Pneumococcal pneumonia: capsular polysaccharide antigenemia and antibody responses. Capsular polysaccharide was detected in the serum in 19 of 46 patients with pneumococcal pneumonia. Antigenemia was strongly associated with bacteremia and with infection by low-numbered serotypes. During antibiotic therapy, the concentration of polysaccharide in the circulation declined progressively, but circulating antigen remained detectable in two thirds of cases for 2 weeks or longer. The development of measurable type-specific antibody was delayed in patients with antigenemia. It is not known whether this delay was due to diminished antibody production or to neutralization of antibody by circulating antigen. Despite effective antibiotic therapy many patients with antigenemia had a severe and protracted illness; this may have been related to diminished availability of antibody early in the infection.


The prevalence of tuberculosis and positive tuberculin skin tests in a steroid-treated asthmatic population. The prevalence of active tuberculosis and positive tuberculin skin tests was assessed in 132 corticosteroid-treated asthmatics for an evaluation period that represented 620 corticosteroid-years of therapy. There was no evidence of active tuberculosis in any of these patients. Positive intermediate-strength tuberculin tests were present in 28% of patients and correlated with increased age. In patients treated with daily corticosteroids, tuberculin negativity was associated with a higher dose of corticosteroids. Positive second-strength tuberculin tests were found in 42.3% of the patients with negative intermediate-strength tests and also correlated with increased age. Based on these data as well as the prevalence of significant liver disease in older patients receiving isoniazid (INH), routine INH chemoprophylaxis for corticosteroid-treated asthmatic patients, regardless of their tuberculin cutaneous reactivity, is not indicated.


Polyneuropathy and anasarca: evidence for a new connective-tissue syndrome and vasculopathic contribution. A 41-year-old woman manifested a polyneuropathy, anasarca, pseudotumor cerebri, hyperhidrosis and hyperpigmentation of the skin, generalized lymphadenopathy, distal esophageal dysphagia, pleuritis, platelike pulmonary atelectasis, fluctuating renal insufficiency, hepatosplenomegaly, amenorrhea, and slight fever suggesting a connective-tissue disorder. Extensive clinical and laboratory evaluation did not support the initial impression of progressive systemic sclerosis or systemic lupus erythematosus but did show nonnecrotizing vascular changes, mild polyclonal gammopathy, and low thyroxin levels similar to the syndrome of polyneuropathy and endocrine disturbances recently reported from Japan. The impressive response to moderate-dose corticosteroids and exacerbation on withdrawal require diagnostic awareness of this insidiously progressive multisystem disorder. A bland vasculopathic process resulting from metabolic or immunologic disturbances appears to be the best explanation for this new syndrome, which has previously been recognized only in Japan.


Observations on decreased serum glutamic oxalacetic transaminase (SGOT) activity in azotemic patients. Serum glutamic oxalacetic transaminase (SGOT) activity may be decreased or even absent in patients with uremia. We correlated urea concentration with SGOT activity by the automated Rush (AutoAnalyzer, Techicon Instruments Corp., Tarrytown, New York) method (SGOT, SMA) and by the Henry-Karmen kinetic assay (SGOT, K). Extremely low SGOT (SMA) activity (less than 10 IU) was found in 6% of 5030 consecutive samples, and 71% of them occurred in patients with azotemia. SGOT activity was inversely proportional to urea concentration. A similar but less obvious pattern was observed with the SGOT (K) assay. SGOT activity increased significantly after hemodialysis in a group of 16 patients studied by both methods. It was not inhibited either by urea or uremic serum added in vitro. The explanation for this phenomenon is not known.


1-alphahydroxycholecalciferol in chronic renal failure. Studies of the effect or oral doses. Four patients with advanced chronic renal failure and osteodystrophy were treated with 1-alphahydroxycholecalciferol, a synthetic vitamin D analogue, in a daily oral dose of 1.5 to 2.0 mug, for periods up to 1 year. They showed increased calcium absorption, positive calcium and phosphorus balances, moderate increases in serum calcium levels, marked reductions in serum alkaline phosphatase levels, a decrease in serum immunoreactive parathyroid hormone levels, and radiologic and histologic improvement in bone disease. One patient with proximal myopathy showed improvement in muscular strength. 1-Alphahydroxycholecalciferol appears to be effective therapy for renal osteodystrophy.


Possible hepatotoxicity of Doxidan.

Possible hepatotoxicity of Doxidan. A patient with chronic constipation developed liver injury and leukopenia following the ingestion of Doxidan, a combination drug consisting of danthron and dioctyl calcium sulfosuccinate. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. The liver injury was associated with deposition of IgE in the Kupffer cells. The mechanism of toxicity remains unclear.


Bone scintiscanning updated.

Bone scintiscanning updated. Use of modern materials and methods has given bone scintiscanning a larger role in clinical medicine, The safety and ready availability of newer agents have led to its greater use in investigating both benign and malignant disease of bone and joint. Present evidence suggests that abnormal accumulation of 99mTc-polyphosphate and its analogues results from ionic deposition at crystal surfaces in immature bone, this process being facilitated by an increase in bone vascularity. There is, also, a component of matrix localization. These factors are in keeping with the concept that abnormal scintiscan sites represent areas of increased osteoblastic activity, although this may be an oversimplification. Increasing evidence shows that the bone scintiscan is more sensitive than conventional radiography in detecting focal disease of bone, and its ability to reflect the immediate status of bone further complements radiographic findings. The main limitation of this method relates to nonspecificity of the results obtained.


Ascorbic acid-induced uricosuria. A consequency of megavitamin therapy. The effect of ascorbic acid on the serum and urinary uric acid was studied in 14 subjects. Two to 6 h after the ingestion of 4.0 g of ascorbic acid, the fractional clearance of uric acid increased to 202% +/- 41% of the control value. This uricosuria was inhibited by pyrazinamide and by low-dose acetylsalicylic acid, but was not accompanied by an increase of the creatinine clearnace. Ascorbic acid did not diminish protein-bound uric acid. In 3 subjects who ingested 8.0 g of ascorbic acid for 3 to 7 days the serum uric acid decreased by 1.2 to 3.1 mg/dl as a result of a sustained uricosuria. These results suggest that ascorbic acid could invalidate studies involving the measurement of uric acid and obscure the diagnosis of gout in some cases. Theoretically it could precipitate attacks of gouty arthritis or renal calculi in predisposed persons. These observations show a pharmacologic effect of megadoses of a simple vitamin.


Combination chemotherapy for advanced breast cancer: response and effect on survival. Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF (P), which included methotrexate, 60 mg/m2, and 5-fluorouracil, 700 mg/m2 intravenously on the first and eighth days, in addition to cyclophosphamide, 100 mg/m2, and prednisone, 40 mg/m2, by mouth daily from the first to the fourteenth day of a 28-day cycle. Only 2 of 25 patients responded to hormonal therapy or endocrine ablation. Twenty-seven of the 40 patients (68%) had a complete response (8 patients) or partial response (19 patients). Lung, soft tissue, and nodal metastases were the most responsive sites. The median survival of 18 months for the responding group. The nonresponders had a median survival of 4 months. The toxicity was primarily hematologic and was especially severe in patients with functional liver impairment due to metastatic disease.


The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Sclerosteosis is a unique autosomal recessive condition in which skeletal overgrowth is associated with syndactyly and digital malformation. Analysis of the course and clinical features in 25 affected individuals showed that the condition is progressive and potentially lethal. Facial palsy and deafness are common complications and raised intracranial pressure may develop. The clinical and radiographic stigmata of sclerosteosis permit differentiation from the other disorders of the "osteopetrosis" or "Albers-Schönberg disease" group, in which bony thickening and cranial nerve palsy occur.


Chronic respiratory disease in hemp workers. A follow-up study, 1967-1974. Many soft-hemp workers with more than 20 years' exposure to dust have chronic respiratory symptoms and obstructive lung function loss. During 7 years of follow-up, these workers had significantly higher occurrences of chronic cough and phlegm and dyspnea than control subjects and a significantly larger annual decline of forced expiratory volume in 1 second (FEV1.0) than control subjects, with a particularly marked difference between 20- to 44-year-old nonsmoking controls and hemp workers. We believe that deterioration of lung function among hemp workers begins before the age of 45 and that it continues even if further exposure to dust ceases. Textile workers should be advised to avoid further exposure to dust at a time when their ventilatory lung function (in the absence of effects of acute exposure) is sufficient to prevent future development of disabling function loss.


Interstital lung disease due to contamination of forced air systems. Eight patients had hypersensitivity pneumonitis due to contaminated home or office forced-air heating or air-conditioning systems. We studied their clinical and laboratory features, and the results indicated that this disease may occur as an acute or insidious form differing in type and intensity of respiratory and systemic symptoms. Thermophilic actinomycetes contaminatinf the forced air systems were identified as the sensitizing agents in most cases. Precipitating antibodies to the organisms could be shown in the serums of the patients and the antigen identified by immunofluorescent studies in the three lung biopsies examined by this method. Inhalation challenge studies with the cultured organism or other materials obtained from the forced air systems reproduced the clinical syndrome in the four patients tested. Avoidance of the contaminated system, and the use of corticosteroids in more severe cases,seems to be appropriate therapy for patients with this disease.


Multiple myeloma in young persons.

Multiple myeloma in young persons. Three young men were found to have multiple myeloma. Because their ages ranged from 17 to 22 years, the diagnosis was not considered initially, and then it was doubted until electrophoretic studies were completed. In none was the disease far advanced. These patients are the first well-documented group of young persons with multiple myeloma.


Marital sexual dysfunction:introductory concepts. The concepts presented in this overview of marital sexual dysfunction are derived from increasing clinical experience with couples who seek help for their sexual problems. These couples, in marked contrast to couples with good sexual functioning, usually report a steady state of emotional dissatisfaction and minimal physical pleasure from sex. The affectual and behavioral consequences of persistent dysfunction are reviewed. Sexual therapy is discussed in terms of its two elements, sensate focus and psychotherapy. The various tastks which the sexual therapist may have to accomplish with individual couples are described. Consideration is given to the specific hypothese usually offered as explanation for sexual dysfunction-i.e., organic factors, varying degrees of relationship failure, poor communication, sexual ignorance, performance anxiety, and intrapsychic residua of past experience. A protocol for the screening physician to use in the formulation of a reasonable clinical plan for dysfunctional couples is included.


Immunotherapy and human tumor immunology. Present knowledge about the immune response to tumors in man is briefly reviewed, and the effects of cancer on immune-system functions are noted. The concepts that human tumors elicit cell-mediated immune responses to tumor antigens are re-examined and modified; for example, cell-mediated immunity may be detectable only at certain stages of tumor growth. Introduction of more sensitive methods for detecting antibodies is providing additional evidence for humoral immune responses to tumor-associated antigens. The present proliminary approaches to immunotherapy, particularly the use of adjuvants such as BCG and Corynebacterium parvum, are assessed, and initial pharmacoimmunologic findings with these agents are reported. The field of tumor immunology is in a dynamic state of development, with input from many areas of immunology and oncology. Carefully controlled clinical trials of these therapeutic regimens will be required to establish the value and indications for the use of such procedures.


Geriatric care in the United Kingdom: an American perspective. Geriatric care is a complex and challenging aspect of health care. The United Kingdom, with 13.6% of its population over 65 years of age, compared to 10.1% in the United States, has given special attention to this field. Characteristics of the British system include financing through the National Health Service, existence of a specialty of geriatrics, absence of "nursing homes," emphasis on home care, and avoidance of "heroics" for the terminally ill. While British life expectancy at birth is longer than that for  Americans, the opposite is now true for those over 65. The British have made efforts to maximize efficiency in a high-demand, comparatively low-resource context. But there are limits to which professional dedication and patient manipulation can be pushed. Some new policy directions-primarily aimed at prevention and other methods of reducing demand, other than reimposing financial barriers-may have to be explored.


An approach to teaching the introduction to clinical medicine. An approach to teaching the introduction of clinical medicine to medical students is described. It is based on (A) gradual exposure to patients and step-by-step introduction to the objectives and techniques of history taking, with emphasis on training for symptom identification; (B) early exposure to the problem-oriented approach; (C) early diagnostic hypothesis generation; and (D) self-directed learning. The objectives of the proposed approach are to teach students to communicate with patients, to teach the skills of history taking and physical examination, and to introduce the problem-solving strategies that characterize the diagnostic reasoning of experienced physicians.


Medical usage and abusage: "prevalence" and "incidence". In view of the frequent misuse of the term "incidence," the concepts of incidence, prevalence, and period prevalence are defined and illustrated. The importance of restricting "incidence" to the rate of development of new events in a population or a group of patients, per unit of time, is stressed. Clearly distinguishing incidence from prevalence or simple proportion can help both in the understanding and the communication of findings in patient groups.


Malignant degeneration of nonirradiated juvenile laryngeal papillomatosis. Malignant degeneration in nonirradiated juvenile laryngeal papillomatosis is exceedingly rare. Review of the world literature reveals one case in the English literature and two in the German literature. A 23-year-old patient, representing the youngest reported case in English literature, is presented.


Caloric and optokinetic nystagmus in cerebellar patients. In certain cerebellar lesions, optokinetic tracking is deficient, especially on tracking or following to the ipsilateral side. However, in many cases optokinetic nystagmus can occur, and apparently in better degree than would be expected from a study of pendulum tracking. This may be due to the patient leading into the stimulus and picking it up as soon as it is presented in far lateral gaze (in the direction of the fast component) and allowing the drift caused by the tone deficit to assist the tracking. An added vestibular tone can eliminate such a pseudo reflex. Induced vestibular nystagmus is enhanced and assumes a more dominant role so that optokinetic nystagmus is overcome, not only on gaze to the side of the tracking, but also on straight ahead gaze and even on some deviation of the eyes in the opposite direction.


Rupture of the round window membrane.

Rupture of the round window membrane. A case of sudden deafness due to rupture of the round window membrane is presented. Nineteen similar cases have previously been reported in the literature. In a review of these twenty patients, it is noted that a history of concurrent physical effort or barotrauma was present in eighteen. This supports the view that the injury is produced by pressure changes acting either along the cochlear aqueduct (the explosive route) or, directly on the middle ear structures (the implosive route). At operation, the rupture may be difficult to see, and a separate leak from the oval window may be present. The timing of any surgical intervention is important. The authors recommend that this should be deferred for one week after the onset of symptoms, as the fistula may heal spontaneously. If no definite improvement has occurred at the end of this time, then tympanotomy should be undertaken during the next week.


Technique for glottic reconstruction following vertical partial laryngectomy: a preliminary report. In order to obtain a good phonatory function after glottic reconstruction following vertical partial laryngectomy, the following basic conditions should be satisfied: (1) adequate glottic closure should occur during phonation; (2) the top of the bulge constructed on the affected side should be located at the level of the vocal cord in order to facilitate vocal cord vibration and to prevent false cord vibration; and (3) the surface of the bulge should be smooth. A technique for glottic reconstruction which appears to meet these conditions is described. The sternohyoid muscle is dissected at the level 5 cm below the vocal cord, and the upper portion is used as a single pedicled flap. The muscle flap is bent approximately 90 degrees at the level of the upper border of the cricoid cartilage and inserted into the intralaryngeal wound so as to make a large bulge. The muscle flap is covered by hypopharyngeal mucosa or a free graft of oral mucosa.


Brain stem and other responses in electric response audiometry. For electric response audiometry of young children who require sedation, an indicator is desired that is more reliable than the slow vertex potential. There are four leading candidates: 1) The electrocochleogram (ECochG) is very reliable with a transtympanic electrode on the promontory, but this is a surgical procedure and requires a general anesthetic. 2) The early midbrain responses give similar information with external electrodes, but they are complex and low in voltage. 3) The muscle reflexes (sonomotor responses) are a crude indicator with high and variable thresholds and are not suited to  precise audiometry. 4) The "middle" responses, perhaps cortical in origin, are good candidates, but they have not yet been adequately validated in the clinic. For the midbrain responses and particularly for the ECochG, close synchronization of nerve impulses is essential. This requires a compromise with selectivity of frequency. High-tone audiometry by electrocochleography and midbrain responses is satisfactory, but limitations are increasingly severe below 2 kHz, where each sound wave is a separate acoustic stimulus. Low-frequency tones stimulate the basal turn of the cochlea at relatively low sensation levels. This makes assessment of the apical portion of the cochlea very difficult, even with the midbrain "frequency-following response" (FFR).


Air humidity and mucociliary activity.

Air humidity and mucociliary activity. The relationship between varying humidity levels in the surrounding air and the mucociliary activity in rabbit trachea has been investigated. At a relative humidity (R.H.) above 70% the risk for ciliestasis is very small in the temperature range between 34 C and 40 C. At 37 C ciliestasis is not obtained until a relative humidity (R.H.)  of 50% has been reached. The critical border is reached already at 60% R.H. if the temperature is 40 C. At 37 C and a decrement from 90% to 60% R.H. the mucociliary wave frequency was reduced by 30%, but at 40 C the corresponding reduction was 60%.


The peripheral hearing mechanism: a biochemical and biological approach. A new approach is described to the problem or hearing at energy levels near threshold. Models depending on the macro-physics of levers are rejected. Instead, evidence is presented for frequency analysis, signal placement and energy transduction by the properties (known or experimentally determined) or the cochlea and of the structures within the scala media. The hypothesis developed rests on the established theorems of Gabor and Brillouin, and at the same time is based on the data of enzymology. Care is taken not only that the hypothesis does not conflict but that it is actually consonant with recent solid state physics. The cochlea by virtue of its internal geometry and contained column of fluid is considered to perform a Fourier analysis to a first approximation. This crude "placement" of the acoustic signal is refined by the semi-solid-state lattice of the tectorial membrane which far from permitting dissipation of the signal energy actually "concentrates" the energy at the membrane surface of the hair processes of a hair cell. Here biochemical transduction, akin to the processes known for other sensory cells, transforms acoustic energy through an ion-shuttling mechanism to the form of energy characteristic of living cells, viz. enzyme conformational changes.


Clinical manifestation of leprous rhinitis. Over 25 million people in the World have leprosy. In the lepromatous form of the illness the nose is involved at a very early stage and in this paper the clinical manifestations are described. The nasal discharge in early untreated lepromatous leprosy contains vast numbers of the causative bacillus (M. leprae) and the important implications of these observations are discussed.


Vidian nerve and the eustachian tube.

Vidian nerve and the eustachian tube. The vidian nerve was stimulated electrically in the dog and this resulted in a reduced patency of the Eustachian tube. The effect was atropine resistant. This physiological evidence in the dog corresponds to anatomical evidence in man of a parasympathetic, vasodilator nerve bundle passing through the vidian to the sphenopalatine ganglion and then via the pharyngeal nerve to the Eustachian tube mucosa. Additional parasympathetic routes to the tube may exist.


Slipping of the capital femoral epiphysis. Experimental and clinical studies have shown that the capital femoral epiphysis slips by rotating backwards and downwards around the curved surface of the metaphysis and remains in a plane that lies posteriorly at right angles to the anteversion plane of the neck of the femur. The relevance of these findings to the diagnosis and treatment of the condition is discussed. A geometric flexion osteotomy designed to correct the deformity is described.


Total knee replacement using the stabilized gliding prosthesis. The stabilized gliding knee prosthesis has been designed as a compromise between the restrained hinged joints and the unconnected surface prostheses. It is a two-piece implant, allowing normal gliding movements of flexion and extension, and is stabilized by a rod between the femoral and tibial components which allows some lateral mobility and rotation while acting in place of the cruciate ligaments and in place of or in addition to the collateral ligaments. The indications for and the techniwue of implantation are described and the results of the first 53 operations are reported. Follow-up time is between 1 year and 2 1/2 years. The results of these operations using the stabilized gliding prosthesis are at least equal to those using hinged or condylar prostheses. So far there has been no case of loosening of either component, and the implant can be used successfully in patients in whom condylar prostheses fail owing to their lac of inbuilt stability.


Parathyroid tumors as lateral pharyngeal masses: report of a case. This is the first reported case in the literature describing a patient free of the systemic biochemical effects of hyperparathyroidism who presented with a lateral pharyngeal mass. Diagnosis of parathyroid adenoma was made by means of a transoral biopsy prior to definitive surgical treatment. The role of parathyroid lesions in lateral cervical masses is discussed.


Neurology of the temporomandibular joints: an experimental study. Experiments on anaesthetized cats are described in which the reflex effects of stimulation of the mechanoreceptors in the temporomandibular joints on the ipsilateral and contralateral mandibular muscles were studied. The effects on this reflex activity and on dynamic manidublar muscle activity of the production of temporary and permanent dysfunction of the mechanoreceptors in different regions of the joint capsule were also studied. The significance of the findings in relation to the maintenance of normal jaw posture and the disturbance of mandibular muscular function by trauma, disease, and malocclusion is discussed.


Presentation and management of aneurysms. The aetiology and pathology of aneurysms, their sites of occurrence, and their general management are outlined. Since the abdominal aortic aneurysm is the type most commonly encountered by the surgeon its presentation, assessment, and operative and postoperative management are discussed in detail.


Sudden deafnfess of vascular origin: a human temporal bone study. Temporal bone changes are described in a 57-year-old man who had sudden onset of dizziness and unilateral deafness two months before death. The patient suffered from hypertension, and congestive and renal failure. At autopsy, subarachnoid hemorrhage with punctate cortical hemorrhages and arteriolar thickening involved the right superior cerebellar hemisphere. The pathological changes involved primarily the right cochlea, saccule and posterior ampulla, and were consistent with vascular embarrassment of the temporal bone of two months duration. The cochlea demonstrated total loss of the organ of Corti and severe degenerative changes of the stria vascularis, spiral ligament, outer sulcus cells and distal cochlear nerve fibers. The saccule demonstrated loss of its macula and nerve fibers. The posterior ampulla showed evidence of previous rupture of its membranous wall with fibrosis and beginning bone formation. Fresh hemorrhage, present in some areas of both temporal bones, was related to the patient's terminal subarachnoid hemorrhage.


Effect of temperature on the rate of the transparent to opaque colony type transition in Mycobacterium avium. The results of drug susceptibility tests were found to be affected by changes that occur spontaneously in populations of Mycobacterium avium maintained in the laboratory. Because the transparent colony type variant was resistant to antituberculosis chemotherapeutic agents and the opaque colony type variant was usually susceptible to these agents, the transition of transparent to opaque colony type was investigated. The rate of the transition was found to be temperature dependent and, in agreement with a previous report, was found to be about 10(-4) to 10(-5) per generation at 37 C. Reversion was found to occur at a rate of 10(-6) to 10(-7) at 37 C. The mutation rate from susceptibility to resistance to rifampin, kanamycin, and erythromycin was about 10(-8) to 10(-9) mutations per bacterium per generation. Judged from our data, the high rate of the transparent to opaque variation was not caused either by mutator effects or by the occurrence of extrachromosomal genes in these bacteria, but could have been due to selective mechanisms still incompletely understood.


Induction of erythromycin resistance in Staphyloccus aureus by erythromycin derivatives. The ability of 53 erythromycin analogues to induce resistance to erythromycin in Staphlococcus aureus was evaluated. Only derivatives with antibacterial activity induced resistance, although some antibacterial compounds did not induce resistance. No derivatives without antibacterial activity but with ability to induce resistance were found.


Pharmacological studies with cefamandole in human volunteers. Serum and urine concentrations were measured after administration of 0.5-and 1-g doses of cefamandole intramuscularly and intravenously to healthy volunteers. Intramuscular doses of 0.5 and 1 g yielded serum concentrations at 1 h of 14.7 and 35.6 mug/ml, respectively. Significant antibacterial concentrations persisted through h 8. Intravenous doses of 0.5 and 1 g resulted in respective peak serum levels of 21 mug/ml at 45 min and 103 mug/ml at 15 min; these serum levels rapidly declined. Very high urine concentrations were achieved during the first 8 h after injection.


Interspecies transformation of streptomycin resistance in oral streptococci. Donor deoxyribonucleic acid extracted from streptomycin-resistant (Str(R)) mutant derivatives of a variety of strains of Streptococcus mutans, S. salivarius, and S. sanguis was used to transform streptomycin resistance into competent S. sanguis strain Challis. Transfer of genetic markers for sorbitol and mannitol fermentation and for extracellular polysaccharide as demonstrated by colonial morphology was not detected in this study. Reciprocal transformation between strain Challis and other oral streptococci could not be demonstrated. Transformation frequencies for Str(R) were relatively efficient among S. sanguis strains, with lower but significant frequencies demonstrated with strain Challis and donor deoxyribonucleic acid derived from other oral streptococci.


Micromonospora-produced gentamicin components. After the chromatographic separation of [methyl-(14)C]gentamicin major (C) components from a large-scale radioactive fermentation (Lee et al., 1974), [methyl-(14)C]gentamicin minor (polar) components (A, B, B(1), X(2), and G-418) were isolated from subsequent chromatography of the remaining antibiotic mixture. When l-[methyl-(14)C]methionine was added at the onset of biosynthesis of the gentamicin components, incorporation of label into the minor components preceded incorporation into the major components. Degradation occurred when [methyl-(14)C]gentamicin major components (C(1), C(2) and C(1)a) were added respectively to the gentamicin-producing culture medium and shaken.


Bone concentrations of antimicrobial agents after parenteral administration. Bone concentrations of seven antimicrobial agents were determined after parenteral administration. Antibiotics were administered in large doses at customary intervals for 12 to 20 h before total hip or knee replacement; anticipated levels of each drug were achieved in the serum. Methicillin, carbenicillin, and clindamycin were detected in bone with greatest frequency. Cefazolin and gentamicin were each detected in bone specimens from only one of four patients. Neither penicillin G nor cephalothin was present in bone in sufficient quantity to be measurable. These data suggest that a number of factors, in addition to serum concentration, affect concentration of antimicrobial agents in bone. The clinical significance of the relationship between bone concentrations of antibiotics and therapeutic outcome is not certain.


Protective effect of cephalothin against gentamincin-induced nephrotoxicity in rats. The possibility that the nephrotoxicity of gentamicin may be potentiated by the concomitant administration of cephalothin was examined in a rat model. Cephalothin given once daily in dosages up to 800 mg/kg per day for 10 days produced no renal damage. Gentamicin, at 6 to 50 mg/kg per day, caused pathological changes which were dosage related and affected primarily the proximal tubular cells. Administration of the two drugs simultaneously resulted in a significant protective effect of cephalothin against gentamicin-related nephrotoxicity (P < 0.01). When the daily injections of the two agents were separated by an interval of 6 h, the protective effect was lost, and the resultant damage was the same as that due to gentamicin alone. The protective effect of cephalothin was reproduced by the administration of equiosmolar amounts of sulfate (sodium sulfate), suggesting that the phenomenon might be related to the presence of nonresorbable anion in the urine. These studies indicate that, in the rat, cephalothin does not potentiate, but, in fact, may prevent the nephrotoxic effects of gentamicin.


Drug resistance and distribution of R factors in Salmonella strains. Drug resistance and the distribution of R factors in Salmonella strains were surveyed using 1,980 strains isolated in Japan from 1955 to 1973. Resistances were mostly restricted to sulfanilamide (SA), tetracycline (TC), and streptomycin (SM), and combinations thereof. The demonstrated frequency of strains resistant to chloramphenicol (CM) was very low as compared with that in Escherichia coli and Shigella strains. In relation to resistance to TC, CM, SM and SA, the frequency of isolation of single resistance was the highest, followed by triple, double, and quadruple resistance in that order. Low frequency of isolation of quadruple resistance was due to the low frequency of CM resistance in Salmonella strains and differed from the E. coli or Shigella group. R factors with single TC resistance was most common, followed by those with TC,SM,SA; SM,SA; TC,CM,SM,SA; and single (SM and SA) resistance, in that order. Kanamycin and ampicillin resistance was unusual and mostly transmissible.


Clinical pharmacology of cefamandole as compared with cephalothin. We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 mug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 mug/ml for cefamandole and 18.2 mug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 mug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t((1/2)) as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m(2)), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m(2)). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m(2), respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.


Viridins, bacteriocins of alpha-hemolytic streptococci: isolation, characterization, and partial purification. Bacteriocin-like activities were detected in 78% of 120 alpha-hemolytic streptococcal isolates. Inhibitory substances from three such isolates (one Streptococcus sanguis strain and two S. mitis strains) were investigated further and termed viridins (A, B, and C). The viridins were unique among bacteriocins of gram-positive bacteria in that they inhibited many gram-negative bacteria in addition to inhibition of a variety of gram-positive organisms. Viridins were obtained in a cell-free state only after mechanical disruption of bacteriocinogenic cells but could not be isolated from supernatant fluids of cultures of such bacteria or from freeze-thaw liquor of agar on which the bacteria had been grown. Viridin B could be partially purified by ammonium sulfate precipitation and by gel filtration on a Sephadex G-100 column. This bacteriocin had some unusual properties including heat lability, a narrow pH range of activity, and lack of adsorptive capacity to susceptible bacteria. Although viridin B was bactericidal to a Neisseria sicca strain, it was only bacteriostatic against a coagulase-negative staphylococcus.


Influence of cephalosporin antibiotics on blood coagulation and platelet function. Administration of cephalothin to normal volunteers in maximal doses of 300 mg/kg per day resulted in a combined defect of platelet function and blood coagulation. No such abnormalities were evident after infusion of cefazolin or cephapirin at a maximal dosage of 200 mg/kg per day. The observed thrombocytopathy was similar to but less severe than that induced by carbenicillin or ticarcillin and was not reflected by a prolonged bleeding time test or impaired prothrombin consumption. Moreover, it was not a consistent finding in those persons receiving cephalothin. A separate defect involving blood coagulation appeared to result from delayed fibrinogen-fibrin polymerization and was evidenced by extended values of the activated partial thromboplastin and thrombin time tests. It remains uncertain whether the abnormalities described may constitute clinically important hemostatic disorders in patients with normal renal function receiving large doses of cephalosporin antibiotics.


Modification of bacterial respiration by a macromolecular polyanionic antibiotic produced by a marine Alteromonas. A macromolecular polyanionic antibiotic produced by a marine bacterium belonging to the genus Alteromonas causes a large modification in bacterial respiration when added to the culture of several bacterial species in their early stage of growth. This antibiotic induces an increase of oxygen uptake and the production of hydrogen peroxide. The latter fact explains the high sensitivity of bacteria with low catalase activity and the antagonistic effect of pure catalase on antibiosis. The antibiotic could act at the level of the respiratory chain by setting up a flavinic respiration.


Beta-indoleethanol and beta-indolelactic acid production by Candida species: their antibacterial and autoantibiotic action. Candida spp. grown in synthetic medium supplemented with l-tryptophan as sole nitrogen source produced beta-indoleethanol (beta-IEA) and beta-indolelactic acid (beta-ILA). These compounds isolated from the culture filtrates were characterized by ultraviolet, infrared, and nuclear magnetic resonance spectral studies. Using dl-[(3)H]trypotophan in the medium, labeled beta-IEA and beta-ILA were isolated. Further, beta-IEA was produced as a result incubating log-phase cells of C. albicans with beta-ILA. Both beta-IEA and beta-ILA inhibited the growth of gram-positive and -negative bacteria. Autoantibiotic action of these compounds on Candida spp. and the reversal of this inhibition were studied.


Oxolinic acid in the treatment of typhoid fever due to chloramphenicol-resistant strains of Salmonella typhi. Of 28 strains of Salmonella typhosa collected in late 1972 in Vietnam, 4 had minimum inhibitory concentrations to chloramphenicol of >100 mug/ml. Median minimum inhibitory concentrations of all strains to oxolinic acid were 0.39 mug/ml; ampicillin, 6.25 mug/ml; amoxicillin, 0.39 mug/ml. Widespread typhoid fever appeared in mid-1973 with more than three-fourths of strains found to be resistant to chloramphenicol. Peak serum concentrations of oxolinic acid average 3.0 mug/ml after the oral ingestion of 1.0 g. In July 1974, a pilot study was begun to evaluate the efficacy of oxolinic acid in vivo, recognizing the discrepancy between in vitro and in vivo results with many agents evaluated in the treatment of typhoid fever. Seven patients with typhoid fever, six with positive blood cultures, were treated with oxolinic acid (1.5 g twice daily by mouth, a daily dose that averaged 75 mg/kg per day) for 5 to 12 days. In four of six patients, blood cultures became negative at 2 to 3 days, with another being negative at 6 days. Despite negative blood cultures, all but one patient remained clinically ill with temperatures of >39.5 C at 4 to 9 days. All strains were susceptible to 0.19 mug of oxolinic acid per ml, and resistant strains did not occur. One patient died after being changed to ampicillin, one left against advice, three responded to amoxicillin, and one died with pseudomonas bacteremia. Toxicity to oxolinic acid did not occur.


In vitro and clinical studies of cefatrizine, a new semisynthetic cephalosporin. Cefatrizine, a new oral semisynthetic cephalosporin, was evaluated in vitro and in the treatment of 18 patients with acute urinary tract infection, pneumonia, and soft tissue infection. In vitro, it was more active than cephalexin for gram-positive and gram-negative bacteria. It was also more active than cephalothin, cefazolin, and cephapirin against most of the gram-negative bacteria but less active against the gram-positive bacteria. Of the patients treated with cefatrizine, only one failed to respond. This patient had pneumococcal conjunctivitis and hypogammaglobulinemia and neutropenia. The mean peak serum level after multiple 6-hourly doses of 500 mg was 6.2 mug/ml. The serum levels of cefatrizine necessary for inhibition of most susceptible organisms were well within the achievable range. The drug was well tolerated, and no renal, hepatic, or hematological toxicity was detected.


Effect of amphotericin B and rifampin against Coccidioides immitis in vitro and in vivo. Amphotericin B, the principal drug used for treating systemic mycoses, possesses undesirable toxic properties. The ability of this antibiotic to potentiate antifungal activity of other compounds suggests that lower doses of amphotericin B could be used in combination with a second drug without loss of therapeutic efficacy. In vitro tests demonstrated that amphotericin B potentiated rifampin against the mycelial growth phase of Coccidioides immitis but not against the spherule-endospore phase. Therapy for murine coccidioidomycosis with a combined amphotericin B-rifampin regimen was not better than treatment with amphotericin B alone; in fact, combined drugs may have been even less effective. This would have clinical significance for therapy of concurrent infections.


In vitro activity of BL-s640 against gram-negative bacilli and Staphylococcus aureus compared with activity of four other semisynthetic cephalosporins. The in vitro activity of BL-S640 (cefatrizine) was determined against 674 recent clinical isolates of Staphylococcus aureus and Enterobacteriaceae. Activity against S. aureus was less than that of cephapirin, cephalothin, and cefazolin, but greater than that of cephalexin. Activity against gram-negative isolates was variable: BL-S640 was slightly less potent than cefazolin against Escherichia coli and Klebsiella, but more active than the other compounds. As for the more resistant gram-negative genera, BL-S640 was significantly superior to the control cephalosporins. The effect of inoculum size on the antibacterial activity was moderate for most organisms except Enterobacter, Providencia stuartii, and indole-positive Proteus, the median minimal inhibitory concentrations of which were 6 to 27 times lower when determined with a 10(-4)-diluted culture compared with the undiluted one. The stability in aqueous solution at 37 C was remarkably high at the lower pH values, but low at the neutral point.


In vitro activity, synergism, and testing parameters of amikacin, with comparisons to other aminoglycoside antibiotics. The activity of the new aminoglycoside antibiotic, amikacin, was evaluated in vitro against 219 clinical bacterial isolates. One hundred eighty-nine of the 219 strains had agar dilution minimal inhibitory concentration values of 8.0 mug/ml or less for amikacin. Comparative agar dilution studies were performed for gentamicin, kanamycin, and tobramycin. Gentamicin was the most active overall, but tobramycin and amikacin also had significant activity against most bacterial groups. The effects of divalent cations on the susceptibility of Pseudomonas aeruginosa to amikacin were evaluated, and the minimal inhibitory concentration values varied sixfold over a range of divalent cation concentrations from 0.2 to 8.75 mg%. The effects of media and inoculum size on disk susceptibility testing with amikacin were also evaluated. In addition, a synergistic interaction between carbenicillin and amikacin against P. aeruginosa was demonstrated. Amikacin appears to be a promising new broad spectrum antimicrobial agent.


Antibiotic susceptibility of the subspecies of Bacteroides fragilis. Strains (115) of Bacteroides fragilis were identified at the subspecific level and were tested for susceptibility to ampicillin, cephalothin, chloramphenicol, clindamycin, penicillin, and tetracycline using an agar dilution technique. We tested the following strains: B. fragilis subsp. distasonis, 12; B. fragilis subsp. fragilis, 39; B. fragilis subsp. ovatus, 10; B. fragilis subsp. thetaiotaomicron, 32; B. fragilis subsp. vulgatus, 10; and B. fragilis subsp. "other," 12. There were no marked differences in susceptibility between the subspecies. One strain of B. fragilis subsp. thetaiotaomicron had a minimal inhibitory concentration of 12.5 mug/ml for clindamycin, but all other strains were susceptible. All the strains were susceptible to chloramphenicol. Susceptibility to tetracycline was variable. Only a few strains were susceptible to the penicillins and cephalothin.


Use of clindamycin in patients with liver disease. Hepatotoxicity has been noted by several investigators during parenteral use of clindamycin, and some have reported that drug half-life is prolonged in the presence of liver disease. We administered 300 mg of clindamycin intravenously at 12-h intervals for 2 days to patients with acute and chronic hepatitis, cirrhosis, and controls to determine whether clindamycin will exacerbate preexisting hepatic dysfunction or whether drug excretion will be delayed in patients with liver disease as compared with controls. Exacerbation of hepatotoxicity was not found in this study. There was a small, but significant, delay in drug elimination between cirrhotics and controls, even after the first dose of clindamycin (P < 0.05); however, half-lives in all categories were in the range usually considered normal. We conclude that clindamycin can be used in liver disease in some circumstances, if proper precautions are exercised.


Efficacy of cinoxacin in urinary tract infections. Cinoxacin, a new synthetic antibacterial agent with in vitro activity against all species of Enterobacteriaceae, was used in the treatment of urinary tract infections in 20 patients. The dose of cinoxacin was 250 mg orally every 6 h for 10 days. The etiological agents were Escherichia coli in fifteen, Klebsiella-Enterobacter in five, Proteus mirabilis in two, and Providencia in one. The minimal inhibitory concentration for these organisms ranged from 2 to 64 mug/ml. Eleven of the 20 patients had renal involvement by defined criteria, whereas the remaining nine were considered to have bladder bacilluria. The initial strain was eradicated during and immediately after treatment in 19 of 20 cases. At 6 weeks, 65% had sterile urine. Bactericidal urine levels of cinoxacin were obtained in all patients. No significant hematological, renal, hepatic, or gastroenterologic toxicity was noted. Cinoxacin appears to be a safe and useful drug in the treatment of urinary tract infections caused by Enterobacteriaceae.


Comparative study of the in vitro antibacterial activity of cefoxitin, cefuroxine, and cephaloridine. The in vitro antibacterial effects of cefoxitin, a semisynthetic cephamycin, cefuroxime, a new cephalosporin antibiotic, and cephaloridine were compared. With gram-positive bacteria, marked differences were found only in the effects against Streptococcus faecalis, where cephaloridine and cefuroxime were superior to cefoxitin. With gram-negative aerobic bacteria, cefoxitin, which is known to be more resistant to beta-lactamases from gram-negative bacteria than any cephalosporin, was found to be more effective than cefuroxime and cephaloridine against ampicillin-resistant strains of Escherichia coli and indole-positive strains of Proteus. Haemophilus influenzae was found to be more susceptible to cefuroxime than to cefoxitin and cephaloridine. When ampicillin-resistant strains of H. influenzae were tested, markedly higher minimal inhibitory concentration values were obtained with cephaloridine in comparison to those obtained with ampicillin-susceptible strains. These increases in the minimal inhibitory concentration values were not observed with cefoxitin and cefuroxime, probably due to the resistance of these two compounds to beta-lactamases. Strains of Bacteroides fragilis were found to be much more susceptible to cefoxitin than to cefuroxime, which in turn was superior to cephaloridine. The results obtained indicate that cefoxitin and cefuroxime both are superior in their antibacterial spectra to the cephalosporins that are now in clinical use.


Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Cefuroxime is a new broad-spectrum cephalosporin antibiotic with increased stability to beta-lactamases. This stability, although no absolute in all cases, has the effect of widening the antibacterial spectrum of the compound so that many organisms resistant to the established cephalosporins are susceptible to cefuroxime. It is active against gram-positive organisms, including penicillinase-producing staphylococci, but it is less active against methicillin-resistant strains. In addition to its high activity against non-beta-lactamase-producing gram-negative bacteria, cefuroxime effectively inhibits the growth of many beta-lactamase-producing strains, including Enterobacter, Klebsiella, and indole-positive Proteus spp. It is highly active against Neisseria gonorrhoeae, Neisseria meningitidis, and also Haemophilus influenzae, including ampicillin-resistant strains. Cefuroxime is rapidly bactericidal and induces the formation and subsequent lysis of filamentous forms over a small concentration range.


Cefuroxime, a new cephalosporin antibiotic: activity in vivo. The pharmacokinetic properties of cefuroxime have been evaluated in laboratory animals. On injection into mice, rats, and rabbits by the subcutaneous or intramuscular routes, high serum level peaks were recorded. There was no significant absorption after oral administration. After injection, the antibiotic was excreted in large amounts in the urine. It was well distributed in the body and penetrated into the tissues at a satisfactory rate. This, coupled with a low degree of serum protein binding, was correlated with a very good protective effect in animals (mice, rats, and rabbits) experimentally infected with a wide range of bacteria, including beta-lactamase-producing strains. It is concluded that cefuroxime should have a good potential for treating a wide range of bacterial infections in humans.


Effects of sesquiterpene lactones on the growth of Bacillus thuringiensis. Two sesquiterpene lactones, hymenovin and tenulin, were tested for their effect on growth of two strains of Bacillus thuringiensis. Growth of both strains was 98% inhibited by 0.6 mg of tenulin per ml, but only 15 to 20% was inhibited by the same level of hymenovin. Hymenovin appeared to have a mutagenic effect on B. thuringiensis cultures resulting in production of several variant strains. Some of the variant strains had lost their ability to form spores and crystals. Hymenovin also induced B. thuringiensis to produce significant levels of bacteriophage. All variant strains were as susceptible to phage as the parent strain. Although the bactericidal activity of tenulin was two times as great as of hymenovin, tenulin did not appear to have a mutagenic effect on the bacteria.


Comparison of the binding of penicillin G to staphylococcal L-form and its parent strain membranes. The binding of penicillin G to a stable L-form from Staphylococcus aureus followed saturation-type kinetics with saturation achieved at 0.75 nmol/ml, the same as with its parent strain.


Inhibition of bacterial growth by the nitrofurantoin solvent dimethylformamide. For quantitative susceptibility tests, stock solutions of nitrofurantoin are often prepared in dimethylformamide. Since 1.0 or 2.0 ml of the solvent will inhibit microbial growth, currently recommended procedures for antimicrobic dilution tests should be modified by adding only 0.1 or 0.2 ml of stock drug solutions to the agar or broth medium.


Enhancement of rIn:rCn-induced interferon production by amphotericin B. When mouse L929 cells are treated with amphotericin B before exposure to polyriboinosinic-polyribocytidylic acid or polyriboinosinic-polyribocytidylic acid-dextran, they make significantly more interferon than do cells not receiving amphotericin. This effect may be due to enhanced cell membrane penetration by the polynucleotide.


Nafcillin treatment of Staphylococcus aureus meningitis. Serial serum and cerebrospinal fluid nafcillin concentrations were determined in a patient successfully treated with nafcillin (200 mg/kg per day) for Staphylococcus aureus bacteremia and meningitis. Nafcillin and methicillin cerebrospinal fluid concentrations were compared.


Factors influencing methoxsalen phototoxicity in vitiliginous skin. A series of experiments were conducted to determine the optimum conditions required to induce methoxsalen phototoxicity in vitiliginous skin. The results revealed that optimum phototoxicity could be obtained only when a lapse of at least 15 minutes was allowed between the application of the drug and exposure to long-wave ultraviolet light (UVA). The duration of methoxsalen's phototoxic potentially, after its application to skin, varied in direct proportion to chemical concentration. Although a high chemical concentration and low dosage of UVA was a less time-consuming method of inducing phototoxicity, our results indicate that lower concentration and longer UVA exposure were less likely to induce undersirable blistering reactions.


Pruritic skin diseases, psychological stress, and the itch sensation. A reliable method for the induction of experimental pruritus. A method of inducing controlled levels of terminable itching was developed. This method consists of administering constant monophasic pulsations of electric current by means of noninvasive electrodes. Once experimental pruritus had been reliably reproduced, two variables, hypothesized to be relevant to the perception of itching, were investigated, viz, the presence of a positive or a negative history of a pruritic dermatosis, and the presence of a high or low level of psychological stress. Both variables were found to be related to the perception of itching, but in different manners. A positive history of a pruritic dermatosis lowered the threshold for the perception of itch stimuli, while a high level of psychological stress enhanced the ability to discriminate among the more intense itch stimuli, with no effect on the itch threshold.


Clofazimine. A new agent for the treatment of pyoderma gangrenosum. Eight patients had pyoderma gangrenosum. They were given a phendimetrazine tartrate derivative, clofazimine (Lamprene [Britain]), which is a chemotherapeutic agent used mainly in certain mycobacterial infections and which also has phagocytosis-enhancing properties. The effect of this drug was remarkably good, with rapid healing of the lesions commencing 3 to 14 days after treatment was started. The mechanism for the effect of clofazimine in pyoderma gangrenosum is not known.


Malignant atrophic papulosis (Degros disease). A report of two cases with clinical and histological studies. Two women had malignant atrophic papulosis that affected the skin only. Immunologic studies showed normal amounts of serum immunoglobulins and complement and normal delayed hypersensitivity skin test results. Fibrinolysis autografts showed complete loss of fibrinolysis within the lesions but normal fibrinolysis in uninvolved skin. Histopathologic studies showed moderate inflammatory infiltration consisting of lymphocytes in addition to the typical cone-shaped regions of necrobiosis. Large amounts of mucin also were seen. Endovasculitis, thrombosis, and perivascular lymphocytic inflammation were noted in the subcutaneous arterioles of the lesions in only one of the patients. Enzyme histochemical studies showed oxidative enzymes, although in reduced amounts, in the epidermal and dermal cells of the affected skin. Electron microscopic studies of lesions showed paromyxovirus-like inclusions in endothelial cells and fibroblasts. The possibility of an unusual viral causation should be examined further.


Cutaneous manifestations of familial Mediterranean fever. Familial Mediterranean fever (FMF) is frequently accompanied by erysipelas-like attacks. These should alert the physician to the correct diagnosis of this systemic disease. Several other nonspecific skin lesions may be seen in FMF. To our knowledge, histologic findings in erysipelas-like skin rashes seen in FMF are not reported elsewhere in the literature.


Disseminated Nocardia brasiliensis infection. We report a 40-year-old man with advanced Hodgkin disease who received combination chemotherapy and developed disseminated Nocardia brasiliensis infection. We discuss opportunistic infections in the compromised host, with particular reference to nocardial disease and certain biologic characteristics of that organism.


Molecular mechanisms of genetic disorders of keratinization. An attempt is made to organize our current knowledge about genetically determined disorders of keratinized tissue, which primarily affect the epidermal structural proteins. Type I defects are those involving a change in a single amino acid and are analogous to sickle cell anemia. Type II defects are associated with abnormal retention of a normal structural protein intermediate. Type III defects are related to alterations in the normal post-translational cross-linking seen in keratinized tissues. Type IV defects are associated with altered proportions of fibrous proteins and are analogous to thalassemia. In type V defects, primary genetic disorders of other tissues profoundly affect keratinization in a secondary fashion. Examples from genetic disorders of the hair and epidermis are used to build this conceptual scheme.


Sick sinus syndrome in children.

Sick sinus syndrome in children. The ages of 6 male patients with the sick sinus syndrome ranged from 10-15 years when their symptoms began. At rest all had a heart rate of 60/min or less. Two had syncopal attacks which threatened life; 1 had only attacks of dizziness; the other 3 had no syncopal attacks but had recurrent attacks of supraventricular tachycardia ('brady-tachycardia syndrome') which were more resistant to drug therapy than is usual in childhood. They were not controlled or suppressed by digoxin when it was given. Substernal pain occurred in 2 patients who had syncope. In all patients the heart rate remained inappropriately slow after exercise and atropine. Cardiac pacemakers were used in the 2 patients with life-threatening syncope. Any patient who has dizziness or syncopal attacks and an inappropriately slow heart rate should have electrocardiograms recorded at rest and after exercise to record the heart rate and to look for abnormal P-waves.


Hereditary tyrosinaemia. Clinical, enzymatic, and pathological study of an infant with the acute form of the disease. A clinical, enzymatic, and pathological study of an infant with the acute form of hereditary tyrosinaemia is presented. Treatment with a diet low in methionine, tyrosine, and phenylalanine was unsuccessful. A selection of specific and nonspecific hepatic enzymes, obtained at necropsy within one hour of the infant's death at 9 1/2 weeks, were studied to try to throw light on the basic defect. The major pathological findings were those of a peculiar hepatic fibrosis associated with bile retention and an abnormal grouping of hepatocytes, islet-cell hyperplasia of the pancreas, and dilatation of the proximal renal tubules. Death was precipitated by bronchopneumonia and liver failure. The difficulty in diagnosing the acute form of tyrosinaemia is pointed out, especially in differentiating it from hereditary galactosaemia (transferase deficiency) and hereditary fructosaemia. All three may present with the same clinical symptoms and liver lesions, and the distinction must be made by enzyme studies and by therapeutic trial.


Neonatal screening for haemoglobinopathy. Results in 7691 Manchester newborns. Over a period of one year the blood samples collected for phenylketonuria testing from 7691 Manchester newborns were screened by haemoglobin electrophoresis. An abnormality was detected in 47 (0-61%) of the babies. No cases of homozygous haemoglobinopathy were found. The overall incidence of sickle-cell trait was 0-38%, but for the Black population it was 10%. Four Black babies and one White baby had alpha-thalassaemia. No other haemoglobinopathies were found in the White babies and no Asian baby had alpha-thalassaemia. Haemoglobin A2 was precociously developed in three babies, two of whom were coloured--probably a further example of the earlier maturity of coloured babies. The screening programme was stopped when it became cleaasily be combined with screening for metabolic disease in places where the incidence of haemoglobinopathies is higher.


Follow-up of children of drug-addicted mothers. During a period of 2 years (1971-72) 19 newborn infants were admitted to hospital because their mothers were drug addicts. To evaluate the prognosis in these children, 17 were followed up by a social adviser, a psychologist, and a paediatrician. During the neonatal period 16 of the infants had withdrawal symptoms, for which 11 required medical treatment. One infant died of congenital malformations. Of the surviving 18 infants 14 were discharged to their mothers and 4 went to a children's home. During follow-up, which varied from up to 2 months to up to 2 years 8 months of age, 10 of the children had to be placed in a children's home for a period. No physical abnormalities were found in the children. Motor and perceptual development were normal in 12 but in 3 speech development was delayed. Five mothers ceased to take drugs after delivery and 2 had done so during early pregnancy. The pre- and perinatal complications and the undesirable environment in which the children grow up show the need for a comprehensive treatment programme.


Transient acute myositis in childhood.

Transient acute myositis in childhood. Eight cases of transient acute polymyalgia with weakness are described. All had abnormal serum creatine phosphokinase levels and most had minor haematological abnormalities at the time of diagnosis. Virological studies were performed with negative findings.


Calcium, magnesium, and glucose levels in blood and CSF of children with febrile convulsions. Levels of calcium, magnesium, and glucose were measured in the blood and cerebrospinal fluid (CSF) of children with febrile convulsions. Calcium and magnesium levels were within the normal range and the blood: CSF ratios were similar to those of normal subjects. Hyperglycaemia was a frequent finding and was reflected in raised CSF glucose levels. Blood glucose levels were only transiently raised and none of the children had diabetes mellitus.


Relation of urinary total hydroxyproline: Creatinine ratio to height velocity in children with retarded growth. The urinary total hydroxyproline:creatinine ratio was measured on samples collected from 18 boys and 11 girls referred to a children's hospital because of small stature. Any serious degree of growth hormone deficiency was excluded and each child's growth and development was recorded over the following year. The hypothesis that the average hydroxyproline:creatinine ratio on random urine samples may be used to predict height velocity was examined. Such a prediction would have been incorrect on 35% of occasions, and it is concluded that this investigation cannot be used reliability to predict growth in height; it is probably only useful with sequential studies of an individual child over short periods while monitoring therapy.


Genetic aspects of nutritional rickets.

Genetic aspects of nutritional rickets. Amino acid excretion was investigated in 21 rachitic infants and in 22 of their parents. There was (a) increased alpha-amino acid excretion in one-third of the infants a long time after the rickets had healed, (b) an abnormally high excretion of alpha-amino nitrogen and of phosphorus in many of the parents (c) an abnormal pattern of amino acid excretion in all 9 infants tested, and (d) a good correlation between the excretion of individual amino acids by an infant and by its parents. Our findings suggest that in at least some cases of nutritional rickets there is a genetic element which may manifest itself only under adverse environmental conditions.


[Investigations on the mechanism of the activity of urea upon the epidermis (author's transl)]. As a reaction of the epidermis subsequent upon contact with urea, a thinning is ascertainable 5 days later, for which corresponding enzymological and autoradiographical findings cause to presume the DNA being the working point. Further information about the mechanism of this reaction was obtained first by short time tests, whence by means of 3H thymidine autoradiography not later than the second day after contact with urea a decreased number of cells synthesizing DNA in the stratum basale were to be secured. These findings obtained using the model of the guinea-pig's ear are also ascertainable in the human skin, an unspecified effect, also to be released by other non-electrolytes, having been excluded by controls of glucose replacing urea. The quick invasion of urea into the epidermis, deducible from the short time tests, was proved by 14C traced urea, ascertainable not later than 15 min after its contact with the skin amongst the blood - even if in little activity. Hence, the urea enters into the cutis speedily, releasing there a disturbance in the process of the epidermal proliferation, which conducts in the sequel to an epidermal thinning.


[Reflexphotometric determinations of vasoconstriction after topical application of steroids. IV. Time slope of vasoconstriction and reactive vasodilatation (author's transl)]. In this study a reflex photometrical technique has been used to examine local steroid induced vasoreactions. When applied but once, steroids cause a maximum vasoconstriction between 8 and 16 h after beginning the test. Followed by a 32 h period, the phase of vasoconstriction is succeeded by a dilatation of dermis blood vessels. It appears, that the stronger the vasocontriction, the smaller the degree of vasodilatation.


[Reflexphotometric determinations of vasoconstriction after topical application of steroids. V. Vasoconstriction phaenomenon and tachyphylaxis after repeated steroid application (author's transl)]. On the basis of reflexphotometrical vasoconstriction tests it is demonstrated, that the intensity of vasoreactions caused by a first topical application of steroids, diminishes rapidly after repeated applications, until there is no response of vessels to a new application. This phaenomenon is know as tachyphylaxis and has been found in all tested glucocorticoids.


[Immunological demonstration of beta-glucuronidase in eccrine sweat (author's transl)]. Electrophoretic and immunological investigations on highly concentrated sweat have shown that human eccrine sweat contains 6 different esterases. Two of them were found to hydrolyze naphthol-AS-Bi-beta-D-glucuronide. One of the two glucuronic acid ester splitting enzymes is likely to be a substrate-specific beta-glucuronidase. The other one is a non-specific carboxyl-esterase occurring in numerous organs and glandular  secretions. This non-specific enzyme of widespread distribution can be mistaken for beta-glucuronidase because it hydrolyzes glucuronic acid esters as well as other synthetic substrates.


Effect of needle puncture and intradermal fluid injection on epidermal cell kinetics of albino guinea-pig skin. The flanks of male albino guinea pigs were used to study the effect of needle puncture with or without intradermal (id) injection of 0.1 ml fluid. The center of the raised bleb was marked and biopsies taken 1,4,8,24,50 and 72 hrs after needle puncture and 1 hr after intraperitoneal (ip) injection of tritiated thymidine (3H-TdR). There were no significant differences in labeling index (LI) or mitotic index (MI) 1 hr after id, ip, or subcutaneous (sc) injection nor in percent labeled mitoses, 7 hrs after id or ip injection. The earliest increase in LI (180% above control) occurred 12 hrs after needle puncture, peaked at 24 hrs (ca. 3X control), and returned to control level by 50 hrs. The area affected had a radius of about 5 mm from the point of needle entry or center of the bleb. Within 12 hrs after needle puncture, there was an increase in labeled cells primarily at the periphery of the bleb area, about 4 mm from the point of needle entry. By 24 hrs, the distribution of labeled cells had moved toward the bleb center (LI = 65%). The first increase in mitoses (MI = 2.5%) was seen 24 hrs after needle puncture. It is concluded that id injection introduces no significant error in LI or MI to 8 hrs after needle puncture. It does, however, trigger many noncycling basal cells into DNA synthesis after 8 hrs, and this may increase the rate of transit of these cells to the granular layer.


Protein leakage in the lungs of mice exposed to 0.5 ppm nitrogen dioxide. Forty-four mice were continuously exposed to 0.47 ppm nitrogen dioxide for ten, 12, and 14 days. The protein content of homogenized lung tissue was assayed fluorometrically after the animals had received intravenous injections of fluorescamine, a new reagent for protein assay. The mean protein value of all exposed animals was higher than that of the control animals (P less than .025). No correlation was noted between serum fluorophor levels and those in the lung homogenate.


Mortality in 1969 from pesticides, including aerosols. Among the 87 deaths in the United States in 1969 for which a causal relationship to pesticides could not be excluded, there were 62 valid accidents, 20 intentionally inflicted deaths, and five deaths incorrectly attributed to pesticides. The reduction in the number of such deaths compared to the decade and a half prior to 1962 probably involves a trend. As in the past, a disproportionate fraction of the victims were children, boys and men, and nonwhites. Findings in four cases (three in 1969) were consistent with the conclusion that intensive inhalation of an aerosol can sensitize the heart to fatal arrhythmia, even though there is no intentional misuse of the aerosol and no attempt to seek a thrill. Medical examiners should be alert to the possibility of such deaths associated with both pesticide and non-pesticide aerosols.


Electron microprobe analysis of particle deposited in lungs. A technique that is based on the combined use of a conventional transmission electron microscope and a conventional electron probe x-ray microanalyzer permits an unambiguous identification of titanium dioxide (TiO2) particles in lung tissue and cells. Quite probably, many other inorganic particles can be identified with the use of this technique.


Histologic fate and endothelial changes of distended and nondistended vein grafts. Sixty-two autogenous cephalic vein segments were grafted into the femoral arteries of 31 mongrel dogs, the left side receiving non-distended (control) grafts and the right side distended (experimental) grafts. Distending media were heparinized blood and saline. Veins were distended at 600 mm Hg for 2 minutes. Specimens were taken at intervals from 15 minutes to 3 months, and were studied by gross inspection, surface observations (light scanning stereoscope to X70 scanning electron microscope to X6,000) and routine histologic techniques (light microscope to X 1000). In general, grafting of veins in the arterial system was followed by progressive degenerative changes in all layers of the vein, including endothelial cell involution, desquamation and re-endothelialization. Often a variable degree of subendothelial fibrous and/or myoepithelial proliferation occurred which might compromise even a lumen lined by healthy endothelium. Distention caused these changes to occur earlier (2-4 weeks) and to be more pronounced. Distention with saline caused more damage to the endothelium than did distention with blood. We conclude that preimplant distention of vein grafts (to overcome spasm) should be employed sparingly, as it adversely affects the endothelial covering of the flow surface, accelerates the development of degenerative changes, and may predispose the graft to early thrombotic complications.


Initial occupational exposure to lead: Chromosome and Biochemical findings. Serial chromosome and biochemical studies were carried out in 11 subjects before and during initial occupational exposure to moderate quantities of lead fumes in a storage battery plant. The rate of abnormal metaphases, mostly with chromatid and one-break chromosome aberrations, was approximately doubled after one month of work; it further increased after two months of work; remained in this range up to seven months of exposure; and then tended to decrease somewhat. Blood lead levels increased progressively in the first few months, then reached a steady state. Urinary lead and coproporphyrin levels increased sharply after one month of work, while urinary delta-aminolevulinic acid (ALA) levels increased moderately. The ALA dehydratase (ALAD) activity of red blood cells (RBCs) was reduced to almost 50% of the initial values after one month, decreased further in subsequent months, and remained decreased through the remainder of the study.


Studies of plasma renin activity in coarctation of the aorta. Experimental and clinical studies were performed to assess the role of the renin-angiotensin system in producing hypertension in coarctation of the aorta. Basal and stimulated peripheral plasma renin activity were determined in the canine model and in four patients with coarctation. The animal studies showed no significant elevation of peripheral plasma renin activity (PPRA), and no increase in the response of PPRA to stimuli. The human studies showed a significant elevation in the response to PPRA to postural change and to exercise in three of four patients with coarctation, as compared to the same patients after correction of the coarctation. It is concluded that hyperactivity of the renin-angiotensin system is not the primary cause in coarctation hypertension in dog or man. It is nonetheless probable that the renin-angiotensin system has a role in coarctation hypertension, and further studies will be necessary to determine its place.


Major hepatic vein ligation necessitated by blunt abdominal trauma. An unusual case involving avulsion of the middle and left hepatic veins secondary to blunt trauma is presented. Operative management of the injury resulted in ligation of both veins without resection of the parenchyma acutely deprived of venous outflow. The postoperative evaluation and review of the literature indicate that liver tissue will survive acute interruption of a major portion of its venous outflow. This case demonstrates that if after ligating major hepatic vein, the condition of the obstructed parenchyma stabilizes or improves under direct observation and if the condition of the patient does not deteriorate, resection may not be required.


Aerosol usage and respiratory symptoms.

Aerosol usage and respiratory symptoms. In an epidemiological study of 3,485 selected individuals in Tucson, aerosol usage appears to be correlated to prevalence of respiratory symptoms. This effect persists after adjusting age and smoking to the prevalence rates for symptoms and appears to exist for specific types of aerosols. Further specification and clarification of these relationships are needed in the epidemiological survey. Critical evaluation within in vitro and in vivo models is of great importance. It is concluded that the propellants, the ingredients of the application, and the combination elements in different circumstances must be studied toxicologically to determine the mechanism and extent of specific actions on organisms.


Effect of chromates on ciliated cells of rat tracheal epithelium. Exposure to chromates is an occupational hazard that may result in disease of the respiratory tract. Specific subcellular effects of exposure to this chemical that might be the basis for observed pathologic findings were assessed in tracheal organ culture and excised whole tracheas. Chromate concentrations of 10 mg/ml or more were found to induce ciliostasis within 20 minutes and to kill cells within 24 hours. Levels between 10mug/ml and 100 mug/ml were not ciliostatic but resulted in cytotoxicity after a delay of several hours. Ultrastructural alterations associated with chromate-induced cytotoxicity are similar to the progressive degenerative changes that result from other chemical injuries. An inhibitory effect of chromate on protein synthesis, RNA synthesis, or succinic dehydrogenase activity could not be demonstrated. The data suggest that damage to the plasmalemma by chromates may be responsible for the observed change.


Mood and lithium in drinking water.

Mood and lithium in drinking water. To assess the possible relationship of lithium in the drinking water to some aspects of mental health, drinking water samples were collected from the homes of 384 individuals in Washington County, Md, who had been randomly selected for interview in a community mental health assessment program. The water was analyzed for lithium by atomic absorption spectrophotometry without knowledge of the interview results. The questionnaire contained the Lubin depression adjective check list, Center for Epidemiologic Studies depression and functioning scales, a general happiness question (Gurin), an aggression scale, and the Cantril ladder for self-rating of present status. In an area with low-to-moderate levels of lithium in the drinking water, there was no evidence to confirm earlier suggestions that the presence of lithium might be beneficial.


Parasympathetic innervation and pancreatic secretion: the role of the gastric antrum. The role of the antrum on vagally mediated pancreatic secretion was studied in 8 conscious dogs prepared with chronic pancreatic and gastric fistulae. After completion of control studies 6 were subjected to antrectomy and 2 to antroneurolysis (to interrupt submucosal nerve connections); secretory studies were repeated. With the animals secreting in response to secretin(0.03 u per kg-min) or secretin with cholecystokinin (0.05 u per kg-min), the following were administered: 1) insulin 0.2 u/kg; 2) atropine 0.2 and 0.4 mg/kg; 3) insulin after atropine. Insulin hypoglycemia elicited a marked enzyme response.  Both antrectomy and antroneurolysis markedly reduced (80%) the enzyme response to insulin hypoglycemia. Atropine 0.2 mg/kg abolished the insulin response and at 0.4 mg/kg inhibited (50%) the enzyme response to cholecystokinin; these effects were unaltered by antrectomy or antroneurolysis. These experiments suggest that the pancreatic enzyme response to insulin hypoglycemia is predominantly mediated through the vagal release of antral gastrin. Furthermore, antrectomy and antroneurolysis do not affect the enzyme response to cholecystokinin nor do they alter the inhibitory effects of atropine. The inhibitio- by atropine suggests that a cholinergic background exerts a permissive effect on CCK-mediated enzyme secretion.


Studies on the effect of small bowel bypass for massive obesity on gastric secretory function. Gastric secretory function was studied in 20 morbidly obese patients both before and after jejuno-ileal bypass. The mean postoperative weight loss was 99.2 pounds during a mean postoperative followup period of 12.6 months. The gastric secretory values we studied included basal and histalogstimulated volume, pH, concentration, and output. No statistically significant changes were observed in any of these variables. Therefore it is suggested that jejuno-ileal bypass, as performed for morbid obesity, is probably not an ulcerogenic procedure.


Treatment of volvulus of the colon by colonoscopy. The flexible colonoscope has notable advantages over rigid instruments and can be offered as an alternative and (probably) preferable method for non-surgical reduction of colonic volvulus. When operative intervention is called for because of repeated bouts of sigmoid volvulus, colonoscopy offers a means of preoperative deflation of the twisted loop, allowing time to prepare the bowel and correct systemic disturbances such as electrolyte imbalance. The first successful management of a case of recurrent sigmoid volvulus using fiberoptic flexible colonoscope is presented. It is suggested that the fiberoptic colonoscope may have similar application for instances of volvulus occurring more proximal than in the sigmoid colon. Sigmoid volvulus in children even though rare might also be amenable to correction by colonoscopy.


The anatomic basis of parathyroid surgery. A study of 645 normal adult parathyroid glands in 160 cadavers revealed that there is a definite pattern of anatomic distribution on the basis of the embryologic development of the parathyroid, thyroid, and thymic glands. The sites of predilection of the upper gland (Parathyroid IV) are, in order of frequency, the cricothyroid junction; the dorsum of the upper pole of the thyroid; and the retropharyngeal space. Those of the lower gland (Parathyroid III) are at the lower pole of the thyroid and the thymic tongue; rarely in the upper, the lateral neck, or the mediastinum. An understanding of the developmental relationship of the parathyroid glands to the thyroid and the thymus is fundamental in the delineation of the embryologic origin of the parathyroid glands. The parathyroid gland, located within the surgical capsule of the thyroid (subcapsular), when diseased, remains in place locally. A gland outside of the capsule (extracapsular) is often displaced into the posterior or anterior mediastinum. A collective assessment of the size, weight, color, shape, and consistency of the parathyroid gland is mandatory in the determination of its normalcy. Frozen section examination for stromal and intracellular fatty content is an added assurance of normalcy. That parathyroid glands sink in saline solution, and fat globules float, may aid in differentiating the two types of tissue. Supernumerary, fused, and intrathyroidal parathyroids, albeit rare, are of surgical importance.


Distribution of myocardial blood flow measured by hydrogen polarography. Distribution of myocardial blood flow was studied by polarographic recording of hydrogen desaturation in open chest dogs. Flow was measured during normal cardiac activity, reactive hyperemia following 60 seconds of coronary artery occlusion, and left ventricular hypertension produced by either partial supravalvular aortic occlusion or subvalvular outflow constriction. During normal cardiac function, blood flows in the subepicardium and subendocardium were approximately equal. Reactive hyperemia increased flow to both the subepicardium and subendocardium. Left ventricular hypertension decreased subendocardial flow relative to subepicardial flow in proportion to the degree of hypertension. Marked supravalvular obstruction with ventricular hypertension reduced subendocardial flow to two-thirds that of subepicardial flow. This decrease was further accentuated when the left ventricular end diastolic pressure was elevated.


Acute anuria secondary to renal artery stenosis. Three patients with acute onset of anuria secondary to renal malperfusion were successfully treated by revascularization. Twelve such patients have previously been reported. The role of surgery for prophylaxis in stenosing renal artery disease is advocated.


Ascending vs descending aortic dissections. One hundred eight patients with spontaneously developing thoracic aortic dissection were seen between 1966-1973, 78 of whom had acute dissection and 30 chronic. The age (49 vs 60 yrs) and incidence of hypertension (32% vs 71%) were significantly lower in the 56 patients in whom dissection originated in ascending aorta than in the 52 patients in whom the dissection originated in the upper descending aorta. The mortality rate in medically treated patients with acute ascending aortic dissection was 88%. Cardiac tamponade was the major cause of death. The mortality rate was significantly lower in those who were treated surgically (24%). Fifteen (54%) of the patients with ascending aortic dissection and significant aortic incompetence did not have aortic valve replacement and only two subsequently (53 and 92 months later) required valve replacement. Although the initial mortality in patients with acute descending aortic dissection treated medically and surgically was similar, the long term survival rate was higher in the surgically treated group. We conclude that ascending aortic dissection and descending aortic dissection have different clinical profiles and prognoses. Immediate surgical intervention is indicated in patients with acute ascending aortic dissection. Patients with acute descending aortic dissection can be treated medically initially followed by early elective operation.


Insulin response to glucose in hypermetabolic burn patients. Fifty-four intravenous glucose tolerance tests were performed in 12 normal individuals and 21 thermally injured patients. In the 17 hypermetabolic burn patients studied between the 6th and 16th days postinjury, fasting blood glucose was elevated (111 +/- 7 mg/100 ml, mean +/- SE compared to 85 +/- 3 in controls, P less than 0.001), but the instantaneous proportionality constant for glucose disappearance (k) was similar to that obtained in normal individuals (5.27 +/- 0.51, 100/min vs 4.01 +/- 0.58 in normals, NS). Fasting serum insulin concentrations were comparable in the 12 normals and 17 hypermetabolic burn patients (22 +/- 3muU/ml in normals vs 22 +/- 2), as was fasting insulin corrected for fasting glucose (24 +/- 3 in normals vs 21 +/- 3, NS), initial insulin response (0-10 min delta insulin, 58 +/- 13 in normals vs 67 +/- 10, NS) or total insulin response corrected per unit glycemic stimulus (insulinogenic index, 0.48 +/- 0.10 in normals vs 0.52 +/- 0.07, NS). With time following injury, the proportionality constant for glucose disappearance and insulin response decreased, and these alterations were related to the posttraumatic weight loss. In the 5 convalescent patients studied between the 37th and 90th days postinjury, glucose and insulin dynamics appeared similar to those observed in starved man. In these burn patients, hypermetabolism and negative nitrogen balance occurred in association with a normal insulin response to glucose. Increased hepatic gluconeogenesis appears to be characteristic of the catabolic response to this stress, directed by increased glucagon and catecholamines, not a decrease in fasting insulin or dampened insulin response.


High-output congestive failure from femoral arteriovenous shunts for vascular access. Femoral arteriovenous bovine shunts (FAVBS) represent an accepted method of vascular access for patients requiring chronic hemodialysis. The authors present 4 patients who required corrective surgery for high-putput congestive heart failure (HOCHF) secondary to high flow rates through the shunt. In order to avoid this serious complication, intraoperative graft flow rates should not exceed 900 cc/min. HOCHF secondary to FAVBS may be refractory to conservative therapy and require either banding of the shunt or its removal.


Use of a left heart assist device after intracardiac surgery: technique and clinical experience. A left heart assist device (LHAD) has been employed in 14 patients. All had advanced heart disease and were in low cardiac output after repair, such that they could not be separated from cardiopulmonary bypass despite prolonged support and adjuvant therapy, including drugs, pacing, and use of intraaortic balloon counterpulsation whenever possible. Apart from special cannulas, the equipment necessary for the LHAD is widely available. An asset of the system (left atrial-ascending aorta bypass of the left ventricle) is that it may be terminated without reentering the thorax to remove the cannulas. This is accomplished with precisely fitting obturators that obliterate the cannula lumens and allow the tubes to be permanently implanted. This concept is believed important since critically ill patients requiring support are precisely those in whom added risk would be imposed by a second operation. Of the 14 patients who have had intraoperative and postoperative support (up to 6.8 days), 9 were weaned from the device and 6 were dismissed from the hospital. Four patients remain alive and are improved, the longest at 22 months since operation. The favorable performance of the LHAD suggests that it may prove useful either when intraaortic balloon counterpulsation cannot be successfully deployed or when it has failed to achieve hemodynamic stability.


An extravascular left ventricular assist device. The hemodynamic efficacy and prosthesis-vessel interaction of a pneumatically activated circulatory assist device was investigated in 12 acute and 12 chronic studies in dogs. A polyurethane balloon encased in Dacron-velour cloth was fastened to the descending thoracic aorta with a spiral wrapping of Dacron graft material. Diastolic augmentation was provided by rhythmic inflation and deflation of the balloon. Hemodynamic results, based on 5 dogs with experimental myocardial ischemia, showed that left ventricular systolic peak pressure decreased by 8.2 +/- 1.9%, cardiac output increased by 13.1 +/- 2.8%, and circumflex coronary artery flow rose by 17.5 +/- 2.5%. In the chronic experiments the prosthesis was asynchronously but continuously activated from one to sixteen weeks at 74 cycles per minute. Postmortem examination of the implantation site in all 12 dogs showed that necrosis had developed but was limited to the outer half of the medial layer beneath the pumping chamber and that the aortic wall was compressed to about 70% of its original thickness. Although the method described represents a simple form of providing ventricular assistance, its applicability for long-term circulatory support remains to be evaluated.


Production of controlled reversible left ventricular failure in calves using intracoronary lidocaine hydrochloride: a useful method of evaluating left ventricular assist devices. The experimental production of stable, controlled, short-term left ventricular failure is valuable in the evaluation of implantable circulatory support systems. Acute or chronic left ventricular failure produced by occlusion or embolization of coronary arteries results in muscle dysfunction and degrees of failure that may be difficult to control. The effects of varying amounts of intracoronary lidocaine were studied during short- and long-term evaluations of intracorporeal left ventricular assist pumping. In 8 Hereford calves the left main coronary artery was cannulated with an intracoronary catheter in open and closed chest preparations. Dose-related negative inotropic effects were noted when lidocaine was injected at individual doses of 50, 75, and 100 mg. Following 100 mg doses, mean aortic pressure, cardiac output, and maximum rate of rise of left ventricular pressure decreased; left ventricular end-diastolic pressure increased fourfold. Similar effects were noted with short continuous infusions of lidocaine. The initial responses to injection or continuous infusions, if effective, were noted within 40 to 60 seconds. Several episodes of failure could be produced with either method following recovery periods of 10 to 15 minutes. In all instances, actuation of a left ventricular assist device immediately reversed the hemodynamic effects of the pharmacologically induced failure.


Factors predictive of perioperative myocardial infarction during coronary operations. The diagnosis of perioperative myocardial infarction (PMI) in our patients was based upon electrocardiography, vectorcardiography, and postoperative enzyme changes. A group of 303 patients operated on between January and September, 1972, formed the basis of this study. Three groups were identified from among these patients. Group A was composed of 90 consecutive patients in whom MI was excluded by all criteria. Group B comprised 25 patients with proved MI and yielded the 8% incidence of MI among our patients. Group C included 34 patients with triple-vessel disease who did not sustain MI. Significantly more patients sustaining MI had preinfarction angina and severe coronary artery disease. The incidence of MI was also higher in patients with diffuse disease and those in whom the lesions could not be totally bypassed. A statistical correlation with longer pump runs and periods of anoxia was obtained. There was some suggestion that the preoperative location of the hypokinetic segment determined the site of MI in patients.


A new approach to repair of pulmonary branch stenosis following ascending aorta-right pulmonary artery anastomosis. Ascending aorta-right pulmonary artery anastomosis may result in branch stenosis or occlusion of the right pulmonary artery from growth or from failure to place the anastomosis on the posterior surface of the aorta at the time of construction. Closure of the anastomosis is usually easily accomplished by simple suture through the ascending aorta. When branch stenosis is present at the site of anastomosis, reconstruction of the pulmonary artery is necessary. A new approach that facilitates repair of pulmonary branch stenosis by transecting the ascending aorta over the obstructed area has been utilized in 2 patients who required reoperation for branch stenosis following repair for tetralogy of Fallot. The method is an alternative approach to gain exposure for reconstruction of the pulmonary artery.


Skid row alcoholism. A distinct sociomedical entity. The physical-disease charcteristics of 125 skid row and 736 non-skid row male alcoholics were compared in detail to determine whether skid row alcoholism is characterized by a distinct medical, as well as a social, profile. Trauma, tuberculosis, venereal disease, and malnutrition were more common in the skid row alcoholics. Epilepsy, peripheral neuritis, acute brain syndromes, chronic brain disease, and lifetime recordings of all nervous system illnesses also occurred more frequently in the skid row group, as did gastritis, gastrointestinal hemorrhage, ulcer surgery, and postgastrectomy syndrome. Fatty liver, hypertension, ischemic heart disease, cardiomyopathy, and cardiovascular illnesses of all kinds, however, were less common. The skid row medical profile is, in part, the product of a unique sociologic environment. Thus, skid row alcoholism may be viewed as a distinct sociomedical entity.


Cardiac failure and upper extremity arteriovenous dialysis fistulas. Case reports and a review of the literature. Nine patients with high-output cardiac failure from arteriovenous forearm dialysis fistulas are reviewed, and six new cases are presented. Decreases in cardiac output with temporary fistula occlusion ranged from 0.3 to 11.0 liters/min (mean, 2.9 liters/min); fistula flow rates varied from 0.6 to 2.9 liter/min (mean, 1.5 liters/min). Surgical correction of high-flow fistulas resulted in notable improvement of cardiac failure in 13 of 14 patients. Although cardiac failure in individuals who are receiving long-term dialysis treatment is usually caused by intrinsic cardiac disease, volume overload, or anemia, forearm fistulas with large flow rates may be an important contributing factor. Correction of these large flow rates may be an important contributing factor. Correction of these large flow rates by banding or closure can substantially improve cardiac function in selected patients.


Spectrum of pleural involvement in sarcoidosis. Pleural involvement has generally been considered an unusual aspect of sarcoidosis. In this paper, five previously unreported cases of sarcoidosis involving the pleura were discussed. Pleural sarcoidosis may be manifested by the presence of a pleural effusion, and the diagnosis is based on the exclusion of all other possible causes and the demonstration of noncaseating granulomas in the pleura. When the pleura is involved without effusion, it may only be recognized if noncaseating granulomas involving the pleura are looked for specifically. Including the five cases form this study, there have been 73 cases of pleural sarcoidosis reported, but only 37 have been verified by histologic evidence. When strict diagnostic criteria are used, clinical involvement of the pleura in sarsoidosis remains an unusual entity, but it may be that histologic involvement of the pleura is more common than generally appreciated.


Intravenously injected marihuana syndrome. Two patients who injected marihuana intravenously developed a syndrome of hypotension, renal insufficiency, thrombocytopenia, and rhabdomyolysis. These clinical abnormalities appear to be reversible without residua.


Early diastolic sound associated with mitral valve prolapse. A patient with the prolapsing mitral valve syndrome demonstrated a most striking early diastolic sound. Noninvasive study with phonocardiograms, external pulse recordings, and echocardiograms lead us to believe that the sound may be related to the initial opening movement of the mitral valve. To our knowledge, such a mechanism for the production of a diastolic sound has not been previously reported.