100 g body weight and the presence of this metabolite of vitamin D, as well as other metabolites, produced during the following 8 h was examined in serum, urine and bile. 2. The chromatography data indicated an excretion of 25-hydroxycholecalciferol both in bile and urine and, in urine, also of 1,25-dihydroxycholecalciferol. In bile, fractions of labelled substances were also obtained which, according to their elution positions, might represent cholecalciferol and conjugated metabolites. 3. The excretion of active metabolites of vitamin D in normal urine might be elevated in chronic renal failure and, in conjunction with a reduced synthesis, contribute to the occurrence of renal osteodystrophy.


Effect of 30% oxygen on local matching of perfusion and ventilation in chronic airways obstruction. 1. Sixteen patients with chronic bronchitis and airways obstruction were given radioactive nitrogen (13N) by intravenous injection and by inhalation, while breathing air and after 10-20 min breathing 30% oxygen. The clearance of 13N from four zones of each patient's whole lung field was monitored. 2. The 13N clearance of each region in these patients with chronic bronchitis was much slower than in normal subjects. Oxygen breathing produced a significant delay in the clearance of intravenously administered 13N in 23 zones in 10 patients but no systematic change in clearance after inhaled 13N. 3. With inhalation of 30% oxygen there was no no significant change in the mean minute ventilation, tidal volume or arterial PCO2. 4. The results suggest that local hypoxic vasoconstriction is present in some patients on breathing air and that this is relieved by 30% oxygen, resulting in a diversion of local blood flow from well-ventilated to more poorly ventilated areas. The fall in VA/Q on 30% oxygen is insufficient to increase arterial PCO2.


Effect of acute hypoxaemia on plasma arginine vasopressin in conscious man. 1. Acute hypoxaemia had been reported to stimulate vasopressin release in animals. 2. Hypoxaemia induced by breathing 9-3% oxygen for 15-20 min failed to produce a rise in plasma arginine vasopressin concentration in six out of eight healthy human subjects. The two subjects who developed an increase in plasma arginine vasopressin concentration had a significant rise in serum cortisol. 3. Breathing 100% nitrogen until impairment of consciousness caused no rise in plasma arginine vasopressin concentration.


A fatality involving methapyrilene.

A fatality involving methapyrilene. Tissue concentrations of methapyrilene are given in a fatal case. There are no indications that methapyrilene had any synergistic or antagonistic effect with the patient's cardiopulmonary condition, although when taken in high overdosages the pharmacologic effects may be altered. This case was supported by other data in an attempt to elucidate as many contributing factors as possible in evaluating lethal levels.


Methapyrilene toxicity.

Methapyrilene toxicity. Seven cases of drug overdosage involving methapyrilene have been presented, five of which resulted in death. Methapyrilene blood levels ranged fron 1.2 to 3.0 mg% (Table 2). Five of the seven cases involved multiple drug dosage with ethanol, salicylamide, amobarbital, secobarbital, and/or scopolamine. Of the remaining cases, involving only methapyrilene, ome fatality occurred at a blood level of 2.7 mg%. The surviving case involved the reported ingestion of 100 tablets of Sleep-eze (2.5 gm methapyrilene), wherein serial lavage removed 1.1 gm of methapyrilene. Urinalysis revealed 2.52 mg% of methapyrilene in 1300 ml of urine. The methapyrilene blood level was too low to quantitate.


A death involving propranolol (Inderal). A 35-year-old female with a history of cardiac problems was found dead. She had been prescribed 40 mg of propranolol (Inderal) to be taken twice daily. Autopsy revealed the presence of a green liquid in the stomach, but there was no anatomic cause of death. Toxicologic analyses of appropriate body fluids confirmed the suspicion that the deceased had ingested a massive overdose of propranolol.


Hemodialysis in a patient with acute mercuric cyanide intoxication. Concentrations of mercury in blood, dialysate, urine, vomitus, and feces. The effectiveness of hemodialysis in removing mercury was examined in a 14-year-old boy with acute renal failure due to intoxication by 1.5 gm of mercuric cyanide. Mercury concentrations in blood, dialysate, urine, vomitus, and feces were measured. In some materials, the total mercury and the "free" mercury (inorganic and weakly bound) were determined separately. With the first hemodialysis, 1.4 mg of mercury was removed, but this amount decreased rapidly with subsequent dialyses. Fecal mercury excretion, on the other hand, was approximately 1 mg daily during the first two weeks. Excretion of mercury in urine did not exceed 126 microgram/day even during the polyuric phase. Losses in vomitus were insignificant. It is concluded that hemodialysis is of little use in elimination of mercury, even if performed after administration of dimercaprol.


Fluoride accumulation in bone and the effect on their physical properties in guinea pigs given different levels of fluoridated water. Guinea pigs were exposed to fluoridated water (2-20 ppm) for a period ranging from 15 to 42 weeks. The fluoride content of the bones increased in proportion to the concentration of fluoride in drinking water and the period of exposure. The rate constant of accumulation of fluoride in guinea pig bones was estimated to be 2.5 X 10(-2) week-1, with a half-life of plateau formation in the order of 28 weeks. This indicated that maximum accumulation of fluoride during a continuous exposure, or a computed complete elimination of fluoride after exposure, will take approximately four years. Although fluoridated water improved the weight gain of guinea pigs, no effect on physical properties of bones was observed. No other toxic effects of fluoride under these conditions were noted.


Rapid identification of drugs in the overdosed patient. A rapid analytical procedure is described for a variety of drugs that could be present in the overdosed patient. The technique used gives quantitative results for most of the drugs analyzed in serum using gas chromatography and incorporates thin-layer chromatography and spot tests for drug confirmation. The procedure is novel for it relies on the initial extraction of acidics, basics, and neutrals from serum acidified with hydroxhloric acid.


Direct extraction procedure for the analysis of neutral drugs in tissue. This paper describes an efficient extraction technique for the determination of neutral drugs in tissue. The extracts are clean and can be analyzed by gas liquid chromatography. The method gives good recoveries of most of the neutral drugs and the sensitivity is such that therapeutic levels can easily be detected.


Women's liberation groups as a primary preventive mental health strategy. As a preventive mental health worker in a community mental health center, I considered it part of my role to explore the possible therapeutic value of women's liberation groups in the community. I was particularly concerned with countering the sense of isolation and powerlessness prevalent among female adults in our suburban catchment area. Subsequent investigation and participant observation of women's groups bore out my expectation that many of the goals, premises, and methods of preventive mental health were compatible with those of women's liberation groups. These groups provided a very effective framework for personal as well as interpersonal and sociocultrual change in the direction of psychological growth.


The ombudsman: a serendipitous mental health intervention. It is proposed that the ombudsman program, originally conceived of as a protection of the political rights of individual citizens, can be profitably viewed as a primary prevention of psychological disorders. The ombudsman attempts to alleviate reality problems prior to the onset of psychological disruption by engaging in active change agentry in public and private bureaucracies. Two hundred randomly selected written complaints were analyzed to ascertain the types of problems brought to this program. The role of the mental health professional and training issues are briefly discussed.


Based on cultural strengths, a school primary prevention program for Asian-American youth. As Asian-American mental health workers in a community mental health center where there is very little being done to provide appropriate services to its Asian-American population, we felt a need to find effective mental health models for the unique cultural and linguistic characteristics of our people. The high-school primary prevention program described in this paper provides Filipino youth with a positive view of their cultural identity and a supportive place to examine how their cultural values and behavior differ from those of mainstream Americans. Recognizing that ethnic minorities need to rely on their own subculture for the kind of psychological and social support required for a positive mental health, the program is aimed at mobilizing the strengths and resources of that particular subculture. In this way, its members can more effectively cope with the larger culture.


Control and service implementation in drug abuse treatment programs. The major purpose of this paper is to examine the relationship between control and implementation of drug treatment services while controlling for the structure of the organization. It is based on a study of 19 drug abuse programs in eight counties of North Carolina. The analysis of the data indicates that greater control will not necessarily increase the effectiveness of organization performance; rather, for change to occur, control by professional personnel will have to decrease. This would allow the organization to be more responsive to environmental concerns, and therefore more effective.


Clinical pharmacology of flurbiprofen: a novel inhibitor of platelet aggregation. Studies are reviewed of the inhibitory effect of flurbiprofen, given in doses ranging from 50 mg to 200 mg per day for 1 week, on platelet aggregation measured by biological tests (adenosine diphosphate and collagen methods). Flurbiprofen at doses of 50 mg and 100 mg daily had a peak time of action of between 1 and 2 hours, the effects usually disappearing after 24 hours, and 100 mg flurbiprofen caused a similar decrease in platelet aggregation to 1 g aspirin daily. In a clinical study of 72 patients with chronic glomerulonephritis treated with doses of flurbiprofen up to 200 daily there was a significant correlation between the parameters of aggregation measured and treatment, and between proteinuria and adenosine disphosphate aggregation when the flurbiprofen dose did not exceed 100 mg daily.


Serum concentrations of flurbiprofen in rheumatoid patients receiving flurbiprofen over long periods of time. Serum concentrations of flurbiprofen were measured following single oral doses of 50 mg to 200 mg in patients who previously had received flurbiprofen over long periods of time. The apparent elimination half-lives in groups of patients who received different doses were not significantly different from each other nor from the value previously obtained in a group of healthy volunteers given a single oral dose of 50 mg. Areas under serum concentration versus time curves were linearly related to dose over the range of doses examined. The results indicate that the pharmacokinetics of flurbiprofen are not significantly dose-dependent over the range of doses studied and that administration of relatively high doses of flurbiprofen over long periods of time neither induces nor inhibits flurbiprofen metabolism.


Interaction study between phenprocoumon and flurbiprofen. The effects of flurbiprofen on various coagulation and haemostasis parameters were studied in 19 patients adequately anticoagulated on a fixed dose of phenprocoumon. Laboratory controls were performed 5 times at weekly intervals. Flurbiprofen 50 mg 3-times daily was given for 2 weeks after an initial control period of 2 weeks. The last control followed 1 week after cessation of flurbiprofen. All changes observed during the administration of flurbiprofen were quantitatively moderate; some reached statistical significance. The prothrombin time (%) Factor II and Factor X values fell; Factor II values remained unchanged. Factor IX values fell only in the first week on flurbiprofen and reached control values thereafter. Phenprocoumon concentration remained constant throughout. There was no change in spontaneous platelet aggregation. Although there was a slight, statistically significant increase in the Ivy bleeding time, it remained within the normal range. These findings suggest that the interference of flurbiprofen with oral anticoagulation is minimal and probably of no clinical relevance.


Flurbiprofen in rheumatoid arthritis therapy. Preliminary findings are reported from an open study of 300 mg flurbiprofen daily in 24 patients and from 6 out of 30 patients treated so far in a double-blind crossover comparison of 300 mg flurbiprofen daily and 150 mg indomethacin daily in the treatment of rheumatoid arthritis. The results indicate that flurbiprofen is effective in relieving symptoms and is better tolerated than indomethacin. Using an experimental model in rats to assess the anti-inflammatory activity of flurbiprofen, data suggest that flurbiprofen is unable to prevent an immunological type of inflammation but is capable of modifying the type and extent of cellular infiltration.


Noninvasive assessment of left ventricular performance in patients with chronic obstructive pulmonary disease. In patients with chronic obstructive pulmonary disease (COPD), the clinical differentiation between dyspnea due to left ventricular dysfunction and that due to pulmonary events is difficult. Invasive techniques have been the only reliable diagnostic approach. To assess the potential value of noninvasive techniques in this context, 27 patients with COPD and with clinically suspected left ventricular dysfunction were studied by echocardiography, radionuclide angiography, and right cardiac catheterization. In 20 (74%), adequate echocardiogram were obtained. Of these 20 patients, 17 had normal pulmonary arterial wedge pressures at rest and during submaximal handgrip exercise. Sixteen of these 17 had normal left ventricular performance by all three echocardiographic criteria used; in one patient, two criteria were not interpretable, but the third was normal. Results of radionuclide studies were normal in 15 patients, borderline in one, and not measurable in one. Of the three patients with abnormal wedge pressures, at least one echocardiographic criterion was abnormal in all. Radionuclide data were abnormal in two and not measurable in one. We conclude that left ventricular dysfunction is infrequently present in patients with COPD in whom such dysfunction is clinically suspected, that the two noninvasive techniques described here can be applied successfully to a high percentage of patients with COPD, and that the agreement among echocardiographic, radionuclide, and wedge pressure data is excellent.


Hemodynamic changes in chronic obstructive pulmonary disease. Right cardiac catheterization was performed in 136 patients with chronic obstructive pulmonary disease. Forty-three of these patients had a second study a mean of 25 months later (range, 18 to 38 months). The changes in hemodynamic data over a period of 25 months were small. The cardiac index decreased 6%, and the mean pulmonary arterial pressure increased 7%. The changes were similar in patients with and those without emphysema.