The specificity of bile salts in the intestinal absorption of micellar cholesterol in the rat.

1. Two aspects of cholesterol absorption; (a) the importance of solubilization and (b) the effects of different bile salts on the mucosal metabolism and lymphatic output of cholesterol, have been investigated using two different in vivo techniques. 2. Bile diverted lymph fistula rats were infused intraduodenally at a steady rate with a constant lipid mixture containing labelled cholesterol, labelled oleic acid and mono-olein. The lipids were completely solubilized in either bile salts or a non-toxic non-ionic detergent, Pluronic F68. Labelled fatty acid was efficiently absorbed from either micellar infusate but virtually no labelled cholesterol appeared in the lymph in the absence of bile salts. 3. Short-term perfusions of the intestine of anaesthetized rats with the same micellar perfusates as above showed approximately 20% of the labelled cholesterol in the mucosa after 30 min perfusion with the bile salt micellar solutions. When the non-ionic micelles were used virtually no isotopic cholesterol left the lumen. 4. Mucosal uptake of labelled cholesterol was linearly dependent on the concentration of solubilized cholesterol in the perfusate and was not dependent on the bile salt concentration. 5. After 30 min the total amount of perfused isotopic cholesterol was recovered from either the lumen or the mucosa, but some fatty acid appeared to have been transported away from the mucosa by this time. 6. The initial rate of mucosal uptake of labelled cholesterol was similar from micellar perfusates using either taurocholate, taurodeoxycholate or taurofusidate. In contrast, after 8 h of infusion, lymphatic output of labelled cholesterol was markedly greater with taurocholate. 7. The increased lymph output with taurocholate was associated with an increase in the esterified fraction of both labelled and unlabelled cholesterol. Fatty acid was absorbed and esterified equally from all three types of perfusate. 8. These results suggested that for the first step in cholesterol absorption, viz. uptake from the lumen, solubilization by a planar detergent was essential. After uptake, the more rapid transfer of cholesterol to lymph in the presence of trihydroxybile acids appeared to be related to a more efficient esterification of cholesterol, but not to a more efficient resynthesis of triglyceride, the other major component of lymph chylomicrons.


The effects of hydrocortisone on responses to and extraneuronal uptake of (-)-isoprenaline in cat and guinea-pig atria.

1. (-)-Isoprenaline-induced positive inotropic effects were assessed in driven left atria and positive chronotropic effects in spontaneously beating right atria from guinea-pigs and cats. 2. Hydrocortisone produced dose dependent shifts to the left in cumulative concentration-effect curves to (-)-isoprenaline in left and right atrial preparations from the cat. 3. Maximal potentiations were produced by 160 muM and 40 muM hydrocortisone in cat left and right atria respectively. 4. No such effects were seen in similar preparations from the guinea-pig even in the presence of concentrations of hydrocortisone as high as 400 muM. 5. Hydrocortisone inhibited the extraneuronal uptake of [7 - 3H](-)-isoprenaline in a concentration dependent manner in both left and right atria of the cat, but not the guinea-pig. 6. These results are consistent with the idea that hydrocortisone potentiates responses to (-)-isoprenaline in cat atria by inhibition of the extraneuronal uptake process.


The effects of 3-hydrazine-6[N,N-bis(2-hydroxyethyl)-amino]-pyridazine dihydrochloride (L6150) on the general and cardiac haemodynamics of the intact dog.

1. The effects of 3-hydrazine-6[N,N-bis(2-hydroxyethyl)amino]-pyridazine dihydrochloride (L6150) were studied in intact anaesthetized dogs. 2. In a dose of 1 mg/kg/(i.v.) the drug increased respiration rate, cardiac output, and left and right ventricular work. 3. It decreased femoral pressure and systemic and total pulmonary resistance. 4. It increased coronary flow and coronary sinus O2 content. 5 The drug also increased whole body glucose, lactate, pyruvate and NEFA values.


A study of the actions of histamine on the isolated rat heart.

1. The effects of histamine on cardiac force, heart rate and coronary perfusion pressure were studied in the isolated rat heart, using the Langendorff perfused heart preparation. 2. Single injections of histamine induced dose-dependent decreases in contractile amplitude, heart rate and coronary perfusion pressure. 3. Perfusions of metiamide (above 1 x 10(-4) m) had a depressant effect on contractile force and heart rate, whereas diphenhydramine (4 x 10(-6) m) reduced only the heart rate. Both agents caused a fall in coronary perfusion pressure. 4. The negative inotropic and chronotropic effects of histamine on the isolated rat heart were not significantly influenced by either metiamide of diphenhydramine, or a combination of these drugs. However, the fall in coronary perfusion pressure induced by injections of histamine was significantly antagonized by metiamide or diphenhydramine. 5. These results suggest that the effects of histamine on the isolated rat heart may not be due entirely to stimulation of H1- or H2-receptors on the cardiac muscle cells. Evidence is presented for the existence of histamine H1- and H2-receptors in the coronary vessels.


Increase in myocardial digoxin content associated with circulatory volume overload in the dog.

1. Tritiated (12alpha-3H) digoxin (0-05 mg/kg body weight) was administered intravenously to conscious dogs with circulatory volume overload induced by previous creation of aorto-caval fistulae. Dogs were killed after 5 min, 1, or 4 h, and the myocardium sampled. Digoxin was extracted and counted and results compared to those in normal dogs. 2. At each time, myocardial digoxin concentration of all cardiac chambers in test dogs was greater than normal. Plasma digoxin concentration measured 5 min after administration was greater in dogs with fistulae but the subsequent levels were not different. 3. Anaesthetized and open-chest dogs with fistulae studied 5 min after digoxin administration had greater myocardial concentrations than similarly studied normal dogs. Although myocardial concentrations of digoxin were higher in anaesthetized than in conscious dogs the group with fistulae had higher values than did the normal group, as was the case for unanaesthetized dogs. 4. The basis for the effect of fistula is probably multifactorial. Diminised peripheral blood flow and peripheral digoxin delivery and uptake, resulting initially in higher digoxin levels in plasma perfusing the myocardium, may play a role. Increased myocardial mechanical and metabolic activity almost certainly are important. Cardiac hypertrophy, cardiac failure per se and plasma electrolyte changes are probably not. 5. The results are consistent with previously demonstrated reduced digitalis tolerance in the dog with circulatory volume overload.


On the role of serotonin in the pathogenesis of pulmonary hypertension induced by anorectic drugs; an experimental study in the isolated perfused rat lung, II. Fenfluramine, mazindol, mefenorex, phentermine and R 800.

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide of phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.


Hepatic sinusoidal responses to intraportal injections of phenylephrine and isoprenaline in the rat.

1. Specific alpha- and beta-adrenoreceptor agonists, phenylephrine and isoprenaline, were injected intraportally into the intact rat liver under direct microscopic observation by an in vivo transillumination technique. 2. The diameter of a hepatic sinusoid and the intra-sinusoidal erythrocyte velocity were quantitatively measured, and the sinusoidal volume flow was calculated from these two parameters. 3. Results show that phenylephrine causes a sinusoidal constriction and an increased sinusoidal blood flow, whereas isoprenaline causes the opposite effects on the sinusoids. 4. All the sinusoidal responses to phenylephrine and isoprenaline were dose-dependent and were possibly related to the direct effect of these drugs on the sinusoids.


Adrenoceptor and cholinoceptor mediated effects in the isolated urethra of cat and guinea-pig.

1. Preparations of isolated bladder-urethral junction from cats and guinea-pigs were suspended in Krebs solution (37 degrees C) which was bubbled with carbogen. The urethral lumen was perfused at a very low rate (1-3 ml/h) with Krebs solution. Resistance to flow and changes in longitudinal tension (initial setting 0-5 g) were recorded. In additional experiments, tension changes in urethral circular muscle preparations were registered. 2. The urethral preparations had a basal resistance to flow within the range 5-20 cm H2O. They had a spontaneous contractile activity that was unaffected by atropine 0-1 mug/ml, phenoxybenzamine 0-1 mug/ml, and tetrodotoxin 0-1-0-5 mug/ml, suggesting it was of myogenic origin. 3. The basal characteristics and the drug-induced changes in the perfused urethras were independent of whether the longitudinal tension was recorded isometrically or isotonically, or whether the perfusion was made retrograde or antegrade. Passive changes in longitudinal tension between 0-5 and 2-0 g did not affect the resistance to flow through the urethra. 4. Adrenaline and noradrenaline, 0-01-1 mug/ml, increased longitudinal tension and resistance to flow in the perfused preparations. The effects, which were sustained and concentration-related, were blocked or reversed into inhibition in the presence of phenoxybenzamine, 0-1 mug/ml. This finding suggests that the stimulatory effects were mediated via alpha-receptors. 5. Isoprenaline, 0-001-0-005 mug/ml, relaxed and inhibited the activity in the cat urethral smooth muscle and decreased the resistance to flow both under basal conditions and when the urethra was contracted by noradrenaline or acetylcholine. The inhibitory effects were blocked by propranolol, 0-1 mug/ml, suggesting that they were mediated via beta-receptors. In guinea-pig preparations, no effect of isoprenaline was observed. 6. Acetylcholine, 0-02-0-5 mug/ml, increased the longitudinal tension and the resistance to flow through the urethras. The latter effect was less pronounced than that produced by noradrenaline, especially in the guinea-pig preparations. Noradrenaline was also more effective than ecetylcholine in contracting the circular muscle of the urethra. The effect of acetylcholine was blocked by atropine, 0-1 mug/ml, suggesting that the contractions were mediated through muscarinic cholinoceptors.


Effect of propranolol on the release of choline from guinea-pig small intestine in vitro.

1. Choline was released into the fluid bathing the serosal surface of segments of guinea-pig small intestine. The mean rate of release (nmol choline per cm of intestine per h) in the first hour was 10-2 and in the second hour 8-0. 2. Propranolol 1 mM in the mucosal fluid caused a significant (P less than 0-01) increase in the rate at which choline was released into the serosal fluid. The mean rates were 15-4 and 19-2 for the first and second hour, respectively. 3. It is suggested that the effect of propranolol observed in the present study is likely to be due to a non-specific direct action on biological membranes.


The effects of propranolol, practolol and metoprolol on exercise-induced tachycardia in relation to plasma levels in man.

1. The effects of single oral doses of propranolol, practolol and a new cardioselective beta-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74-3 (s.e.m. = 6-8) to 153-8 (s.e.m. = 9.8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluorometrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1-5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50-60 ng/ml (half-life 2-75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050-1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140-150 ng/ml (half-life 1-7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting beta-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.


The action of histamine on pulmonary vessels of cats and rats.

1. The actions of histamine on pulmonary vascular smooth muscle have been studied in isolated cat and rat lungs perfused with blood, lobes of cat lung perfused in vivo and isolated strips of rat, cat and rabbit pulmonary artery. 2. In all the lung preparations histamine caused both dilatation and constriction. In the rat strips it caused both contraction and relaxation. Dilatation was only well shown when the vessels were in a prior constricted state. In any one lung dilatation occurred with smaller doses than constriction. 3. Histamine caused both increases and decreases in pulmonary artery pressure in collapsed lungs. In this condition these effects are unlikely to have been a consequence of changes in airway pressure. 4. From forward and reverse perfusions of lungs in the waterfall state, where changes in postalveolar vessels do not affect pulmonary artery pressure, it appeared that histamine caused both dilatation and constriction on both sides of the point of collapse caused by alveolar pressure. 5. Plots of the relationship between left atrial and pulmonary artery pressure (at constant alveolar pressure and blood flow) showed that histamine caused both increases and decreases in pulmonary vascular resistance and sometimes also increased the "Starling resistor" properties of lung vessels. 6. In plethysmograph experiments histamine caused moderate dilatation and constriction without affecting lung volume but strong vasoconstriction was accompanied by increases in lung volume.


Lethal effects of reserpine plus physostigmine and neostigmine in mice.

1. The interaction between the reversible cholinesterase inhibitors, physostigmine and neostigmine and reserpine was studied. 2. A combination of reserpine plus a cholinesterase inhibitor significantly increased lethality in adult male Swiss-Webster mice above that caused by either neostigmine, physostigmine, or reserpine alone. 3. Methscopolamine completely reversed this effect. 4. It would appear that the presence of the antiadrenergic agent, reserpine, increases the toxicity of cholinomimetic agents. 5. The above results may have clinical significance, since reserpine and cholinesterase inhibitors are used in the practice of medicine.


Plasma carbamazepine determinations: a simple gas chromatographic method.

1. A simple, rapid and specific gas chromatographic method for the measurement of plasma carbamazepine concentration is presented. 2. The extraction is a single step method, and the drug is measured by derivatization using on column methylation and standard instrumentation. 3. Other anticonvulsant agents do not co-extract. Other drugs do not interfere in the chromatogram. 4. Stability, recovery and reproducibility make this procedure suitable for routine carbamazepine measurements.


Circulating dopamine-beta-hydroxylase (DbetaH) and catecholamines in a paediatric phaeochromocytoma.

1. Circulating catecholamines and dopamine-beta-hydroxylase (DbetaH) have been studied in a child with bilateral phaeochromocytoma. 2. Venous catheterization showed a great increase in catecholamine efflux from the left adrenal vein while DbetaH activity in the latter was only slightly elevated. 3. Circulating catecholamines fluctated greatly while DbetaH activity decreased gradually during the removal of the tumours. 4. Post-operatively, circulating catecholamines declined to normal values while DbetaH activity returned to pre-operative levels. 5. It is concluded that these tumours released circulating catecholamines independent of an exocytotic secretion of DbetaH and that the circulating DbetaH reflected the activity of the sympathetic nervous system.


Effects of amiodarone and L8040, novel antianginal and antiarrhythmic drugs, on cardiac and coronary haemodynamics and on cardiac intracellular potentials.

1. The effects on the coronary and systemic haemodynamics of intravenous and intracoronary injections of two benzfuran derivatives, amiodarone and its brominated analogue (L8040), were studied in open-chest anaesthetized dogs. The effects of L8040 on cardiac intracellular potentials after 6 weeks of 20 mg/kg intraperitoneal injections in rabbits were also investigated. 2. Both compounds produced dose-related and quantitatively similar decreases in coronary vascular resistance following their intracoronary administration; threshold effects occurred with about 0-25 mg of each drug and maximal effects with 4 mg. Larger intracoronary doses produced measurable systemic effects. 3. Intravenous injections of amiodarone and L8040 (2-5-10 mg/kg) produced dose-related decreases in heart rate and aortic pressure with a fall in total peripheral resistance. The left ventricular output was either unaffected or increased with a consistent augmentation in stroke volume. 4. The bradycardia produced by both drugs was associated with prolongation of the P-R interval of the electrocardiogram with no significant effect on the QRS duration or the Q-T interval. 5. Each drug produced a decrease in the total peripheral vascular resistance with no change  in left ventricular end diastolic pressure except after 10 mg/kg doses which led to an increase in this parameter. 6. Cardiac contractile force and peak LV dp/dt were reduced by both drugs in a dose-related manner. 7. Chronic intraperitoneal administration of L8040 in rabbits caused a prolongation of the duration of the atrial and ventricular intracellular potential without an effect on the maximal rate of depolarization. 8. The effect of amiodarone or L8040 on the coronary circulation and arterial pressure may be attributed to their vasodilator properties but their depressant actions on cardiac contractile force and peak LV dp/dt with an increase in left ventricular end diastolic pressure at high doses, also suggest intrinsic negative inotropic propensity for both compounds. 9. It is concluded that the overall effects on coronary and systemic haemodynamics of amiodarone and its brominated analogue are likely to permit a favourable influence on the balance of oxygen supply and demand in myocardial ischaemia; in addition, their actions on sino-atrial and atrio-ventricular conduction as well as those on cardiac repolarization suggest potential antiarrhythmic properties which merit investigation.


The effects of mazindol and 46-034 (Sandoz) on glucose oxidation and insulin binding by rat isolated fat cells.

1. The anorexic agent mazindol and its major metabolite 46-034 (Sandoz) in high concentrations ( greater than 0-4 mM) abolished basal and insulin-stimulated conversion of 1-14C-glucose to 14CO2 by rat isolated fat cells. 2. High concentrations (1mM) also inhibited specific binding of 125 I-insulin to fat cells. 3. The observed effects appeared to be due in part to perturbation of the plasma membrane since there was a rise in the lactate dehydrogenase content of the incubation medium, increased 125I-insulin degradation and a reduction in cellular tritiated water space. 4. These effects are unlikely to be relevant to the therapeutic action of mazindol.


Changes of bone histology during maintenance hemodialysis at various levels of dialyzate Ca concentration.

Bone histology (iliac crest biopsies; undecalcified sections; micromorphometry) was studied by repeated biopsies in 19 patients on maintenance hemodialysis. Sampling error was assessed by taking two biopsies at one time. After an initial biopsy, patients were dialyzed either against 3.6 mEq Ca/l dialyzate or 3.9 mEq Ca/l dialyzate for 9-16 months before a second biopsy was taken. Bone histology failed to normalize irrespective of the dialyzate Ca concentration. Surface density of endosteal fibrosis diminished in a considerable proportion of the patients (9/19). Volumetric density of osteoid fell in 5 and rose in 4 of the patients.


Circulatory changes in cold-acclimation and cold stress.

1. The cardiovascular changes of conscious cold-acclimated (CA) and warm-acclimated (WA) rats during exposure to 5 degrees C or 28 degrees C were studied. 2. The cardiac output, heart rate and stroke volume of Ca rats exposed to 5 degrees C and of WA rats during cold stress were significantly greater, and their calculated total peripheral resistance significantly less than those of WA rats ats exposed to 28 degrees C. These results show that circulatory changes participate in cold acclimation and cold stress. The circulatory changes in the two conditions were compared and the mechanism of the observed differences were discussed. 3. CA rats exposed to 28 degrees C showed a striking decrease of oxygen consumption and arterio-venous O2 difference, but significant circulatory changes were decreased heart rate and cardiac index only, indicating that the response was mainly metabolic.


The binding of chloramphenicol to serum proteins in patients with chronic renal insufficiency.

The binding (r) of chloramphenicol to serum proteins is significantly lower in patients with chronic renal failure than in normal subjects. Before hemodialysis, the mean r value in patients with chronic renal insufficiency was 0.165 mg/g (+/-0.003) versus 0.188 mg/g (+/-0.004) in healthy individuals. Hemodialysis produced a significant rise in r (to 0.182 mg/g, +/-0.004). Decrease in the serum concentration of albumin in patients with chronic renal insufficiency does not seem to be the sole factor responsible for decreased r.


Quadricepsplasty: a review, case presentations, and discussion.

The operation of quadricepsplasty as described by T. C. Thompson, if followed by satisfactory after-treatment, can be expected to lead to a substantial gain of knee motion in patients who have fibrous ankylosis of the knee.


Complications of polycentric knee arthroplasty.

Results of 89 polycentric knee arthroplasties are assessed from 2 years to 7 1/2 years after operation. Seventy-two arthroplasties (81%) are considered to improve the mobility of the patient, with 17 arthroplasties producing no improvement. Infection after operation in 6 arthroplasties (7%) required arthrodesis of 3 arthroplasties. Loosening of prosthetic components occurred in 9 arthroplasties (10%).


Diphosphonate treatment of Paget's disease.

Ethane-1-hydroxy-1, 1-diphosphonate (EHDP) was administered in a dose of 20 mg/kg/d to 21 patients with symptomatic Paget's disease. All patients were treated for 6 months and then followed for an additional 6 months. There was a striking decline in serum alkaline phosphatase and urinary hydroxy-proline excretion observed after 3 months of therapy which was not significantly improved in the succeeding 3 months. Concomitantly there was marked improvement in clinical symptoms and bone scans. Following cessation of therapy, continued biochemical and clinical evidence of remission persisted. Several patients on repeat treatment with EHDP appeared to respond promptly. Side effects were minimal except for a possibly related osteomalacia and increased incidence of pathologic fractures.


Curettage and acrylic cementation in surgery of giant cell tumors of bone.

True giant cell tumors of bone (osteoblastomas) are comparatively rare but often large at time of discovery, making the surgical treatment controversial. Simple curettage or resection with bone filling is used when the lesion is small. Resection with arthroplasty or arthrodesis and possibly amputation is used in advanced cases. Thorough curettage with acrylic cementation is presented in a series of 6 cases from Rotterdam and Lund with a follow-up time between 2 and 7 years. The advantages of this method are full and early mobility and stability as well as a simplified postoperative X-ray control, especially when barium sulphate contrast has been added to the acrylic cement. Finally, if this technique is used in cases where more extensive surgery becomes necessary later, there is much to gain and little to lose. The operation may turn out to be the method of choice for this special type of tumor when a simple curettage or resection is no longer possible without loss of function. No recurrences or spread have been observed among these 6 cases. It is suggested that the heat generation could be an advantage of the method.


Spontaneous fractures in the brain-crippled, bedridden patient.

This report deals with the treatment of 31 spontaneous fractures which occurred in 50 institutionalized patients who were bedridden primarily because of severe cerebral palsy associated with brain injury. More than one-half of the group sustained a spontaneous fracture. Satisfactory healing of all fractures with a minimum of complications occurred without any immobilization or realignment. In 4 patients with delayed compound wounds, the treatment consisted of resection of the protruding portion of the bone after allowing the bony protrusion to wall itself off.


Valgus osteotomy for osteoarthritis of the knee.

Recent reports indicate that proximal tibial osteotomy for osteoarthritis of the knee is contraindicated if subluxation of the joint is evident clinically or on weight-bearing X-rays, or if the angular deformity of the joint is greater than 15 degrees. The purpose of this paper is to present evidence that a proximal tibial osteotomy, properly planned and performed, can give consistently sat-sfactory results even in osteoarthritic knees which have preoperative varus deformities greater that 15 degrees or are subluxated. A proper planning requires an exact measurement of the deformity on full length X-rays, a precise preoperative drawing and a very exact osteotomy giving some overcorrection. The overcorrection must compensate for the weakness of the lateral muscles, the most frequent cause of the condition.


Total condylar knee replacment: preliminary report.

The Total Condylar Prosthesis is a non-hinged unit designed to: replace the patellofemoral articulation; improve fixation of the tibial component by means of a stout central peg; permit accurate and reproducible insertion. The cruciate ligaments are excised to obtain better tibial fixation. Instability has not been a problem except in a few cases of a technical error (removal of excessive bone from the tibia creates instability in flexion). The prosthesis cannot be positioned by "eye" and the instrumentation must be applied exactly.


Displaced fracture of the lumbosacral spine with delayed cauda equina deficit: report of a case and review of literature.

A 41-year-old man with a fracture of the upper sacrum and forward and downward displacement of the superior sacral fragment and upper spine on the lower sacrum, developed partial deficit of cauda equina function. Similar fractures rarely have been reported. Signs of lumbar pain, contusion, and fractured transverse processes should lead the surgeon to carefully examine the radiologic fractures of the area of injury; otherwise, this lesion may heal unrecognized. With the spine in flexion, the fracture may create mechanical instability. Early closed or open reduction is theoretically ideal. Surgical treatment must be weighed in terms of the risks and needs of the individual.


Tibial torsion?

A longitudinal study evaluating the degree of rotation of the bimalleolar axis of tibia and fibula at birth, 6 month, 12 months and 24 months revealed a gradual statistically significant external rotation from a mean of 4 degrees at birth to a mean of 11 degrees at 24 months. There was no correlation with the sex or race of the child or with the age at which the child began independent walking. It is concluded that this external rotation is a part of normal growth and development of the infants' lower extremities.


Vertical transarticular pin fixation for unstable ankle fractures: impressions after 16 years of experience.

The usage of vertical transarticular pin fixation combined with plaster immobilization for severe ankle injuries has been reviewed in 92 consecutive cases over a period of 16 years. Moderately simple in application and without a skin incision, the procedure has been found to provide efficient and reliable short-term stabilization of the ankle and subtalar joints with minimal complications. A new technique is described for accurate placement of the pin and the prevention of its migration. It is a reasonable alternative treatment for certain unstable distal tibial and ankle fractures when open reduction with conventional internal fixation cannot be done. In particular, the method is recommended in treating displaced fractures at the ankle and deltoid ligament ruptures in geriatric patients. It is often useful as a salvage or last-resort procedure in unusually severe ankle injuries with circulatory or neural deficits. In many instances additional trauma to the head, thorax or abdomen may have been sustained. Thus total patient care is essential and priorities must be recognized. The treatment of ankle trauma, furthermore, in a physiologically-aged diabetic patient is often not the same as that for similar injuries in a young healthy adult. The clinical judgement and experience of the operator is the basis for selection of the procedure. The simplest method is often the best. Pin fixation, however, is not for everyone. It should be done only by surgeons qualified to treat bone and joint trauma and even then only for those situations in which its usage is specifically indicated.


Forearm fractures in children: pitfalls and complications.

Five hundred fourty-seven consecutive forearm fractures in children were studied, with special emphasis on complications encountered. The most important apparent conclusion reached from this study is that greenstick and complete fractures are different, and that some of the pitfalls and complications seen following these injuries can be avoided if different methods of reduction are used for each. Greenstick fractures should be reduced by manipulating them into the correct proper plane of rotation; i.e., maximum pronation for distal third fractures, neutral for middle third fractures, and supination for proximal third fractures. Application of this familiar "rule of thirds" to complete fractures, however, may result in ratational deformity at the fracture site. Completer fractures should be reduced by finger trap traction, allowing the fracture to seek its own level of rotation. Several other observations were also noted. Angulation into radial deviation was found to remodel and equally as well as volar angulation, and remodeling may contine for as long as two years after injury. Growth disturbance following fractures through the distal radial epiphyseal plate is uncommon, but premature closure of the epiphysis did occur in one patient with a typical Type II fracture. Six concomitant nerve injuries were seen; all recovered spontaneously within 3 weeks.


A statistical evaluation of polycentric total knee arthroplasties.

Four hundred nineteen knees in 299 patients were examined preoperatively and at two years after polycentric total knee surgery. One hundred forty-three knees were in 109 patients with osteoarthritis. Two hundred seventy-six knees were in 190 patients with rheumatoid arthritis. Pain decreased significantly, use of aids decreased significantly, and distance walked increased significantly in both groups. Rheumatoid patients did not fare as well as osteoarthritics in the use of aids and distance walked. Osteoarthritic knees had proportionately more implant settling, implant loosening and reoperations than did rheumatoid arthritic knees.


Acute carpal tunnel syndrome secondary to pseudogout: case report.

Acute carpal tunnel syndrome secondary to chondrocalcinosis seems not to have been previously reported. In a 75-year-old woman, with arthropathy and calcification of the triangular fibrocartilage of the wrist, hyperparathyroidism was suspected, but not proven. Hydroxyapatite and calcium pyrophosphate crystals were found together in the pathological specimen. The patient obtained complete relief from sectioning of the transverse carpal ligament.


Treatment of the triphalangeal thumb.

The triphalangeal thumb is a rare congenital malformation, but not as rare as the literature would imply. Forty-two patients with 68 triphalangeal thumbs, represent an incidence of about 3 per cent of a population of upper extremity abnormalities. Although little is written about the details of treatment, surgery is frequently necessary. Age makes a great difference as to hom the extra phalanx should be treated. The associated abnormalities present major surgical problems that must be treated early.


The osteoclast: review of ultrastructure, origin, and structure-function relationship.

Multinucleated cells of the giant cell tumor and the genuine osteoclasts exhibit a number of common morphological characteristics and may or may not originate from similar progenitor cells. Judging from the present preliminary results, it is obvious that the differentiation of the plasma membrane into a specialized area, the ruffled border, is not as conspicuous in the giant cell as in the osteoclast. A series of interrelated investigations including histochemical methods at the ultrastructural level applied both in giant cell tissue and cultured giant tumor cells are in progress. These studies may further elucidate the possible relationship between the osteoclast and the multinucleated giant cell tumor as well as the possible relationships between giant cells and other cell types of tumors.


Newer knowledge of the immunology of bone and cartilage.

By the use of modern techniques, the nature of the immunological response to bone and cartilage grafts is becoming clear. Fresh bone, whether cancellous or cortical, will elicit a cell-mediated immunological response; removal of the bone marrow has little effect in reducing immunogenicity. Antibodies against cellular components of the graft are detectable in the recipient only when host and donor have a disparity for the major histocompatibility (H) antigen. Treatment of bone grafts, for the bone bank, by freezing removes their immunogenicity with regard to antibody production but leaves them capable of stimulating the cellmediated immune response. Freeze drying, on the other hand, impairs immunogenicity for both types of responses. Cartilage, grafted alone, is probably non-antigenic as far as both immune responses are concerned and, although there have been a few reports of stimulation of CMI and antibody production by cartilage, these have not been confirmed. Cartilage cells do, however, possess antigens of the major H-antigen system. The cartilage graft is therefore antigenic but only feebly immunogenic, as the matrix proteoglycans protect the cells from the afferent arm of the immune response. Osteoarticular allografts, consisting of both bone and cartilage, sensitize the host due to their bone components. The effect of the immune response upon the bone allograft is to destroy the graft-derived first phase of osteogenesis which, in turn, leads to a poor or non-existent host phase of new bone formation in most allografts. The exact effector mechanism by means of which this destruction is brought about is not known. Bone grafts may be protected from the immune response by use of immunosuppressive measures. Cartilage enjoys a considerable measure of protection from immunological effectors by virtue of its matrix. If this breaks down then the cartilage can become permeable to antibodies. It is suggested that "lymphokines," produced by sensitized lymphocytes, may play some role in destroying the cartilage graft.


Cell proliferation in the bone marrow and thymus following fractures in rats.

Skeletal trauma in rats (tibial and femur fractures) stimulates bone marrow and thymus to increased mitotic activity during the first 2-3 days after the fracture. The stimulation is roughly of the same degree as that described in earlier investigations on the effects of calcium ion injections and moderate or major hemorrhages. The cause of increased mitotic level might be due to the release of kinins from the fracture area, factors which are known to stimulate mitoses of the bone marrow and thymus.


Pathogenesis of scoliosis.

Scoliosis often occurs in otherwise normal individuals or it may be associated with many widely differing diseases. The curve patterns are fairly uniform and the vertebrae always rotate in the frontal and horizontal planes producing convex side rotation with little displacement of the spinuous processes. Many small curves do not increase. Progressive scoliosis increases linearly and the rate of increase accelerates at puberty. No endocrine abnormalities have been observed in these patients. Usually the deformity is not caused by abnormal vertebral growth nor by abnormal collagen in verterbral ligaments. The glycosaminoglycans of nucleus pulposus are decreased in patients with idiopathic scoliosis. We speculate that loss of proteoglycans will affect the viscoelastic properties of the intervertebral discs which may result in permanent deformation. The etiology of scoliosis appears to be multifactorial with a genetic tendency to the deformity which is triggered in different individuals by different factors, some medical, some mechanical and some genetic.


A statistical evaluation of geometric total knee arthroplasties.

Seventy-five knees in 56 patients were examined preoperatively and at two years after geometric total knee surgery. Thirty-three knees were in 28 patients with osteoarthritis. Fourty-two knees were in 28 patients with rheumatoid arthritis. Pain was significantly decreased and the use of aids was significantly decreased in both groups. The distance walked increased significantly for the osteoarthritic group but not for the rheumatoid group. Rheumatoid patients did not fare as well as osteoarthritic patients in distance walked and use of aids. Knees with osteoarthritis had more evidence of lucent lines and implant loosening than did the rheumatoid patients.


UCI knee replacement.

Between March 9, 1972 and December 31, 1973, a total of 103 UCI knee replacements were performed. Follow-up data are available on 83 knees with an average follow-up of 33 months. Patient evaluation of the end results indicates that 78.3 per cent were better, 9.6 per cent unchanged, and 12.1 per cent worse. Patient evaluation of their own knee function averaged 55 per cent preoperatively and 79 per cent postoperatively. Patients were also evaluated on a 100 point Modified Larson Analysis Form. The average preoperative score was 46, and the average postoperative score was 70. There were six (5.8%) biological complications in the 103 knee replacement. Biological complications included infections, wound healing problems and unexplained pain. Mechanical complications were seen in 18 (17.4%) knees, and included knee instability, tibial component loosening or deformation, and patellar problems. Additional surgery was required in 18 (17.4%) knees. Failure of the procedure eventually requiring removal of the prosthesis and fusion or amputation occurred in 4 (3.9%) knees. The intermediate-term results of UCI knee replacement have been clinically satisfactory. We currently recommend consideration of this procedure for patients with disabling arthritis of the knee.


Results of knee replacement with the Walldius prosthesis: an interim report.

Fourty-two knees replaced with the Walldius prosthesis have been followed for an average of almost 6 years. The rating of the average knee on a 100 point clinical scale improved 29 points as a result of the procedure. Complications were carefully documented and were numerous, although relatively few affected the end result.


Guepar hinge prosthesis: complications and results with two years' follow-up.

Experience with the GUEPAR prosthesis in 292 cases of which 103 have been followed for more than 2 years, suggests that: implanting a hinge prosthesis is major surgery on elderly patients in whom severe complications have occurred and for this reason, the operations should be reserved for extremely damaged and unstable knees; the most important local complications have been deep sepsis for which we have noted a rate of 6.6 per cent; in the treatment of sepsis, everything must be done to preserve the prosthesis because arthrodesis is difficult to obtain; pain relief has been significant as a result of the operation. The prosthetic design allows flexion of more than 90 degrees in 85 per cent of the cases and 120 degrees in 26 per cent; after two years, the results seem relatively stable. We have not observed aseptic loosening after this period but a longer observation period is necessary to be reassured on this point; patellar pain remains a major concern because this arthroplasty has not solved the problem, and other solutions will have to be found.


Statistics of total knee replacement: partial and total knee replacement, design St. Georg: a review of a 4-year observation.

Since 1969, we have used 2 different types of knee prostheses to reconstruct arthritic knees. The surface replacement prosthesis (sledge) is indicated where ligamentous stability is present and angular deformity is not severe. In addition, the sledge prosthesis may be implanted with good results in selected acute comminuted tibial plateau fractures. The total hinged prosthesis of metal design is recommended in knees which are severely deformed, and unstable, and therefore not suitable for the sledge prosthesis. Marked relief of pain was the most significant result in our patients. Residual knee pain was most frequently due to patello-femoral pain and, when severe, this was satisfactorily controlled by performing a patellectomy. Motion was usually maintained at the preoperative range or improved, mainly by reducing or eliminating the knee flexion contracture. In a high percentage, the unicompartmental sledge prosthesis has given excellent results. However, we tend to insert a bi-compartmental sledge prosthesis because experience has shown that even slight damage of the articular surfaces of the opposite side is likely to further deteriorate rapidly. Although a significant number of complications occurred, these have been minimized by further conservative and operative treatment. We anticipate a further reduction in complications based on our initial experience, and prosthetic revisions.


ICLH (Freeman/Swanson) arthroplasty in the treatment of arthritic knee: a 2 to 4-year review.

A prospective follow-up using a standardized data recording form was carried out by independent, experienced orthopedic surgeons on a small number (116) of knees operated upon at The London Hospital in the period January 1, 1971 to October 31, 1973. An additional 93 knees have been operated upon at other hospitals and followed prospectively using the same data recording system. A total of 159 knees have been reviewed 2 to 4 years after operation. The complications specific to ICLH arthroplasty have been unremarkable and generally correctable. Two tibial components have sunk and have been revised at The London Hospital. The results show that ICLH arthroplasty has been used to correct satisfactorily flexion deformities up to 70 degrees, valgus deformities up to 45 degrees, and varus deformities up to 35 degrees. (Deformities of greater magnitude can be corrected but were not present among the knees in this study.) The operation may be said to be "worthwhile" with reference to pain in 94 per cent of the knees, with reference to the ability to walk in 80 per cent of the knees, and with reference to the range of movement in 71 per cent. Overall, 47 per cent of the knees had no complaint postoperatively, while a further 47 per cent were improved; thus for 94 per cent the procedure was "worthwhile."


Duo-condylar knee arthroplasty: hospital for special surgery design.

This is a report of 94 knees in 88 patients with the duo-condylar type of knee arthroplasty. The follow-up period of time was between 2 to 4 years with an average of 3 years. The rheumatoid to osteoarthritic patient ratio was 3 to 1. The overall results were excellent in 37.5 per cent, good in 37.5 per cent, fair in 16 per cent, and poor in 9 per cent. The main causes of failure and poor results were: (1) under or over correction of deformity leading to subluxation and/or instability of the knee; (2) loosening of the tibial component, and (3) symptoms arising from the patellofemoral joint. The revision rate is 5.5 per cent. The progressive radiolucency at the cement bone bond is 26 per cent of which 16 per cent is up to 1 mm and 10 per cent is between 1.5 to 3 mm. To further improve the results of arthroplasty, one should take into consideration (1) replacement of the patellofemoral joint, (2) insertion of the prosthesis in the proper anatomical location under correct tension of the ligaments and capsule with the help of proper instrumentation and (3) improvement in fixation of the tibial component.


Unicondylar knee replacement.

Unicompartmental knee arthroplasty was conceived for the treatment of osteoarthritic knees with deterioration of either the medial or lateral compartment of the knee. The Unicondylar prosthesis was used in 19 medial and 5 lateral compartment arthroplasties. A two to 4 year follow-up evaluation of these patients was somewhat disappointing as only 5 knees could be rated excellent and 6 rated a good result. The best results were seen in the lateral compartment arthroplasties. Such deformities may be the only future indication for the use of this operation as these knees do not do well when treated by tibial osteotomy. However, when only the medial compartment is involved, osteotomy may still remain the treatment of choice.


The Modular (Marmor) knee: case report with a minimum follow-up of 2 years.

A follow-up of 2 years or more on 105 patients with the Modular (Marmor) knee replacement revealed that 88 per cent of the patients had a successful result. The complications and failures are analyzed in depth. Late loosening of the components was not observed except with the 6 mm tibial plateau. Pain relief was dramatic as well as improved function, stability and motion.


Hematological and vascular concepts in relation to stroke.

This review has highlighted some of the factors which influence the formation and fate of thrombi. Rheology and flow, the coagulation mechanism, the fibrinolytic enzyme system, and the properties of platelets to adhere and aggregate all play a significant role. Of paramount importance to neurosurgeons is the role of the vascular wall in thrombogenesis. The ulcerated atherosclerotic plaque demonstrates this point. Factors contributing to thromboembolism in this setting include stenosis and reduced flow, turbulence, and the elements in the lesion with which blood interacts. These are principally collagen, ADP, fatty acids, and the thromboplastic activity of vascular subendothelial tissue. Current concepts of the etiologies of atherosclerosis were discussed. Along with other predisposing factors, platelets may play a significant role in the initiation of the process. The current status of clinical trials with inhibitors of platelet function in the treatment of cerebrovascular disorders was reviewed. In vascular reconstructive surgery, the principles which underlie good technique are those which best insure against thrombosis. The briefest possible period of stasis during surgery should be maintained. The reconstruction should result in a smooth blood flow pattern with rapid runoff and minimal stenosis or gaps between apposed endothelial surfaces.


Host--dose--time: a concept for atherosclerosis.

Advances in knowledge about atherosclerosis in the past 25 years were discussed. Areas of disagreement and agreement were identified. A concept of HOST-DOSE-TIME was introduced for the skeptical analysis of past, present, and future observation and treatment of atherosclerosis.


Cardiogenic factors in the stroke syndrome.

The cardiogenic factors which may contribute to the stroke syndrome have been discussed (Table 14.7). Pathophysiological mechanisms include emboli from rheumatic coronary and congenital heart diseases. Atherosclerotic disease and hypertension can involve both intracranial and extracranial arteries. Disturbances in cardiac rhythm can significantly reduce cerebral blood flow. The development of cerebral hypoxia with resuscitation is described. Treatment of these disorders is reviewed, and the potential role of metabolic support of the ischemic tissue both with cerebral and myocardial damage has been presented.


The radionuclide cerebral angiogram in stroke diagnosis.

The radionuclide cerebral angiogram using intravenous radiopertechnetate has been found to be of value in confirming the early diagnosis of stroke. The isotopic perfusion study is of value in detecting ischemic carotid and middle cerebral lesions. It can also provide a rapid means of demonstrating intracerebral hemorrhages. Nuclear angiography is not recommended for detection of vertebrobasilar artery disease unless a posterior cerebral artery occlusion is suspected.


Shunt complications.

To some extent our greatest problem is the philosophic answer to the question, "who shall be treated, how intensely and to what expense?" The cost of care is almost always greatest in the child who is borderline in selection and least likely to survive. Over half of the children shunted after application of searching criteria appear to this author to be compensated (Table 28.13).


The role of vascular proliferation in the growth of brain tumors.

The formation of new blood vessels, i.e., angiogenesis, is a critical step in the evolution of a brain tumor from the earliest avascular phase to the clinically overt, vascular stage. For cerebral astrocytomas, intense capillary proliferation is a poor prognostic sign, associated with rapidly growing tumors. The in vivo production of a vasoformative substance can be demonstrated by transplanting human and experimental gliomas to the rabbit cornea. Intense neovascularization is elicited by the tumor and not by control tissues. If the same tumor is transplanted to the vitreous, thereby interrupting the vasoformative signal, the tumor remains in a dormant state for a prolonged period of time, despite its malignant potential. Inhibition of angiogenesis would be an important adjunct to the surgical treatment of gliomas.


Complications of percutaneous surgery for pain.

Percutaneous procedures are proving themselves to be useful additions to the group of neurosurgical procedures for treating pain. They demand a different style of careful operating technique and they place heavy reliance on the gradual production of lesions to achieve the desired degree of denervation. Control of lesion position and extent through further advances in neurophysiological monitoring should give these procedures an even wider margin of safety and reliability.


Complications of surgery for subdural hematoma.

In this report we have discussed the complications of surgery for subdural hematoma. The complications are varied and many depend primarily on the type of treatment required by the patient. We have considered the problems associated with: percutaneous tap in infants, subdural shunts in infants and children, craniotomy for membranectomy, twist-drill drainage, and burr holes, craneictomy, and/or craniotomy. Infection, epilepsy, and reaccumulation of the subdural hematoma are common to all forms of therapy, while other complications are related to the specific form of subdural hematoma treatment. In addition, significant serum and electrolyte abnormalities which may occur as a consequence of subdural hematoma surgery have been reviewed. In general, the over-all complication rate of surgery for subdural hematoma is low in relationship to the morbidity and mortality associated with this lesion. Because of the frequency of subdural hematoma, the neurosurgeon should be ever vigilant in the prevention, recognition, and management of these complications.


ICP monitoring: complications and associated factors.

1. Patients with complications when compared with those not developing a complication: a. Were older, 44.4 vs. 34.5 years; b. Were monitored longer, 14.0 vs. 6.5 days; c. Were treated with steroids longer, 18.3 vs. 10.3 days; d. Were hospitalized longer, 35.7 vs. 27.7 days; e. Are twice as likely to die; f. Average age of those dying is older, 46 vs. 30 years; g. Have no clear relationship to antibiotics; h. Do not have a preponderance of single diagnostic category to account for these differences; i. Complications were always controlled with standard therapy; j. An ICP complication was almost never responsible, per se, for death. 2. Over all complication rate was 18%; due to monitoring was 4.5 to 11.5%. 3. Monitoring was responsible for, or contributed to, 25 to 60% of the complications. 4. No complications occurred when monitoring was discontinued within 3 days. 5. Long periods of treatment with steroids increased the risk of a complication developing. 6. Long periods of monitoring were associated with an increased risk of complication. 7. "Individual" factors are partly responsible for the development of a complication, and death. 8. There are two groups of complications: "early" and "late." A. Those most likely to be monitor related occur "late" and account for 35% of the complications. B. Those developing "early" infection account for 65% of the complications and are most likely caused by factors other than monitoring. While there are complications directly attributable to monitoring, the rate is low and they are readily controlled by standard neurosurgical management. While monitoring may increase the morbidity, it does not increase the mortality. We feel that the over-all risk is small and that the returns are great--both in terms of knowledge and patient benefit.


Radical surgical treatment of craniopharyngioma.

There is evidence from this publication and those of Matson and colleagues that a determined effort at total excision of these tumors as the initial therapy is a tenable course of action. The main bases for this concept are: (1) that the dense gliosis characteristically intervening between these epithelial tumors and normal brain constitutes a margin of safety for the surgeon at least for the first several years such tumors are growing in the 3rd ventricle; (2) improved early diagnosis and better operative instruments, magnification, lighting, and technique are decreasing operative morbidity and mortality; and (3) new knowledge and new replacement therapy are reducing the burden of the metabolic and endocrine defects. Competing with this is the concept that rotationally delivered or even more precisely focused high energy photons and intracavitary beta-radiation have lower morbidity and mortality. The detailed and long term data on which to draw conclusions are not yet available. My medical colleagues and I are preparing case-by-case tables with all of the relevant facts to supply one component of the total picture.


Controlled thermocoagulation of trigeminal ganglion and rootlets for differential destruction of pain fibers: facial pain other than trigeminal neuralgia.

I describe the results of retrogasserian differential lidocaine block to aid in the selection of patients for a differential thermal lesion in the trigeminal ganglion and rootlets. This procedure temporarily duplicates the state of analgesia without anesthesia one seeks to make permanent with the radiofrequency heating. The results of this heating procedure are described in the treatment of 71 patients with facial pain of cancer, postherpetic, periodic migrainous neuralgia, acromegaly, trigeminal neuropathy, central pain, post-traumatic facial neuralgia, and atypical facial neuralgia.


The prognostic significance of fever in childhood urinary infections: observations in 350 consecutive patients.

All infants and children with proven bacteriuria require urologic investigation and surveillance, but their prospects for developing chronic renal disease are variable. These differences are related to whether or not the bacteria have access to the kidneys. Such access correlates closely with the presence of an underlying congenital anomaly, particularly vesicoureteral reflux. Fever during an episode of active urinary infection is a strong indication that the patient has vesicoureteral reflux or some other significant uropathy and probably pyelonephritis.


Tuberculosis among urban black children: failure of comprehensive health care services to influence incidence rates.

Over a three-year period, in 2,700 children aged two weeks to 19 years in a South Philadelphia ghetto, the new case rate for tuberculosis was 177 per 100,000 per year and the rate for new conversions was 673 per 100,000 per year. Children with recent conversions or with active disease were, on the average, slightly older and had older mothers and more adults and siblings at home than the rest of the child population. Parents or other residents of the home were the contacts. Children 10 to 14 years of age were the most frequently affected. Children who had been receiving continuous comprehensive health care for more than three years had the same attack rates as new children in the program.


Effect of furosemide on the renal excretion of digoxin.

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin


Renal failure, hemodialysis, and nafcillin kinetics.

Nafcillin (N) pharmacokinetics was studied in 27 subjectswith and without renal failure (RF) (determined by endogenous creatinine clearance, Ccr). Elimination rate constants (K) were calculated from serial serum levels of N measured from 2 to 12 hr after a single 500-mg intramuscular injection. Only 4 of 9 hemodialysis patients had measurable levels of N at 24 hr. The K values for the groups with normal renal function,moderate RF, severe RF, and on hemodialysis were 0.477 hr(-1), 0.432 hr (1), 0.369 hr(-1), and 0.306 hr (-1), respectively...


Amobarbital--a probe of hepatic drug oxidation in man.

Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of orally available over intravenously injected amobarbital was established as 0.99 +/- 0.11 (SD), by comparing integrated concentration-time curves, indicating complete absorption and absence of a first-pass effect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first-order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 +/- 1.8 [SD]ml/min) exhibited remarkable constancy, while biologic half-lives (26.5 +/- 3.1 hr) and distribution volumes (73.6 +/- 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half-lives (23.8 +/- 6.7 hr) appeared to be normally distributed, while the clearances (36.7 +/- 10.0 ml/min) might not follow a normal distribution.


Protein binding of salicylate in uremic and normal plasma.

Protein binding of salicylate was studied by equilibrium dialysis at 37 degrees C in plasma from uremic patients and healthy subjects. The protein binding was considerably lower in the uremic plasma at all salicylate concentrations studied (14 to 1,400 mug/ml). Scatchard plots of the data were computer-analyzed assuming binding to the classes of binding sites. According to this analysis, the binding to the class of primary binding sites was considerably decreased in the uremic plasma. In addition to the effect of the uremic state, the binding was considerably decreased at high therapeutic plasma levels and at low albumin levels. The combined effect of two or three of these factors may lead to unexpectedly high unbound fractions of salicylate, which should be considered in the monitoring of plasma salicylate levels in patients.


Antipyrin clearance in homozygous beta-thalassemia.

Serum half-lives for antipyrine were normal or shorter than normal in 19 subjects between 7 and 23 yr of age with beta-thalassemia major. The mean antipyrine serum half life (+/-SE) for the group as a whole was 8.5 +/- 0.6 hr. The mean antipyrine half-lives (t1/2) for the younger subjects were within the range reported for normal children, while the mean t1/2 for the older males approached the values reported for normal adult males. The mean t1/2 for the older females was shorter than has been reported for normal adult females. The mean apparent volume of distribution for antipyrine (+/-SE) in the subjects with thalassemia was 0.69 +/- 0.01 L/kg. Thus, total body water appears to be increased in thalassemia. The mean metabolic clearance rate for antipyrine (+/-SE) in the group as a whole (1.07 +/- 0.08 ml/min/kg) is substantially higher than the metabolic clearance rates for antipyrine reported in normal adults. Thus, the relatively short t1/2s of antipyrine in subjects with thalassemia are attributable to rapid rates of clearance of the drug. The data indicate that antipyrine clearance is unimpaired in patients with thalassemia despite evidence of liver damage and iron overload. Our study supports the proposition that hepatic microsomal hemoprotein synthesis is not adversely affected in homozygous beta-thalassemia.


Aminopyrine demethylation measured by breath analysis in cirrhosis.

The method of measuring the rate of aminopyrine demethylation by breath analysis was assessed in 23 normal subjects and 20 patients with cirrhosis. Carbon 14 aminopyrine specifically labeled at the two N-methyl groups was administered by mouth in a dose of 9 mg/kg, including a total radioactivity of 2 muCi. The decay of the specific activity of 14CO2 in breath (kb) was found to correlate (r = 0.91) with the disappearance of aminopyrine from plasma (KP). In normal volunteers, kb was 22.4%/hr; in patients with alcoholic and nonalcoholic cirrhosis it was depressed to 8.4%/hr (p less than 0.001). The degree of functional impairment found with the breath test was similar to the sulfobromophthalein (BSP) disappearance curve and the galactose elimination capacity. Although many questions relating to the aminopyrine breath test remain open, our data confirm and extend previous studies of 14CO2 breath analysis after 14C-aminopyrine administration. It is concluded that it represents a simple and noninvasive procedure which quantitatively reflects the microsomal function of the cirrhotic liver.


Pharmacokinetics of succinylcholine in infants, children, and adults.

The elimination of succinylcholine appears to follow first-order kinetics with a linear relationship between intensity of effect and logarithm of the dose. Determination of the time-course of neuromuscular blockade following succinylcholine in infants and children allowed us to compare the rate of recovery and elimination rate constant with those determined by others in adults. The rate of recovery was independent of dose for each age group. The rate of recovery was faster in children than in infants; the rate of recovery of infants was faster than that of adults. The elimination rate constant for infants was similar to that of children; for both the infants and children the rate constants appeared dissimilar from those of adults.


Intravenous propranolol administration: a method for rapidly achieving and sustaining desired plasma levels.

A model for the intravenous administration of propranolol by a bolus-infusion technique designed to rapidly produce, then maintain, predicted plasma drug concentrations was derived from elimination kinetics in single-dose studies. Prospective testing of this model in 6 adult male subjects revealed a close correlation between predicted and observed drug levels; desired plasma concentrations were achieved within 5 min and maintained over the 30-min study period. By subtracting previously given bolus doses from the dose calculated as needed to produce a desired plasma level, progressive increases in predicted propranolol levels could be effected, with apparent maintenance of equilibrium. Correlations between the bolus doses and infusion rates and the plasma drug levels were consistent and significant, and constitute nomograms from which the dose of drug required to produce a desired plasma level may be approximated. The clearance of propranolol declined slightly as the drug plasma level increased, but did not significantly affect the accuracy of the model.


Systemic availability of orally administered meperidine.

A comparison of the areas under the plasma concentration-time curves after intravenous and oral administration of meperidine in 4 normal subjects indicated that 48% to 56% of the oral dose avoided "first-pass" metabolism and was systemically available. Similar estimates were obtained by applying the Loo-Riegelman method for calculating drug absorption viz, 47% to 60%. Oral availability predicted from a knowledge of drug clearance (blood) after intravenouration-time curves after oral administration exhibited irregularities and double peaks possibly indicative of the action of meperidine on the gut or a recycling process.


Gastric and biliary excretion of meperidine in man.

The role and importance of enterogastric secretion in the disposition and elimination of the weak base, meperidine (pKa 8.63), was studied after intravenous administration (50 mg) of the drug to 6 normal volunteers. Continuous collection of the gastric fluid over a 4-hr period demonstrated the establishment of high gastric fluid/plasma concentration ratios for meperidine (mean about 50, range, 10 to 200). However, the total amount of drug recovered, even after correction for incomplete collection, was only a small percentage of the administered dose. Under basal conditions a mean +/- SE of 1.9 +/- 0.3 mg, equivalent to 3.7% of the administered dose, was found in the total gastric aspirate. Stimulation of gastric secretion by subcutaneous injection of betazole (1.5 mg/kg) increased this recovery to 3.6 +/- 0.3 mg (7.2%) primarily due to the increase in gastric volumen output. Aspiration of the gastric fluid in either the basal or stimulated situation had no observable effect upon the plasma concentration/time profile of meperidine whether assessed by the terminal half-life, t 1/2 beta, or the plasma clearance; control values were 3.8 +/- hr and 1,190 +/- 130 ml/min, respectively. In 2 subjects "bile fluid" was also collected for 2.5 hr and found to contain less than 0.2% of the administered dose. Enterosystemic recycling is therefore of minor importance in the disposition and elimination of meperidine in man.


Titration of nicotine intake with full-length and half-length cigarettes.

Titration, the self-regulation of nicotine intake, was studied in 12 smokers by gas chromatograph assays of urinary nicotine levels. Results demonstrated that excretion of urinary nicotine in the proximal condition (half cigarette close to the filter) did not differ significantly from the whole cigarette condition; however, less nicotine was excreted in the distal condition (half cigarette farther from the filter) because of a rod filtration effect. Subjects extracted proportionately more nicotine from the half than from the whole cigarettes; titration was approximately the same in both half-cigarette conditions. On scales of strength and satisfaction, full-length cigarettes were given the highest rating, followed by proximal and then distal cigarettes.


Comparison of the hydroxylation of zoxazolamine and benzo[a]pyrene in human placenta: effect of cigarette smoking.

The in vitro hydroxylation of zoxazolamine was compared with the hydroxylation of benzo[a]pyrene (BP) in full-term placentas from 11 nonsmokers and from 13 women who smoked cigarettes during pregnancy. Cigarette smoking increased the average zoxazolamine and benzo[a]pyrene hydroxylase activities 13- and 39-fold, respectively. A 59-fold range in benzo[a]pyrene hydroxylase activity and a 28-fold range in zoxazolamine hydroxylase activity were found in the placentas of cigarette smokers. A plot of these two enzyme activities showed that zoxazolamine hydroxylase activity was highly correlated, with benzo[a]pyrene hydroxylase activity in the 24 placentas studied (r = 0.98; p less than 0.001). A strong correlation between the above enzymatic activities was also found in 8 placentas which had been stored for 2 yr at -20 degrees C (r = 0.95; p less than 0.001). The results suggest that benzo[a]pyrene and zoxazolamine are metabolized in the human placenta by the same enzyme or by different systems that are under the same regulatory control.


Fluoride kinetics after enflurane anesthesia in healthy and anephric patients and in patients with poor renal function.

Enflurane, a fluorinated methylethyl ether, is metabolized, in part, to inorganic fluoride. Methoxyflurane has similar metabolism, and cases of fluoride ion-induced renal failure have been reported after its use. This prospective study was initiated to determine fluoride ion kinetics after enflurance anesthesia in 16 healthy patients, 18 anephric patients, and 6 patients each having a creatinine clearance of less than 5 ml/min (on dialysis). Serum and urine inorganic fluoride levels were determined. There was no clinical or statistical significance difference among the 3 groups with respect to maximum inorganic fluoride ion concentration or the time to reach it. The fluoride ion values were never above the 50 muM level that has been reported to cause subclinical renal toxicity. The fluoride ion concentration in serum fell rapidly after termination of anesthesia even in the anephric patients. This is presumed to be due to uptake of the ion by bone. Patients with low creatinine clearance also have low fluoride ion clearance. Statistical but not clinical significance was found in the comparison between pre-enflurane and the 24-hr fluoride ion values in the anephric and low creatine clearance patients, but this did not persist after one dialysis.


Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients.

Thirty otherwise healthy patients received a 100-mg oral dose of chlordiazepoxide HCl just prior to surgical procedures using spinal anesthesia. Fourteen of these patients had also received 100 mg on the night before surgery. Simultaneous samples of venous blood and cerebrospinal fluid (CSF) were taken immediately prior to injection of spinal anesthesia and were assayed for concentrations of chlordiazepoxide (CDX) and its major metabolite, desmethylchlordiazepoxide. Plasma concentrations of CDX ranged from 2.32 to 13.34 mug/ml. Simultaneous CSF concentrations were considerably lower, ranging from 0.04 to 0.34 mug/ml. Equilibration of CDX between plasma and the lumbar sampling site appeared to be complete within 2 hr of the most recent dose. After attainment of distribution equilibrium, simultaneous plasma and CSF concentrations of CDX were hightly correlated (r = 0.76), with a mean CSF-plasma concentrations ratio of only 0.043 (range; 0.02 to 0.06). The limited passage of CDX into human CSF is probably due to extensive binding to plasma protein. Assuming that transfer of CDX from plasma to CSF is governed by passive diffusion, the extent of plasma protein binding of CDX in healthy individuals averages about 96%.


Observations in man on some pharmacologic features of cefamandole.

Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in 11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p less than 0.05) at all times. The terminal half-lives (t 1/2) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was similar for both drugs regardless of dose and mode of administration. Continuous-infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p less than 0.05) over a 5-day period. There was no evidence of drug accumulation in the multiple-dose studies. Both the single- and multiple-dose schedules were well tolerated.


Hemodialysis for severe procainamide toxicity: clinical and pharmacokinetic observations.

A 67-yr-old woman who ingested approximately 7 gm procainamide developed severe hypotension, renal insufficiency, and life-threatening cardiac toxicity. Hemodialysis doubled the rate of procainamide elimination and increased fourfold the clearance of NAPA, the N-acetylated metabolite of procainamide. Observations of procainamide and N-acetylprocainamide (NAPA) plasma levels during the patient's recovery suggest that lethargy and profound hypotension can be expected when these levels total 60 mug/ml and that severe cardiac toxicity should be anticipated with levels totaling 42 mug/ml or more. Hemodialysis also permitted investigation of the effects of hypotension on the pharmacokinetics of these compounds. The apparent volume of procainamide distribution was reduced from a normal value of 2 L/kg to 0.76 L/kg, and that of NAPA from 1.4 L/kg to 0.63 L/kg. The elimination + 1/2 of procainamide was prolonged from the normal of 3 hr to 10.5 hr, and that of NAPA from 6 to 35.9 hr. Procainamide absorption was also slowed in this clinical setting, causing procainamide plasma levels to continue rising for some time after toxicity was first recognized.


The radiology of thoracic disc protrusion.

The radiological features of 20 surgically proven thoracic disc protrusions are reviewed. In 15 (75%), characteristic plain film changes were found to be very helpful in making the correct diagnosis. Calcified disc material in the spinal canal was clearly demonstrated in 11 (55%) cases, and this, in association with linear calcification in the adjacent disc space, has been shown to be diagnostic of the condition. At myelography, central protrusions (55%) were found to be predominant, while lateral protrusions were uncommon. The differential diagnosis of a calcified lesion in the spinal canal includes thoracic disc protrusion, osteochondroma and meningioma.


Complications of percutaneous transfemoral coronary arteriography.

Complications statistics in 1625 patients undergoing selective coronary angiography by Judkin's technique have been analysed for four major areas-death, myocardial infarction, cerebral vascular accidents, and femoral thrombosis. Over a six-year period, considerable decrease in the number of complications has occurred. Myocardial infarctions have decreased from 2.4% (1967-71) to 0.44% (1973), an improvement related to careful catheter flushing, guidewire insertion technique and careful pressure monitoring within the coronary arteries. Cerebral accidents have decreased from a maximum of 1.3% (1972) to none (1973). This is also related to catheter guidewire techniques, and to avoidance of entering the cerebral vessels inadvertently when crossing the aortic arch with the coronary catheter. Femoral artery thromboses have decreased from 2.7% (1967-71) to none (1973). This is due to monitoring the dorsalis pedis pulse when compressing the femoral artery and avoiding complete femoral arterial obstruction with the associated lack of flow ultimately leading to thrombosis. Death rate has remained essentially unchanged (0.3-0.6%).


Oliguria in the incubating neonate. Emergency aortography and urography in neonates using mobile X-ray equipment.

Neonates in incubators underwent umbilical aortography, excretory urography and suprapubic cysto-urethrography using a mobile X-ray machine in the Premature Baby Unit to define the cause of their oliguria. The techniques were easy to perform without endangering the infants by moving them. The radiological findings in the four neonates investigated contributed significantly to the management of their illnesses.


Progeria in siblings.

Progeria or 'prematurely old' is an autosomal recessive trait that appears insidiously at or after the age of 6 months. Two affected siblings are reported showing radiologically progressive attenuation of the clavicles and terminal phalanges, widening of cranial sutures and mandibular hypoplasia. Scleroderma was also present. Out of 59 previously published cases five had scleroderma before the age of 2 years. Only three families with affected siblings have been previously recorded.


Articular mass fracture: a neglected cause of post-traumatic neck pain?

Fifty-one compressed distorted cervical articular masses were found in 29 patients seen at this institution over a nine-month period. The significance of these findings is discussed and it is concluded that in most instances these represented compression fractures with deformity of the articular process. Selected signs suggestive of a compressed articular mass are identified on various views. These include (1) neuroforaminal encroachment or narrowing, (2) triangular appearance of the lateral mass in the oblique view, (3) unilateral anterior displacement of the superior facet with respect to the inferior facet, (4) minor anterior subluxation of one vertebral body over another, (5) double outline sign on the lateral view, (6) abnormally visible posterior articulations on the routine AP view. The articular processes are best shown on anteroposterior angled caudad views and lateral tomography. Articular mass deformity frequently appears to be associated with persistent post-traumatic neck pain and a relationship between this deformity and primary or secondary degenerative cervical disc and joint disease is suggested.


The 'tilt deformity' of the femoral head in osteoarthritis of the hip: a poor indicator of previous epiphysiolysis.

Apparent superomedial migration of the femoral head producing the 'tilt deformity' is the most frequent pattern of femoral head deformity in osteoarthritis of the hip. Previous reports have suggested a relationship to minor degrees of epiphysiolysis in the adolescent. Radiological and pathological examination of femoral heads obtained at the time of total hip replacement for osteoarthritis demonstrate characteristic abnormalities accompanying the 'tilt deformity'. It would appear that, in most patients, this pattern of femoral head migration results not from epiphysiolysis but from a remodelling process in the osteoarthritic joint.


Peripheral arteriographic studies in leprosy.

There is a considerable controversy regarding the frequency and significance of vascular lesions in leprosy. Twenty-six cases of leprosy below the age of 40 years, without any local or systemic arterial disease and normal looking hands were subjected to brachial arteriography. One patient had posterior tibial arteriography also. The diagnosis of leprosy was confirmed by histology or bacteriological staining techniques. Biopsy material was studied from the involved areas and similar material was obtained from nine matched control subjects at autopsy. Skin thermometry and reflex vasodilatation was studied in eight cases. Arteriographic abnormalities such as occlusion, narrowing, tortuosity, dilatation, irregularity and incomplete filling were seen in more than two vessels in the hand in 50%, and in the digits in 75% of the cases. The ulnar artery was more frequently involved than the radial. Superficial and deep palmar arches were equally affected. Marked increase in arcuate vessels was noticed in nearly three-quarters of the patients, and in some, arcuate vessles were serving as collaterals. Histologically all sizes of vessles, including the capillaries, showed changes in nearly half the cases. Reflex vasodilation was lost in three cases of dimorphous leprosy and impaired or absent in three out of five cases of lepromatous leprosy. There was no predilection for any form of leprosy to show arterial changes more than the other. This study clearly demonstrates that the arterial involvement in leprosy is very frequent and must be playing an important role in causing mutilation and deformities of hands and feet.


Mammograms on medichrome film.

When medichrome film is vacuum packed and used in combination with a single high definition intensifying screen exposure times of 0.06-0.1 s and a skin radiation dosage 0.5 rad per exposure can be achieved. The diagnostic accuracy of the system is similar to that obtained on conventional black and white film currently used for mammography.


The role of the physicist in a diagnostic radiology department.

A physicist working full-time within a department of diagnostic radiology has found himself concerned with the development of investigative techniques using non-X-ray apparatus, such as thermography, as well as with testing and assessing new X-ray techniques, such as xerography. The scientific training of the physicist enables him to advise and instruct on other research projects. His links with physicists elsewhere are advantageous because of the larger range of specific expertise and available technology. It is thought that the arrangement is successful, should continue, and be tried elsewhere.


A system of organisation of an X-ray film library.

The physical arrangement of radiographs and a method for their retrieval is discussed. The aim is to facilitate access to examples of various conditions from several possible approaches by a method of specific classification of each item and a comprehensive card index. A system to maintain consistency and to achieve relevance for the potential user is described.


Thermography in lower limb arterial disease.

Skin temperature distributions are described which correspond to different levels of arterial obstruction in the lower limbs. These temperature distributions are conveniently observed using thermography. Thermography may be used to measure the change in skin temperature when the limb performs work. These skin temperature changes have been correlated with the impairment of blood flow to the lower limb.


Review of parameters characterising response of normal connective tissue to radiation.

A comparison is made of the formalisms which have been proposed to characterise the response of normal connective tissue to levels of radiation which may lead to end points other than tissue tolerance; namely, Partial Tolerance, Time-Dose-Fractionation factor, and the Cumulative Radiation Effect. It is shown that, in most situations, conclusions which may be drawn using any one formalism are essentially the same as those which follow from the use of any other.


Automated analysis of phencyclidine in urine by probability based matching GC/MS.

A novel form of selected ion recording mass spectrometry using a microcomputer-managed mass spectrometer was employed to automatically identify and quantitate phencyclidine (PCP) in cyclohexane extracts of urine by Probability Based Matching. Seventy urine samples from known abusers were assayed for PCP content. The positively identified PCP concentrations ranged from 0.01 to 10.5 mug/ml for 65 samples, 26% of which fell in the 0.35-1.0 mug/ml range and 30% in the 1.0-3.4 mug/ml range. Five specimens had no detectable PCP (less than 10 mug/ml). Cyclohexane extraction efficiency for PCP in urine exceeded 95%. Selected ion monitoring was found to be necessary in order to avoid gas chromatographic interferences produced by co-elution of contaminants at the same retention time as PCP.


Phencyclidine: tissue distribution in the rat.

This study was performed to provide knowledge of the tissue distribution of phencyclidine and has demonstrated the lipophilic nature of the drug. The distribution of phencyclidine in blood, brain, and adipose tissue of rats has been determined at various time intervals during a 48-hr period. The affinity of phencyclidine for adipose tissue and the demonstration of the presence of this drug in brain tissue long after it is no longer detectable in blood provides some correlation between the tissue distribution of phencyclidine and its clinical manifestations occuring 24-48 hr after administration.


Metabolites of phencyclidine.

The results of the animal experiment demonstrate that oxidative hydroxylation is the major mode of metabolism of phencyclidine. It is evident that this process takes place in all three rings of the molecule. Hydroxylation of the piperidyl moiety probably also accounts for the formation of the N-dealkylated metabolites. Metabolism of phencyclidine in humans appears, at least in part, to be similar to that in the rat. Hydroxylation is still the principal mode in the case of humans though of a lesser extent. Metabolites hydroxylated in the phenyl moiety as well as dihydroxy derivatives of phencyclidine have so far not been observed in humans. Furthermore, most of the monohydroxy metabolites exist as conjugates in the human urine. It should also be pointed out that no metabolites have yet been detected in human blood samples.


Proteolytic enzymes in human cartilage: the pathogenesis of osteoarthritis.

It is evident that human articular cartilage possesses, in addition to multiple forms of cathepsin D, multiple forms of other acid cathepsins, and, most important, a family of at least four closely related neutral protease enzyme forms, all of which degrade proteoglycan. In addition, caseinase and histonase activities are present. The search for these enzymes in human cartilage ahs been presented in some detail in order to give an idea of some of the problems faced in such research, as well as the hypotheses and hopes that flow from it and prepare the ground for further research. The actual role of proteolytic enzymes in the physiologic and pathologic condition of cartilage remains to be determined. It is hoped that these enzymes, especially the neutral protease forms, will be sufficiently purified to enable preparation of antibodies to them. This will help to clarify what controls their release from the chondrocytes and where they function in the cartilage. Meanwhile, it seems appropriate to study the neutral protease forms and their role in initiating the degradation of proteoglycan in the early stages of osteoarthritis. The chief role of cathepsin D and the new acid cathepsins is most likely in intracellular digestion. One may hypothesize a three-step sequence of the degradation of the matrix proteoglycan: (1) initial extracellular attack by the neutral matrix, (2) endocytosis of the fragments by the cells, and (3) completion of their degradation within the lysosomal digestive system of the cell. The initial degradation of the matrix proteoglycan would facilitate the entrance of other degrading enzymes from the synovium to aid in total destruction of the cartilage. While awaiting knowledge of the primary events that trigger the development of osteoarthritis, enzymatic research offers the real hope of finding a way to control the enzymatic degradation of proteoglycan occurring in the early stages of the disease. Research into the nature of these degrading enzymes will lead to the development of therapeutically suitable inhibitors.


The single hot joint.

Several points may be stressed.  (1)When in doubt, perform joint aspiration and look for crystals of micro-organisms. A joint tap is nearly always indicated.  (2)Do not rely on a coincidental elevated serum uric acid level.  Question the patient regarding drug therapy and other causes of secondary hyperuricemia.  (3)Examine all of the patient, looking for tophi (gout), skin lesions (gonococcal infection, psoriasis), erythema nodosum (allergic reactions, fungal infections), and other clues.  (4)Monoarticular rheumatoid arthritis is a rare cause of a single hot joint, but it is much more common that the real rarities (e.g., pigmented willondular synovitis).  (5)Anky-losing spondylitis and Reiter's syndrome are common, yet frequently overlooked.  (6)Radiologic examination is usually not helpful.  (7)Having ruled out infection, crystal synovitis, and hemorrhage, it is sufficient to introduce symptomatic treatment and await the natural development of the joint disease.  Follow-up in four to six weeks and simple blood studies often reveal the definitive diagnosis.  Most of the time, natural healing processes are effective , and reward the patience of the conservative physician.  Blind management must always be avoided.


Medical management of rheumatoid arthritis.

The overall management of RA is multifaceted. It includes rest, both systemic and articular; physical therapy; utilization of the techniques and appliances of occupational therapy; drugs, both those that suppress inflammation and those that are capable of altering the disease course itself; a knowledge of specific articular and nonarticular complications; and the ability to refer for appropriate surgical management. Judicious, energetic application of these principles can favorably affect the outcome of rheumatoid disease in most patients.


Infection in rheumatoid arthritis.

Sepsis is an unusually common cause of illness and death in RA. All sorts of infections occur, but pyarthrosis produces exceptional problems. Clinically, pyarthrosis, empyema, and purulent pericarditis mimic bland rheumatoid effusions. Aspiration of the attendant effusions is the only reliable diagnostic procedure. Subcutaneous nodules on the sacrum and back are easily overlooked. Necrosis and ulceration of these nodules may provoke septicemia. Those with Felty's syndrome do not uniformly have problems with recurrent infection. Splenectomy may not benefit such patients. The belief that corticosteroids cause increased infections in rheumatoid patients is not totally justifiable at present. Steroids can, however, disguise underlying sepsis and hamper proper diagnosis.


Treatment of asymptomatic diabetes mellitus.

A large number of individuals currently diagnosed as having diabetes mellitus are asymptomatic. In order to provide rational therapy for this patient population, it is necessary to focus upon the differences between these patients and the classic prototypes with polyuria and weight loss, who require insulin for survival. Patients with asymptomatic diabetes do not need insulin for survival, and, by definition, they do not need it to alleviate symptoms. They tend to be middle-aged and overweight, but they can be young and thin. Their degree of hyperglycemia is moderate, often indistinguishable from that of normal individuals in their day-to-day existence. Indeed, they can often be differentiated from normal persons only on the basis of their blood glucose response to the stress of a large dextrose challenge; in this regard, the potential problem of over-diagnosing diabetes has been discussed. Since the major problem facing patients with asymptomatic diabetes is accelerated atherogenesis, the therapeutic approach must be based upon efforts to delay or prevent the onset of vascular disease. It has yet to be shown that any therapeutic intervention helps such patients, but an argument has been made in support of the following goals in subjects with asymptomatic diabetes whose fasting blood glucose level is less than 170 mg/100 ml: (1) stop smoking, (2) control hypertension, (3) attain ideal body weight, and (4) maintain blood triglyceride and cholesterol levels well within normal limits. Attempts to lower blood glucose with either insulin or oral agents do not seem indicated in the majority of patients within this defined diabetic population.


The management of diabetes in the elderly.

It appears inevitable that with increased longevity, the management of the elderly diabetic will place even greater demands on hospital services. It seems reasonable to adopt a more liberal attitude to the regulation of control of diabetes in the elderly than in younger patients. However, the view that diabetes in the elderly is always mild can be dangerously misleading. A significant number of elderly diabetics develop ketoacidosis or other serious forms of metabolic disturbance, and in these patients the mortality is high. Cardiovascular disease and peripheral vascular disease are major problems in the elderly, the former being the main cause of death. For best results, it is desirable that management of diabetes not be isolated from management of other, coexisting disorders, but rather that it be considered as part of the overall patient problem. As Malins pointed out, we should think in terms of diabetics rather than diabetes.


Impotence in diabetes mellitus.

Long-standing psychogenic factors underlying impotence in diabetic males may, in many cases, play a more significant role than does prematurely presumed organic disease. With an explicit sexual history, a committed couple, an explanation of the sexual responses, and specific exchange at home, the physician may comfortably and competently intervene to provide enlightened sex therapy.


Diabetes mellitus and left ventricular function.

Chronic diabetes mellitus can alter left ventricular function independent of vascular effects. On the basis of available morphologic data in human and canine diabetics, alterations of myocardial interstitium may be the basis for this preclinical abnormality. The abnormal function is independent of apparent duration and treatment by diet, insulin, or hypoglycemic agents. It occurs in both sexes and is independent of age. Whether the observed functional abnormality progresses to clinical heart failure may depend on intensification of the underlying pathophysiology of the myocardium or superimposition of complications such as hypertension, obesity, and obstructive disease of the coronary vessels.


Permanent pervenous atrial pacing.

A new J-lead has now been designed and manufactured for both animal and clinical studies. This lead has silastic tines proximal to the electrode, arranged so that they become entangled in the trabeculae of the appendage and hold the lead in place. Studies in ten dogs have shown excellent tissue fixation at the site of the tines, and only minimal scarring occurs at the site of the terminal electrode, with preservation of good P-wave amplitude and good stimulating thresholds for a period of four to five months (Figure 8, see next page). The lead designed for humans has been used successfully in 12 patients. Follow-up now extends to 19 months, with stable P-wave-triggered atrial pacing in eight patients, fixed rate atrial pacing in one, and A-V synchronized pacing in three. No lead dislodgement has occurred.


Chromosome anomalies in Canadian Guernsey bulls.

The performance records of a group of Guernsey bulls used for artificial insemination revealed lower 60 to 90 day non-return rates as compared to that for bulls of the Holstein breed, and nine out of the 19 Guernsey bulls in this group exhibited fertility level below the average for this group. A cytogenetic survey to test whether or not the reduced fertility of these bulls was due to chromosome anomalies revealed a relatively high frequency of chromatid breaks and achromatic gaps in three out of 19 bulls while two carried 59 chromosomes each including a translocation chromosome. The 1/29 translocation heterozygote and the bulls showing achromatic gaps and chromatid breaks were among the five bulls which were consistently below the breed average in fertility as evidenced by the t test (P less than 0.01), whereas the bull with translocation 27/29 (G3) exhibited a non-return rate slightly higher than the breed average (P less than 0.01). It is possible that the chromosomally abnormal bulls contribute to increased returns to service not only because of the defective gametes they themselves might produce but also through their influence on the performance of their daughters.


Experimentally induced lead poisoning in goats: clinical observations and pathologic changes.

The effects of orally administered lead acetate were investigated in 9 adult and 3 kid goats by clinical and necropsy studies. One kid and 6 adults died after having received from 100 to 1392.5 Gm each, given over periods of from 10 to 52 days. Anorexia, diarrhea and body weight loss occurred in all lead treated goats in the study. Basophilic strippling of red blood cells was found in 6 of 8 animals on which weekly hemograms were performed. The pathologic changes were essentially the same as those that have been recorded for other ruminant species with lead poisoning. Intranuclar acid-fast inclusions in the cells of the proximal convulted tubules of the kidney were demonstrated in 9 of 12 lead treated goats and in the liver parenchymal cells of 2 of these animals.