[Effect of the ionic composition of the environment on the intracellular potential of the alga Acetabularia]. Concentration of K+-, Na+-, Mg++-, Ca++-, Cl-ions defined in Acetabularia crenulata cell was the same as that of Acetabularia mediterranea, both were cultivated under the same conditions. At the variations of the ionic composition of the external medium it has been shown that the potential of Acetabularia (A.) cell depends on K+-, Cl-ions and alga A. can accumulate K+- Cl-ions and lose Na+, Mg++ ones when there is a deficiency of these ions in the medium. Na+-, Mg++-ions participation in the generation of the rest potential of Alga A. is insignificant. K+- ion is able to change the ionic permeability of the membrane. There is a possibility of the existance of essential H+-, -OH-, or HCO3- ions flux in A. cell.


Medical imaging by NMR.

Medical imaging by NMR. Application of the new nuclear magnetic resonance (NMR) method of fast scan proton imaging is described. Cross sectional proton scans of a human finger in vivo are measured and reveal considerable anatomical detail, particularly of the soft tissue regions. Imaging of tumour tissue is also briefly discussed.


Immunological studies in patients with malignant melanoma of the uvea. Antibodies directed against different components of ocular melanoma cells were identified by indirect immunofluorescence in the sera of 12 patients with histologically proven malignant melanoma of the uvea. Antibodies reacing with autologous surface membrane antigens were found only in the sera of the 5 patients with the smallest tumors. The sera from most of the patients with small, large, or extraocular tumor contained antibodies directed against autologous cytoplasmic components while about one-half of the tests for antibodies reacting with allogeneic cytoplasmic antigens were positive. The incidence of positive tests with cytoplasmic antigens, in 67 patients with clinically diagnosed benign uveal nevi and 56 other individuals not showing evidence of proliferative lesions of uveal melanocytes, was 25%.


The effects of ocusert pilocarpine on anterior chamber depth, visual acuity and intraocular pressure in man. The duration of intraocular pressure reduction by Ocusert Pilocarpine was found to be 10 days for P20 and 12 days for P40. Ocusert Pilocarpine reduced visual acuity and anterior chamber depth less than the aqueous pilocarpine drops.


A clinical study of the autorefractor, an antomatic refracting device. Four hundred eyes were examined with the Autorefractor, an automatic refracting machine, and the results compared with those found by standard techniques of clinical refraction with and without cycloplegia. Agreement was good for spherical power, cylindrical power and spherical equivalents, but less so for cylinder axes.


Results after vitrectomy in trauma.

Results after vitrectomy in trauma. We report the results of vitrectomy in 15 consecutive cases of ocular trauma operated on during one year. The cases are divided into three groups according to whether the main damage involved the anterior, posterior, or anterior segments. Of the 15 cases two thirds had a successful outcome. A penetrating injury and total retinal detachment with massive preretinal retraction were two features associated with poor results.


Pars plana vitrectomy.

Pars plana vitrectomy. Sixty-four consecutive pars plana vitrectomies were performed with the Douvas roto-extractor for anterior and posterior vitreous opacities. Eighty-four per cent of the anterior segment vitrectomy patients obtained improvement in visual acuity after surgery. Only 60% of the posterior segment patients obtained improvement in visual acuity, while only 45% of the eyes with active proliferative diabetic retinopathy had improved vision.


[Corneal response to 'off' in the intact rabbit eye]. The corneal electrical responses of the retina to light OFF are described in this report. The results reveal that high intensities of stimulation evoke an OFF response containing a positive wave. Since this wave was resistant to Sodium aspartate it is concluded that it arises from the receptor level. Negative wave are of double origin a) a negative potential evoked with low light intensities which is resistant to Sodium aspartate b) a second negative wave which is sensitive to the latter drug and thus arises from the internal layers of the retina. It is concluded that, because of the absence of a prominent b wave, the OFF responses permit a more sensitive evaluation of retinal electrophysiology.


Orbital meningoencephalocele in a healthy adult. A 28-year-old white female had a two month history of a slightly painful right eye without proptosis. A radiolucent area was noted in the roof of the right orbit. Orbital exploration demonstrated brown friable tissue without any communication to the cranium. Microscopic examination revealed brain tissue, glial cells and fibrous tissue compatible with dura.


Symposium on diarrhea. 1. Definition and mechanisms of diarrhea. Diarrhea, an increase in frequency of evacuation and in water content of the stool, is the result of three categories of mechanism--solute malabsorption, secretion of fluid and motility disturbance. Before diarrhea is considered an abnormal condition, any alteration in stool frequency and content must be related to an individual person's normal bowel habit and to norms for the population, but more than three bowel movements or the passage of liquid stools exceeding 300 g daily should, in general, be considered abnormal. A useful way of understanding the mechanism of diarrhea is to become familiar with the normal functions of the bowel in regard to water and electrolyte absorption and motility, and then to relate these functions to solute malabsorption, fluid secretion and motility disturbance.


Symposium on diarrhea. 2. Clinical diagnosis of the causes of diarrhea. Elucidation of the cause of diarrhea is facilitated by considering which of three principal determinants are of relevance in a particular case. These determinants relate to the onset (whether diarrhea is acute or chronic), to infection or an absence ofinfection and to the presence in the stool of blood or mucus, or both. Diagnosis is also facilitated by taking an accurate and full history, conducting a physical examination, performing sigmoidoscopy and, with proper care, attempting a therapeutic diagnosis. Findings from investigations should then enable one to arrive at a diagnosis. The diagnosis can be reached in an orderly fashion by classifying the types of diarrhea into eight categories: with respect to the acute or chronic onset a case of diarrhea may be noninfectious, without blood or mucus in the stool; noninfectious, with blood or mucus, or both; infectious, without blood or mucus; and infectious, with blood or mucus in the stool.


Symposium on diarrhea. 4. Diarrhea in the irritable colon syndrome. The irritable colon syndrome comprises two predominant symptom patterns -- "spastic colon" with pain and constipation, and painless "nervous diarrhea". The two patterns frequently overlap. Low intake of dietary fibre is common to patients in both groups. Diagnosis of the irritable colon as a cause of diarrhea requires the characteristic symptom pattern and exclusion of organic disease. Management is based on common sense, careful reassurance of the patient, detailed explanation of the symptom pattern and explicit dietary advice. Increasing fibre in the diet is of prime importance in most patients.


Symposium on diarrhea. 5. Postoperative diarrhea. Under normal circumstances many physiologic mechanisms prevent diarrhea. The most important are the normal processes of gastric emptying, digestion and absorption, the functioning of the ileocecal valve and elimination of bacteria from the small bowel. A surgical procedure may disrupt any of these mechanisms or may unmask a previously asymptomatic disorder that now requires appropriate treatment. Treatment of diarrhea related to surgery may be directed toward the diarrhea itself with such agents as tranquilizers and opiates but if these are not soon effective any disrupted functions must be analysed and specific measures taken to correct or compensate for these disruptions. The most useful measures in appropriate cases are the prevention of the dumping syndrome and the administration of pancreatic enzymes, cholestyramine, hydrophilic stool thickeners and broad-spectrum antibiotics. These measures may be ineffective or inadequate and surgical revision may be necessary.


Symposium on diarrhea. 6. Infectious diarrhea. Diarrhea may be primarily infectious in origin. Causes can be conveniently classified according to the etiologic agent, which may be viral, chlamydial, bacterial, protozoal, helminthic or fungal. The most common type of infectious diarrhea in Canada is viral. Bacterial infection, particularly staphylococcal and salmonellal, also is relatively common.


Difference in the distribution of e antigen among different ethnic groups in a population of blood donors. Sensitive techniques were used to detect e antigen and the corresponding antibody (anti-e) among 368 voluntary blood donors positive for hepatitis B surface antigen in the Montreal area and 310 people living in close contact with them. Neither e nor anti-e was found in the absence of markers of hepatitis B virus (HBV). Among the blood donors e antigen was detected in 23 and anti-e in 313, and 32 were negative for both markers. Of the 368 blood donors 330 were of French origin and 38 from other ethnic groups. The 23 e-positive subjects were unequally distributed among the ethnic groups: only 14 (4.2%) were recruited among the French group while 9 (23.7%) were recruited among other ethnic groups (P less than 0.001). This differences among ethnic groups might be related to the vertical or horizontal mode of dissemination of HBV infection.


Typhoid outbreak in Kingston, Ont: experience with high-dose oral ampicillin. Twenty-four children contracted typhoid fever at a summer camp near Kingston, Ont. Six were treated with chloramphenicol alone and 15 with high doses of ampicillin (300 mg/kg-d) by mouth. Ampicillin in this dosage was well tolerated except in three children in whom severe urticarial rashes developed and two who had significant diarrhea. However, high-dose oral ampicillin therapy had no advantage over that with lower doses or over chloramphenicol as judged by the rate of defervescence after the start of treatment, the rate of clinical relapse and the frequency of excretion of Salmonella typhi during convalescence.


Carcinoembryonic antigen: 3 years' experience in a cancer clinic. Long-term studies on multiple plasma samples of 988 patients with carcinoma of entodermal origin indicate that, especially for patients with colorectal cancer, repeatedly elevated or rising carcinoembryonic antigen (CEA) values are a sign of poor prognosis when found preoperatively, postoperatively or during chemotherapy. Persistently elevated CEA values in postoperative patients apparently free of disease are a useful marker for early detection of recurrence or metastases. Normal CEA values are of little or no prognostic value.


Further experience in conjoint psychotherapy of marital pairs. Conjoint therapy of marital partners is a technique that lends itself to the counseling efforts of health professionals. Its growing use has, however, brought with it seemingly inevitable pitfalls, such as inadequate assessment of individual needs and psychopathology, overzealous application and disregard of certain contraindications, management problems and goal definition that may be unclear to patients or more related to the therapist's personality than to an objective view of the marriage dynamics. Despite the difficulties and pitfalls of this relatively new field, conjoint therapy can be the treatment of choice when the primary difficulties are related to the inability to cope in the marital situation, even though functioning in other social roles is adequate.


Do risk factor interventions prevent or reverse arteriosclerosis? We have attempted to summarize the current controversies regarding risk factors and preventive measures for control of arteriosclerosis and coronary heart disease. Recognizing that the genesis and development of the disease process are extremely complex and the basic knowledge is limited, it is not likely that conclusive answers to questions will be forthcoming soon which will provide more effective preventive or therapeutic measures. It might be desirable to institute educational and control program aimed at curtailing, at a young age, known AS risk factors such as heavy smoking, particularly if the family history indicates severe risk. Few will question the normal approaches to the treatment of complications of coronary heart disease by control of hypertension, elevated cholesterol, and smoking. However, great caution must be exercised when trying to institute large scale modifications in prevailing life patterns, particularly when based on indefinite risk factor studies and in the face of potentially profound and frequently unknown consequences. The unknowns of atherosclerotic heart disease risk factors, coupled with uncertainties and even doubts about protracted and expensive population studies, lead us to propose an emphasis on alternate selective approaches. We strongly believe that fundamental to progress in the field of arteriosclerosis is an amplification of preventive research efforts with stronger attention focused upon influencing the atherosclerotic processes within the arterial wall. But, more immediately, we urge systematic gathering and careful evaluation of patient data in particular population subsets which exhibit and accelerated mode of arteriosclerosis. Comparative studies of patients, particularly twins, families, and ethnic populations with redilection to early or accelerated arteriosclerosis may be extremely rewarding. Our repeated review of the enormous literature suggests that worldwide collaboration is needed to perfect more meaningful protocols as well as to correlate and critically evaluate existing data provided by population studies of this insidious disease process which represents an evermounting burden to society.


What is the role of invasive monitoring procedures in the management of the critically ill? In summary, therefore, to effectively apply invasive methods and beneficially use data derived from these procedures, it is essential that physicians have an understanding of the pathophysiology of ischemic heart disease and power failure, and of other situations in cardiology including the management of the complex problems of the critically ill from a variety of causes. There should be an experience and proficiency in the techniques from the optimal application and use of invasive methods including direct arterial puncture and recording of arterial blood pressure, and the use of the Swan-Ganz catheter systems. This must be reinforced by continuous educational experiences and updating with the newer techiniques as they become available. All personnel concerned must have a knowledge of and respect for the complications inherent in any invasive procedure, particularly involving the vascular system. In addition, they must have the ability to translate the relative hemodynamic measurements into meaningful diagnostic and therapeutic decisions. Under these circumstances, invasive methods have a major and valuable role to play in the management of all forms of critical illness.


Antithrombotic agents are indicated in the therapy of acute myocardial infarction. Although there is no statistical proof of the efficacy of coumarin drugs in the therapy of acute myocardial infarction, the numbers of patients at risk from thromboembolism are sufficiently great and the favorable clinical and pathologic impressions are sufficiently strong that, conversely, the possibility of benefit cannot be excluded. This delicate balance is indeed a Hobson's Choice. In this therapeutic dilemma, we would interpret one acceptable course in regard to the use of anticoagulants among patients with acute myocardial infarction as follows: all patients with proved acute myocardial infarction should be treated with anticoagulants while hospitalized unless there are relative or absolute contraindications to the therapy or deficiencies in laboratory facilities. Patients with questionable infarcts should be treated with anticoagulants only until the diagnosis is established or rejected. If the latter occurs, the administration of the drug should be discontinued. When, in a patient suspected of having an acute myocardial infarction, there is reason to believe that the pain may be due to pericarditis, dissecting aneurysm, or gastrointestinal abnormalities, anticoagulant therapy should be withheld until this is resolved.


Clinical judgement is not sufficient for the management of conduction defects (indications for diagnostic electrophysiologic studies). Although analysis of the surface electrocardiograms is usually sufficient in the diagnosis and management of patients with cardiac arrhythmias, electrophysiologic studies can improve diagnostic, therapeutic, and prognostic decisions. Indications for electrophysiologic studies appear to include the following: (1) asymptomatic patients with chronic second degree AV block, both type I and type II with or without bundle branch block; (2) asymptomatic patients with complete AV block; (3) symptomatic patients with bundle branch block and 1:1 AV conduction; (4) patients with bundle branch block complicating acute myocardial infarction; (5) patients with electrocardiograms suggesting pseudo AV block; (6) symptomatic patients with sinus bradycardia, in whom the causal relationship is not clear enough to justify pacing therapy; (7) patients with frequent, troublesome paroxysmal supraventricular tachycardia; (8) patients with Wolff-Parkinson-White syndrome and frequent paroxysmal supraventricular tachycardia; (9) patients with recurrent paroxysmal ventricular tachycardia; (10) patients with syncope or severe dizziness in whom the causal mechanism is not defined.


Should valvular replacement be reserved for symptomatic valvular heart disease? Valvular replacement should generally be reserved for patients with valvular heart disease who are symptomatic. With the exception of an occasional case of tight aortic stenosis, morbidity and mortality are less in the asymptomatic patient managed medically versus surgically with prosthetic valve replacement. Therefore, patients with valvular lesions are best managed without prosthetic valve surgery until less than ordinary exertion makes the patient clearly symptomatic. At this point, significant hemodynamic impairment at rest is present, and the prognosis is worse if the patient is managed medically rather than surgically. Until then, however, one should not operate on an asymptomatic or minimally symptomatic patient with valvular heart disease, particularly when the surgical procedure can be expected to require valve replacement.


Lymphocytosis induced by polyanions in rats. More than twenty different polymers, mostly polyanions, were tested in rats for their ability to mobilize lymphocytes into the peripheral blood within 2--3 h. The various polyanions differed in basic structure, in side-chain (size and type), in molecular weight and configuration and in amount and type of anionic charge along the molecule. Neutral polymers and a polycation were also tested for comparison. Some of the polyanions were found to be very effective, others less so and some completely ineffective. Some were also toxic. The basic polymer to which the others were compared was polymethacrylic acid (PMAA), an already recognized mobilizing agent. The best agents were the heparinoids, sulphated polyanions, and the best of these, causing a 3--4-fold increase, were dextran sulphate and polyvinyl sulphuric acid (PVSA). Heparin, although the strongest anticoagulant, was the weakest mobilizer. Some factors that appear capable of modifying mobilization to varying degrees were molecular weight, size and configuration, sulphate content and mode of administration. In the case of PVSA, the smaller molecular weight substance gave a more prolonged lymphocytosis in blood. The high molecular weight substance gave a peak after 2 h, slightly earlier than with PMAA (2--3 h). The administration of protamine chloride to the rat (i.v.) caused an immediate reversal of mobilization, following a course to control values which was essentially identical to the normal decline, only earlier. Dextran sulphate of low molecular weight seems to be the polyanion of choice in subsequent mobilization experiments dealing with determination of the specific mononuclear cell type being mobilized. The single factor that all mobilizing polyanions have in common is a negative molecular charge. It is not yet known exactly how this charge induces the mobilization of mononuclear cells, nor what causes the variability in effectiveness among polyanions.


Methylation of DNA in rat liver and intestine by dimethylnitrosamine and N-methylnitrosourea. A chromatographic procedure for improved separation of deoxyribonucleosides and methylated deoxyribonucleosides is described. DNA was isolated from liver and small intestine of rats treated with [14C]dimethylnitrosamine ([14C]DMN) or N-[3H]methyl-N-nitrosourea ([3H]MNU), and the purified DNA was hydrolyzed enzymatically. The deoxyribonucleosides were chromatographed on an Aminex A-6 cation exchange column at 37 degrees C with 0.4 M ammonium formate, pH 4.5, as eluant. In addition to showing the presence of the expected alkylated products, N7-methyldeoxyguanosine (determined as N7-methylguanine) and O6-methyldeoxyguanosine, several other minor methylated products were found in liver and intestinal DNA of rats treated with DMN or MNU. Two of these products are believed to be N3-methylthymidine and O4-methylthymidine.


Interactions between selenium and methylmercury in rat brain. The interaction of selenium with methylmercury was investigated in brain of animals labeled with 75SeO2-3 and CH3203Hg+. Brains were fractionated into subcellular components and the cytosol was further fractionated by chromatography on Sephadex G-150 and G-200. The main result of these studies was evidence suggesting a shift of 75Se from the cytosol to the mitochondrial fraction in brain when CH3Hg+ was given. Concurrent equmolar (10 micronmoles/kg) selenite injections increased the uptake of Hg but did not alter 203Hg distribution in brain. Changing the dose of CH3Hg+ from 1 to 38 micronmoles/kg had little effect of Hg uptake (% of dose per g). Gel filtrations on Sephadex G-150 and G-200 revealed that 203Hg in cytosol followed a pattern more closely related to protein (A280) than to 75Se, although a considerable portion of both isotopes eluted with proteins in the void vulume. Assays of whole brain homogenates revealed a slight reduction in glutathione peroxidase activity in CH3Hg+-treated rats which was not seen when equimolar selenite was injected with the CH3Hg+


Excretion of pyrrolic metabolites in the bile of rats given the pyrrolizidine alkaloid retrorsine or the bis-N-ethylcarbamate of synthanecine A. (1) A comparison has been made in male rats between the biliary excretion of pyrrolic metabolites from the pyrrolizidine alkaloid retrorsine and a synthetic analogue 1-methyl-2,3-pyrroline-bis-N-ethyl-carbamate (Synthanecine A bis-N-ethylcarbamate). (2) When bile duct-cannulated rats were given retrorsine (40 mg/kg) and the bile collected at 1 h intervals, the relative concentration of pyrrolic metabolites was greatest in the first 1 h sample and was negligibly small by 7 h after dosing. By 7 h, about 25% of the dose had been excreted as pyrrolic metabolites. (3) In rats given [3H]synthanecine A bis-N-ethylcarbamate (40 mg/kg), the amounts of radioactivity and the relative levels of pyrrolic metabolites in the bile were greatest in the first 0.5 h sample and became negligibly small by 4 h after dosing. Within this time, about 25% of the dose had been excreted as [3H]radioactivity in the bile only about 5% as pyrrolic metabolites. (4) When rats were given [3H]2,3-bishydroxymethyl-1-methyl pyrrole (10 mg/kg), a proposed pyrrolic metabolite of synthanecine A bis-N-ethylcarbamate, about 17% of the dose was excreted for as [3H]radioactivity in the bile but only about 3% could be accounted for as pyrrolic metabolites. (5) Thin-layer chromatography of bile from rats given [3H]2,3-bishydroxy-methyl-1-methylpyrrole or [3H]synthanecine A bis-N-ethylcarbamate showed little redioactivity or Ehrlich-positive pyrrolic metabolites with an RF value corresponding to that of 2,3-bishydroxymethyl-1-methylpyrrole. A large proportion of the radioactivity label and most of the Ehrlich positive pyrrolic metabolites were associated with highly polar derivatives at the origin of the TLC plate. (6) It was concluded that biliary excretion plays an important role in the disposal of metabolites from both retrorsine and synthanecine A bis-N-ethyl-carbamate though not for the parent compounds. The expected hydroxy-methyl pyrrolic metabolites undergo further modification to more polar derivatives. In the case of retrorsine, these retained their abilities to react with Ehrlich reagent, while with pyrrolic metabolites from synthanecine A bis-N-ethylcarbamate, substatial conversion to Ehrlich negative derivatives occurred. (7) When bile of rats given [3H]synthanecine A bis-N-ethylcarbamate was injected intraduodenally into recipient animals, reabsorbtion of the radioactive label accounted for less than 4% of the dose given to the donor animals, indicating the enterohepatic circulation is probably only of minor importance influencing the elimination of these compounds.


Alkylating esters. X. The reaction of some aziridine alkylating agents with methionine and S-methyl cysteine. Two biologically active aziridine ring-containing compounds, N,N-ethylene urethane (I) and N,N-ethylene urea (II), have been shown to react with methionine in dilute phosphate buffer (pH 7.4) at 37 degree C. Degradative procedures indicate that the aziridine ring effectively alylates the thio ether group of methionine and other thio ether-containing amino acids to produce sulphonium salts (V). By using [35S]methionine, the sulphonium salts have been shown to be quite stable under physiological conditions (t1/2 7--9 days) hydrolysing to convert the methionine residue to homoserine. It is proposed that similar alkylations of methionyl residues in vivo by aziridine-alkylating agents may explain the complex, and al yet unknwn, metabolic fate of the aziridine ring and could also be a factor contributing to the diverse effects that these agents have on living cells.


Reaction of cis and trans isomers of platinum(II) diamminedichloride with purine, adensine and its derivatives in dilute solutions. Reactions of the cytostatic and antitumour agent, cis-platinum(II) diamminedichloride, and its trans isomer with purine, adenine and its N-9 derivatives were followed spectrophotometrically in dilute aqueous solutions. While the cis isomer formed with all compounds studied complexes with the metal-to-ligand ratios ML, ML2 and M2L, it was found that the trans isomer did not form the complexes ML2 with adenosine and AMP. The values of dissociation constants, reaction rate constants and activation energies of the reactions of the cis and trans isomers with purine, adenine, and its derivatives were in most cases comparable. Lower stability was exhibited only by the complexes of trans-platinum(II) diamminedichloride (trans-Pt(II)) with AMP as well as by its complexes M2L with adenine and adenosine. The ability of cis-platinum(II) diamminedichloride (cis-Pt(II)) to react with two adenine residues can explain the greater tendency of the cis isomer to form intrastrand cross-links in nucleic acids as compared with the trans isomer.


Cytotoxicity and DNA damage to mammalian cells by nitrofurans. Nitrofurazone, nitrofurantoin, furazolidone, furaltadone and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) were toxic to cultured mouse L cells. The extent of toxocity and the rate of reduction of nitrofurazone increased markedly as the oxygen content of the incubation medium was lowered. The toxic effect of nitrofurans was decreased by addition of serum and was much greater in phosphate-buffered saline containing glucose (PSG) than in medium. Damage to L cell DNA by nitrofurans increased as the oxygen concentration decreased from 21% to 0%. The concentration of nitrofurazone and duration of exposure also determined the number of DNA single-strand breaks. It is suggested that toxicity and DNA damage may result from the actions of toxic intermediates in the metabolic reduction of nitrofurans.


Re-entrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarction zone. Dogs 3-7 days following ligation of the anterior descending coronary artery representing a remarkably stable model for re-entrant ventricular arrhythmias (RVA) and allowed detailed electrophysiologic studies of the re-entrant mechanism. In these dogs, we could regularly illustrate the presence of continuous electrical activity originating from the infarction zone (IZ) and bridging the diastolic interval between the initiating and re-entrant beats as well as between consecutive re-entrant beats. Conduction in the IZ was highly complex, with multiple potentially re-entrant pathways, functionally dissociated areas, and areas of localized ventricular fibrillation. Conduction disorders in ischemic myocardium were consistently tachycardia-dependent with the spontaneous onset of RVA specifically associated with a Wenckebach-like conduction pattern in a potentially re-entrant pathway. Both manifest and concealed re-entry, as well as re-entrant beats with regular extrasystolic grouping, constant or variable coupling, uniform multiform and bidirectional QRS configurations, were related to characteristic conduction patterns in the IZ. In summary, the study provides the first direct in vivo evidence of ventricular re-entry and demonstrates propensity for RVA and sudden death in the late myocardial infarction period.


Re-entrant ventricular arrhythmias in the late myocardial infarction period. 2. Patterns of initiation and termination of re-entry. The electrophysiologic mechanisms for the initiation and termination of re-entrant ventricular arrhythmias (RVA) were critically analyzed in dogs 3-7 days following ligation of the anterior descending coronary artery, utilizing direct recordings of the re-entrant pathway (RP) from the epicardial surface of the infarction zone. Re-entry could occur during a regular cardiac rhythm if the heart rate is within the narrow critical range during which conduction in a potentially RP exhibits a Wenckebach-like (W) pattern with a beat-to-beat increment of conduction delay until the activation waveform is sufficiently delayed to re-excite normal myocardium. If a regular cardiac rhythm is associated with limited conduction delay in a potentially RP, premature beats within a critical range of coupling intervals could result in sufficient conduction delay to induce re-entry. Re-entrant ventricular arrhythmias may be unmasked on abrupt termination of a critical fast rate of cardiac pacing only if pacing was terminated during those beats of a W pattern associated with marked conduction delay in a RP. RVA could be ended by one or more properly timed premature beats that would pre-excite part of the RP. An electrophysiologic mechanism for R-on-T and its relationship to onset of ventricular fibrillation was shown, based on markedly delayed RP conduction of the beat prior to the one apparently coupled to the premature beat.


Evaluation of precordial orthogonal vectorcardiographic lead ST-segment magnitude in the assessment of myocardial ischemic injury. Relationship has been established between epicardial ST-segment elevation, considered a reliable estimate of ischemic injury in experimental myocardial damage, and ST changes by multiple-lead precordial electrocardiography. However, 35-lead precordial mapping is time-consuming and suitable only for anterior infarctions. An alternate, more rapid method for recording ST segments is an external 3-lead orthogonal vectorcardiographic (VCG) system which also can assess the entire ventricle. Accordingly, validity of VCG ST magnitude was evaluated by direct comparison with changes in epicardial ST magnitude (EST) induced by occlusion of major coronary arteries, reperfusion, and pharmacologic interventions in 15 closed-chest dogs. A total of 404 data points (average 27/dog), 20 epicardial grid and 3 Frank XYZ leds each, demonstrated close correlation (least squares linear regression) between VCG ST and EST changes (r = 0.921 +/- 0.02 SEM). These data document the accuracy of precordial VCG ST in noninvasive assessment of ischemic injury in various areas of myocardium and its practicality for clinical application.


The effect of exercise training on heart rate during coitus in the post myocardial infarction patient. The effect of interval exercise training on the peak coital heart rate in post myocardial infarction patients was studied. Sixteen men (ages 46-54) underwent a 16-week bicycle ergometer training program 12 to 15 weeks following their first myocardial infarction. Portable ECG tape recorders were used to record the ECG during coitus twice before and twice after the training program. The maximum minute oxygen consumption (VO2max) was measured in each subject during bicycle ergometer ECG examinations before and after the training program. A control group of six post myocardial infarction patients who were not trained was evaluated in the same manner. The exercise-trained group had an average increase in VO2max of 11.5%(2.7 to 3.0 L/min) and an average decrease in peak coital heart rate of 5.5%(127/min to 120/min). The control group demonstrated a 2% increase in VO2max and no significant change in peak coital heart rate. The increase in aerobic capacity (VO2max) and the consequent reduction in peak coital heart rate in our trained group suggests the potential value of exercise training in improving sexual function in the patient with angina during coitus.


Correlation of mean pulmonary artery wedge pressure, left atrial dimention, and PTF-V1 in patients with acute myocardial infarction. The mean pulmonary artery wedge pressure (PAWP), left atrial dimension (LAD) by echocardiography, and PTF-V1 in the electrocardiogram were correlated with each other in 16 patients with acute myocardial infarction in the control period and after therapeutic intervention with either Dextran or furosemide and/or nitroprusside. No significant correlation was found between a normal control PAWP and the LAD. An increased control PAWP correlated well with an increased LAD (r = 0.98). No significant correlation was found between the LAD and the PAWP whether normal or elevated after therapeutic intervention. No significant correlation was found between the PAWP whether normal or elevated and the PTF-V1. No significant correlation was found between the LAD and the PTF-V1. We conclude in acute myocardial infarction 1) the PTF-V1 is not useful in assessing PAWP before or after therapeutic intervention, 2) the LAD correlates poorly with a normal control PAWP but correlates well with an elevated control PAWP, and 3) the LAD cannot be used to assess PAWP after therapeutic intervention.


Effect of angina on the left ventricular diastolic pressure-volume relationship. The increased left ventricular end-diastolic pressure associated with myocardial ischemia was studied in 19 patients at cardiac catheterization. Single plane left ventriculograms were performed using high fedelity micromanometer tipped catheters before and immediately following rapid atrial pacing. Left ventricular diastolic properties were evaluated by constructing diastolic pressure-volume curves from the simultaneous pressure and volume data. In seven control patients, there was no significant change in left ventricular hemodynamics or the diastolic pressure-volume curve after atrial pacing. Twelve patients with significant coronary artery disease developed angina during pacing and had an increased left ventricular end-diastolic pressure (18 +/- 2 mm Hg, control, vs 30 +/- 2 mm Hg, angina, P less than .01) in the immediate post-pacing period. In these patients, the post-pacing ejection fraction was modestly decreased (0.63 +/- 0.03, control, vs 0.57 +/- 0.03, angina P less than 0.01), and left ventricular volumes at end systole (59 +/- 8 cc, control, vs 74 +/- 9 cc, angina, P less than 0.0125) were increased. The post-pacing diastolic pressure-volume curves in all 12 patients were shifted upward as compared with control so that for any given diastolic volume, pressure was higher during angina. The data indicate that the increased left ventricular diastolic pressure during myocardial ischemia is the result of both impaired left ventricular systolic performance and altered left ventricular diastolic properties.


Cross-sectional echocardiographic assessment of the severity of aortic stenosis in children. Real-time, cross-sectional echocardiographic studies of the aortic valve were performed in 28 children with congenital valvular aortic stenosis and in 22 normal subjects. The presence of a stenotic valve was indicated by increase in echo production, abnormal motion pattern, and abnormal systolic position of the valve leaflets. Comparison of the maximum aortic cusp separation (MACS) to calculated aortic valve area yielded an r of 0.91. MACS was then expressed as a percentage of aortic root diameter (AOD) to correct for patient size. In normals MACS averaged 72.7% (range 63-92%) of AOD. With mile aortic stenosis MACS averaged 53.1% of AOD (range 42-62%) (P less than 0.001 vs normal). With moderate and severe aortic stenosis MACS averaged 29.9% of AOD (range 20-35%) (P less than 0.001 vs mild AS). Comparing the ratio MACS/AOD to peak systolic gradient yielded an r of 0.88. Further comparing this ratio to calculated aortic valve area yielded an r of 0.80. Cross-sectional echocardiography can detect the presence of aortic stenosis in children and, by comparing the ratio MACS/AOD, can provide information concerning the severity of the stenotic lesion.


Natriuretic response to saline infusion in normotensive and hypertensive man. The role of renin suppression in exaggerated natriuresis. Previous studies have reported an exaggerated natriuresis in hypertensive man; however, a systematic appraisal of this response in various forms of hypertension has not been made. We measured fractional excretion of sodium (FENa) during a four hour intravenous infusion of 2 liters normal saline in 162 normal subjects and 120 hypertensives. Of these, 13 had primary aldosteronism (ALDO), 19 high renin (HRH), 30 low renin (LRH), and 57 normal renin (NRH) essential hypertension. FENa for normals (1.42%), NRH (1.57%), and HRH (1.46%) was similar. That for LRH (2.56%) and ALDO (4.18%) was elevated compared to the other three subgroups (P less than 0.001). Although the four hour FENa during saline infusion was associated with mean atrterial blood pressure (MABP) within the entire hypertensive population (r = 0.51), when the subgroups of the hypertensive patients were considered separately no association between FENa and MABP was identified. Moreover, the MABP of subjects with HRH was greater (P less than 0.05) than in those with NRH, although the FENa of the two subgroups was similar. Patients with ALDO and LRH have a greater natriuretic response to a salt load than do other subgroups of essential hypertension or normal subjects. The exaggerated natriuresis appears to be a feature of hypertension with renin suppression. The degree of exaggerated natriuresis in not solely a function of an elevated mean arterial blood pressure.


Cryodynamic hand angiography in the diagnosis and management of Raynaud's syndrome. Cryodynamic hand angiography (CHA) with angiograms done before, just after, and during rewarming following hand immersion in ice water was performed in 39 patients with Raynaud's syndrome and eight volunteers without it. The normal response to cold stimulus was angiographically evident as mild, transient digital arterial constriction. Most of the patients with Raynaud's syndrome, in addition to organic obstructive disease, exhibited basal vasoconstriction and exaggerated persisting cryogenic vasospasm of the hand arteries. Similar angiographic studies done in 32 cases two days after the selective intra-arterial administration of reserpine revealed no differences in normal subjects but substantially decreased vasospasm in patients with Raynaud's syndrome. CHA with postreserpine studies was found to be diagnostically useful in Raynaud's syndrome, revealing the degree of organic arterial disease and functional vasospasm. In addition, correlation of postreserpine studies with observed clinical responses to long-term vasodilator drug therapy indicated that CHA has a good chance to predict the probable outcome of such therapy in Raynaud's syndrome.


Rupture of ventricular septum or papillary muscle complicating myocardial infarction. Ninety-eight specimens with rupture of some portion of the left ventricle complicating acute myocardial infarction from atherosclerotic coronary disease were studied. In 90, a single structure (so-called isolated rupture) had ruptured as follows: free wall of left ventricle, 52 cases; ventricular septum, 18 cases; a papillary muscle, 20 cases. In eight cases, two structures had ruptured, the most common combination being rupture of ventricular septum and left ventricular wal. Inferolateral location of underlying infarction was the common situation in ruptured papillary muscle, while anteroseptal myocardial infarction was more common in rupture of the ventricular septum. Transmural infarction underlay each case of ruptured ventricular septum, while in ruptured papillary muscle 11 of 20 cases showed subendocardial infarction. There was no association between the type of papillary muscle rupture and the type of infarct. Clinically, collapse of the circulation was common in cases of ruptured ventricular septum and ruptured papillary muscle. Death within one week after rupture was usual when the papillary muscle was involved totally or when the ventricular septum was involved. With partial rupture of a papillary muscle, longer survival (months) was observed in two of ten cases.


Network of immune-neuroendocrine interactions. In order to bring the self-regulated immune system into conformity with other body systems its functioning within the context of an immune-neuroendocrine network is proposed. This hypothesis is based on the existence of afferent--efferent pathways between immune and neuroendocrine structures. Major endocrine responses occur as a consequence of antigenic stimulation and changes in the electrical activity of the hypothalamus also take place; both of these alterations are temporally related to the immune response itself. This endocrine response has meaningful implications for immunoregulation and for immunospecificity. During ontogeny, there is also evidence for the operations of a complex network between the endocrine and immune system, a bidirectional interrelationship that may well affect each developmental stage of both functions. As sequels the functioning of the immune system and the outcome of this interrelation could be decisive in lymphoid cell homeostasis, self-tolerance, and could also have significant implications for pathology.


Serum effects of mitogenic reactivity in subjects with systemic lupus erythematosus, rheumatoid arthritis and scleroderma. Technical considerations and lack of correlation with anti-lymphocyte antibodies. Methodological problems which affect the assessment of humoral effects on mitogenic reactivity include: (1) the source and concentration of serum used to support cell cultures; (2) the day to-day variability of inhibitory effects and (3) the specific activity of [3H]thymidine added to the culture. These problems were alleviated by addition of half concentration (7-5%) of pooled normal human serum to all cultures, the intoruction of anti-lymphocyte serum as a suitable internal control for monitoring the suppressability of lymphocytes and a reduction of specific activity of the [3H]thymidine to 1-3 C2/mM. Inhibitory factors were loosely bound to the lymphocyte surface and eluted off after incubation at 37 degrees C for 1 hr. Cells from twenty-five subjects and paired controls were cultured simultaneously in medium containing either 15% normal human serum (NHS) or 7-5% patient and 7-5% NHS. The cells were stimulated with various dilutions of phytohaemagglutinin, Con A or pokeweed mitogen. Lupus serums suppressed the reactivity of autologous lymphocytes to PHA and pokeweed mitogen. Serums from subjects with RA and scleroderma did not significantly inhibit blastogenesis of autologous lymphocytes. One-half of the lupus serums significantly inhibited the reactivity of homologous lymphocytes to two of three mitogens. Only one of eight scleroderma serums and none of twelve RA serums and none of twelve RA serums had this effect. All patients serums were examined for antilymphocyte antibodies by microcytotoxicity and immunofluorescent techniques. These antibodies were usually found in SLE, and were often observed in subjects with rheumatoid arthritis but not scleroderma. A firm relationship between serum suppressors of lymphocyte blastogenesis and anti-lymphocyte antibodies was not found.


Cell-mediated immunity in amyloidosis secondary to lepromatous leprosy. Cell-mediated immunity in lepromatous leprosy patients with and without amyloidosis has been studied. Amyloidosis occurred mostly in patients with a history of recurrent erythema nodosum leprosum (ENL) reactions. For this reason, two control groups of leprosy patients were included, one having a history of recurrent ENL and the other little or no ENL. The lack of responsiveness to lepromin in vivo and in vitro, characteristic of lepromatous leprosy, was not altered by the presence of amyloidosis or a history of ENL. No significant difference between the patient groups was observed in the response to PPD in vitro, but skin reactivity to PPD was significantly lower in the patients with amyloidosis than in those without amyloidosis. In contrast, the PHA responses of patients with amyloidosis were significantly higher than those of control patients without a history of ENL, but not significantly different from those of control patients with a history of recurrent ENL. Lepromatous leprosy patients who develop amyloidosis thus appear to belong to a group, susceptible to repeated attacks of ENL, whose PHA responses are higher than those of other lepromatous leprosy patients. The lower skin reactivity to PPD observed in the amyloid group may reflect a general impairment in delayed cutaneous hypersensitivity.


PPD and mitogen responsiveness of lymphocytes from patients with atopic dermatitis. Lymphocytes from twenty-five patients with atopic dermatitis were investigated for their in vitro reactivity to stimulation with tuberculin (PPD), lipopolysaccharide (LPS), phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). The response to a low dose of Con A was increased, and the reactivity in unstimulated cultures tended to be lower than similar cultures from the control group. Addition of inactivated autologous plasma to the cultures had an inhibitory effect, when the plasma came from patients with high levels of IgE. The patients' in vitro reactivity to PPD in a leucocyte migration test was equal to that found in normal persons and no effect was observed after addition of autologous serum. The mean percentage of E rosette forming cells was significantly reduced in patients with high levels of IgE. The number of EAC rosette forming cells was within normal range. It is hypothesized that the observations could reflect the existence of suppressor mechanisms in patients where the immune system is strongly stimulated.


Inhibition of human lymphocyte stimulation by steroid hormones: cytokinetic mechanisms. The steroid hormones estradiol, progesterone and testosterone, in addition to cortisol, inhibited stimulation of human peripheral blood lymphocytes by phytohaemagglutinin (PHA) and Con A. This effect upon lymphocyte transformation was assayed by three methods: quantitation of [3H]thymidine incorporation into acid precipitable material, microscopic assessment of blastic transformation and determination of the labelling index. Addition of steroid hormones at the initiation of culture resulted in a marked inhibition in all three parameters, which was observed with lower concentrations of cortisol than the other hormones. The inhibition was not attributable to cell death and could be partially reversed by removing hormones from the incubation medium after culture for 48-72 hr. Late addition of steroid hormones, 52 hr after addition of mitogen and 18 hr prior to pulse-labelling with [3H]thymidine, also resulted in reduced [3H]thymidine incorporation, accompanied by a nearly 50% reduction in the labelling indices and only a minimal decrease in the per cent transformed cells. Inhibition of lympohcyte stimulation by steroid hormones operates by the following cytokinetic mechanisms: (1) suppressed recruitment of cells from G3 to G1 phase of the cell cycle, as indicated by the diminished per cent blasts; (2) inhibition of progression from G1 phase into S phase, as evidenced by the reduced ratio [labelling index/blasts]; and, in the case of estradiol and progesterone, (3) reduced rate of DNA replication or altered intracellular [3H]thymidine specific activity as shown by the decreased ([3H]thymidine incorporation/labelling index) ratio. Late addition of steroid hormones to stimulated cultures reduced the per cent of cells in S phase, but did not revert previously transformed cycling lymphocytes to the G3 state.


A second case of human C3b inhibitor (KAF) deficiency. The second case of C3b inhibitor deficiency is described in an 11-year-old girl who presented with recurrent attacks of meningitis, in between which she was well. Her serum showed all of the complement component changes noted in the first described case, although showing only a relatively slight defect in its ability to opsonize bacteria for phagocytosis and killing by polymorphonuclear leucocytes. This correlated with the patient's freedom from other infections.


The cold activation of the classical complement pathway: The cause of the differences between plasma and serum complement in liver cirrhosis. The mechanism responsible for making the differences between plasma and serum complement (CH50) was studied on eight patients with hepatitis-B(s) antigen negative alcoholic liver cirrhosis. CH50 and C4 activities of the sera of all patients were equal to those of the corresponding EDTA-plasma, when sera wre separated after clotting the blood at 37 degrees C. CH50 and C4 activities of the sera, prepared at 21 degrees C or 4 degrees C, from four of eight patients were very low. When serum from one of these four patients was added to normal human serum, C4 activity of the serum mixture markedly decreased at 4 degrees C but not at 37 degrees C. The inactivation of C4 was prevented by adding EDTA or heparin to the serum mixture. These results indicated that very low complement in the sera, prepared at 21 degrees C or 4 degrees C, of the four cases were due to the cold activation of the classical complement pathway.


HLA in eczema and hay fever.

HLA in eczema and hay fever. The presumed HLA haplotype A1:B8 was more frequent and the combination of A3 and B7 was less frequent in allergic subjects presenting with eczema, than in those presenting with hayfever. A1:B8 was most frequent (36%) in eczema complicated by asthma and/or hay fever, and least frequent (5%) in hay fever alone, considerably above and below the frequency in the general population (17%).


Studies on HLA antigens and cellular and humoral autoimmune phenomena in patients with myasthenia gravis. The HLA phenotype of fifty-four patients with myasthenia gravis (MG) was compared to that of 600 controls. When male and female patients were compared separately with the control group, HLA-B12 was increased in MG males (P less than 0-023) and HLA-A1, B8 in MG females (P less than 0-023). In addition, HLA-A1, B8 was correlated with the early onset type of MG and with a more severe clinical course (Osserman scale IIb-III) in female patients. Cell-mediated immune responses were studied in a twenty-one hospitalized MG patients. Specific cell-mediated immunity to highly purified muscle proteins was investigated using the two-step-leucocyte migration agarose test and general cell-mediated immunity was studied by determining the cutaneous response to four extrinsic antigens. Cellular immune activity to muscle antigens occurred in fourteen out of twenty-one patients (67%) with MG and with one exception, in none of the controls. There was no significant difference in the LIF inducing ability of the different muscle antigens. A statistically significant correlation between HLA-A1 and B8 and either cell-mediated immune reactivity to muscle antigens or humoral autoimmune phenomena or clinical parameters was not found. Only a trend toward an association between HLA-A1 and B8 and a cell-mediated immune response to muscle antigens could be demonstrated. Positive delayed skin reactions to extrinsic antigens were observed with the same frequency as in healthy blood donors.


Macrophage responses to mouldy hay dust, Micropolyspora faeni and zymosan, activators of complement by the alternative pathway. Mouse peritoneal macrophages in culture exposed to mouldy hay dust, Micropolyspora faeni or glycopeptide or protein/glycoprotein fractions from this organism show marked biochemical changes. For comparison the interaction of cultured macrophages with zymosan has been investigated. All these agents induce the release of hydrolytic enzymes from macrophages, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of these agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosomal enzyme secretion from cultures of macrophages is discussed. The in vitro phenomena seen with mouldy hay dust, M. faeni, the protein/glycoprotein and the glycopeptide derived from it, may be relevant to understanding the role of mononuclear phagocytes in the disease farmer's lung and other inflammatory reactions.


Peripheral blood leucocytes in thyrotoxicosis (Graves' disease) as studied by conventional light microscopy. Peripheral blood leucocyte counts in 104 thyrotoxic (Graves' disease) patients were compared with those in 107 normal subjects of similar age and sex. The thyrotoxic patients had a significant leucopenia with an absolute and relative neutropenia. They also had a relative lymphocytosis but the absolute lymphocyte count was within normal limits. The relative and absolute monocyte counts were normal.


C4 in glomerular lesions of NZB/NZW mice. Antisera to human C4 can discriminate circulating Ss protein (C4) levels in mice. Since there has been no information on early complement components (C1, C4, C2) in the renal lesions of B/W mice, we applied the indirect immunofluorescence technique to post-mortem sections of kidney from B/W female mice with advanced renal disease. C4 was present in fifteen of the sixteen specimens, usually in a distribution similar to that of IgG or C3. Specificity was demonstrated by differential absorptions with high-Ss serum from C57BL/6 male mice and low-Ss serum from C3H/HeJ female mice. High-Ss-absorbed antiserum did not stain, while low-Ss-absorbed antibody retained much of its activity. This finding parallels the demonstration of early complement components in lesions of clinical lupus nephritis, and is consistent with classic complement pathway activation in B/W disease.


HLA antigens in sarcoidosis.

HLA antigens in sarcoidosis. The HLA antigens were identified in sixty-five patients with sarcoidosis, comprising forty-five with uveitis, twelve with erythema nodosum and eight with arthritis. In the group with arthritis, B8 was present in seven of eight (P = 0-0016) and the haplotype 1,8 in five of eight (P = 0-0053). A1 was present in 44% with uveitis (P = 0-04). There was no other significant disturbance of antigen frequencies in uveitis or in erythema nodosum, but it was noteworthy that B27 was present in only two patients with uveitis.


The spectrum of human tuberculosis.

The spectrum of human tuberculosis. Clinical, morphological and immunological studies of human tuberculosis have enabled the spectrum of the disease to be determined. We have investigated the cell-mediated immune responses by means of skin tests and leucocyte migration inhibition to PPD, and the humoral immune responses by means of immunodiffusion and haemagglutination tests. Patients with tuberculosis can be classified into two polar groups--reactive (RR) and unreactive (UU), the former showing good cell-mediated immunity and little or no antibody formation and the latter poor cellular responses and exuberant antibody production. The intermediate forms show characteristics of the neighbouring polar groups. The existence of a spectrum of immune response in tuberculosis, which has long been suspected, is now demonstrated.


Evidence for immunological cross-reactivity between smooth and skeletal muscle. In 1965 Johnson, Holborow & Glynn showed that some patients with chronic liver disease have antibodies which react with smooth muscle by indirect immunofluorescence. This work was rapidly confirmed and it was soon showed that the same serum may also react with renal glomeruli and other tissue components. Reactions with skeletal muscle were not demonstrated. In 1960 Strauss and co-workers deomonstrated that patients with myasthenia gravis may have antibodies which react with skeletal muscle. Subsequent work has suggested that these antibodies are specific for skeletal as opposed to smooth muscle. More recently smooth muscles antibodies (SMA) have been shown to react with a wide range of tissues and cells including neoplastic cells (Gabbiani et al,, 1973; Holborow et al., 1975). Throughout this work it has been assumed that such reactivity is due to the presence of smooth muscle contractile proteins. This conclusion was further supported by the demonstration that animals immunized with smooth muscle contractile proteins developed antibodies which produce similar patterns to those found with the naturally occurring antismooth muscle antibodies (Trenchev, Sneyd & Holborow, 1974). From these studies it appeared that there was very little if any cross reactivity between smooth and skeletal muscle, although Bray (1974) pointed to the need to re-examine this conclusion. In the course of screening human sera for autoantibodies we have been impressed by the occasional occurrence of sera which gave both smooth and skeletal muscle staining patterns. In this report we describe selected sera which react with antigens which appear specific for either smooth or striated muscle, and additional sera which react with antigens which appear common to both smooth and striated muscle. Immunization of rabbits with skeletal muscle contractile protein has provided further evidence for such cross reactivity,


Fixation of human anti-actin autoantibodies on skeletal muscle fibres. Sera from five patients with chronic aggressive hepatitis containing smooth muscle autoantibodies were tested by means of indirect immunofluorescence for their binding to isolated rabbit skeletal muscle myofibrils. In all cases, the immunofluorescent staining was sharply localized to I bands. After incubation of these sera with skeletal muscle troponin-torpomyosin complex, purified troponin or purified tropomyosin, no changes in immunofluorescent staining of myofibrils were noted. However, the staining was abolished after incubation of the sera with skeletal muscle actin. In double immunodiffusion experiments, a single precipitation line was obtained after diffusion of the sera against crude or purified actin. It is concluded that, at least for the sera examined, smooth muscle autoantibodies are anti-actin autoantibodies. The high titre of such autoantibodies and their availability in clinical immunology laboratories make them a useful tool to study actin distribution in muscular and non-muscular cells.


Restoration of "normal" membrane function in CLL cells by patients' serum. Direct labelling of cell surface protein with 125I has enabled measurements to be made of lymphocyte membrane turnover. In CLL cells this is evidently much retarded in comparison with normal lymphocytes and it was thought that slow replacement of cell surface proteins might be responsible both for lack of membrane mobility and poor immunological responses. Serum from CLL patients has been found to enhance viability of the leukaemic cells in culture and the interaction of these serum factors with the CLL cell membrane gives rise to rapid replacement of surface proteins. Thus the rate of membrane turnover in vivo would be comparable with that of normal lymphocytes. Lack of cell-surface mobility and poor membrane biosynthesis can not be held responsible for poor immunological activity in vivo and it is suggested that autoimmune antibodies binding to the surface of CLL cells may spatially inhibit activation by ligands.


A comparative study of the microcirculation in the guinea-pig thymus, lymph nodes and Peyer's patches. The circulatory patterns in three lymphoid tissues were compared macro- and microscopically. Indian ink or a viscous silicone rubber compound were used as contrast materials and serial 75 micronm sections examined. The findings were checked with the benzidine stain for red blood corpuscles in uninjected tissues. Thymic lobules showed a "through circulation"--capillaries penetrating the cortex from within outwards and draining into surface veins, comparable with the circulation in liver lobules. By contrast, lymph nodes and Peyer's patches showed a looped capillary distribution. The outer thymic cortex and primary follicles in lymph nodes contained the maximum capillary density, correlating with the highest mitotic index of thymocytes and lymphocytes in the respective tissues. The lowest vascular density in the thymus was in the medulla, particularly in Hassall's corpuscles, in secondary follicles of lympho nodes and Peyer's patches, which correlates with the storage capacity of antigens and antibodies at those sites. Postcapillary venules in lymph nodes and Peyer's patches showed a characteristic pattern with Indian ink. These venules were absent from the thymus.


School: child advocate or adversary?

School: child advocate or adversary? Pediatricians who see many children with learning problems are likely to encounter situations caused by school misunderstandings. This essay includes examples of frightening labeling of children, direct cruelty at school, confused academic goals, and administrative bungling. Some possible remedies and practical suggestions are presented.


Orbital involvement in acute sinusitis. Lessons from 24 childhood patients. The possibility of acute bacterial sinusitis should be considered in any child with sudden swelling about the orbit. Management is determined by the stage of the disease as well as by the sinus predominantly involved. Extraocular movements and proptosis are the best guidelines for therapy. When there is no proptosis and extraocular mobility is normal, conservative therapy with intravenous antibiotics and nasal decongestants is usually effective. When ocular mobility is impaired or proptosis develops, intranasal or external surgical drainage are usually required. Of 24 patients summarized in this paper, the ethmoid was the predominantly involved sinus in 12, the frontal in 7, the maxillary in 5. Only 4 of the 12 with predominant ethmoiditis required surgery. All 7 were predominant frontal involvement needed surgical drainage.


Efficacy and acceptability of different dosage schedules of clonidine. In 12 hospitalized patients with hypertension, clonidine 3 times a day led to better control of blood pressure than did the same total dose administered once daily. Compared to the uniform control of blood pressure on divided dose regimen, the single daily 8 P.M. dose led to wider fluctuations and inadequate control 18 hr after dosing. However, 10 of the 12 patients preferred the single daily dose at 8:00 P.M. to the divided dose regimen because of no drowsiness during the day. In 2 patients administration of clonidine twice daily resulted in better control of blood pressure than that during the single or thrice-daily dose regimens. Since there appeared to be a correlation between the dose and the duration of adequate blood pressure control, administration of clonidine twice a day with a larger dose at bedtime and a smaller dose before noon could limit unwanted drowsiness and combine the convenience of less frequent dosing with superior blood pressure control.


Studies on digitalis. X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment. The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method modified for analysis of myocardial samples. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respectively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).


Naloxone-precipitated withdrawal: a method for rapid induction onto naltrexone. We examined naloxone-precipitated withdrawal as a means for rapid opiate detoxification and induction onto naltrexone. In 29 patients dependent on methadone (5 to 20 mg/day), abstinence was precipitated by an injection of naloxone. Repeated injections of naloxone were given subsequently until symptoms of abstinence were no longer induced. Successive injections induced less intense withdrawal assessed by vital signs and ratings on abstinence scales. The most rapid procedure consisted of 1.2 mg naxolone every 30 min for 3 to 6 hr, for 3 to 6 hr, followed by hourly increasing doses of naltrexone. This procedure allowed transition from opiate dependence to naltrexone maintenance (50 to 100 mg/day) within 48 hr. The results are consistent with assumptions that antagonists actively displace opiates from receptor sites.


Prolactin and psychophysiologic measures after single doses of thioridazine. Six normal men ingested thioridazine, high and low doses, and placebo on three occasions. Their plasma and urinary thioridazine and mesoridazine plus sulforidazine were measured over 5 hr, together with their plasma prolactin, and a battery of psychophysiologic variables. Drowsiness and EEG changes correlated highly with rise in prolactin, but not with drug plasma concentrations. Finger tremor increased, and some psychologic tests were impaired by thioridazine; other psychologic tests, the auditory-evoked response, and palmar skin conductance were unaffected and showed no relationship to drug or prolactin levels. This suggests that plasma prolactin may be a useful indicator of some aspects of the individual's response to a psychotropic drug, and possibly a better guide to the selection of a suitable drug and its appropriate dose in clinical practice than the measurement of plasma concentrations of the drug itself.


Pharmacokinetics of chlorpromazine after single and chronic dosage. Plasma concentrations of chlorpromazine and its sulfoxide were measured after single intramuscular, single oral, and multiple oral doses of chlorpromazine. In four out of nine patients, intramuscular doses gave stable chlorpromazine plasma levels which were maintained for 12 hr or longer. Chlorpromazine sulfoxide was found in plasma from all patients after oral doses but not after intramuscular doses, which indicates that sulfoxidation took place presystemically. The biologic availability of single oral doses relative to single intramuscular doses ranged from 10 to 69%, and was on average 32%. After 33 days of oral dosing, the plasma levels of chlorpromazine were on average 37% lower than might have been predicted from the single oral dose curves. This was not due to decreased biologic t 1/2 of chlorpromazine, but apparently to a decrease in the biologic availability by oral administration, possibly by increased presystemic metabolism.


Effect of long-term lithium administration on renal phosphorus handling. Renal phosphorus handling was evaluated in 12 lithium carbonate-treated psychiatric patients. Serum phosphorus was normal and serum lithium values were within the therapeutic range in all subjects. Serum calcium concentrations measured in 6 of the patients were found to be within the normal range; in the same patients serum parathyroid hormone levels were normal in 4 and slightly elevated in 2. Phosphorus clearance (14 +/- 3 [se] ml/min) and tubular reabsorption of phosphorus (88 +/- 2%) during oral sodium bicarbonate loading were not significantly different from those in 10 healthy control subjects. In a subgroup of 5 patients and 5 control subjects, phosphorus excretion did not increase after bicarbonate loading. In these subjects, phosphorus excretion rates after bicarbonate loading were not different. Although experimental studies suggest that lithium inhibits renal cortical adenylate cyclase stimulation by parathyroid hormone, our data did not indicate any striking effect of long-term lithium administration on serum calcium and serum phosphorus or on renal phosphorus handling.


Cigarette smoking and plasma nortriptyline levels. Cigarette smoking was found to have no effect on the steady-state plasma levels of nortriptyline in a group of 22 smokers and 31 nonsmokers. Smokers achieved a mean steady-state nortriptyline concentration of 191.2 +/- 141.3 ng/ml; nonsmokers had a level of 169.3 +/- 92.4 ng/ml. Age, sex, and number of cigarettes smoked had no effect on the plasma concentrations achieved.


Variations in the bioavailability of thiazinamium methylsulfate. Bioavailability after oral administration of the anticholinergic drug thiazinamium methylsulfate (Multergan), a phenothiazine derivative with a quaternary ammonium group in the molecule, has been studied in patients and volunteers by measuring the drug concentrations in plasma or the excretion of the parent drug in urine. The relative bioavailability as compared to intramuscular injection seems to be of the order of 10%. Much more of the drug is absorbed, however, but is metabolized during the first liver passage. Moreover, there seems to be a substantial interindividual variation in the bioavailability of the drug. Studies in a group of eight volunteers showed that there is also a substantial intraindividual variation, but its magnitude is smaller than that of the interindividual variation.


Influence of rifampicin on drug metabolism: differences between hexobarbital and antipyrine. Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half-life of hexobarbital had decreased from 407 to 171 min and its metabolic clearance had increased almost threefold. In contrast, the average elimination half-life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolic clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not influence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D-glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half-lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.


A computer program for fitting multimodal probability density functions. A FORTRAN IV program is described, which may be run interactively with tutorial assistance or in batch and which allows a user to selectively fit any of seven probability density functions (p.d.f.'s) or a combination of the p.d.f.'s to a unimodal or multimodal histogram of empirical data. A "best-fit", uni- or multimodal p.d.f., which may be obtained by a method of nonlinear least squares or a generated p.d.f. may be displayed on a Tektronix 4010 terminal as a continuous curve against the background of a bar, square wave, symbol or point-plot histogram. The following, supportive statistical information is also displayed: (1) Kolmogorov-Smirnov probability of goodness of fit, (2) mean square error, (3) correlation coefficient, and (4) parameter estimates. The resident driver program and six overlayable segments have been implemented on a Digital Equipment Corporation LAB-11 minicomputer (PDP-11/20).


A computer program for the analysis of controllability, observability and structural identifiability of biological compartmental systems. A computer program to check structural identifiability of biological compartmental systems, that is the priori possibility of estamating all unknown system parameters through a multi input-multi output tracer experiment is presented. The procedure, as based only on the adopted compartmental structure and the chosen input-output experiment, is independent of the numerical values of the parameters: therefore the program can be usefully employed before parameter estimation algorithms, to assure that all the unknown parameters evidenced in the model can be estimated from the experimental data. After a short review on compartmental models, controllability observability and structural identifiability are defined and techniques to check them are provided. The digital computer implementation of the whole procedure is discussed in detail. Some typical program runs regarding the application to biological systems are given.


A computer program for the on-line computation of cardiac output from thermodilution curves. An accurate, rapid calculation of Cardiac Output is of great importance during the treatment of critically ill patients. This paper describes a complete, self-contained mini-computer system, based on a Data General NOVA 1220 which can accurately sample data and compute the results in about 30 sec. The system uses the thermodilution method with a Swan-Ganz catheter to collect data and a weighted least-squares technique to compute the results.


Application of a programmable calculator in data fitting according to one and two compartment open models in clinical pharmacokinetics. The plasma or blood concentration profiles are fitted by single or two compartment open models using log-linear regression analyses. For two compartment models, "feathering" is performed at 95% equilibration time obtained from raw pharmacokinetic data. The equations have been programmed onto a Texas Instrument SR 52 pocket calculator and recorded on 8.5 X 1.7 cm magnetic strips, facilitating drug dosage regimen calculations through individual patient titrations in a clinical setting.


Description of DIANA 2.

Description of DIANA 2. DIANA 2 is an improved version of a Fortran program DIANA for the analysis of electrophoresis and ultracentrifugation patterns by a sum of Gaussian-like distributions. This description may serve as manual for the use of the program DIANA 2.


Use of a PDP-12 computer for an on-line analysis of TC-chromatograms by a scanning system. A software system, Chromscan, has been developed on a PDP-12 computer for quantitative analysis of TC-chromatograms and correlated problems in an on-line scanning system. The program controls a one- or two-dimensional scanning process of either a microscope stage or a modified TC-chromatogram photometer (Zeiss) storing the data on tape. The results can be obtained directly or in an off-line calculation by different Focal-12 programs. For spot evaluations a two-dimensional scan is performed with an aperture. The area of spots is measured and the integrated values of absorbed or remitted light represent the amount of separated substances. For line-scans slits are used. The pherogram is displayed on the scope to keep for baseline corrections peak-integration and some other handling under operators control.


Hemorrhoidectomy--how I do it: current views in Britain. It is clear that there is no uniform treatment for hemorrhoids in Britain. Indeed, there is often considerable debate about the merits and disadvantages of the various methods available. It would seem that a more scientific way of assessing the management of patients is needed so that the various therapeutic measures may be properly evaluated, comparing like with like. It may then be possible to tailor the treatment for each individual more accurately, in order to confer the maximum benefit.


Hemorrhoidectomy--how I do it: results of 444 cryorectal surgical operations. Based on a three-year personal experience with a large number of patients, cryorectal surgery is a reliable and valuable alternative to excision for the removal of all types of hemorrhoids and most other concomitant pathologic conditions found in 44% of these patients. Excellent results should be anticipated, and complications are minimal. No contraindication has yet been detected.


Ileostomy complications requiring revision: Lahey clinic experience, 1964-1973. From 1964 to 1973, 50 patients who initially underwent ileostomy for inflammatory bowel disease at the Lahey Clinic required 84 revisions. The commonest reason for revision was stenosis. Fistula, prolapse, and retraction followed in order of frequency. Patients with Crohn's disease seemed to have a higher incidence of revision, but this was not statistically significant. Other reasons for revision were analyzed, and recommendations for treatment were discussed. Retrospective study revealed that 50% of ileostomy revisions were performed for probably preventable complications.


Combined treatment with BCG and chemotherapy for metastatic gastrointestinal cancer. The survival of patients who have cancers of the gastrointestinal tract is poor even after surgical resection of all gross disease. In an initial consecutive series of patients with metastatic or recurrent cancers, an attempt to improve survival with combined nonspecific immunostimulation by the intraperitoneal administration of BCG followed by oral BCG cycled with chemotherapy was studied. The results suggested that a population of patients with gastric and colonic cancers showed improved survival with this treatment. A randomized trial of combined chemoimmunotherapy versus chemotherapy alone was begun on November 1, 1974, for all cancers of the stomach and pancreas and all colorectal cancers beyond stage C by Dukes' classification. The initial results with patients entered by December 31, 1975, and followed until March 1, 1976, are reported.


Umbilical colostomy: a better intestinal stoma. This study was undertaken to evaluate our experience with umbilical colostomy. There were 101 cases available for review. Four patients had major complications that necessitated reoperation, an incidence of 3.9%. One patient was operated on for necrosis of the stoma, one for retraction, and two for periostomal evisceration of omentum and small bowel. Three patients had minor strictures requiring digital dilatation, and one needed minor revision under local anesthesia. No patient had a peristomal hernia or prolapse, making this a distinctly better colostomy than the conventional left-lower-quadrant colostomy. The ease and comfort in the care of this colostomy were evident during follow-up visits. We feel that this procedure has all the advantages of a conventional matured colostomy and has extra advantages of easy accessibility and absence of peristomal hernias and prolapse. For any elderly patient who needs a permanent colostomy, umbilical location of the stoma offers distinct advantages.


The localization of rectosigmoidal tumors or biopsy sites by methylene blue marking. Methylene blue marking of small tumors, biopsy sites, or any tumor in an obese patient is a simple, safe and direct method for accurate identification and resection of rectosigmoidal lesions.


Spontaneous ischemic colitis.

Spontaneous ischemic colitis. Eighteen cases of spontaneous ischemic colitis are reviewed. The diagnosis was established according to the following criteria: 1) clinical background, 2) clinical characteristics, 3) morphologic characteristics, and 4) clinical and morphologic course. The last three constituted the diagnostic criteria. The cases were divided into mild-to-moderate, moderate-to-severe, and gangrenous categories. Although data on clinical background did not establish the diagnosis of spontaneous ischemic colitis, they were essential in strict diagnosis. Patients who had histories of Crohn's disease, chronic ulcerative colitis, and recent antibiotic administration were excluded from consideration. Appropriate stool examinations obtained in all of the mild-to-moderate and all except two of the moderate-to-severe cases excluded colitis due to pathogenic bacterial organisms or parasites. Spontaneous ischemic colitis generally occurs in older individuals; the average age in our patients was 60 years. Twelve of the 18 patients had at least some evidence of major cardiovascular disease.


Epidermoid carcinoma of the anorectum: review of 31 cases. Thirty-one cases of epidermoid carcinoma found in 106 cases of carcinoma of the rectum and anal canal are reviewed. Clinical presentation and management are presented. Probable factors in the greater than usual incidence of epidermoid carcinomas of the anorectum are discussed. Indications for radiation therapy, local excision, and abdominoperineal and inguinal block dissection are presented.


Radiographic and clinical sequelae of the duodenocolic anatomic relationship: two cases of Crohn's disease with fistulization to the duodenum. The posterior surface of the proximal transverse colon and the anterior surface of the descending duodenum are intimately related. The clinical importance of this apposition is re-emphasized with presentation of two cases which had the uncommon phenomenon of benign duodenocolic fistula. These two rare cases of duodenocolic fistulas secondary to Crohn's disease are added to the literature. It is also suggested that in some cases, duodenal mucosal alterations with adjacent Crohn's disease of the colon might be the result of reactive inflammatory changes, and do not necessarily indicate continuous extension of the granulomatous disease.


Unsuspected perforated adenocarcinoma of the appendix as a second colonic neoplasm: report of a case. The case of a patient who had an unsuspected perforated adenocarcinoma of the appendix discovered during operation for a sigmoid carcinoma is presented. The problems in diagnosing carcinoma of the appendix are discussed and the literature is reviewed.


Characteristics of drug abusers in an adolescent in-patient psychiatric facility. Characteristics related to the abuse of drugs in 143 adolescents who had been institutionalized in an inpatient psychiatric facility were investigated. A factor analysis generated the following clusters: (1) multiple drug usage, (2) male narcotics procurement, (3) drug history, (4) prognostic index, (5) family drug usage, (6) entrepreneurial procurement of drugs, and (7) social procurement of drugs. Results also indicated that our patients are coming to us at increasingly younger ages and that patients admitted in 1969 appear more seriously involved in drug abuse than those admitted before or after this time.


Hypokalemic vacuolar myopathy of chronic alcoholism. A histological and histochemical study. Recent reports have emphasized the occurrence of a myopathy in chronic alcoholism associated with hypokalemia. This report of hypokalemic myopathy in a chronic alcoholic, emphasizes the primary myopathic nature of the condition and attributes it to a possible non-specific effect of the hypokalemia on skeletal muscle. It is pointed out, that histological and histochemical changes of muscle in this type of myopathy are indistinguishable from other types of hypokalemic myopathies like periodic paralysis. It is conjectured that in alcoholic myopathy, the underlying disorder might be related to a primary disturbance of potassium metabolism, though in most cases, serum potassium is normal. It is likely that studies aimed at studying total body potassium content and turnover in alcoholic myopathy would help in understanding its pathogenesis and possible relationship to disturbed potassium metabolism.


Pure word deafness. (Auditory verbal agnosia). The selective inability to comprehend the spoken word, in the absence of aphasia or defective or defective hearing, is defined as pure word deafness (auditory verbal agnosia). Reported cases of this rare disorder have suggested the site of involvement to be strategically placed, interrupting fibers from left and right primary auditory receptive areas which project to Wernicke's are in the dominant hemisphere. Our patient is a 44-year-old male who suffered from an uncertain illness complicated by fever, jaundice and generalized seizures seven years previously. Following an apparent convulsion, the patient was noted to be unable to understand spoken language without loss of ability to recognize and respond to sounds or marked impairment of speech or reading. The evidence suggested bilateral cerebral hemisphere disease more marked on the right. The abrupt onset without progression is consistent with a vascular or ischemic etiology. Conclusions about the nature of the lesion and areas involved must await further studies and ultimately tissue examination.


[Sodium nitroprusside in the treatment of left-sided heart failure in acute myocardial infarction (author's transl)]. 27 patients (8 women, 19 men) aged 39-79 (mean 61) years with acute transmural mycoardial infarction and limitation of left ventricular function were treated in the acute stage for 24-72 (mean 55) hours with intravenous infusions of sodium nitroprusside in concentrations of 10-200 microng/min. Haemodynamic measurements before and 12 hours after onset of treatment showed a significant reduction in mean arterial pressure by 19%, in end-diastolic pressure in the pulmonary artery by 33% and in the total peripheral resistance by 32%, whereas stroke volume and cardiac index rose by 12% and 17%, respectively. The percentage improvement was most marked in those patients most severely affected. The mortality rate of cardiogenic shock was reduced to 25%. In a control group with haemodynamically similar left ventricular failure the mortality rate was 55%. However, the total mortality was nearly unchanged as the number of sudden unexpected deaths after the fourth day rose from 23 to 50%. Further investigations will show how these sudden deaths, mainly due to arrhythmias, can be prevented.


[Functional assessment of coronary-artery stenosis (author's transl)]. Left-ventricular angiography was performed in 28 patients after measuring ascending aortic and left ventricular pressures and during isometric exercise (hand grip, 0.3-0.4 kg/cm2 for 3 min). In 13 patients coronary blood flow was measured at rest and during hand-grip exercise by means of the argon method. Eight patients without heart disease served as controls. In 14 patients with coronary heart disease abnormal left-ventricular kinetics, demonstrated already at rest, got worse during hand-grip exercise. In five patients with normal left-ventricular angiograms at rest hypokinesia and dyskinesia occurred during isometric exercise. The coronary artery supplying the abnormal ventricular wall had a 50-75% decrease in diameter. One patients with isolated 25% stenosis had normal left-ventricular kinetics both at rest and on hand-grip exercise. In all patients coronary blood flow rose by 60-90% during isometric exercise. It iducing a significant rise in myocardial oxygen demand and increased coronary blood flow.


[Pericarditis after acute myocardial infarction (author's transl)]. 909 patients were treated between 1970 and 1975 in an intensive-care unit for acute myocardial infarction. 91 (10%) had associated pericarditis. In these patients the clinical course was characterised by a significantly high incidence of haemodynamically severe complications such as left and right heart failure and cardiogenic shock, as well as rhythm and conduction disturbances. High grade atrioventricular block, intraventricular conduction disturbances, ectopic and tachycardic supraventricular arrhythmias and ventricular ectopic rhythms occurred much more frequently in patients with infarct-pericarditis than in those without it. The occurrence of pericarditis indicates an extensive infarction and thus a worse prognosis. The hospital mortality of pericarditis was significantly higher (61%) than in the remaining 818 patients without it (24.4%). Anticoagulation did not increase the risk of haemopericardium.


[Treatment of arterial hypertension with sotalol, a beta-blocker (author's transl)]. Plasma concentrations and the effect of sotalol, a beta blocker, on arterial blood pressure and other haemodynamic variables (determined by echocardiography) were measured in 15 patients with arterial hypertension of different severity, after acute administration and during long-term treatment for 3 to 16 months. Sotalol absorption was relatively constant, the correlation coefficient between plasma concentrations and administered dose being r=0.67. The biological half-life was about eight hours, The effects of the drug on blood pressure, heart rate and other haemodynamic variables were small after acute administration. But in ten patients blood pressure returned to normal during chronic treatment with sotalol alone, while in five others it was necessary to combine sotalol with a diuretic and dihydralazine. These results show that sotalol is suitable for long-term treatment of arterial hypertension.


A comparative study of antiestrogen action: temporal patterns of antagonism of estrogen stimulated uterine growth and effects on estrogen receptor levels. Studies were undertaken to ascertain the effects of structural modification of two well-known antiestrogens (CI-628 and U-11,100A) on their estrogenic and antiestrogenic potencies and temporal patterns of effectiveness in the immature rat uterus. Changes in the chemical structures of these anti-estrogens produce compounds with markedly different affinities for the uterine estrogen receptor as measured in an in vitro cell-free cytosol system; binding affinities relative to estradiol (100%) are: CI-628, 4%; CI-680, 34%; 94X1127 (94X),222%; U-11,100A (UA), 6%; and U-23,469 (U-23), 0.1%. Although all five antiestrogens (daily injections of 50 microng over three days) appear equally effective in stimulating 72 h uterine weight when given alone, or in blocking the estradiol-stimulated weight increase when given with estradiol, marked differences in their potencies are noted when the effects of the compounds are monitored beyond 24 h following a single injection. The compounds CI-628, CI-680 and UA (50 microng sc in saline), which have a methylated hydroxyl group (at the site analogous to the steroid position 3), show a prolonged maintenance of elevated levels of nuclear receptor (beyond 48 h) and elevated uterine weight (until 72 h); this correlates with a prolonged period of depressed cytoplasmic receptor levels (beyond 48 h) and prolonged uterine insensitivity to estrogen (beyond 36 h as monitored by 3 h wet weight response). In contrast, a single injection of 50 microng of 94X (having a free hydroxyl group) or U-23 (with a side chain and central ring different from UA) maintained nuclear receptor levels elevated for only 12 h (94X) or 36 h (U-23) and uterine weights declined after 36-48 h; cytoplasmic receptor levels remained depressed for only 12 h (94X) or 24 h (U-23) and then returned to control levels or above by 36 h. These latter compounds likewise evoked the shortest period of uterine insensitivity to estrogen (ineffective as antagonists by 36 h). Comparative studies with these five compounds indicate that they are effective as estrogen antagonists only so long as they maintain cytoplasmic receptor levels low, and that the magnitude of the responsiveness to estradiol after antiestrogen correlates with the extent of reappearance of cytoplasmic receptor. Thus, chemical modifications of antiestrogen structure have significant effects on their temporal patterns of effectiveness as estrogens and as estrogen antagonists.


Fundamental differences in the action of estrogens and antiestrogens on the uterus: comparison between compounds with similar duration of action. In order to understand differences in the mechanism of action of estrogens and antiestrogens, it is essential to make comparisons between compounds with similar duration of action. Hence, in these studies, we compare the action of a long-acting estrogen (17alpha-ethinyl estriol-3-cyclopentyl ether, EE3CPE) and a long-acting antiestrogen (U-11,100AUA) on the immature rat uterus and analyze different dosage regimens (single and multiple injections) in studying the effects of these compounds on the uterine estrogen receptor and on uterine growth and sensitivity to estradiol. During the first 24 h, UA (50 microng) and EE3CPE (5 microng) evoke remarkably similar receptor distribution patterns and uterine wet weight increase; however, pronounced differences are seen with long-term, multiple injection regimens (every 12 or 24 h for 72 h). Such treatment with UA results in maintenance of high nuclear receptor levels and very low cytoplasmic receptor levels (ca. 10% of total), but no further increase in uterine weight, DNA or protein content, or total receptor content beyond 24-48 h. In contrast, multiple injections of EE3CPE produce not only a prolonged nuclear retention of receptor, but a progressive increase in total receptor content in the tissue and 35-50% of total receptor is cytoplasmic; uterine weight and DNA and protein content also continue to increase markedly above the 24 h level, and responsiveness to estradiol is maintained. However, regardless of whether the uterus continues to grow (as the EE3CPE) or stops growing after 24-48 h (as with UA), the receptor content on a cell basis is similar. Hence, uterine responsiveness to estradiol and continued uterine growth appear not to be related to the total content of receptor per cell, but rather are correlated with the cytoplasmic receptor level within the cell. As there is a continuous translocation of cytoplasmic receptor to the necleus in the growing uterus, the antagonistic action of antiestrogens appears to derive from their ability to effect a marked perturbation in the subcellular distribution of receptor, whereby very little of receptor (ca. 10%) is cytoplasmic, and further estrogen receptor accumulation (most likely synthesis) is blocked.


Metabolism of radioiodinated salmon calcitonin in rats. Synthetic salmon calcitonin (CT) was iodinated by an electrolytic method. The iodinated hormone retained full biological activity as determined in both an in vivo and in vitro bioassay. The metabolism of this hormone was studied in rats of two different ages, 24 days and 8 months old. Two types of uptake were observed: Rapid accumulation followed by rapid loss or degradation, as represented by the liver, and sustained accumulation with slow degradation, as represented by the kidney and bone. The liver accumulated a large fraction of the dose in 1 minute. Most of this was degraded or gone by 10 min and nearly all by 30 min. The kidney was a primary target organ in terms of concentrating the hormone. Nearly 50% of the initially accumulated CT, however, remained undegraded 60 min post-injection. The bone, to a lesser extent, concentrated the hormone where 70% remained undegraded 60 min post-injection. The bone accumulated significantly less CT while the kidney and liver accumulated more in 8-month-old rats compared to 24-day-old rats. This suggests that the relative ineffectiveness of CT in older animals as a hypocalcemic agent may be due in part to the inability of the bone to accumulate available hormone.


Effect of somatostatin on neurotensin-induced glucagon release and hyperglycemia. Administration of neurotensin to dogs resulted in rises in circulating blood glucose, glucagon and insulin levels, the rise in glucagon being more pronounced than that in insulin. Infusion of somatostatin along with neurotensin suppressed glucagon and insulin responses to neurotensin and prevented the rise in blood glucose levels. These results suggest that the hyperglycemia seen after neurotensin is due to neurotensin stimulation of glucagon release over insulin release.


Isoproterenol stimulation of heme synthesis in cultures of human fetal liver from early gestation. The role of isoproterenol in the synthesis of heme associated with hemoglobin has been studied in primary cultures of human fetal liver. This drug (10-10M) stimulated the incorporation of 59Fe into heme associated with hemoglobin in cell cultures of livers obtained from human fetuses 8 to 10 weeks gestation but was inactive in cell cultures prepared from livers of older fetuses. Isoproterenol has its optimal activity at a much earlier time in gestation than that previously reported for testosterone or erythropoietin. The interpretation of these results is that there is present a cell population in human fetal liver early in gestation with the appropriate isoproterenol-receptors and capable of erythroid differentiation after exposure to the drug.