On the chemistry of 'black' pigment stones from the gallbladder.

Radiolucent (33 cases) and radiopaque (17 cases) black pigment gallstones from patients who underwent cholecystectomy were studied using several spectroscopic and chromatographic methods. Radiolucent pigment stones (mean Ca percentage 2.1%) are composed chiefly of degenerated tetrapyrrolic bile pigments (mean 85.3%) deriving from bilirubin and bilirubinates. Degeneration includes both polymerization and bacterial reduction and leads to products of different grade of polymerization. Final extraction residues (mean 55.5%), called the 'black pigments' are considered to be degenerated bile pigments of high molecular weight. The mean percentage of bilirubin (free and inorganic bound bilirubin) was 8.5%, while the percentage of lipids was very low (mean of total lipids approximately 2.7%). Radiopaque black pigment stones (Ca: 12.4%) were composed of 'black pigments', too, but contained large amounts of calcium phosphate (carbonate apatite) and/or calcium carbonate. 65% of the radiopaque stones were calcified by calcium phosphate. 'Black pigments' were degraded by chromate to maleimides and 2,5-pyrroledialdehyde. These degradation products can be prepared in the same way from normal bile pigments with a tetrapyrrole structure. Polymerized dipyrrolic bile pigments like polymer propentdyopent or 'mesobilifuscin' did not give 2,5-pyrroledialdehydes during chromate oxidation. Thus we conclude that the formation of 'black pigments' starts from the polymerization of tetrapyrrolic, but not from dipyrrolic units. Accumulation of unconjugated bilirubin and bilirubinates within the gallbladder will precede the development of 'black pigments' which play an important role in pigment gallstone formation.


Radioenzymatic estimation of noradrenalin in small plasma samples without prior extraction.

We have developed a radioenzymatic method for the estimation of noradrenalin in small plasma samples by utilizing partly purified phenylethanolamine-N-methyltransferase. Noradrenalin can be estimated in deproteinised plasma without prior extraction. The sensitivity of the assay is better than 2.5 pg. Inclusion of an internal standard with each sample is necessary as the enzyme reaction is slightly influenced by some components of the plasma. Prior extraction with alumina severely decreases the sensitivity of the assay.


Glycolic acid in urine. A colorimetric method with values in normal adult controls and in patients with primary hyperoxaluria.

An improved Chromotropic acid-sulfuric acid assay for urinary glycolic acid is described. The sample (0.5 ml or less) is precleaned by filtering through strongly acidic and strongly basic ion-exchangers and compared with a standard made up in normal urine. From the many compounds tested, only glyceric acid in pathologically high concentrations interfers partially; this interference can be recognized at 776 nm and eliminated by a second determination. Per man-day, 8--12 samples can be analyzed. Recovery of 0.8 mmol/l glycolic acid added to the urines of 12 persons was 100.6 +/- 4.7% (1 S.D., n=12) without, and 101.9 +/- 5.3% (1 S.D., n=12) with correction for isotope dilution of [1-14C]glycolic acid, respectively, using 0.5-ml sample volumes. The variation coefficients of a single determination were 1.5 and 2.1% without and with correction for isotope dilution, respectively (n=7). The method was checked by mass fragmentography. The following normal values were found in adults (n=15; x +/- 1 S.D. (range)): 47.3 +/- 10.1 (24.4--63.7) mmol/mol creatinine and 0.60 +/- 0.15 (0.29--0.91) mmol/day or 45.8 +/- 11.3 (22.2--69.0) mg/day. Two patients (F.G. and A.S.) with primary hyperoxaluria type I excreted glycolic acid between 112 and 379 mmol/mol creatinine and 1.21--5.64 mmol/day or 92--429 mg/day. Under vitamin B-6 treatment, urinary excretion decreased in one patient (F.G.) to 71--131 mmol/mol creatinine and 0.92--2.0 mmol/day or 70--152 mg/day.


Continuous monitoring in vivo of blood glucose, lactate, alanine and 3-hydroxybutyrate.

Methods are described for simultaneous continuous in vivo monitoring of blood glucose, lactate, alanine and 3-hydroxybutyrate. The methods use dialysis, immobilized enzymes and measure generated reduced pyridine nucleotides fluorimetrically. The methods are accurate, sensitive, stable, and are suitable for use in emergency situations or in clinical investigation.


Pancreatitis-like isoamylase pattern in normal persons.

On the assumption that a rise in the pancreatic type isoamylases may not necessarily indicate underlying pancreatitis, genetic studies of human serum and urinary amylase isoenzymes have been performed with the use of electrophoresis. Although the preponderant increase in the two principal pancreatic isoamylases Amylase-1 and 2 has been accepted to be a specific index of pancreatic involvement, 1.68% of normal persons had Amylase-2 with an elevated amylase activity (named "Dominant Amylase-2") up to the same levels as the major isoenzymes. Results of pancreozymin-secretin test and other laboratory findings of these persons with Dominant Amylase-2 were all within normal ranges. Pedigree studies confirmed an autosomal dominant mode of inheritance for this variant. The important of serial determination and pedigree investigations has been shown to distinguish normal persons having Dominant Amylase-2 from patients with pancreatitis without elevated amylase activity. The existence of an inherited trait of pancreatitis-like isoamylase pattern in healthy individuals must be born in mind before coming to a conclusion when amylase isoenzymes are used for clinical medicine, though preponderance of the pancreatic type isoenzymes in serum and urine has been revealed to be a characteristic finding in pancreatitis. Knowledge of amylase genetic polymorphism provides a scientific basis for amylase isoenzyme interpretation.


Quantitation of red cell porphyrins by fluorescence scanning after thin-layer chromatography.

This paper reports a new method for the quantitative determination of erythrocyte and plasma porphyrins by fluoroscanning of the methyl esters separated by thin-layer chromatography (TLC). After esterification overnight in the dark the polycarboxylated porphyrin methyl esters were extracted into chloroform and aliquots applied to the TLC plates within the range of quantities shown in a preliminary study to be directly proportional to fluorescence intensity. The accuracy and reliability of the technique was tested by comparison of RBC protoporphyrin values obtained by TLC with an established quantitative porphyrin solvent extraction method and with a rapid method presently in common use. Good correlation was demonstrated between the solvent extraction and the TLC techniques. The high sensitivity and adaptability of the TLC technique and its ability to clearly separate all the porphyrins present in the samples are discussed, along with the fluorescence mechanisms involved and the effects of instrumentation.


Interpretation of urinary oestrogen:creatinine ratio for monitoring fetoplacental function in late pregnancy.

In pregnancies with a normal outcome the oestrogen:creatinine ratio in early morning samples of urine showed a smaller day-to-day variation than the ratio in 24-h urine or the 24-h total oestrogen excretion, and a significant fall could be detected more easily. Patients admitted to hospital who eventually delivered a healthy baby provided a reference range which, after logarithmic transformation, increased linearly with period of gestation. A fall in log10 oestrogen:creatinine ratio exceeding 40% of this range is unusual in pregnancies with a healthy outcome, and suggest impaired fetoplacental function.


Separation fluoroimmunoassay methods for phenytoin in serum.

A separation fluoroimmunoassay system for phenytoin was established based on the use of a specific rabbit antiserum, a fluorescein-labelled ligand, and precipitation of the antibody-bound fraction of the labelled ligand with sodium sulphate. Simple measures were taken to obviate non-specific binding and matrix effects. Either the free fraction (in the supernatant) or thebound fraction of the labelled ligand was quantitated fluorimetrically. Assays of patient serum samples by either method correlated well with established gas-liquid chromatographic and radioimmunoassay techniques. Advantages of a separation based procedure as compared with previously described non-separation hapten fluoroimmunoassay techniques are that only simple instrumentation and assay reagents are required, and that the separation step may enable the removal of any interfering intrinsic fluorescence of serum samples.


The fatty acid composition of various lipid fractions isolated from erythrocytes and blood plasma of patients with Duchenne and congenital myotonic muscular dystrophy.

Ten lipid fractions, both neutral and phospholipids, were isolateed from erythrocytes of patients with Duchenne and congenital myotonic dystrophy. These fractions were: phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, sphingomyelin, lysophosphatidylcholine, phosphatidic acid, glycosphingolipids, triglycerides, diglycerides and one unknown. The fatty acid compositions were compared with control values. The major deviation was a decreased level of palmitoleic acid (16 : 1omega7) in three neutral lipid fractions. It was lowered from 9.1 to 1.3% in diglycerides and from 10.6 to 2.6% in triglycerides in myotonic dystrophy. In Duchenne muscular dystrophy this percentage was decreased from 9.1 to 4.0 in diglycerides. From blood plasma were isolated phosphatidylcholine, lysophosphatidylcholine, sphingomyelin and phosphatidylethanolamine. The myristic acid (14 : 0) content was raised in lysophosphatidylcholine (from 4.4 to 8.6%) and in sphingomyelin (from 3.3 to 5.0%) in myotonic dystrophy, In the latter phospholipid the stearic acid level was decreased from 18.6 to 12.8%. In phosphatidylcholine from plasma in myotonic dystrophy the level of eicosatrienoic acid (20 : 3omega6) was lowered from 3.1 to 2.0%. Plasma fractions from Duchenne dystrophy showed no deviation. The results do not constitute an explanation for the various biochemical abnormalities found in dystrophic erythrocytes. Neither do they point to a defect in a major pathway in lipid metabolism. However, an aberration in the de novo synthesis of lipids in immature red blood cells cannot be excluded.


Experimental optimization of the detection limit of two-step solid-phase radioimmunoassay.

For two-step inhibition radioimmunoassay (sequential saturation or delayed addition of labeled antigen) generally a higher sensitivity than for one-step inhibition radioimmunoassay (equilibrium assay) is expected. The detection limit of a two-step solid phase inhibition radioimmunoassay for human serum immunoglobulin A was minimized by statistical methods of experimental optimization. Under optimal conditions the detection limit was 2.3 ng IgA. This is about 1.8 times lower than the minimal detection limit of the one-step assay under similar conditions of the qualitative variables such as the origin of the antibody. This increase in sensitivity was associated with a decrease in the precision of the assay. The results are discussed with respect to the comparison of the one-step and the two-step assay and the usefulness of a sensitive radioimmunoassay in practice.


A simple screening method for plasma lipids by thin-layer chromatography with flame ionization detection.

Thin-layer chromatography was carried out on glass rods coated with Silica gel (chromarod) and the fractions were detected with a flame ionization detector (FID). This system was applied to the fractionation and screening of plasma lipids. As the relative response of the flame ionization detector depends on the nature of the lipids, correction factors had to be introduced. These correction factors were derived from comparison of the results of the thin-layer chromatography with flame ionization detection with those obtained by conventional chemical analysis of the same sample. The coefficients of variation of the lipid profiles were comparable for both techniques. The absolute lipid concentration for the various fractions obtained by combination of the concentration of the total lipids with the relative lipid profile, correlate very well with the values obtained by conventional chemical analysis of the various lipids.


A new approach to determining cholinesterase activities in samples of whole blood.

A sensitive method, especially suitable for clinical laboratories, for the routine determination of cholinesterase activities in whole blood is presented. This method is based on the hydrolysis of propionylthiocholine and the spectrophotometric determination of the thiocholine produced by reaction with 4,4'-dithiodipyridine. The reaction product 4-thiopyridone has an absorption maximum at 324 nm, so that measurement in the presence of hemoglobin is possible. Propionylthiocholine is used at the substrate for both plasma butyrylcholinesterase and erythrocyte acetylcholinesterase. These two enzymes, in the relative amounts at which they are present in human blood, split this ester at about the same rate. Consequently, a first determination gives the total activity of which each individual activity is about 50%. A second determination in the presence of a selective inhibitor ("Astra 1397") for plasma butyrylcholinesterase gives the activity of the erythrocyte acetylcholinesterase. The difference between the two values represents the activity of the plasma enzyme. The validity of the method and the reliability of the results were checked with each blood sample in two ways: (1) by determining the activities of whole blood with an earlier gasometric technique which uses blood sample dried on filter paper; and (2) by measuring the activities in separated plasma and erythrocyte hemolysate eith propionylthiocholine as the substrate.


Rapid quantitative surface immunofixation of proteins in polyacrylamide gels.

A new method is described which allows rapid identification of sub-microgram amounts of protein in polyacrylamide gels. The technique has been applied to samples of cerebrospinal fluid and serum and is suitable for localisation of both discrete protein bands and diffuse zones. Results from cerebrospinal fluid confirm that IgG is localised in the oligoclonal bands seen in multiple sclerosis. Given antibody excess, there is a linear relationship between the amount of protein applied to the gel and the density of the stained immune complexes on the gel surface.


Magnesium and phosphate in the serum of patients with medullary carcinoma of the thyroid.

Magnesium, phosphate, immunoreactive parathyroid hormone and calcium were measured in the serum of nine patients with medullary carcinoma of the thyroid and high serum calcitonin, and compared with the values in nine patients with normal serum calcitonin. Serum phosphate was significantly higher in the group of patients with high serum calcitonin (P less than 0.025). No correlation was observed between the serum concentrations of magnesium and calcitonin, nor of immunoreactive parathyroid hormone and calcitonin.


Indoleamine compartmentation in human blood.

Improved methods are described for the fluorimetric determination of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan (TRP) in plasma, platelet and RBC blood compartments. The methods for 5-HT and 5-HIAA utilize ion exchange chromatography and allow simultaneous determinations to be made on the same blood sample. The tryptophan assay is a modification of an existing extraction method. All of the 5-HT in whole blood was found to be associated with the platelet fraction (122.6 ng/ml), whereas all 5-HIAA was distributed between the plasma (78.3 ng/ml) and RBC (124.0 ng/ml) compartments. Tryptophan was found in all three compartments although the majority of this amino acid was in the plasma (4.3 microgram/ml) and RBC (1.7 microgram/ml) fractions.


Human erythrocyte phenol O-methyltransferase: radiochemical microassay and biochemical properties.

A radiochemical microassay for the determination of phenol O-methyltransferase (PMT) activity in human red blood cell membranes has been developed. Acetaminophen was used as the substrate. The apparent Michaelis-Menten (KM) value for acetaminophen was 21.2 X 10(-3) M. The apparent KM value for S-adenosyl-L-methionine, a co-substrate for the reaction, was 4.8 X 10(-6) M, and the pH optimum of the reaction was approximately 9.0 with four different buffer systems. Phenol was also tested as a substrate and had an apparent KM value of 2.0 X 10(-3) M. Human erythrocyte (RBC) membrane PMT activity did not have the biochemical characteristics of catechol O-methyltransferase, another RBC membrane methyltransferase enzyme activity. Blood samples obtained from 212 randomly selected adult white subjects had a mean activity of 134.5 +/- 41.5 pmol of p-acetanisidide formed per mg protein per hour (mean +/- S.D.). Activities varied from 44 to 282 units. There were no differences in the mean activities of samples from men and women. Experiments in which mixtures of "low" and "high" activity RBC membrane preparations were assayed for PMT provided no evidence that the variations in enzyme activity were due to the presence of endogenous PMT activators or inhibitors. RBC membrane PMT activity in blood from 9 patients with renal failure, a pathological state in which there are elevated circulating levels of phenols, was found to be significantly decreased with average activity of 76.2 +/- 9.7 (mean +/- S.E.M., P less than 0.001).


beta-Sitosterol as a nonabsorbable marker of dietary lipid absorption in man.

beta-[14C]Sitosterol was evaluated for its usefulness as a nonabsorbable marker of lipid absorption in intubation studies. A liquid meal, including [3H]triolein as a marker of absorbable lipid, was used. The beta-sitosterol was shown to remain well mixed with triolein in the gastric antrum, validating its suitability for this type of study. In small bowel fluid, the beta-sitosterol was shown to partition into the aqueous phase in proportion to triolein and its hydrolysis products. With this system, lipid absorption was shown to take place chiefly in the jejunum in normal individuals.


A preparative method for the isolation of genetic variant forms of glucosephosphate isomerase and a study of five variants.

A method has been developed for the rapid, quantitative separation of normal and abnormal glucosephosphate isomerase allozymes from individuals heterozygous for genetic variant forms of the enzyme. The method utilizes a substrate gradient elution of the enzyme from carboxymethyl Biogel and is far superior in terms of resolution and recovery to methods based on electrophoresis and isoelectric focusing. Five different genetic variant forms of the enzyme were isolated and subjected to a systematic comparison of their physical, catalytic and stability properties. While the physical and catalytic properties of most of the variants were similar, clear differences in the stability of the allozymes were apparent. In order to detect mutations affecting the stability, a series of different stability tests are required.


Cerebrospinal fluid enzymology: creatine kinase, lactate dehydrogenase activity and isozyme pattern as a brain damage index.

Blood serum and cerebrospinal fluid from a 4.5-year-old girl suffering from convulsive episodes of toxic origin were investigated for lactate dehydrogenase (LDH) and creatine kinase (CK) activities. Elevated levels of both enzymes were found. Furthermore CK was higher in the CSF (680 I.U./1) than in blood serum (160 I.U./1). The CSF activity was demonstrated mainly as the BB form (96%) for CK and H4 (63%) was the predominant form for LDH. Identical investigations were performed 45 h later and results compared with the first set. These data provide an additional example of interest in CSF enzymatic studies as a brain damage index.


Interference with the kinetic determination of acid phosphatase.

This study advocates cautious use of the kinetic determination method for acid phosphatase with alpha-naphthylphosphate as substrate and a diazonium salt for colour development. The occurrence of considerable blank rates due to the spontaneous hydrolysis of the substrate was noticed. Of the diazonium salts which were tested as alternatives for Fast Red TR, diazotised p-nitroaniline seemed to be useful. Also the interaction between plasma components and diazonium salts may influence the results of the determination. In this respect a number of possible interfering compounds was investigated and from these a structural element which may lead to side reactions was deduced.


Substrates for the assay of alpha-L-iduronidase.

Procedures are described for the preparation of two disaccharides, 4-O-alpha-L-iduronosyl-2,5-anhydro[3H]mannitol and 3-O-alpha-L-iduronosyl-2,5-anhydro[3H]-talitol, from heparin and dermatan sulfate, respectively. These disaccharides lend themselves to an easy assay of alpha-L-iduronidase which is based on the fractionation of the liberated neutral anhydro[3H]mannitol or anhydro[3H]talitol from the unreacted substrate by adsorption of the latter to Dowex 1. Investigation of the reaction conditions showed that the alpha-L-iduronidase activity (enzyme from human fibroblasts and Helix pomatia) was optimal at pH 3.6 in acetate buffer containing 0.01 M NaCl with iduronosyl-2,5-anhydro[3H]mannitol as substrate. For iduronosyl-2,5-anhydro[3H]talitol the pH optimum was 4.0 with the H. pomatia enzyme. The KM for iduronosyl-2,5-anhydro[3H]mannitol was 0.23 mM with human fibroblasts and 0.04 mM with Helix enzyme; a KM value of 0.02 mM was determined for iduronosyl-2,5-anhydro[3H]talitol with the Helix alpha-L-iduronidase.


An enzymic determination for serum phospholipid.

A new colorimetric determination for serum phospholipid is described. Firstly, serum phospholipid is incubated with phospholipase C from Bacillus cereus, and then the released diglyceride and triglyceride are hydrolyzed completely to fatty acid and glycerol by lipoprotein lipase from Pseudomonas fluorescens. Secondly, the glycerol produced is enzymatically determined by glycerol dehydrogenase in the presence of NAD+, using phenazine methosulfate-nitro blue tetrazolium as color reagents. The absorbance at 570 nm is recorded. The amount of the glycerol from phospholipid is calculated by subtracting the amount of glycerol from triglyceride from the amount of total glycerol. The present method requires only 20 microliter of serum and a 40 min incubation and is highly reproducible. The results obtained show good correlation with those obtained by a chemical method (correlation coefficient, 0.925) or the phospholipase D-choline oxidase method (correlation coefficient, 0.936). These results strongly suggest that the proposed method can be utilized as a routine clinical test.


Lysosomal hydrolases in cystic fibrosis livers.

The specific activity of several lysosomal hydrolases in normal and cystic fibrosis (CF) livers has been investigated. Neuraminidase activity with respect to two natural substrates (fetuin and bovine submaxillary mucin) is normal in CF livers. No significant differences were found between CF and normal livers in 4-methylumbelliferyl-alpha-D-mannosidase specific activities determined at three different pH values (4.3, 5.65 and 6.5) corresponding to lysosomal, golgi and cytosolic components of the enzyme, respectively. The specific activities of p-nitrophenyl-beta-D-mannosidase and 4-methylumbelliferyl-beta-N-acetylglucosaminidase were also both similar in CF and normal livers.


3,4-Dimethoxyphenylethylamine excretion of normals and schizophrenics, behaviour during total fasting.

A specific and sensitive radioimmunoassay for the determination of 3,4-dimethoxyphenylethylamine (3,4-DMPEA) in urine was developed. In 5 fasting healthy volunteers excretion of 3,4-DMPEA was not diminished, indicating that this substance can be regarded as an endogenous metabolite. In addition, the time profile of the excretion of 3,4-DMPEA was measured in one patient during total fasting. In 25 patients with schizophrenic psychoses, 9 psychiatric patients without schizophrenia and 80 control patients excretion of 3,4-DMPEA was compared. No significant differences could be observed between these three groups.


Isoelectric focussing of proteins on thick (500 micron) modified cellulose acetate gel membranes.

A method is described for isoelectric focussing proteins on thick (500 micron) cellulose acetate gel membrane modified by boron trigluoride in methanol. Longer pH gradients could be formed and larger sample volumes could be applied than on the normal thickness product.


Acute endocrine profile of sulpiride in the human.

Normal men and normally menstruating women received i.m. injections of 0.1 to 4.0 mg/kg sulpiride. This psychotropic drug induced a very rapid (already significant after 5 minutes) and sustained (still significant after 7 hours) elevation of prolactin (PRL) concentrations in all subjects with no consistent modification of LH and FSH. After injection of 4.0 mg/kg, there was similarly no modification of mean TSH concentrations in the women tested in the luteal phase, as well as of mean GH levels in men. Sulpiride prevented the inhibitory effect on PRL levels of 500 mg levodopa, administered orally simultaneously; levodopa administered 2 hours prior to sulpiride failed to counteract the PRL-stimulatory effect of sulpiride. Under chronic sulpiride-induced hyperprolactinaemia, levodopa exhibited however a very slight inhibitory effect on PRL concentrations. These data are in agreement with the hypothesis that sulpiride acts mainly at the pituitary level by blocking dopamine receptors of the lactotropes and support the concept that the menstrual cycle perturbations observed under chronic sulpiride administration result from hyperprolactinaemia itself or from a mechanism quite similar to that by which sulpiride induces hyperprolactinaemia.


Autoimmune thyroid disease and the polymyalgia rheumatica-giant cell arteritis syndrome.

In a study of 250 patients with autoimmune thyroid disease, seven (2.8%) were found to have polymyalgia rheumatica or giant cell arteritis. All cases occurred in female patients over the age of 60 years, a prevalence in this group of 9.3%. No cases of either disorder were seen in a control population of 150 female patients over the age of 50 years attending a cardiac clinic at the same hospital. Awareness of this association may allow earlier diagnosis and treatment of this syndrome in elderly patients with thyroid disease.


Thyroidal hormone metabolism in obesity during semi-starvation.

Six obese subjects were studied over a period of 12 weeks whilst on a 1260 kJ (300 kcal) formula diet. Weight loss was initially rapid, but later slowed markedly despite good patient compliance. The basal metabolic rate (BMR) fell in all patients during the study. Plasma triiodothyronine fell in all patients, whilst the plasma half-life of thyroxine increased. Plasma thyroxine, reverse triiodothyronine (reverse T3) and the serum prolactin and thyrotropin response to thyroliberin all showed no significant change.


Pituitary-gonadal function in XYY and XXY men identified in a population survey.

Evidence on pituitary-gonadal function in XYY subjects has been inconclusive and based, for the most part, on selected samples such as institutionalized individuals or subjects examined for particular behavioural or medical characteristics. We report the results of a double-blind hormonal study of a sample from an entire well-defined birth cohort of men. The starting population included all males born in Copenhagen during the period 1944-1947 comprising 31,436 individuals. Chromosome determinations conducted on 4139 men representing the top 15.9% of the height distribution of the sample identified 12 XYY and 16 XXY men. All the XYY subjects and 14 XXYs consented to participate in an individual case study and were individually matched to XY controls selected from the total sample. The XYY men had significantly higher plasma concentrations of LH, FSH and testosterone than matched XY controls. There were no differences in testicular size and in the reported number of children between the XYYs and control group. XXY men from the same population showed significantly higher LH and FSH, lower concentrations of testosterone, had smaller testes and reported fewer children than their matched controls.


Hyperprolactinaemia in renal disease.

Basal prolactin concentrations in 357 patients with renal disease of defined pathology have been compared with those in 210 control subjects. Elevated prolactin concentrations were found in 113 renal patients (32%) including 53 patients in whom elevated concentrations were possibly attributable to drug therapy. In the remaining 60 patients who had hyperprolactinaemia not attributable to drugs, elevated concentrations (P less than 0.005) were found exclusively in patients with impaired renal function. A significant correlation was observed between prolactin and creatinine concentrations in these patients (r = 0.45 P less than 0.005) and prolactin reverted towards normal after successful renal transplantation. A significant arteriovenous prolactin concentration difference across the kidney (mean 16% range 8-29% P less than 0.02) was found in seven patients with non-renal non-endocrine disease. It is concluded that the hyperprolactinaemia found commonly in patients with impaired renal function is only partly attributable to drug therapy. The positive correlation between prolactin and creatinine reversion of prolactin towards normal after successful transplantation and arteriovenous hormone concentration differences across the normal kidney suggests that the kidney has a important role in prolactin metabolism. Abnormal regulation of prolactin secretion in renal failure may also be involved.


Effect of acute myocardial infarction on pituitary-testicular function.

The effect of acute myocardial infarction on the secretions of LH, FSH and testosterone was studied in thirteen male patients. Plasma testosterone fell transiently on the fourth day after acute myocardial infarction. This was accompanied by a rise in LH on the same day which persisted for a week after infarction. Serum FSH showed no significant change. The data suggest that following the medical stress of myocardial infarction, testosterone concentration was suppressed resulting in a compensatory rise in LH.


The effect of alpha adrenergic receptor blockade on the glucagon-induced growth hormone response.

The effect of a alpha adrenergic blockade (phentolamine) on glucagon induced growth hormone response was tested in five normal men. There was no significant difference in growth hormone concentrations between the glucagon test and the glucagon-phentolamine test (mean maximum level, 23.4 +/- 3.7 ng/ml and 23.1 +/- 5.9 ng/ml, respectively). Insulin secretion was significantly higher (P less than 0.025) 30 and 60 min after an injection of glucagon in the glucagon-phentolamine test. The results suggest that the stimulation of growth hormone secretion by glucagon is not mediated through an alpha adrenergic mechanism.


Pharmacokinetics of 1-desamino-8-D-arginine vasopressin (DDAVP) in patients with central diabetes insipidus.

The pharmacokinetic parameters and biological duration of action of DDAVP were measured in five patients with central diabetes insipidus of differing severity. Plasma half-life correlated significantly with the duration of action (r = 0.89, P less than 0.05), 0ut there was no correlation between the severity of diabetes insipidus and either plasma half-life or duration of action of DDAVP.


Urinary excretion of 3,3',5'-triiodothyronine (reverse T3).

A simple and sensitive radioimmunoassay for reverse T3 in urine using small Sephadex G25 fine columns is described. The recovery of rT3 added to urine was on average 101.0 +/- 4.2% (mean +/- SEM). Detection limit was 4 pg/column. Urine excretion of rT3 (mean +/- SD) was 72.0 +/- 32.1 ng/24 h in 61 healthy euthyroid subjects with a slight increase with age (P less than 0.05), 28.8 +/- 18.2 ng/24 h in 12 hypothyroid patients and 183.6 +/- 79.7 ng/24 in 25 hyperthyroid patients.


Glucose-induced insulin secretion in patients with parathyroid disorders.

Glucose-induced insulin secretion was studied in ten patients with primary hyperparathyroidism and two with idiopathic hypoparathyroidism both before and after treatment. In each individual, insulin secretion during an intravenous glucose tolerance test was greater when the plasma calcium was higher. No consistent change in insulin secretion with plasma calcium concentration was observed during an oral glucose tolerance test. These findings could be explained by the suggestion that insulin secretion provoked by orally administered glucose is enhanced by gut hormones which may stimulate insulin secretion by a mechanism independent of extracellular calcium.


Johanson-Blizzard syndrome in a large inbred kindred with three involved members.

An infant with aplastic alae nasi, imperforate anus, focal aplasia cutis over the fontanels, microcephaly, and mental retardation is presented as an example of the Johanson-Blizzard syndrome. The infant failed to thrive and had evidence of malabsorption. He died at 4 months of age. The occurrence of extensive consanguinity in his family and the occurrence of two other members of the kindred with a similar syndrome indicate that this disorder is transmitted by an autosomal recessive gene.


Autosomal recessive inheritance of metaphyseal dysplasia (Pyle disease).

Two young adults with Pyle disease have been investigated in a large Afrikaner kindred in South Africa. Consanguinity was present in the family, and it is likely that the condition was inherited as an autosomal recessive. This contention is supported by the radiographic demonstration of minor degrees of widening of the distal femora in obligatory and potentially heterozygous relatives. Apart from genu valgus of moderate degree, the patients enjoyed good health and their gross radiographic skeletal abnormalities contrasted with the innocuous clinical presentation. Differentiation of Pyle disease from the autosomal dominant and autosomal recessive forms of cranio-metaphyseal dysplasia is of prognostic importance in view of the potentially serious complications in these latter disorders.


Creatine kinase isoenzyme patterns in Duchenne muscular dystrophy.

Serum creatine kinase isoenzymes were studied in 41 patients suffering from Duchenne type muscular dystrophy and 20 mothers of patients (carriers) by cellulose acetate electrophoresis. Both the MM and MB types were found in all cases of Duchenne type dystrophy patients, and in carriers with highly elevated total creatine kinase activity BB was not observed above the detection limits of the methods used. However, a so-called atypical CK--BB band has been demonstrated.


Autosomal dominantly inherited adductor laryngeal paralysis--a new syndrome with a suggestion of linkage to HLA.

A family is reported with autosomal dominantly inherited congenital bilateral adductor paralysis of the larynx. This disorder has apparently not been described previously. A search for linkage in this family with the loci for 19 other genetic markers showed a suggestion of linkage with HLA and GLO, and accordingly a suggestion that the locus for this disorder may be assigned to chromosome 6.


The effect of maintenance dialysis on lymphocyte function. II. Peritoneal dialysis.

Lymphocyte function, as assessed by PHA-stimulated DNA synthesis, was studied in chronic renal failure patients maintained by peritoneal dialysis. In contrast to patients on haemodialysis, peritoneal dialysis patients had normal lymphocyte responsiveness pre-dialysis. There was no deterioration in the post-peritoneal dialysis plasma's ability to support control lymphocyte responsiveness as occurred after haemodialysis. Plasma dilution and reconstitution studies indicated that haemodialysis depleted the patients' plasma of nutrients and also added toxins, but peritoneal dialysis had neither effect.


Complement-mediated immune mechanisms in renal infection.

The belief that the inactivation of complement by renal ammonia enhances the susceptibility of renal tissue to infection has been held for some years. This thesis has been investigated in the present experiments using cultures of renal tissue maintained in vitro under physiological conditions. The experiments have confirmed that exposure of normal serum to renal issue in culture does result in the rapid loss of complement activity, but that the inactivation was not due to renal ammonia. Furthermore, in quantitative experiments, the liver was found to have even greater anti-complementary activity than renal tissue. In experiments where the biological significance of this phenomenon was examined, it was shown that the bactericidal capacity of serum was maintained even after exposure to renal tissue. The results of these investigations suggest that the biological significance of the inactivation of complement by renal tissue in vitro has been over-emphasized and requires further studies in vivo.


Spontaneous and lectin-dependent cellular cytotoxicity by lymphocyte subpopulations against cell lines susceptible or resistant to spontaneous cytotoxicity.

In the present study we have investigated whether cell lines, which are resistant to spontaneous cytotoxicity, can be killed by lectin-dependent cellular cytotoxicity (LDCC), the expression of EAC (7S) receptors on LDCC effector cells, and the relationship between spontaneous cytotoxicity and LDCC when EAC (7S) receptor-positive or -negative subpopulations are tested against different target cell lines. We found that target cells which are resistant to spontaneous cytotoxicity can, indeed, be killed by LDCC, and that there is an inverse relationship between spontaneous cytotoxicity and LDCC, both when unfractionated lymphocytes were tested against different target cells and when fractionated cells were tested against cell lines highly susceptible to spontaneous cytotoxicity. The implications of these findings, in relation to the relative specificity of the spontaneous cytotoxicity system, are discussed.


Defective neutrophil motility and recurrent infection. In vitro and in vivo effects of levamisole.

Eighteen patients with primary abnormalities of neutrophil chemotaxis are described. The most common clinical presentation was one of recurrent upper respiratory tract infection (nine patients) or recurrent pyoderma (seven patients), and two children had a history of oropharyngeal candidiasis and recurrent skin sepsis. Of these eighteen patients, sixteen had intrinsic polymorphonuclear leucocyte (PMN) defects as shown by diminished random migration and movement towards endotoxin-activated serum. PMN chemotaxis towards casein was, however, normal. In nine out of the latter patients, there was an associated inability of the serum to generate chemotactic factors. PMN from two adult patients, both suffering from recurrent boils, moved normally both in random and directed systems, but sera from these patients contained heat-stable inhibitors of neutrophil chemotaxis. In vitro levamisole treatment (10(-3) M) markedly improved the PMN function. When patients were treated with levamisole, however, no clinical response was noted, although PMN movement improved in a number of cases.


Correlation between hypersensitivity to parenteral chymopapain and the presence of IgE anti-chymopapain antibody.

A solid phase radioimmunoassay, similar to the RAST, was developed in an attempt to predict anaphylactic reactions in patients injected with the proteolytic enzyme chymopapain, used in therapy for prolapsed intervertebral disc. The test measured the serum content of anti-chymopapain antibodies of the IgE class. Of 1263 patients tested, twelve gave anaphylactic reactions. The test was predictive for seven of them (58%), while sixty were false positives. Measurements were also made of anti-chymopapain IgE or other classes of antibodies which developed in the sera of patients after chymopapain injection. The presence of antibodies to chymopapain in individuals who had not been injected was also demonstrated.


Analysis of immunosuppression during early acute infection of mice with Ascaris suum.

Immunosuppression was examined at 10 to 12 days following oral inoculation of 10,000 to 12,000 embryonated Ascaris suum eggs. Reduced antibody responses to sheep red cells (SRC) following systemic immunization were confirmed in CD-1 and C57Bl/6 mice. Infection alone induced antibody reactive with DNP equivalent to that observed after immunization with DNP--Ficoll. There was a decrease in thymus and spleen size by day 8 of infection, followed by a splenic proliferative response during the second week. In the second week, serum antibodies reactive with SRC, chicken erythrocytes, DNP and bacterial lipopolysaccharide were demonstrated, suggesting polyclonal B-cell stimulation. The cellular basis of immunosuppression was investigated by in vitro culture of splenocytes from C57Bl/6 mice. Differential leucocyte counts of splenocytes before culture demonstrated a relative increase in plasma cells, blastoid cells, complement receptor-bearing lymphocytes and eosinophils, with a relative decrease in small lymphocytes. The splenocytes had reduced responses to T-cell mitogens, as measured by thymidine incorporation in vitro, and reduced antibody responses to SRC and DNP--Ficoll. In vitro, cell mixing experiments did not demonstrate suppressor cells in the spleens of infected mice.


The acquisition and loss of antigen-specific cellular immune responsiveness in acute and chronic schistosomiasis in man.

To characterize the development and evolution of cellular immune responsiveness in individuals infected with the parasite Schistosoma mansoni, we studied fifteen patients with acute, subacute and chronic schistosomiasis. Lymphocytes from the three acutely infected patients responded vigorously to schistosome antigens in an in vitro blastogenic assay. By contrast, cells from nine chronically infected individuals were essentially unreactive to these same antigens. Patients infected for an intermediate period of time (9 months) generated responses between those of acute and chronic patients. The diminished responsiveness of chronically infected individuals was specific for schistosome antigens and did not extend to humoral immune responses. Following treatment of the infection with niridazole, these patients temporarily regained responsiveness to schistosome antigens. From these data we speculate that during the course of this parasitic helminth infection there develops a progressive and specific modulation of antigen recognition and proliferation by lymphocytes to schistosome antigens, and that such diminished immune reactivity may be important in maintaining the unique biological relationship which exists between a host and its parasites.


Inhibition of lymphocyte cytotoxicity in chronic active hepatitis.

Inhibitory factors were investigated, using 51Cr-labelled Chang cells as targets, based on the inhibition of lymphocyte-mediated cytotoxicity (LMC) in patients with chronic active hepatitis (CAH). A significant reduction of LMC was noted (P less than 0.001) when autologous sera of patients with CAH was added. The addition of HBsAg-positive and -negative homologous sera from CAH, which were as capable of inhibiting LMC as autologous sera, decreased LMC significantly (P less than 0.001). The LMC fell significantly (P less than 0.001) in the presence of sera of patients with rheumatoid arthritis. A significantly higher inhibition (P less than 0.001) by rheumatoid factor (RF) positive autologous sera of patients with CAH was observed when compared to that of RF-negative sera. Such autologous sera inhibiting LMC contained increased IgG levels (P less than 0.01) when compared to those that failed to inhibit LMC. A significant reduction of LMC was also induced with the addition of anti-HBs (P less than 0.05), HBsAg--anti-HBs (P less than 0.001) and IgG--anti-IgG (P less than 0.01) complexes, or aggregated IgG (P less than 0.001). The LMC was reduced significantly (P less than 0.001) after adding a purified liver-specific membrane lipoprotein (LSP) from human livers. There was some evidence for the inhibition of LMC being effected by these additives as a result of their acting on an effector cell level. These findings suggest that humoral factors including immune complexes, aggregated IgG and LSP play an important role for lymphocyte cytotoxicity in the pathogenesis of CAH.


The effect of maintenance dialysis on lymphocyte function. I. Haemodialysis.

The effect of haemodialysis on mitogen-stimulated lymphocyte DNA synthesis was determined in twenty-four uraemic patients. Lymphocytes pre-haemodialysis were significantly less responsive to phytohaemagglutinin (PHA) than were control lymphocytes and showed the same degree of impairment as uraemic lymphocytes. Intrinsic lymphocyte responsiveness improved immediately after each haemodialysis. Pre-haemodialysis plasma inhibited control lymphocyte responsiveness and this inhibition was even greater in post-haemodialysis plasma. This effect of haemodialysis on plasma lasted for 4--8 hr. Similar alterations of response were noted, despite the use of different dialysers and also when two other mitogens were substituted for PHA. This deleterious effect of haemodialysis on lymphocyte function is important for its possible immune consequences, and may indicate a deficiency in current haemodialysis technique.


Operative treatment of displaced Salter-Harris III distal tibial fractures.

Displaced, isolated Salter-Harris III fractures of the distal tibia are infrequent. Typically, the mechanism of injury is an external rotation stress to the adolescent ankle. The distal tibial growth plate fuses from medial to lateral during adolescence. If the anterior tibiofibular ligament remains intact, lateral distal epiphysis of the tibia. Closed reduction of displaced fractures is usually unsuccessful. In 5 displaced fractures, periosteal flaps were frequently found to have blocked closed reduction. Follow-up evaluation after open reduction and internal fixation revealed anatomic healing and normal ankle strength.


Foreign body (palm thorn) in knee joint.

A child who lives in a semitropical or tropical zone and has monarticular symptoms involving the knee joint and a history of playing in the vicinity of plams should be examined for the possibility of a palm thorn within the joint. The diagnosis, made after careful elimination of more common entities, can only be confirmed by surgical exploration.


A standardized method for the radiographic evaluation of clubfeet.

A new standardized technique is presented for positioning patients for the radiographic evaluation of clubfeet. The main reasons for inadequacy of the usual techniques are inaccuracy in measurement, movement of the patient and improper positioning of the patient or X-ray equipment. Means are proposed to avoid or minimize these problems. The critical views are those taken immediately preoperatively to assess deformity combinations and those taken before wound closure to verify completeness of surgical correction. These films are taken with the patient asleep to eliminate movement. Unacceptable films which do not conform to the standard technique are rejected and new films obtained. The method has proven to be acceptably accurate.


Stress fractures in the calcaneus of a child. A case report.

An 11-year-old girl with splastic quadriplegia, and immobilization atrophy developed a stress fracture of the calcaneus, are rare cause of heel pain in children. There was complete remission of symptoms with healing of the fracture.


Muscle transfer for abduction paralysis of the shoulder in poliomyelitis.

Muscle transplantation in deltoid paralysis in poliomyelitis has been practiced only sporadically and considered ineffective. Trapezius transfer to humeral shaft with fascia lata extension was performed to restore abduction power of the shoulder in 24 patients between 4--10 years of age. It is recommended that the muscle re-education program and bracing be continued for a sufficiently long time so that the muscle may develop enough strength to function. If a forward subluxation of the joint develops and persists, a Nicola procedure is effective. The functional results obtained in a follow-up of 1--3 years has been encouraging in these children, especially when the accessory muscles were not paralyzed.


Anterior subglenoid dislocation of the shoulder in an infant following pneumococcal meningitis.

A 7 1/2-month-old boy had an anterior inferior dislocation of the shoulder. Dislocations of the shoulder in infants have previously been reported, and were either congenital dislocations with associated anomalies of the glenohumeral joint with dislocations from Erb's palsy or septic arthritis. In the present case, dislocation of the shoulder was associated with spastic brain damage. The marked spasticity of the deltoid muscle may have been the deforming force. Capsular and subscapularis plication plus recession of the deltoid corrected the deformity and prevented further dislocations.


Tardy ulnar nerve palsy in children.

Tardy ulnar nerve palsy in the child is an infrequent occurrence. In 5 cases all occurring after injury about the elbow, the lesion involved not only lateral but also medial structures. The latency period from elbow injury to palsy was not always long and ranged from 2 months to 29 months. Possibly because of the age of the patients and short duration of the palsy, anterior transposition promoted prompt remission of symptoms and signs.


Solitary bone cyst in the infant radius. A case report.

The exceptional case in the distal radius of an 18-month-old girl demonstrates the natural history and characteristic features of solitary bone cyst at an early age. There were recurrent pathological fractures and even recurrence of the cyst, but spontaneous complete healing occurred after a period of 7 years. Splinting of the fractures, curettage and bone graft were performed per primum. Aspiration of the cyst and collapse of the cyst walls were secondary procedures. The recommended treatment is biopsy and prolonged immobilization until spontaneous healing of the cyst is complete.


The relationship of intravascular coagulation and fibrinolysis to venous thrombosis following total hip replacement.

Soluble fibrin complexes, fibrin degradation products, and anti-thrombin III levels were determined in the plasma of 20 patients undergoing elective total hip replacement. The presence of deep venous thrombophlebitis was determined by venography at the end of the first postoperative week. Patients who developed thrombosis exhibited impairment of fibrinolysis as de-Patients who developed thrombosis exhibited impairment of fibrinolysis as detected levels of anti-thrombin III and soluble fibrin complexes were not useful in indicating the presence of deep venous thrombosis. However, the preoperative level of soluble fibrin complexes closely correlated with the subsequent development of thrombosis. Elevated soluble fibrin complexes appear to identify a group of patients with activated coagulation systems who are prone to develop thrombosis during total hip replacement.


Proximal femoral focal deficiency: Treatment and classification in forty-two cases.

A review of the surgical experiences in 42 patients with proximal femoral focal deficiency has led us to propose a new classification system. This simplified system consists of 4 definite classes based on the roentgenographic appearance of the proximal shaft, and includes distinct prognosis and treatment groups. Early and accurate prognostication facilitates rational prosthetic design and appropriate surgical treatment in all degrees of involvement. In the less severely involved classes, emphasis is placed on the utilization of the proximal shaft signs of Fixsen and Lloyd-Roberts to identify those hips with an unfavorable prognosis.


Ligamentous laxity and scar formation.

The character of scar tissue is relative to or influenced by ligamentous laxity. Patients who are able to passively hyperextend the terminal interphalangeal joint of the index finger to 45 degrees and beyond have a tendency to leave broad scars. This proved to be statistically significance (p less than .001). It is suggested that in female patients in particular, assessment of the passive hyperextensibility of the terminal interphalangeal joint of the index finger can be used preoperatively to determine whether the patient will be left with a cosmetically displeasing scar following any operative procedure.


Acromioclavicular dislocations: treatment by transfer of the conjoined tendon and distal end of the coracoid process to the clavicle.

A retrospective study of 23 acute and 6 chronic acromioclavicular dislocations treated by surgical transfer of the distal 1/2 inch of the coracoid process with the attached conjoined tendon of the coracobrachialis and short head of the biceps to the clavicle revealed 14 excellent, 14 good and one fair result. Results were determined according to symptoms, range of motion at the shoulder and elbow, strength, anatomic reduction, and return to previous activities. Although most patients with this injury are treated conservatively, this procedure is reserved for the athlete or manual laborer below age 45 years, especially with involvement of the dominant-extremity. The 29 cases were evaluated 20--108 months following surgery. Thirteen additional cases with less than 18 month follow-up have also been good or excellent. Weakness and pain have not been as pronounced following this procedure in vigorous individuals as have been noted after conservative treatment. Few postoperative complications developed, and early return to competitive athletics was possible.


Forces at the glenohumeral joint in abduction.

The purpose of this study was to determine the forces in the glenohumeral joint for isometric abduction (including all directions of rotation) in the plane of the scapula. The lines of actions of muscles were obtained from 3 upper quarter specimens, electromyographic data was used, as well as geometrical parameters of shoulder motion. The main assumption made in the analysis was that the force in a muscle was proportional to its area times the integrated electromyographic signal. The resultant force reached a maximum of 0.89 times body weight at 90 degrees of abduction, while the shearing component up the face of the glenoid was a maximum of 0.42 times body weight at 60 degrees of abduction.


Barbotage of the shoulder with image-intensified fluoroscopic control of needle placement for calcific tendinitis.

In 9 patients with symptomatic calcific deposits in the rotator cuff, followed for an average of 9 years, good to excellent results were obtained by barbotage (needle irrigation and aspiration). The deposit was localized with a needle using an image intensifier. Postbarbotage X-rays show residual deposits, but films taken on follow-up show complete disappearance of the lesion except in one instance where a small density was seen. One patient had early recurrence of symptoms out of the 3 who had postbarbotage cortisone injection. Barbotage is simple, effective, with virtually no complications. Failures of the method were apparently due to difficulty in locating the deposit with the needle. Barbotage is most indicated in the acute phase of the disease but may be used in cases with chronic symptoms to remove dry granular deposits. It is not essential, however, to completely remove the deposits because the resorption process continues. Local cortisone injection either as a primary procedure of after barbotage is not recommended because it aborts the natural course of the disease and promotes recurrences.


Extensor fasciotomy for tennis elbow: a long-term follow-up study.

In 37 of 43 cases (86%) the late results of fasciotomy for chronic lateral epicondylitis were excellent or good. The initial result was maintained for an average of 8.0 years. The procedure is simple and morbidity is minimal. Patient selection and technical factors appeared to account for the failures.


Management of redislocated Colles' fractures.

One question which often confronts the clinician is whether or not a Colles' fracture, shown to be redisplaced, should be subjected to renewed reduction. Earlier reports have shown a rather good correlation between the accuracy of reduction and the functional and cosmetic end result. Roentgenograms of 40 rereduced Colles' fractures are reviewed in order to answer the following questions. What are the chances of a lasting improvement resulting from a renewed reduction of a redislocated Colles' fracture? What is the most suitable time for renewed reduction? Permanent improvement was found in about 1/3 of all the case. To establish the most suitable time for rereduction the material was divided into early rereduced (1-6 days after primary reduction) and late rereduced (7-15 days) fractures. It was found that early rereduction led to lasting improvement of the fractures position in only 2 of the 15 cases. Late rereduction led to permanent improvement in 15 of 30 cases with respect to dorsal angulation and in 9 cases to radial compression. If a rereduction is to be performed, it should be done during the second week after primary reduction.


Experiences with U.C.I. total knee.

In 200 low friction knee arthroplasties with a minimum follow-up of 2 years the primary goal of relief from pain was accomplished in most patients. However, the evaluation of the result of a knee arthroplasty is difficult. Many of the patients who rated good or better had, to some extent, patellofemoral complaints. Cold flow deformation and prosthetic loosening is a definite concern about the tibial component. A longer follow-up study is needed to better evaluate the significance of the one to 2 mm radiolucent line at the bone cement interface of the tibial component. Collateral and cruciate ligament deterioration with time is also of concern and warrants careful follow-up. Although most patients patients in this series were greatly relieved of pain, even better results might have been obtained if the arthroplasty included the patellofemoral joint and a more substantial tibial component with better fixation. By our rating criteria, rheumatoid patients, in general, were benefited the most. Patients, surgeons and engineers realize that the natural human knee joint is a remarkable product of adaptive evolution, and that it may be imitated with increasing success though it can never be duplicated.


Ultrastructural localization of alkaline phosphatase in initial intramembranous osteogenesis.

Developing fetal calvariae in which calcification of woven bone has been initiated, have been decalcified with formic acid, buffered with citrate at pH5 to remove all traces of calcium and phosphate from the tissue. The decalcified bone was then incubated in medium containing sodium-beta-glycerophosphate, an artificial substrate for alkaline phosphatase. The Hugon and Borgers-modified Gomori reaction revealed the sites of A-Pase activity as electron dense deposits of lead phosphate. 23,24 One site of A-pase localization was in Golgi vesicles. Another site, at the cell membrane, indicated that A-Pase was apparently secreted from the osteoblasts into the calcifying matrix. A strong reaction in the matrix vesicles and at the periphery of bone nodules (vesicles) indicated that A-Pase was localized ultrastructurally in the precise zones of calcification during initial intramembraneous ossification.


Short-term effects of varying doses of 1 alpha-hydroxyvitamin D3 on blood and urine chemistry and calcium absorption of osteoporotic patients.

During a period of 4-7 days, synthetic 1 alpha-hydroxyvitamin D3 (1alpha-OH-D3) was given to osteoporotic patients with hip fractures in 3 different dose levels, viz. 1 microgram, 2 microgram, and 4 microgram, in combination with calcium. The increase in serum calcium level was more prominent during treatment with 2 microgram and 4 microgram doses of 1 alpha-OH-D3 and was also dependent on the duration of treatment. The level of serum phosphate was only slightly elevated. The urinary calcium excretion increased, while the urine phosphate and hydroxyproline excretion decreased. The intestinal absorption of calcium increased in rate during treatment with 1 alpha-OH-D3. On discontinuation of treatment, values did not normalize within 6 days. The administration of small doses of 1 alpha-OH-D3 did not seem to expose osteoporotic patients to the risks of hypercalcemia. The efficiency of vitamin D metabolites in the treatment of osteoporosis requires further investigation.


Interim report on treatment of osteoporotic patients with 1 alpha-hydroxyvitamin D3 and calcium.

Fifteen patients, 13 women and 2 men (mean age 60 years) with osteoporosis of different types have been under treatment with 1 alpha-hydroxyvitamin D3 and calcium. The responses were observed clinically and by the use of roentgen morphometry, photon absorptiometry and by blood and urine chemical analyses. The treatment had beneficial clinical effect in all but 3 patients. The intestinal calcium absorption rate increased significantly. Slight hypercalcemia and a significant hypercalciuria occurred during treatment. Serum and urine phosphate levels, alkaline phosphatase and parathyroid hormone values were within normal ranges. The bone mineral content increased significantly during treatment. 1 alpha-hydroxyvitamin D3 and calcium was well tolerated by the patients. Three patients had coincidental acute attacks of spinal pain and 2 had further vertebral crush fractures. A period of time longer than one year is necessary to further evaluate the effects of 1 alpha-hydroxyvitamin D3 therapy on the clinical course of severe osteoporosis.


The in vitro production and activity of 24, 25-dihydroxycholecalciferol in cartilage and calvarium.

Previously reported results from our laboratory have indicated that 24, 25-dihydroxycholecalciferol can be formed in vitro during incubations of cartilage tissue or cartilage cells with 25-hydroxycholecalcified. They have also demonstrated the high potency of this dihydroxymetabolite of vitamin D3 in stimulating in vitro the sulfate incorporation into proteoglycans of cartilage cells in culture and in decreasing in vitro the parathyroid hormone action on rat calvarium phosphatases activities. The present report shows that 24, 25-)OH)2 D3 can also be produced during rat calvarium incubations with 25-hydroxycholecalciferol and that therefore calvarium as well as cartilage might be both a site of formation and a site of action for 24, 25-(OH)2 D3. The review of recent experimental and clinical investigations strongly suggests that this metabolite has a physiological significance and may be specifically active on some parameters of bone mineralization. Further studies on the cartilage and calvarium abilities to convert 25-hydroxycholecalciferol into 24, 25-(OH)2 D3 shows that this transformation occurs in the mitochondrial fraction but that it does not seem modified by factors known to control the 25-hydroxycholecalciferol metabolism in the kidney. Finally the analysis of experimental and clinical results published so far does not yet bring enough information to understand the significance of this extrarenal metabolism of 25-hydroxycholecalciferol.


Femoral bifurcation with tibial aplasia. A case report and review of the literatures.

An extremely rare femoral bifurcation in combination with ipsilateral tibial aplasia, lumbosacral myelomeningocele, anomalies of hand and feet occurred in a premature infant. Review of the pertinent literature suggests that femoral bifurcation usually occurs in association with ipsilateral tibial aplasia. The pathogenesis of this rare congenital anomaly may be associated with an ectopic tibial anlage in the femur and insertions of disorganized muscles.


Corticosteroid-induced avascular necrosis: an experimental study in rabbits.

New Zealand white rabbits were divided into 4 groups for the study of the etiology of corticosteroid-induced osteonecrosis (avascular necrosis). Group A and B received intramuscular injections of methylprednisolone acetate and methylprednisolone succinate respectively. Group C, on semirestricted diets, and Group D, on ad libitum diets, were controls. Osteocyte death, necrotic debris and intravascular fat emboli were evident in sections of proximal and distal femur by the 2nd week in experimental animals. Blood analysis revealed elevated lipid and prostaglandin levels. Osteoporosis was first observed at 6 weeks. Evidence of advanced osteonecrosis was present histologically at 18 weeks. It is concluded that osteonecrosis probably develops as the result of the interaction of several corticosteroid-induced alterations, including circulating fat emboli and inflammatory unbound free fatty acids or prostaglandins. Osteoporosis may also be a factor in explaining the sporadic nature of the disorder.


Delayed surgical repair of ruptured ligaments: a comparative biomechanical and histological study.

The importance of prompt surgical repair of complete ligament ruptures was quantitated using 38 rabbits with standardized transection injuries ofthe medial collateral ligament of one knee. Tensile testing of the mechanical properties, coupled with histological evaluation allowed assessment of the integrity of suture repairs performed immediately after ligament injury, versus those with 3 and 10 day delay times as well as those with non-operative management. Surgical repair performed within the first 3 days is beneficial in terms of final repair strength. Irreversible ligament strength and stiffness deficits progressively accumulate during the 10 days immediately following injury. Surgical repair after more than 10 days postinjury is contraindicated since the postoperative mechanical properties of the healed ligament do not differ from those for non-operative injury management.


The strength of metal reinforced methylmethacrylate fixation of pathologic fractures.

Fixation of the pathological fracture in terminal patients has in the past added the trauma of an extensive surgical procedure to an already weakened patient. Intramedullary fixation with single and double rods in conjuction with polymethylmethacrylate have been compared to ascertain the effect of different loading conditions using torque and analysis under compression measurements of the strength of repair bone. Extensive intramedullary reaming can be avoided with polymethylmethacrylate. The cement effectively transmits the load from the proximal to the distal fragment. The single large rod method would be more desirable for stiffer bones while the double thin rod technique may be applicable to more flexible bones.


Blount disease. A review of etiological factors in 110 patients.

The infantile form of Blount disease is common in the African Negro population of South Africa, although it is very rare in other groups in this country. A series of 110 affected children, investigated in an attempt to elucidate the pathogenesis of this condition, demonstrates an approximately equal sex incidence while geographic distribution is patchy. Bowing of the legs, which is symmetrical in 82% is usually the presenting feature and develops at the onset of ambulation. There is no preceding illness, either local or systemic, and no dietary inadequacy. The children do not differ from their peers in age of walking, weight or range of joint movements. There are no biochemical or hematological abnormalities and no radiographic evidence of involvement of joints other than the knees. Twenty-two of the patients had never been carried in the traditional "pick-a-back" position and it is therefore unlikely that this posture is a significant causative factor. The children had a total of 231 siblings, of whom 10 had bowlegs, while 16 parents had been similarly affected during their own infancy. On this basis, Mendelian dominant or recessive inheritance is unlikely although it is possible that Blount disease is multifactorial in etiology.


An experimental model of osteogenesis: a closed in vivo culture system using diffusion chambers.

Part of young mouse radii were isolated and transplanted into an intraperitoneal Millipore diffusion chamber. The survival of the implants was followed for 22 days, using morphological criteria, and by autoradiography with tritiated thymidine. Periosteal cells and epiphyseal plate chondrocytes survived well for one to two weeks. DNA synthesis was noted up to the twenty-second day of culture. Osteogenetic cells proliferated well in transplants of shorter duration, but in the third week there was overgrowth by fibroblasts. The method seems well suited for the culture of osteogenetic cells as whole-bone pieces for at least one to two weeks.


Cementum-like bone production in solitary bone cysts. (so-called "cementoma" of long bones). Report of three cases. Electron microscopic observations supporting a synovial origin to the simple bone cyst.

Three cases of simple bone cysts (S.B.C) in association with cementum-like bone production are reported. Analysis of our cases and the 2 previously reported in the literature as so-called cementomas has led us to conclude that the "cementoma" of long bone is not a distinct entity, but merely, a form of S.B.C. associated with a peculiar, poorly cellular form of bone which mimics tooth cementum by light microscopy only. Electron microscopic studies of this substance demonstrate collagen fibers and numerous matrix vesicles which form the initial sites of calcification. Matrix vesicles are a product of osteoblastic activity and are never found in the cementum of the tooth or oral cementum producing tumors. We also report the first ultramiscroscopic observations on the wall of the simple bone cyst and its lining. Two cell types constitute the lining, having features identical to those described for type A and type B synovial cells. Because of this new observation, we believe, the most reasonable explanation for the simple bone cyst is that it represents a congenital "rest" of synovial tissue displaced into the thin, cortical metaphyseal region of bones at the synovial-capsularbone reflection. Its benign nature and slow growth would explain its discovery in early childhood and the marked preponderance of its proximal humerofemoral location dependent upon the fact that these 2 bones have the largest area of capsular to metaphyseal bone reflection.


Congenital synostosis of the knee.

Three congenital synostoses of the knee occurred in 2 patients. Complete bony epiphyseal fusion was present on the radiographs. This condition is a failure of joint formation in the early mesenchymal stage at 4--5 weeks gestation and appears as connected cartilaginous cell masses which later ossify. Involvement of other joints has been reported in the literature, but these may be the first documented cases of the condition in knee joints.


Dysplasia epiphysealis hemimelica of the ulna.

A 3-year-old boy developed an abnormality of the forearm and wrist characterized by asymmetrical overgrowth, premature ossification of the distal ulnar epiphysis, shortening of both bones of the forearm, dorsal bowing of the ulna and formation of an enlarged lunate from 2 ossification centers. The eccentric overgrowth of the distal ulnar epiphysis was similar to the abnormality seen in dysplasia epiphysealis hemimelica of the long bones of the lower limbs, tarsal and carpal bones.


Supracondylar osteotomy in thalassemia.

The skeletal system manifestations of thalassemia are characterized by severe osteoporosis, frequent fractures and delayed healing. Permanent deformity and disability can complicate the fractures. Surgical correction of deformity by osteotomy of severely osteoporotic bone and immobilization without internal fixation was successful in a 20-year-old woman. While operative correction of deformity is not routinely recommended, the good experience with this case suggests that similar orthopedic procedures can be included in the treatment of thalassemia.


Proximal tibiofibular synostosis.

The occurrence of a proximal tibiofibular synostosis is indeed a rare condition with only 2 cases unassociated with other diseases reported to our knowledge to date. Two skeletally immature patients presented with a synostosis of the proximal tibiofibular region associated with shortening of the limb in the affected segments. Although the shortening and the synostosis seem interrelated no explanation of their relationship is evident from these 2 cases.


The multiple synostoses syndrome. A plea for simplicity.

Case reports are presented of a father and daughter suffering from what has formerly been called the Nievergelt-Pearlmansyndrome, and now termed "multiple synostoses syndrome." Features of the condition include: proximal symphalangism; tarsal and carpal coalitions; short first metacarpals and metatarsals; elbow fusions or dysplasias; conductive nerve deafness. This syndrome appears to be inherited as an autosomal dominant trait of variable penetrance, and probably caused by a single gene abnormality.


Pain provoked scoliosis. Observations on the evolution of the deformity.

The case reports of 5 children with scoliosis provoked by painful vertebral lesions of osteoid osteoma and eosinophilic granuloma reveal that the final outcome of the deformity is determined by the interaction of 2 factors: the age of the child (in relation to his growth velocity); the duration of symptoms. Complete resolution in 2 children with scoliosis of 10 months' and one year's duration respectively, and partial regression of a curve which has been present for 6 years in another child draws attention to the fact that spontaneous correction of structural scoliosis can and does occur in a growing child. In the light of this and other evidence it is suggested that early idiopathic scoliosis could possess the potential for spontaneous correction.


Oxacillin induced neutropenia. A case report.

Oxacillin-induced neutropenia is reported in a 16-year-old boy being treated for osteomyelitis. The startling neutropenia developed after 20 days of 200 mg/kg/day of intravenous oxacillin. The neutropenia was not associated with symptoms and was rapidly reversible upon stopping the antibiotic. This reaction may happen with any of the betal lactam antibiotics and is believed to be a direct toxic effect on white cell precursors in the bone marrow.


Acquired os odontoideum. A case report.

A 7-year-old boy presented with os odontoideum after a 5 story fall at 19 months of age, at which time roentgenograms documented a normal odontoid. Current flexion-extension films revealed a marked altlantoaxial instability related to the acquired "os." The treatment consisted of an atlantoaxial arthrodesis. Acquired os odontoideum is a recognized, though uncommon entity in which it is hypothesized that trauma produces vascular insufficiency, with subsequent resorption of the central portion of the odontoid, resulting in the classical features of os odontoideum. It is often associated with instability, with potential danger to the spinal cord. Instability in cases of os odontoideum is a positive indication for atlantoaxial arthrodesis.


Autotransfusions in scoliosis surgery. Review of 20 Harrington fusions.

A significant blood loss during a Harrington fusion for scoliosis is usually replaced with homologous bank blood transfusion. To decrease the risk of potential severe complications for the patient, autotransfusions were used in 20 patients undergoing posterior spinal fusions for scoliosis. To have fresh blood at the time of surgery the previous stock was recirculated at each weekly session. The last of the 3 sessions was one week before surgery. The mean age was 17 years and 4 months. On average the hemoglobin before donation was 12.85 g, the volume donated 1455 ml, and the hemoglobin preoperatively 12.04 g. Blood loss averaged 1175.0 ml at surgery and 635.0 ml subsequently by vacuum drainage. Two days after operation the hemoglobin averaged 10.4 g. No complications related to transfusion occurred. Three patients received additional homologous blood. The rationale, modes, technique, value, and underutilization of autotransfusion are noteworthy.


Congenital calcifying hamartoma. A resolving lesion producing gastrocnemius contracture--report of a case.

An 18-month-boy developed a calcifying mass in the gastrocnemius muscle. The lesion presented on the day of birth and resolved completely within 5 months leaving only a fibrous cord replacing the medial head of the gastrocnemius. There were no facts in the history to suggest the etiology of this lesion. Calcification of a vascular hamartoma with subsequent fibrosis is proposed as a possible explanation. The benign course of this lesion is evidence of the value of conservative treatment.


Role of innominate osteotomy in the treatment of children with Legg-Perthes disease.

Innominate osteotomy is based on the supposition that coverage of the femoral capital epiphysis is necessary. The morbidity is minimal, early postoperative weight-bearing is permissible, even encouraged. No further evidence of deterioration of the contour of the hip joint appears following surgery. Prompt consolidation of the fragments may occur. In selected cases innominate osteotomy can provide a better prognosis than non-operative treatment.


Valgus slip of the capital femoral epiphysis.

Valgus slip of the capital femoral epiphysis, a rare entity which may be acute or chronic, occurred in a 12-year-old boy. The displacement may be associated with a pre-existing coxa valga. The patient also had a varus slip of the capital femoral epiphysis on the contralateral side. Both hips were successful treated by in situ pinning. A review of the English literature reveals only 8 previously reported cases of valgus slipping of the capital femoral epiphysis. Either valgus or lateral slips are unusual.


Slipped capital femoral epiphysis. A study of 50 cases in black children.

In 50 black children with 70 slipped capital femoral epiphyses, a satisfactory result was obtained in 87% of the hips. Chondrolysis developed in 6% of the hips, occurring only when there was persistent intraarticular protrusion of the transepiphyseal fixation device. The chondrolytic process resulted in a relatively painless fibrous ankylosis of each hip. Avascular necrosis developed in 7% of the hips, and occurred only in the presence of a valgus reduction of an acute slipped epiphysis. Each case of avascular necrosis was of the whole-head type and was severely progressive. Biplane subtrochanteric femoral osteotomy was employed as a reconstructive procedure in the severely-displaced slipped epiphysis; it was delayed until after epiphyseal plate closure, and restored satisfactory hip function in all cases. Black children are not predisposed to poor results after slipped capital femoral epiphysis contrary to a commonly held impression.


The hazards of tibial pin replacement in 90--90 skeletal traction.

Tibial pin placement and 90--90 traction may lead to serious knee difficulties. Not only proximal tibial epiphyseal insult, but also serious displacement of the tibia on the femur may occur. In light of these potential complications, distal femoral pin placement should always be preferable for 90--90 traction in treatment of fractured femurs in children.


Nuclear anatomy of diversionary central nervous system shunts in children.

A simple method of demonstrating shunt morphology with 99m technetium diethylene triamine penta-acetic acid (99m Tc-DTPA) is described. The anatomic abnormalities are illustrated. Demonstration of the site of obstruction is useful in selecting the neurosurgical approach. The procedure is minimally invasive, accurate, and simple to interpret.


Detection of active bleeding from ruptured aortic aneurysm by emergency radionuclide angiography.

Radionuclide angiography of the abdominal aorta provides hemodynamic information of the kidneys, aorta and aneurysm as well as the location and extent of aneurysm. Visualization of early abnormal activity in the pelvic region simultaneously with iliac artery visualization is thought to be a specific finding of active bleeding from a ruptured aneurysm of the abdominal aorta.


Radionuclide demonstration of relative increased blood flow in uniappendicular secondary hypertrophic osteoarthropathy.

A rare case of hypertrophic osteoarthropathy (HO) limited to one lower extremity is described in a male with a history of familial polyposis coli and bilateral aortofemoral grafts. The precise etiology remains unknown. Radiography depicted the HO, but 99m Tc-methylene diphosphonate imaging showed more extensive involvement. An intra-aortic injection of 99m Tc-macroaggregates of albumin portrayed a larger blood flow to the involved limb compared to the contralateral extremity. The major part of this increase was in bone rather than in the adjacent soft tissue.


Adrenal scintigraphy in low renin essential hypertension.

Adrenal scintigraphy was performed on 23 patients with low renin essential hypertension (LREH). After baseline scintigraphy was shown not to be helpful, 13 of these 23 patients underwent dexamethasone suppression adrenal scintigraphy. Four adrenal imaging patterns were observed: unilateral imaging with adenoma; bilateral early or late imaging with hyperplasia; no uptake with normal adrenals. These imaging patterns were shown to be predictive of the individual patient's response to spironolactone administration of functional adrenal cortical abnormalities in LREH supplies direct evidence for the hypothesis that LREH has an adrenal mineralocorticoid etiology.


Splenic infarct associated with diaphragmatic eventration: case report illustrating the non-specificity of splenic focal defects.

The authors report a scintigraph of a 76-year-old man interpreted as being of a partially herniated spleen constricted by the diaphragm. The constriction proved illusory.


Unusual bone scan presentation in osteomalacia: symmetrical uptake--a suggestive sign.

Osteomalacia presents radiographically as deossification, coarsening of the trabecular pattern, and pseudofractures. Contrary to the usual bone scan manifestation of osteomalacia, consisting of a generalized increase in periarticular radionuclide accumulation and pronounced costochondral junctional uptake, this report describes an unusual bone scan presentation with negative radiographic studies showing only some deossification. Symmetric distribution of the focal lesions is considered a suggestive sign of osteomalacia.


Scintilymphangiography with 99 mTc-antimony sulfide colloid in hereditary lymphedema (Nonne-Milroy diseases).

A family of four patients suffering from Nonne-Milroy disease has been examined by pedal scintilymphangiography. Lower limb edema was present in three patients and was bilateral in two instances. Scintilymphangiographic abnormality was invariably present, ranging from almost total obstruction of lymphatic flow to lymphatic pooling. The inguinal, iliac and para-aortic nodes on the affected sides were also noted to be small and few in number. The examination is safe and simple and may be used to distinguish Nonne-Milroy edema from edema due to other causes.


Kinematics of the cervical spine.

This has been a review of some of the movements of the cervical spine. Much data remain to be accumulated and certainly much work must be done to evaluate the effect of forces in various directions upon these movements. Perhaps an improved understanding of these movements in association with an understanding of the pathogenesis of disc degeneration will enable us to better understand the development of spondylosis. Most important this review uncovers the fallacy of laying the blame for the development of cervical spondylosis solely at the door of increased or decreased mobility at certain area. Physical stress and tissue degeneration must be playing a significant role.


Microsurgical anatomy of the orbital apex and principles of transcranial orbital exploration.

Although many problems may present with unilateral proptosis, a careful clinical investigation can narrow the differential diagnosis to those problems which can be treated best by the neurosurgeon. The primary indication for transcranial exploration is when the pathological process is found to involve both the orbit and the cranial cavity as in all cases of optic nerve glioma, orbital meningioma, encephalocele, and some mucoceles, hemangiomas, aneurysmal bone cysts, and ossifying fibromas. Transcranial exploration may also be indicated for some tumors which crowd the orbital apex, such as, neurofibromas and osteomas; tumors in this location can be more widely exposed and safely dealt with by this route. A prime objective in these cases, however, must be preservation of function with a good cosmetic result. It is of equal importance to be aware that many conditions producing exophthalmos can be cured by direct orbital exploration, radiotherapy, or medical management. Malignant orbital tumors should never be exposed to the cranial cavity by transcranial exploration, whereas, radical exenteration may be curative in some carefully studied cases. Accuracy in clinical diagnosis and the proper selection of treatment modality for conditions in the orbit requires a clear understanding of this regional anatomy. I hope that this brief review of the pertinent microsurgical anatomy of the orbital apical region has helped to substantiate a strong neurosurgical claim to all primary optic nerve tumors; and, incidentally, I hope it provides an explanation for why I sent so many other patients back to Dr. Algernon Reese with the recommendation that transcranial surgery did not seem indicated. The success of this attitude may be attested to by the fact that we performed no unnecessary craniotomies nor did we pass by problems which would have best been treated by transcranial orbital exploration.


Role of aldosterone in the antihypertensive effect of spironolactone in essential hypertension.

In order to evaluate the relationship between aldosterone status and the blood pressure-lowering effect of spironolactone, 38 patients with essential hypertension were treated with spironolactone (400 mg/day) during one week in hospital on a rigidly sodium-restricted diet. The degree of hyperaldosteronism was assessed by the aldosterone secretory rate after 5 days of salt loading (315 mmol Na+/day). The mean arterial pressure decreased 5.6% (range, -21 to +8%). When the patients were divided into subgroups with low and normal renin activity, there was no difference in the change in mean arterial pressure (-5.0% and -6.1%). When the patients were divided into three groups with low, normal, and supranormal aldosterone secretory rates, the last group had a significantly greater fall in blood pressure after the spironolactone than the other groups (-1.0, -7.1, -11.1%). Thus there was a correlation between the aldosterone secretory rate after sodium loading and the blood pressure-lowering effect of spironolactone (r = -0.53, p less than 0.01). The blood pressure-lowering effect was not related to changes in body weight, kidney function, or plasma electrolytes. Our findings do not provide solid arguments for the view that the blood pressure-lowering effect of high dose spironolactone is due to its antimineralocorticoid activity, but the correlation between the degree of hyperaldosteronism and the blood pressure-lowering effect strongly suggests that aldosterone does play a role in the genesis or maintenance of the hypertension in these patients.


Lidocaine and its active metabolites.

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.


Disposition of metformin (N,N-dimethylbiguanide) in man.

Kinetic parameters of metformin (N,N-dimethylbiguanide), an anti-diabetic reported to be associated with a lower number of episodes of lactic acidosis than phenformin, were determined in volunteers with normal renal function and in patients with different degrees of renal impairment. Drug in body fluids was measured by a highly specific and sensitive mass fragmentographic method, after the formation of a triazine derivative, obtained with heptafluorobutyric anhydride. The half-life (t 1/2) for the elimination of drug from plasma after intravenous injection in 5 normal subjects (1.52 +/- 0.3 hr) (mean +/- SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr). The mean t 1/2 in 5 renal patients was 4.94 +/- 1.11 hr, and a correlation was observed between t 1/2 of drug from plasma and creatinine clearance. After oral administration of metformin tablets, drug recovery in urines was only 37.6%, possibly not as a consequence of low bioavailability (a similar low recovery was found after oral administration of the metformin solution used for the intravenous studies), but of binding to the intestinal wall, as shown in animal and clinical studies with metformin and other biguanides. Metformin is rapidly eliminated through active secretion by the kidney (mean renal clearance, 440.8 ml/min)--it is neither metabolized nor protein bound in plasma. The very brief plasma t 1/2 makes significant cumulation, with a standard tid regimen, unlikely. These findings may help explain the lower incidence of toxic effects, particularly lactic acidosis, than after phenformin.


Protein binding of tolmetin.

The protein binding of the new nonsteroidal anti-inflammatory agent tolmetin to human serum albumin (HSA) and to the plasma of 8 healthy subjects was studied by equilibrium dialysis at 37 degrees and pH 7.4 with 14C-tolmetin. Over the total concentration (Ct) range 3.0 to 28.7 microgram/ml (therapeutic range), the fraction of tolmetin unbound to 4% HSA was largely invariant at 0.3%. At 100 microgram/ml the unbound fraction rose to 0.8 and at 434 microgram/ml to 3.6%. Within the therapeutic concentration range, tolmetin binding to 0.4% HSA was reduced in accordance with the law of mass action and at Ct = 26.2 microgram/ml, 10.5% was free. Analysis of the 0.4% HSA data showed tolmetin had 3 classes of binding sites (n1 = 1, K1 = 8.3 X 10(5) M-1; n2 = 4, K2 = 2.4 X 10(4) M-1; n3 = 44, K1 = 7.9 X 10(1) M-1). By studying the binding to 0.4% HSA at 23 degrees, it was established that the free energy change in binding for the first two classes of sites was entirely entropic in nature. Albumin accounted for almost all the binding of tolmetin in human plasma. The effect of other drugs, the tolmetin metabolite McN 2987 (5-p-carboxybenzoyl-1-methylpyrrole-2-acetic acid), tryptophan, and oleic acid on tolmetin binding to 4% HSA was studied using ultrafiltration and 14C-tolmetin. Aspirin and salicyclic acid decreased tolmetin binding and a combination of aspirin and salicyclic acid exerted a synergistic displacing effect. Indomethacin and ibuprofen had no effect while phenylhbutazone and acetaminophen increased tolmetin binding slightly. Tolmetin binding was decreased slightly by McN 2987 and tryptophan and markedly increased by oleic acid. McN 2987 was not bound as extensively as tolmetin. Binding of 14C-tolmetin to the plasma of 4 arthritic patients was studied by ultrafiltration and found to be less than to normal plasma and 4% HSA. Distribution of tolmetin in the whole blood of 8 healthy subjects using a centrifugation technique showed that the drug was not taken up by red blood cells at therapeutic concentrations.


The role of radiology in the assessment of bladder cancer.

Bipedal lymphography and intravenous urography were carried out in 44 patients in an attempt to define the role of these procedures in the assessment of the patient with carcinoma of the bladder. Evidence of lymphatic involvement, even though unsupported by histological proof and a major abnormality on urography, conferred a worse prognosis than if these examinations were thought to be normal. Implications for therapy are considered.


Representative planes of dose distribution for intracavitary radiotherapy of cancer of the cervix.

Four different frontal planes have been evaluated for their usefulness in considering the dose distribution from intracavitary applications for carcinoma of the uterine cervix, in relation to the subsequent planning of supplementary external beam therapy. For the primary tumour and its immediate zone of direct invasion the most useful planes are those passing through the radioactive sources in the body of the uterus. Not one of the planes examined gave satisfactory information concerning the dose in the regional lymph node areas. In order to combine the dose distributions from intracavitary and supplementary external beam irradiation, it is found that every case must be considered individually, particularly in regard to the degree of anterversion or retroversion of the uterus. The dose in the lymph nodes may be calculated directly from coordinates determined by the authors, for each specific regional lymph node group.


Percutaneous needle biopsy in the management of solitary lesions of bone.

Needle biopsies were performed in 12 patients with solitary bone lesions, employing a simple 18 gauge cutting needle. Material sufficient for reliable diagnosis was obtained from eight of our 12 cases, thereby avoiding exploratory surgery. It is concluded that percutaneous needle biopsy of bone is a safe and simple procedure of value in the management of solitary lesions of bone.


Computed tomography in the diagnosis of diseases of the paranasal sinuses.

The authors investigated 31 patients suffering from benign and malignant lesions of the paranasal sinuses. Clinical, conventional radiological methods and computed tomography were used. In benign lesions CT added little significant information to that obtained by conventional radiological methods. In malignant lesions, however, CT provides additional valuable information. It gives a clear picture of the posterior, superior and orbital extent of paranasal tumours. It also shows the extent of the tumour into the infratemporal fossa.


Technetium 99Tcm pyrophosphate scanning in the assessment of the painful hip prosthesis.

Technetium 99Tcm pyrophosphate bone scans were done on 35 patients who complained of persistent hip following total hip replacement. The scans of six patients were normal and the symptoms of these patients either resolved (three) or greatly improved (three) without further treatment. Twenty-nine patients had abnormal scans. Seventeen of these were due to infection or loosening of the prosthesis. Paget's disease of bone, protrusion of the prosthesis and heterotopic ossification also caused scan abnormalities. These causes could not be distinguished from one another on the scan. A radiograph of the hip is essential for interpreting the scan correctly. Scanning of the painful hip prosthesis helps to detect patients in whom serious complications are present or are likely to develop.


Primary adenocarcinoma of the upper oesophagus.

Adenocarcinoma of the upper one-third of the oesophagus is an uncommon entity. A review of the literature reveals 20 reported cases. This paper reports an additional case. The lesion may arise from oesophageal glands, foci of ectopic gastric mucosa, or a Barrett's oesophagus. In contrast with squamous cell carcinomas submucosal spread is not prominent; however, transverse penetration through the oesophageal wall is common. The prognosis is grave. Treatment modalities that have been employed include supportive care, surgery alone, pre-operative radiation therapy and surgery and radiation therapy alone. Survival statistics produced by these various regimens are similar. There is little documented evidence for the radioresponsiveness of primary adenocarcinoma of the oesophagus. The case described demonstrates marked tumour regression following a course of external radiotherapy as shown by serial oesophagrams. Optimum treatment for adenocarcinoma of the upper oesophagus remains to be determined. It is felt that the role of radiation therapy should be further evaluated.


Correlations between duodenal loop size and external body measurements.

Measurements of the area, height and width of duodenal loops in male and female controls were correlated with their body height, weight, surface area, lean body mass and adjusted body surface area in order to assess the possibility of predicting loop size from body habitus. In male subjects the most marked correlations were between bodyweight and loop area (r = 0.58) and between true body surface area and loop area (r = 0.57). No relationship was observed between the size of the duodenal loop and body size in females.