T7- and T3-specific RNA polymerases: characterization and mapping of the in vitro transcripts read from T3 DNA. The late genetic region of the T3 bacteriophage genome is transcribed by a phage-specified RNA polymerase, the product of T3 gene 1. In vitro, purified T3 RNA polymerase acting with T3 DNA template synthesizes six major RNA products, with molecular weights of 5.5 X 10(6), 4.2 X 10(6), 1.7 X 10(6), 0.87 X 10(6), 0.52 X 10(6), and 0.23 X 10(6). These are designated T3 RNA species I through VI, respectively. These RNAs are formed in equimolar amounts, with the exception of T3 species V, which is made in approximately twice this amount. T3 RNA species I, II, and VI have been mapped by the use of terminally deleted templates and are found to originate from promoters located at 56, 67, and 98% genome length, respectively, and to share a common terminator at approximately 100%. T3 species III, IV, and V must originate from the class III region of the T3 genome between 37.5 and 56%. Although the pattern of transcription by T3 RNA polymerase in vitro closely resembles that of the RNA polymerase from the related phage T7, neither polymerase is able to use major promoter sites for the other enzyme at an appreciable rate.


Isolation of recombinants between T7 and T3 bacteriophages and their use in vitro transcriptional mapping. A variety of T3 X T7 recombinants were isolated from crosses between T3 and T7 parental phages carrying amber markers in various genes (gene 1 to gene 19). The genetic constitution of these recombinants was determined by reference to the selected markers and also directly by analysis of the proteins translated from the T3 X T7 recombinants in vivo. Although T3 and TM phages are closely related, most T3 and T7 proteins differ slightly in size, and hence the genetic origin of a gene can be determined by protein analysis. The major transcripts read by T3 and T7 RNA polymerases from T3 X T7 recombinant phage DNAs vary, depending on which regions of the T3 or T7 chromosome are present. T7 RNA polymerase is unable to utilize major promoter sites employed by T3 polymerase at an appreciable rate, and the converse is also true. Hence the transcriptional pattern for a recombinant phage DNA obtained with the T3 or T7 polymerase allows a determination of the identity of the different promoter sites on the genome. The transcriptional analysis of T3 X T7 recombinant DNAs together with earlier observations has been used to map the promoter sites for five out of seven major T3 and T7 RNA species on the genetic maps of T3 and T7. The promoter sites for the T7 and T3 RNA species IIIa, IV, and V originate at the beginning of genes 7, 9, and 10, respectively; the promoter sites for the T7 and T3 RNA species I and II are located to the left of gene 11 and gene 13, respectively. No T3 X T7 recombinants were found for which the specificity of the phage RNA polymerase was not correlated with the corresponding promoter sites for species IIIa and I (the transcription of which covers 60% of the genome). That means that the RNA polymerase specified by the recombinant genome is able to read all of the information encoded in sequences read normally from major promoters by the enzyme on the wild-type phage genome. This suggests that the in vitro specificity for promoter site selection by the phage polymerases is also maintained in vivo.


Structure of the inverted terminal repetition of adenovirus type 2 DNA. Several secondary structure features involving the ends of single strands of adenovirus type 2 DNA have been studied by electron microscopy by both the gene 32-ethidium bromide technique and a modification of the standard formamide-cytochrome c technique. A duplex stem of length 115 +/- 10 nucleotide pairs due to pairing between the two members of the inverted terminal repetition is observed in the single-stranded circles that form upon annealing single-stranded linear molecules. This duplex stem is shown to lie at the ends of the DNA by using several reference markers: (i) a newly discovered secondary structure feature (a loop of length ca. 500 nucleotides with a 20-nucleotide pair duplex stem) that maps 73% of the full length from the left end of the molecule and (ii) a duplex region due to a hybridized restriction fragment. There is also some secondary structure within each end of linear single strands. There is some variation in the morphology of the end strucures, and we propose that these involve base pairing, as in a tRNA clover leaf, rather than an exact single hairpin-type inverted repeat. These observations are consistent with the hypothesis that there is a foldback structure at the 3' ends of the DNA that functions as a primer for the initiation of replication.


Interaction of Sindbis virus glycoproteins during morphogenesis. In cells infected with the Sindbis temperature-sensitive mutants ts-23 and ts-10 (complementation group D), which contain a defect in the envelope glycoprotein E1, the precursor polypeptide PE2 is not cleaved to the envelope glycoprotein E2 at the nonpermissive temperature. This defect is phenotypically identical to the defect observed in the complementation group E mutant, ts-20. The lesion in ts-23 is reversible upon shift to permissive temperature, whereas that of ts-10 is not. Antiserum against whole virus, E1, or E2 also prevents the cleavage of PE2 in cells infected with wild-type Sindbis virus. Because the cleavage of PE2 is inhibited by the lesion in mutants that are genotypically distinct and by anti-E1 or -E2 serum, it appears that PE2 and E1 exist as a complex in the membrane of the infected cell.


Rifampin and vaccinia DNA.

Rifampin and vaccinia DNA. The effect of rifampin on the replication of vaccinia DNA was studied in mouse L cells by a cytochemical techinque and by alkaline sucrose sedimentation analysis of newly synthesized viral DNA molecules. By the use of a fluorescent DNA-binding compound (Hoechst 33258), the sequential appearance, size, and location of the viral "factories" in rifampin-treated, virus-infected cells were found to be indistinguishable from those observed in untreated, infected cells. Sedimentation analysis in alkaline scurose gradients of the viral DNA molecules labeled in pulse-chase experiments showed that formation of small fragments, elongation into "intermediate"-sized molecules, and maturation into full-length viral DNA and, finally, into cross-linked viral DNA molecules occurred in the absence or presence of rifampin. The results support the view that the primary effect of the drug is related to assembly or morphogenesis.


Gene A protein of bacteriophage S13 is required for singel-stranded DNA synthesis. The product of gene A of the small icosahedral DNA phage S13 has been found to be needed for single-stranded DNA synthesis in vivo in addition to its previously known role in progeny replicative-form DNA synthesis.


Renal changes in primary aldosteronism.

Renal changes in primary aldosteronism. The clinical presentations and renal biopsy specimens of 18 patients with primary aldosteronism were reviewed to determine the characteristic pathologic features of the kidney in this syndrome. All patients were hypertensive with a mean blood pressure of 192 nm. Hg systolic and 122 mm. Hg diastolic. The average duration of hypertension was 6.88 years. The mean serum potassium was 2.88 mEq. per l. and the mean plasma carbon dioxide was 31.4 mEq. per l. A significant history of urinary tract disease was noted in 8 patients. Laboratory and diagnostic studies evaluating renal structure and function were abnormal in 11 patients. Renal biopsies from all 18 individuals showed evidence of parenchymal damage. Hypertensive and hypokalemic changes were the most significant abnormalities and were considered moderate to severe in 78 and 89 per cent of the patients, respectively. Histologic evidence of pyelonephritis was noted in 2 patients only and no renal specimens contained characteristic changes of metabolic alkalosis. The preoperatively hypertensive and renal evaluations did not reflect the severity of the renal changes noted histologically. The extent of renal injury caused by hypertension and hypokalemia in these patients emphasizes the consequences of primary aldosteronism. Early diagnosis  and treatment of this disorder are essential if these consequences are to be avoided.


Improved diagnostic accuracy of renal venous renin ratios with stimulation of renin release. Fifty patients who underwent renal angiography and bilateral renal venous determinations had reconstructive or ablative surgery. The importance of stimulating renin release was underlined in 11 patients who attained a renal venous ratio greater than 1.5 to 1 only after being in an upright posture and in 5 who were studied with and without salt depletion. A protocol designed to suppress or stimulate peripheral plasma renin activity was followed in 19 patients. Stimulated peripheral plasma renin activity was not useful in identifying hypertension of renovascular origin but 10 of 12 patients whose plasma renin activity was not suppressed normally were improved by an operation. Satisfactory surgical responses were obtained in 81 per cent of the patients with unilateral and 91 per cent with bilateral atherosclerosis, and 88 per cent with unilateral and 60 per cent with bilateral fibromuscular hyperplasia. Our observations indicate that renal artery stenosis can be identified consistently only by angiography. A stimulated renal venous renin rate of 1.5 to 1 appears to have the best predictive value in surgical control of renovascular hypertension.


Yo-yo renal pelvis: an unusual cause of flank pain. Herein we describe 2 patients in whom a bifid renal pelvis was associated with peristaltic dysfunction and pyelopelvic reflux, causing pyelocaliectasis and flank pain. The patients were improved with pyelopyelostomy. Previous explanations for the yo-yo phenomenon have indicated that there is functional obstruction because of a higher resting pressure in the common stem. The asynchronous peristaltic waves a coincident with a relatively low pressure in the oal fold that acted as a baffle to direct the flow of urine from the lower segment of the bifid pelvis down the ureter. This baffle favored reflux into the upper segment.


The short ileal conduit: rationale and description of a technique. Although selection of a short ileal segment in the formation of an ileal conduit usually is recommended it is apparent that a truly short conduit is not used often. Therefore, a technique for the construction of a short ileal conduit is presented. It is suggested that many reported series of ileal diversions with subsequent renal deterioration may have used long ileal segments and consequently, may not be valid. Prospective series with short ileal segments seem necessary prior to the complete abandonment of the now widely used procedure of ileal conduit diversion.


Experience with the electrohydraulic disintegrator. Experience with the electrohydraulic lithotrite in treating 14 cases of bladder calculi is reported. This revolutionary lithotrite is applicable to most bladder stones and is associated with few complications.


The treatment of the uninhibited bladder with dicyclomine. Symptomatic treatment of the uninhibited bladder has presented a challenge because of the lack of an effective, well tolerated smooth muscle relaxant for the bladder that can be used during an extended interval. In a preliminary study oral dicyclomine produced resolution or significant improvement of symptoms in 24 of 27 patients and an increase in bladder capacity by an average of 137 plus or minus 26 ml. (91 plus or minus 22 per cent) after 8 weeks of therapy. Additional controlled trials definitely are warranted.


Bladder rehabilitation in patients with old spinal cord injuries with bladder neck incision and external sphincterotomy. Seventy-five patients with neurogenic bladders underwent bladder neck incision and/or external sphincterotomy to establish effective vesical emptying and reverse progressive hydronephrosis. A second operation to achieve these goals was necessary in 11 cases. The over-all success rate of these procedures in improving urinary tract stability was 94 per cent. Complications were infrequent, with hemorrhage and impaired penile erection being the principal problems. Eradication of established urinary tract infections was poor. However, infection-related morbidity was improved.


Complications of a single stage radical cystectomy and ileal conduit diversion: review of 214 cases. Single stage radical cystectomy and ileal conduit diversion were performed on 214 patients for treatment of bladder carcinoma. The over-all operative mortality rate was only 3.3 per cent. Early complications occurred in 27.6 per cent of the patients and late complications were noted in 41.1 per cent of the patients followed 6 months or longer. We refute recent arguments for staged procedures as a necessity for reducing operative mortality and morbidity.


Progressive testicular atrophy in the varicocele patient. We examined 82 healthy volunteers, 61 subfertile men with varicoceles and 27 subfertile men without varicoceles for testicular size and semen quality. In 13 volunteers we found unsuspected varioceles and a left testicle significantly smaller than the other 69 volunteers. The size of the right testicle and the sperm density in these patient groups were similar. Both testicles of subfertile male subjects with varicoceles were significantly smaller than the testicles of subfertile male subjects without varicoceles. However, the sperm densities of these 2 groups were similar. Finally, although subfertile male subjects with varicoceles had obviously statistically lower sperm densities than volunteers with varicoceles, the testicular sizes were similar. Perhaps varicocele ligations should be performed on all male subjects with this lesion at an early age to prevent progressive testicular atrophy and decreased fertility potential.


Sex cord-stromal (gonadal stromal) tumors of the testis: a report of 5 cases. Sex cord-stromal (gonadal stromal) tumors of the testis account for less than 4 per cent of the testicular tumors. The Leydig cell tumor in a child may produce isosexual virilization (case 3). In the adult it may have no endocrine manifestation (case 1) or gynecomastia and decrease in libidio may result from production of estrogens (case 2). Sertoli cell tumors (case 4) and granulosa cell tumors (case5) are rare.


Ultrasonographic examination of scrotal masses. Diagnostic ultrasounds is a simple, rapid, harmless and painless method to visualize intrascrotal contents. It may provide information that is difficult to obtain on clinical examination. Abnormalities such as testicular neoplasms, inflammation and hydroceles are discussed herein.


Correlation of circulating antisperm antibodies to functional success in vasovasostomy. The serum of 45 men with sperm in the ejaculate post-vasovasostomy was tested for antisperm antibodies. Agglutinating antibodies were found in 48 per cent of the men whose partners became pregnant and in 94 per cent of those whose partners did not become pregnant (p less than 0.01). No such correlation was found for sperm immobilizing antibodies. Spontaneous in vivo autoagglutination was not demonstrated in any of the patients. Although functional failure seems likely to be associated with an immunologic event neither sperm agglutination nor sperm immobilization seems to be the mechanism of that event.


Incidence of vesicle neck contracture complicating prostatic resection in hemodialysis patients. Four hemodialysis patients with no or minimal urine output underwent transurethral resection of the prostate. Bladder neck contractures developed postoperatively in all 4 cases. A review of the literature demonstrated no emphasis on the relatively high incidence of this complication in hemodialysis patients. A discussion of the possible etiology, diagnosis and therapeutic modalities is presented.


Urethral strictures following transurethral prostatectomy: review of 2,223 resections. There were 2,223 consecutive transurethral prostatectomies reviewed in regard to the incidence and possible etiology of postoperative urethral strictures. Possible etiologies were evaluated and a mode of stricture formation was postulated. Factors considered to be important were 1) initial calibration of the urethra to determine anatomical adequacy prior to instrumentation, 2) gentle urethral dilatation, 3) the use of perineal urethrostomy in patients with strictures noted at the time of initial endoscopy and 4) the size of the urethral catheter used postoperatively.


Pelvic lymphadenectomy for the staging of apparently localized prostatic cancer. Staging pelvic lymphadenectomy has been done on 87 patients with clinically localized prostatic carcinoma. With this method nodal metastases can be discovered, although they are undetectable by any other means. There were 44 patients with negative pelvic lymph nodes by surgical staging subjected to radical prostatectomy. Only 6 patients (14 per cent) had microscopic invasion of the prostatic capsule and there was just 1 instance of microscopic seminal vesicle invasion in those with negative pelvic lymph nodes.


Pelvic lymphadenectomy for stage B1 adenocarcinoma or the prostate: justified or not? Of 47 consecutive patients who had undergone staging pelvic lymphadenectomy for clinically localized adenocarcinoma of the prostate 26 had clinical stage B1 disease. Only 2 of these patients (8 per cent) had positive pelvic nodes. The low incidence of lymphatic spread, the potential complications of lymphadenectomy and the role of regional lymphatics in generating an immunological defense raise the question of the efficacy of lymphadenectomy in the treatment of rigidly defined, clinical stage B1 adenocarcinoma of the prostate.


A comparison of the morbidity associated with radical retropubic prostatectomy with and without pubectomy. Radical retropubic prostatectomy with bilateral pelvic lymphadenectomy for prostatic carcinoma was done with pubectomy in 8 patients and without pubectomy in 8 other patients. A comparison of the postoperative courses reveals an excess morbidity in patients who had pubectomy, with severe protracted pelvic girdle pain in 75 per cent, lower extremity thrombophlebitis in 37 per cent (one of which resulted in a non-fatal pulmonary embolus) and varying degrees of urinary incontinence persisting for 6 months or more in 75 per cent. In contrast, in patients who did not have a pubectomy mild transient pelvic girdle pain was noted in only 25 per cent of the cases, late lower extremity thrombophlebitis in 12 per cent and no late urinary incontinence. Pubectomy should not be used routinely with radical retropubic prostatectomy.


Morbidity of pelvic lymphadenectomy and radical prostatectomy for prostatic cancer. Radical retroperitoneal pelvic lymphadenectomy is associated with rather minimal morbidity but, when combined with radical prostatectomy, the morbidity is increased. The only complication that seemed to be solely owing to the lymphadenectomy was lymphocele formation, which occurred in 10 per cent of the patients. This rate is below that reported in the gynecologic-oncology literature.


Radical prostatectomy for carcinoma of the prostate: 1951-1976. A review of 329 patients. Surgical therapy for early adenocarcinoma of the prostate has been  an effective mode of cure since it was described by Young in 1905. The retropubic and perineal approaches of radical prostatectomy have been used at our hospitals for 25 years. Herein we examine 329 cases at the 2 hospitals. Although there were only 2 deaths (0.61 per cent) immediately attributable to the operation the surgical morbidity was significant. Patients of the attending staff had a 46 per cent complication rate while that of patients of the resident staff was 59 per cent. The 5 and 10-year survival rates of patients with stages A and B prostatic adenocarcinoma were 82 and 63 per cent, respectively, and the 5 and 10-year survival rates of patients who had stage C prostatic adenocarcinoma were 67 and 29 per cent, respectively. Our survival rates compare favorably to the national average survival for patients of all ages with localized or regional adenocarcinoma of the prostate. We believe that these data support the position of urologists who believe in radical surgical treatment of prostatic cancer.


Radiation therapy for carcinoma of the prostate 5-year followup. Our original series of patients with prostatic carcinoma treated with irradiation as the initial modality has been updated. The over-all 5-year survival rate for patients with stage III carcinoma of the prostate was 55 per cent--26 per cent were alive with residual disease and have had post-irradiation hormone manipulation, while 29 per cent were alive without metastases at 5 years.


Male genitourinary abnormalities and maternal diethylstilbestrol. In view of the risk of vaginal cancer developing in young female subjects exposed in utero to maternally ingested diethylstilbestrol a pilot study was undertaken of male subjects similarly exposed. A healthy questionnaire was mailed to 306 male subjects whose mothers were known to have taken diethylstilbestrol in the early part of their pregnancies and to 231 age and sex-matched controls identified from the same record source. Although there was no increased history of cancer, heart disease or asthma when the groups were compared there was a higher incidence of reported urinary tract symptoms and genital abnormalities in the group exposed to diethylstilbestrol. The presence of these abnormalities was confirmed by physical examination of 15 respondents. Studies in experimental animals also have shown that in certain species maternally ingested stilbestrol may result in abnormalities of the genitaltensive clinical studies be undertaken to determine the level of risk, if any, to which many thousands of young men are subject.


Positive urinary cytology in patients without evident tumor. Of 267 patients with a positive urinary cytology during a 5-year period 9 did not have a tumor identified at the initial diagnostic stidy, which included cytoscopy. However, a tumor was documented in 8 of these 9 patients between 1 and 61 months later.


Preliminary report: radioimmunoscan of sympathetic ganglia and adrenal medulla. The nerve growth factor is a polypeptide isolated from the salivary glands of certain laboratory animals. Its greatest physiological effect is on the autonomic nervous system. When antiserum against this nerve growth factor was injected in newborn animals nearly total destruction of the sympathetic ganglia was noted, a procedure known as immunosympathectomy. The anti-nerve growth factor labeled with 131iodine was injected in rats to determine organ distribution at different intervals (2, 4, 6, 8 and 24 hours). A selective concentration was obtained in the sympathetic ganglia and adrenal medulla (adrenal ganglia) 4 hours after the intravenous injection of 50 muCi. 131Iodine anti-nerve growth factor, with a specific activity of 0.001 gm. per mCi., permitted scanning of this structure for the first time. No intolerance or radiotoxicity has been observed in the animals and the results are encouraging. Radioimmunoscanning of the sympathetic ganglia and adrenal medulla in the human and radioimmunosympathectomy of the structures are being studied currently and will be subjects of future communications.


The non-neurogenic neurogenic bladder.

The non-neurogenic neurogenic bladder. The records of 21 children with neuropathic bladder disease are reviewed. The natural history in these cases has been consistent with that of an acquired disorder and the results of urodynamic testing have supported Hinman's contention that the disease is basically a functional one, caused by a discoordination between detrusor contraction and sphincter relaxation. Bladder retraining and specific medication have yielded far better results than were obtained previously by surgical measures alone.


Intraoperative compression cystourethrograms: a measure of adequate resection of posterior urethral valves. The technique of intraoperative compression cystourethrograms is described. This procedure has proved to be a safe, reliable objective means of determining adequate destruction of the valvular tissue is complete, the characteristic dilatation of the posterior urethra seen on preoperative cystourethrograms immediately disappears.


Ultrasound litholapaxy of a staghorn calculus. A method for removal of a staghorn calculus from the kidney through 1 channel of a U-tube nephrostomy is presented. An ultrasound lithotriptor provided a safe and quick alternative to surgical treatment.


Reversible renal hypertension secondary to renal arteriovenous fistula and renal cell carcinoma. A 40-year-old woman with hypertension (179/100) and a massive renal arteriovenous fistula involving most of the right kidney is reported. A 131I hippuran renogram, split urinary function studies and renal vein renins were normal. The renal arteriovenous fistula was removed by total nephrectomy and blood pressure returned to normal. A renal cell carcinoma was found within the fistula. This case confirms the association of renal cell carcinoma with renal arteriovenous fistulas and demonstrates the potential curative effects of nephrectomy for the hypertension associated with and demonstrates the potential curative effects of nephrectomy for the hypertension associated with it. The normal split function studies, renogram and renal vein renins do not support the concept of secondary hyperreninemia as a causative factor in the hypertension seen with renal arteriovenous fistulas.


Inverted Y ureteral duplication with a ureteral stone in atretic segment. A case of inverted Y ureteral duplication accompanied by a calculus in an atretic ureteral segment is described. This anomaly was confirmed by surgical and histological explorations on the left side. Extirpation of the calculus, excision of the distended ureter below the bifurcation and Y-V plasty just above the bifurcation were performed. Urography suggested a similar ureteral anomaly on the right side but the patient has had no symptoms 2 years postoperatively.


Intermittent catheterization in the treatment of acute purulent urethritis: case report. Acute purulent urethritis is a complication associated with an indwelling. Foley catheter in male patients. A refractory purulent urethral discharge, fever and the sequelae of urethral stricture, periurethral abscess and epididymitis are familiar problems to the urologist. The usual therapy is removal of the catheter, antibiosis and provision for another type of vesical drainage. Our recent successful experience using clean intermittent catheterization to treat an acute urethritis is presented.


A new approach to the treatment of priapism. A 26-year-old man  with post-traumatic priapism was treated successfully by occlusion of the left internal pudendal artery with an autologous clot. The recovery was marked by the return of entirely normal sexual function. This excellent result suggests that autologous clot injection of the internal pudental artery should be considered as an appropriate form of therapy for the treatment of selected patients with priapism.


Testis tumors associated with congenital adrenal hyperplasia: a continuing diagnostic and therapeutic dilemma. A 9-year-old boy with documented congenital adrenal hyperplasia owing to a deficiency in C21 hydroxylation is described. Precocious virilization and testicular asymmetry were noted when he was 5 years old. Both of these conditions persisted despite progressively larger doses of replacement steroid therapy. The right testis was 3 times larger than the left testis and serum testosterone was well within the adult male range. A right inguinal orchiectomy was performed. Pathologic diagnosis was interstitial cell tumor. A review of the literature emphasizes the continuing dilemma of separating interstitial cell tumors from hypertrophy of adrenal rest tissue in the presence of congenital adrenal hyperplasia. Possible methods of distinction are discussed.


The management of mature teratoma of the testicle. A case of mature teratoma of the testis, representing the longest documented interval between diagnosis and metastases, is reported. A review of the clinical features, pathology, treatment and survival indicates that mature teratoma is a malignant neoplasm. The need for aggressive treat and long-term followup in patients with this tumor is stressed.


Retroperitoneal seminoma.

Retroperitoneal seminoma. A case of retroperitoneal seminoma is discussed, emphasizing the importance of diagnosing the primary lesion. Although the testes were normal to palpation and exploration a focus of seminoma was recognized in the left testicle. We prefer radical treatment of this potentially curable disease.


Factors in successful resuscitation by paramedics. The out-of-hospital reports of 2152 consecutive paramedic fire rescue responses were reviewed. Examination of emergency department records and outcome was conducted in all cardiopulmonary arrests (120), major trauma (59) or nontraumatic hemorrhage (9) and one half (95 of 199 patients) with chest pain or possible myocardial infarction. Predominant age was 50 to 70 (66%) and men outnumbered women by four to one. At the scene arrival was under five minutes in over 70% of the cases. Thirty of the 120 patients with cardiopulmonary arrest (12 occurred after paramedic arrival) responded to initial cardiopulmonary resuscitation, 24 patients entered the coronary care unit, and 16 were discharged alive. Ventricular fibrillation (50) and asystole (40) were the documented rhythms. All survivors had ventricular fibrillation. Evaluation of the trauma and nontraumatic blood loss victims indicated that, after the paramedic places an intravenous line, the paramedic role is less well defined. Mean transportation time was 36 (trauma) and 38 (hemorrhage) minutes to the hospital.


Impact of medical training on ambulance dispatching. This study was designed to assess the ability of trained individuals to screen calls for emergency medical services to allow for safer or more appropriate responses. The degree of urgency of calls, as judged by dispatchers and a panel of physicians, was compared to estimates of the severity of the patient's illness or injury. Physicians were more likely to designate calls as emergencies than were dispatchers. Neither physicians nor dispatchers were able to discriminate between the severely ill or injured and those without severe problems. The emergency medical technicians were better able to assess severity and degree of urgency than were physicians or dispatchers. A tentative conclusion is that rapid response by an emergency medical services system will be based upon the caller's description of the situation rather than medical assessment of patient condition.


Cardiac telemetry exercise program.

Cardiac telemetry exercise program. To train cardiac consultants who interpret electrocardiogram rhythm strips from the field, we designed a series of prerecorded telemetered rhythms and discussions which can be sent into telemetry consoles. The patterns represent cardiac arrhythmias (eg, ventricular tachycardia, complete heart block, etc), as well as equipment problems (loose leads, misplaced leads, etc). We selected and modified some of the patterns of "Arrhythmia Resusci Anne" (Laerdal Medical Corporation), sent these through ambulance radios (to create a tone), recorded the signal on a standard tape recorder and dubbed in the monologue. The physician is asked to interpret the pattern and give instructions to the ambulance attendant. The answers and response times are recorded by the technician running the taped exercise. At the end of the quiz, the rhythms are replayed along with a discussion of each pattern.


Emergency department staffing to improve patient management. The emergency department records at the St. Louis County Hospital were reviewed for 1973, 1974, and 1975. The distribution of patients was considered by the day of the week and hour of the day. For the three year period, the daily average showed that one third of patients had been seen by 2:36 pm and two thirds by 8:14 pm. An analysis of peak patient load showed the first peak was around 11:00 am and the second, a higher peak, around 7:00 pm. By day of the week, more patients were seen on Tuesday and Saturday. Using data from such an analysis, emergency department personnel can devise an appropriate staffing pattern for their own situation.


[Clinical and pharmacokinetic studies in patients with digitalis intoxication (author's transl)]. 6 patients with severe digitalis intoxication were studied while hospitalised in a coronary care unit. 2 and 4 patients had ingested high doses of lanatosid C and digoxin, respectively. In three cases ventricular arrhythmias, in one of these and two further cases SA blocking and an additional A-V-block in one case were observed. Maximum blood levels of digoxin between 3.4 and 20 ng/ml were determined several hours after the ingestion. The maximal blood levels were achieved in one patient only 52 h after ingesting lanatosid C and in one patient taking digoxin after 12.5 h. Potassium concentrations in plasma were elevated in 4 patients. Antiarrhythmic and electrolyte therapy is discussed and the usefulness of a stomach lavage for diminishing the quantity of absorbed lanatosid C is shown in one patient who had a maximal blood level of 3.4 ng/ml after taking 23.7 mg of lanatosid C. Cumulative urinary excretion of this patient was 0.68 mg within 5.5 days. This result confirms the minimal enteral absorption under the therapy chosen.


[Determination of glycoside concentrations in human tissue by means of radioimmunoassay (author's transl)]. After extraction of myocardial and skeletal muscle biopsy and autopsy specimens tissue glycoside concentrations can be determined by radioimmunoassay. Total tissue extraction of digoxin and beta-methyl-digoxin varies between 87 and 95%, the variation coefficient for repeated determinations is 10.2%. Glycoside concentrations of left ventricular papillary muscle obtained after mitral valve replacement were 69.0 +/- 25.05 ng/g with a tissue to serum relation of 46.6 +/- 8.96:1 and a correlation coefficient of r = 0.8442. In autopsy left ventricular papillary muscle glycoside concentrations were 105.2 +/- 27.35 ng/g with an almost identical tissue to serum relation of 46.2 +/- 9.57:1 and a corresponding serum concentration of 2.3 +/- 0.63 ng/ml. In adults glycoside concentrations of autopsy specimens of the right ventricle were significantly lower by 28 to 30% than those of the left ventricle. Glycoside concentrations of skeletal muscle specimens (m. pectorialis major) were 14.7 +/- 10.35 ng/g with a tissue to serum relation of 9.7 +/- 3.00:1 (r = 0.8377), which corresponds to approximately 1/5 to 1/4 of the concentrations of the left ventricular myocardium.


[A case of systemic Pfeiffer-Weber-Christian Syndrome complicated by DIC (author's transl)]. The authors report on a case of fatal systemic P-W-Chr syndrome accompanied by DIC. The coagulation disturbance of the patient stopped after the administration of heparin, but this had no effect on the prognosis of the illness. The basic illness that had caused the syndrome could not be demonstrated either in vivo, or during the autopsy so that the above case is thought to be a sui generis form. According to the author's opinion the DIC is not an inducing factor but an accompanying phenomenon in the course of the basic disease.


[Psychological examinations in dialysed patients (author's transl)]. Psychological achievement tests were applied to 27 chronic dialysis patients two times, firstly just before being connected with the hemodialyser early in the morning, and then 24 h later. - Regarding basic intelligence functions like reasoning, closure, and a verbal factor concerning general knowledge the patients, neither before dialysis nor 24 h later, showed any significant differences compared to the healthy population. -On the contrary, attention performances, faculty of mental concentration, and reaction speed were definitely diminished in the morning following the treatment, whereas directly before starting hemodialysis there were no specific deviations from the control groups.


[Plasma erythropoietin and hematocrit under the influence of chronic hemodialysis treatment (author's transl)]. Hematocrit and plasma ESF titers were determined at 2 to 3 weeks intervals in 21 patients with chronic renal failure prior to and during a 15-weeks' period following initiation of chronic intermittent hemodialysis. While hematocrits increased from 22 to 27%, plasma ESF titers were found unchanged between 31 and 35 mU/ml. It can be excluded therefore that the improvement of erythropoiesis following initiation of dialysis was in part due to an increase in plasma ESF titers. The increased erythropoiesis observed is probably not dependent on increased ESF production. A 30-fold ESF deficit existed in patients with renal failure prior to the initiation of hemodialysis when compared with 5 patients with aplastic anemia (hematocrit 23%, plasma ESF titer 1115 mU/ml). At one exception ESF titers up to 500 mU/ml were found in dialysed patients only in combination with anemia due to acute bleeding or iron deficiency. ESF production is appropiate to the degree of anemia in patients with proper renal function after kidney transplantation.


[Prophylaxis and therapy of shunt thrombosis in terminal renal insufficiency (author's transl)]. In terminal renal insufficiency thrombosis occurs almost exclusively in the arteriovenous shunt. The management of this acute, life threatening thrombosis is hardly contested. On the other hand, few results are available concerning effective thrombosis prophylaxis. In addition to the effectiveness, the pharmacokinetics of a substance and also possible bleeding complications must be taken into account. The parenteral administration of heparin and its short half life restrict it to use in thehospital. Oral anticoagulants, because they are difficult to dose, should be avoided when possible. Dextrans (Rheomacrodex) and acetylsalicylic acid (Colfarit) appear to be best suited for thrombosis prophylaxis in renal insufficiency. Dextran has the disadvantage of volume overload, and acetylsalicylic acid that of stomach intolerance. Sulfinpyrazone (Anturano) also appears to be effective, although its pharmacokinetic behaviour in renal insufficiency is still not known. Dipyridamole (Persantin), whose effectiveness for this purpose has not yet been demonstrate, should be administered even more cautiously.


[Enzyme activities in normal platelets of different specific gravity (author's transl)]. Platelets of normal persons were separated into five fractions by centrifugation in discontinuous Ficoll density gradients. Enzyme activities of lactic dehydrogenase, phosphoglycerate kinase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, glucose-6-phosphate dehydrogenase and content of protein were constantly higher in the heavy fraction IV compared with the light fraction I. With regard to the platelet volume, however, these differences were compensated almost completely.


Human mammary cancers in nu/nu-mice. A model for testing in research and clinic. 37 (85%) of 44 human breast cancers are successfully transplanted on thymus-aplastic nu/nu-mice without adjunctive immunotherapy. 16 weeks after transplantation 4 rapidly growing tumours are showing human, female karyotypes. Subsequent investigations proved a good correlation between original tumour and transplant: histology, 3H-thymidine marking index and receptors of androgen and estorgen.


[Quantification of the effects of fibrinolytic therapy upon the flow behavior of blood (author's transl)]. The effect of Streptokinase-infusion upon the flow properties of blood was investigated by viscometric and aggregometric methods. Under fibrinolytic therapy, we found in all cases a significant fall in fibrinogen content, as well as a strong reduction in plasma viscosity, velocity of red cell aggregate formation and shear resistance of red cell aggregates. In addition, a drop in apparent blood viscosity at all shear rates was found. In no case, a total desaggregation of red cell was noted. The hematocrit value remained practically constant; consequently, the drop in apparent blood viscosity at high (160 s-1) shear rates and intermediate (8 s-1) shear rates can be solely accounted for by the observed drop in plasma viscosity. At low shear rates (2.3 s-1) the observed drop in apparent viscosity is partly caused by aggregation desaggregation, but mainly by a drop in plasma viscosity. The presented results again confirm that the method of rotational viscometry only incompletely records the improvement in the flow properties of blood that are caused by a therapy aimed at a reduction of the plasma fibrinogen content.


The human peripheral lymphocyte--a model system for studying the combined effect of psoralen plus black light. The effect of psoralen plus long wavelength ultraviolet light (UVA) on 3H-thymidine uptake of PHA stimulated human lymphocytes was investigated. PHA induced lymphocyte transformation was inhibited by the combined action of psoralen and UVA irradiation in a dose related manner. Inhibition of DNA-synthesis occurred at concentrations of psoralen that can be expected in the serum of patients treated by systemic photochemotherapy. No effect was noted at these psoralen concentrations in the absence of UVA irradiation. Also did UVA irradiation in the absence of psoralen not inhibit 3H-thymidine incorporation into PHA stimulated lymphocytes.


[Biotin supply and pyruvate carboxylase in blood (author's transl)]. Assaying the activation of pyruvate carboxylase in erythrocytes by measuring the enzyme activity before and after addition of biotin and ATP to the reaction mixture enables to estimate the biotin supply in vitro. According to this method in biotin deficient rats the pyruvate carboxylase-activity increased to 70%, while the increase of activity in supplemented animals amounted to 16%.


Dependence proneness, a key target for alcoholism research. Many alcoholics appear to be especially susceptible to developing tolerance to and physical dependence on alcohol. Elucidation of a biochemical abnormality associated with this special proneness could lead to advances in both diagnosis and treatment of alcoholism.


Polydipsic and home-cage fluid choices: the effects of sweetening. When rats were offered a choice of alcohol, butanediol and noncaloric saccharin solutions in a home-cage situation, consumption of saccharin dominated fluid choice, whether or not the animals were deprived of food.


Delay of development of responses to ethanol in mice: associated delay in another parameter. C3H and CF1 mice that showed a delay in developing an aversive response to a 3% alcohol solution also had a delay in development of the parameter, total fluid intake per gram of body weight, which was not the result of alcohol consumption per se.


Discriminant analysis of MMPI profiles for demographic classifications of male alcoholics. Discriminant function analysis of MMPI profiles of alcoholics on variables of age, education, occupation and marital status did not yield a common discriminant space, suggesting that other pertinent sociocultural factors must be incorporated to obtain a valid and informative discriminant space.


A sociological property of drugs: acceptance of users of alcohol and other drugs among university undergraduates. An analysis of student social acceptance of drug users reveals attitudes similar to those held by society at large. Student users of the drugs most established in the general society--alcohol and nicotine--were more accepted by their peers than were users of other drugs. Implications for prevention are discussed.


Drinking drivers who complete and drop out of an alcohol education program. Of 855 convicted drunken or alcohol-impaired drivers who participated in an alcohol education program, those who needed the program most (i.e., the young and those with high blood alcohol concentrations at the time of their arrest) were most likely to drop out of the program.


In vitro evidence for increased cellular immunity to lung cancer antigen during Levamisole immunotherapy. Levamisole, a potentiator of cell-mediated immunity, has been reported to increase survival in patients with resectable carcinoma of the lung. Cell-mediated immunity can be measured in vitro by the leukocyte migration inhibition test. We have previously reported that this test detects cell-mediated immunity to human lung tumor antigens. In the present studies, patients with lung cancer were treated with Levamisole. Their leukocytes were evaluated in the leukocyte migration inhibition assay before, during, and following Levamisole therapy. Small increases in cell-mediated immunity were observed when patients had a high pre-existing tumor immunity. When tumor-associated reactivity was absent prior to therapy, larger increases were measured. Although Levamisole is a nonspecific immunostimulant, these data indicate that in vitro anti-tumor immune responses are enhanced by Levamisole therapy. Augmentation of cell-mediated immunity to tumor antigens may explain the clinical benefits of Levamisole therapy.


Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. IV. Topical atrial hypothermia in normothermic beating hearts. This study compares (1) the effects of slowing heart rate by topical hypothermia in hearts perfused at 37 degrees C. with bradycardia produced by perfusion hypothermia (28 degrees C.) and (2) the consequences of counteracting the bardycardic effects of perfusion hypothermia by atrial pacing. Topical atrial hypothermia (myocardial temperature 37 degrees C.) produced a level of bradycardia comparable to perfusion hypothermia (82 vs. 71 beats per minute), but reduced myocardial oxygen requirements 25 per cent more than perfusion with 28 degrees C. blood. Myocardial oxygen uptake per beat did not change with topical atrial hypothermia but increased 40 per cent with perfusion hypothermia. Counteracting the bradycardic effects of perfusion hypothermia with atrial pacing (to 130 beats per minute) reduced subendocardial flow 25 per cent, caused a redistribution of flow away from the subendocardium, and produced evidence of ischemia on the intracavitary electrocardiogram. This study shows that (1) topical atrial hypothermia with systemic normothermia reduced myocardial oxygen demands as effectively as perfusion hypothermia and (2) subendocardial ischemia develops in beating empty hearts when the expected bradycardia of hypothermia does not occur.


Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. V. Profound topical hypothermia during ischemia in arrested hearts. This study compares the effects of 60 minutes of ischemic arrest with profound topical hypothermia (10 dogs) on myocardial (1) blood flow and distribution (microspheres), (2) metabolism (oxygen and lactate), (3) water content (wet to dry weights), (4) compliance (intraventricular balloon), and (5) performance (isovolumetric function curves) with 180 minutes of cardiopulmonary bypass with the heart in the beating empty state (seven dogs). Studies performed before and 30 minutes after 1 hour of ischemic arrest with profound topical hypothermia showed: (1) total left ventricular blood flow increased 50 per cent but became redistributed away from the subendocardium (endocardial/epicardial flow ratio fell from 1.13 to 0.77,(2) left ventricular oxygen consumption fell 30 per cent while left ventricular oxygen extraction fell from 51 to 29 per cent; (3) lactate extraction fell from 15 to 4 per cent (two dogs produced lactate); (4) left ventricular endocardial (papillary muscle) water content rose 2.4 per cent; (5) left ventricular compliance decreased from 1.68 to 1.01 ml. H2O/mm. Hg (at 25 ml.); (6) left ventricular performance was depressed 49 per cent below control values. In contrast, 3 hours of cardiopulmonary bypass in the beating empty heart produced only minimal changes in these variables.


Traumatic rupture of the ascending aorta and aortic valve following blunt chest trauma. Traumatic rupture of the aorta at the level of the isthmus is a well-recognized injury following blunt chest trauma. By contrast, rupture of the ascending aorta and of the aortic valve in a road traffic accident is rare and does not appear to have been previously reported. The occurrence of such an injury in a 56-year-old man involved in a road traffic accident is reported. The diagnosis was made preoperatively following aortography and successful surgical correction involved aortic valve replacement with resection and grafting of the damaged area of the ascending aorta. The probable mechanisms involved in the production of this unusual injury are discussed.


Potassium replacement during cardiopulmonary bypass. Sixty patients undergoing cardiopulmonary bypass (CPB) with the Travenol 6 L. variflow oxygenator bag and total hemodilution with Ringer's lactate with 5 per cent dextrose were observed for their variances in potassium (K+) levels and the degree of potassium replacement. We have seen that the potassium level drops before CPB bypass in relation to the preadmission to  the operating room potassium level. During bypass the level rises and following bypass it once again falls to be preceded by a rise after the first 24 hour postoperative period...


Techniques for localized injections and topical applications of carcinogens at specific endobronchial sites in dogs. We seek to create a canine lung cancer model with sharply localized carcinomas analogous to human lung cancers. Toward this goal techniques for recurrent endobronchial transbronchoscopic submucosal injections and topical applications of the carcinogens 3,4-benzo(a)pyrene and N-methyl-nitrosourea have been developed. After 2 years of experience with 2,868 endoscopic manipulations and varying dosage schedules in 59 dogs, safe effective techniques for recurrently delivering carcinogens and sequential biopsies of the same sites have evolved. Predominantly during the first year of experience, 10 dogs died as a consequence of technical problems such as exsanguinations after 1 mm. punch biopsies. There were also 39 instances of nonlethal technical complications of endoscopy in the face of immunosuppression and local irritation caused by the carcinogens. By the techniques and dosage schedules described, it has now become possible reliably and safely to create impressive localized bronchial preneoplasia with squamous metaplasia and atypia among the prominent features.


Prostaglandin influence on pulmonary intravascular leukocytic aggregation during cardiopulmonary bypass. A variety of pharmacologic agents have been infused during cardiopulmonary bypass in an attempt to prevent intravascular leukocytic aggregation in the lung. To date corticosteroids have been advocated because of their ability to stabilize lysosomes. We have studied two additional agents, prostaglandin E1 (PGE1) and dipyramidole (DIPYR) and compared their effects with those of methylprednisolone sodium succinate (MPSS) and a control group. The drugs were infused into the dog during perfusion and lung biopsies obtained before, during, and at the end of 2 hours of cardiopulmonary bypass using whole blood prime of the Bentley bubble oxygenator. The biopsies were interpreted by a pathologist who was unaware of the modality of treatment. Our results indicate that PGE1 provides more protection from intravascular pulmonary leukocytic aggregation than DIPYR and MPSS.


Pericarditis with effusion complicating esophageal perforation. Among 24 patients with esophageal perforation treated during the past 6 years, 3 patients developed pericarditis with effusion as a life-threatening complication. In the first patient pericarditis was found at autopsy, the diagnosis having been suspected but not proved during life. In the other 2 patients pericardial decompression was performed and both survived. Common denominators in the 3 patients were delayed diagnosis and treatment of the perforation, with resultant empyema. Further, the diagnosis of pericarditis with effusion was difficult and delayed, because mediastinitis and associated pleuritis and pneumonia obscured the cardiac silhouette on chest roentgenogram. It is recommended that a high index of suspicion of pericarditis be maintained in patients with esophageal perforation, especially in those in whom the perforation is diagnosed late.


The ventricular endocardial electrogram and pacemaker sensing. During cardiac pacemaker implantation and pulse generator replacement, unipolar, right ventricular electrograms were recorded from 133 patients (77 at implantation and 56 at pulse generator replacement) at 200 mm. per second with a band pass of 0.1 to 2,000 Hz on photographic paper. Each signal was analyzed for electrogram structure, peak-to-peak voltage deflection, ST-segment displacement, and maximum voltage deflection/time (slew rate [dv/dt]). The QRS designation of the peripheral electrocardiogram was used for the endocardial electrogram wave forms, which are sufficiently similar to allow QRS terminology to be used. Of the acute electrograms (at implantation) 58 per cent had a small Q followed by an R wave which was 10 per cent or more of the S amplitude; 30 per cent had an R wave less than 10 per cent of the S; all had a straight line segment, within the QRS complex, exhibiting maximum amplitude and slew rate and a large ST-segment elevation. In 12 per cent the Q was followed by an R wave only. The mean voltage was 12.4 mv. +/- 5.5, the slew rate mean 2.9 v. per second +/- 1.5, and the ST displacement 4.0 mv. +/- 2.6. All chronic (over 6 months after implantation) electrograms but one had no ST-segment elevation, and all had an inverted T wave and a straight line segment extending from the highest to the lowest peaks of the QRS complex. The chronic voltage amplitude is 15 per cent lower and the slew rate 41 per cent lower than that of the acute electrogram. The margin of amplitude and slew rate required at implantation to maintain adequate postimplant sensing must accommodate these changes. The possibility of satisfactory pacing threshold associated with poor sensing exists. Knowledge of the amplitude and slew rate allows the determination of the optimal position for electrode placement and the sensitivity required for satisfactory pulse generator selection, design, and operation.


Demonstration of a depressor reflex in acute cardiac tamponade. Studies from our laboratory have demonstrated the presence of a vagally mediated reflex in acute cardiac tamponade. To determine the effect of thisreflex on cardiac performance, we continuously recorded hemodynamic parameters during induction  of tamponade in 16 closed-chest mongrel dogs anesthetized with alpha chloralose. The studies were done 1 to 7 days following the insertion of a catheter in the pericardial sac. With increasing pericardial volume, there was a progressive deterioration of cardiac performance, the most marked changes occuring in the late phases of cardiac tamponade...


Aortic venting. Comparison of vent effectiveness. Three commercially available aortic vents have been evaluated as to effectiveness in removing small volumes of air introduced into a mock circulatory circuit. Without aspiration, Vent 2 was the most effective and removed 58 per cent of 0.1 ml., 90 per cent of 0.5 ml., and 74 per cent of 1.0 ml. boluses at a cardiac output of 2 L. At a cardiac output of 4 L., Vent 2 removed 42, 76, and 49 per cent, respectively. With aspiration (Vent 2 not designed for aspiration) and a 2 L. cardiac output, Vents 1 and 3 removed 84 to 98 per cent of 0.1 ml., 68 to 92 per cent of 0.5 ml., and 74 to 86 per cent of 1.0 ml. boluses. With aspiration and a 4 L. cardiac output, Vent 3 was significantly more effective than Vent 1 and removed 92 to 94 per cent of 0.1 ml., 82 to 86 per cent of 0.5 ml., and 77 to 80 per cent of 1.0 ml. boluses. One liter of canine blood was aspirated through Vents 1 and 3 and a flow rate of 250 ml. per minute. For Vent 1, serum hemoglobin levels increased from 40 to 249 mg. per 100 ml. and for Vent 3 from 49 to 212 mg. per 100 ml. There are significant differences in the ability of commercially available aortic vents to remove small air bubbles trapped in the heart after initial direct cardiac venting. Vents having the capability of aspiration are more effective and result in acceptable hemolysis.


Fungal endocarditis: need for guidelines in evaluating therapy. Experience with two patients previously reported. Successful treatment of fungal endocarditis is being described with increasing frequency. Two patients, previously reported as free of disease by two different groups of investigators, subsequently died in our institutions with evidence of continued disease. Both patients had been receiving antifungal chemotherapy at the time their case histories were reported. The lack of clinical signs and symptoms in fungal endocarditis, the suppression of manifestations of infection by chemotherapy, and the uncertain reliability of laboratory aids led us to suggest guidelines in reporting results of therapuetic regimens. These include avoidance of terms implying cure in patients who are concurrently maintained on chemotherapy, indication of attempts to evaluate fungemia, and minimum follow-up of 1-2 years' duration. The potential utility of serologic studies is illustrated by the course of one of these patients.


Management of an infected Hancock prosthesis after repair of truncus arteriosus. This report described a case in which purulent mediastinitis involving a Hancock prosthesis developed after repair of truncus arteriosus in a 6-year-old boy. The graft and surrounding area became sterilized after having been irrigated with povidone-iodine and antibiotic solutions for 6 weeks. At his most recent visit, the child was completely active and asymptomatic.


Evaluation of hemolysis following replacement of atrioventricular valves with procine xenograft (Hancock) valves. Twenty-two patients who had undergone valve replacement with the porcine xenograft were studied 6 to 62 months postoperatively (mean 30.5 months) for evidence of intravascular hemolysis. Hemolysis was not detected in any patient and postoperative red cell indices and iron studies were normal for the majority of patients. Five patients had significantly elevated serum lactic dehydrogenase (LDH) values preoperatively which returned to normal following operation. Our evidence suggests that the glutaraldehyde-fixed porcine xenograft valve does not cause detectable hemolysis.


A new audit prodecure applied to an old question: Is the frequency of T&A justified? A  unique medical audit procedure has been employed to combine the scope of population data with the detail of case histories. All tonsillectomy and adenoidectomy (T&As) in Manitoba for one year were studied. A group of individuals treated for respiratory illness but not having T&As were also identified. Individual histories were reconstructed from medical insurance claims. These cases were reviewed to test conformity between practice and authoritative standards for surgical intervention. The quality of the data on which this procedure depends withstood a battery of challenges. The analysis indicates that most cases selected for surgery lack evidence of meeting authoritative standards. However, a sizeable group of individuals not selcted for surgery perhaps should have been, if the same standards are applied. Also, those physicians performing the most operations had the highest criteria for patient selection.


The impact of physician consultation on care-seeking during acute episodes of coronary heart disease. The care-seeking behavior of 262 patients who experienced acute episodes of coronary heart disease (CHD) was analyzed to determine: the incidence and duration of physician consultation; the proportion of total time from acute symptom onset to hospital arrival consumed by medical evaluation; and the impact of medical evaluation on mode and duration of travel to the hospital and  the duration of medical evaluation and administrative procedures in the hospital emergency room. The results of this analysis suggest that physicians and ancillary medical personnel and the patient and lay others are about equally responsible for "delay" in obtaining definitive medical care. Extended medical evaluation was likely to occur when a patient's physician was an internist-cardiologist and the patient was young or without CHD, and a patient had numerous pre-existent chronic diseases. If effective techniques to bring patients under definitive medical care during the first critical hour of acute coronary episodes are to be developed, both lay and medical behavior should receive research attention.


The effect of medical training factors on physician utilization behavior. The purpose of this study is to determine the  influence of medical school, teaching hospital, and specialization on physicians' use of clinical and technical resources. The universe of the study consists of 34 internists practicing in the prepaid gorup practice setting of Kaiser in Portland, Oregon. The data reported here show that physicians trained in medical schools and hospitals with a scientific medical orientation generally use fewer such resources than other physicians. However, under conditions of uncertainty, that is, when diagnosis is unknown, they tend to use more services. In other words, these physicians are conservative in theri use of resourses when ambiguity is low, and liveral when ambiguity increases. Graduates of the more scientifically oriented institutions seem therefore more flexible in adjusting to the demands of the disease situation.


Receptivity of physicians in a teaching hospital to computerized drug interaction monitoring and reporting system. Physicians at Stanford University Medical Center were surveyed to evaluate their responses to a computerized drug interaction warning system one year after its installation. While one-fourth of the 862 respondents had personally received at least one warning report, the educational benefits of the system had diffused to many physicians in the hospital. Reports were found to be useful for patient management and 44 per cent of the physicians who had received reports indicated they had changed their behavior in response to the information. The system was particularly beneficial for interns and medical students, and appears to have potential as an educational tool for training in therapeutics. While several problems with the system were noted, the overall attitude of the respondents toward it was favorable. The drug interaction warning system appears to have a promising future for reducing the problem of drug interactions among hospitalized patients.


Technology evaluation: a case study of MARS (Missouri Automated Radiology System). A health care technology evaluation framework is presented along with its application to the Missouri Automated Radiology System (MARS) project. The framework is made up of the following components: evaluation objectives, evaluation design, system documentation, analysis model, evaluation measures, and data collection. The results of applying the framework indicate that MARS incerases the cost of diagnostic radiology 2.3 per cent, significantly decreases report response time, and successfully performs the film management function.


Quantitative changes in insoluble collagen during ontogeny in rodents (collagen type I and type III). It has been proved in three rodent species that in the insoluble collagen fraction which accumulates in skin collagen with age of the two categories of collagen present (collagen type I and collagen type III), their proportion alters in favour of collagen type I with the advancing age. Since it has also been shown that collagen type I is less resistant towards proteolytic cleavage than is collagen type III its accumulation can be explained either by rapidly advancing cross-linking of this collagen type or more likely by different proteosynthesis. The second alternative is preferred since a step-wise polymerization of collagen type III was also observed. No information revealing to what extent the lysine derived cross-links can combine both collagen types is at present available. On the basis of this information the rapid decrease in insoluble collagen in very early ontogeny (rats below 8 weeks of age) is explained.


Selection at implantation and longevity. A tentative theory. Women enjoy a superior longevity, possibly at the price of a heavy loss of female conceptuses at an early stage of gestation. An immunological mechanism is proposed. A theory of selection at implantation is developed and generalized which leads to a new approach of longevity.


Hupolipidemic activity of (--)-hydroxycitrate. The influence of (--)-hydroxycitrate, a potent competitive inhibitor of adenosine triphosphate (ATP) citrate lyase, on serum triglyceride and cholesterol levels, and in vitro and in vivo rates of hepatic fatty acid and chloesterol synthesis was investigated in normal and hyperlipidemic rat model systems. (--)-Hydroxycitrate reduced equivalently the biosynthesis of triglycerides, phospholipids, cholesterol, diglycerides, cholesteryl esters, and free fatty acids in isolated liver cells. In vivo hepatic rates of fatty acid and cholesterol synthesis determined in meal-fed normolipidemic rats were suppressed significantly by the oral administration of (--)-hydroxycitrate for 6 hr, when control animals exhibited maximal rates of lipid synthesis; serum triglyceride and cholesterol levels were significantly reduced by (--)-hydroxycitrate. In two hypertriglyceridemic models-the genetically obese Zucker rat and the fructose-treated rat-elevated triglyceride levels were due, in part, to enhance hepatic rates of fatty acid synthesis. (--)-Hydroxycitrate significantly reduced the hypertriglyceridemia and hyperlipogensisi in both models. the marked hypertriglyceridemia exhibited by the triton-treated rat was only minimally due to increased hepatic lipogenesis;(--)-hydroxycitrate significantly inhibited both serum triglyceride levels and lipogenesis in this model.


Effects of colestipol hydrochloride and neomycin sulfate on cholesterol turnover in the rat. Three groups of male rats were fed diets containing the bile acid sequestrant colestipol hydrochloride (1%), neomycin sulfate (0.25%), or basic diet during the test. After 15 days, each rat was injected IV with 3.9 muCi cholesterol-1,2(-3)H complexed with serum lipoproteins; specific radioactivity of the total serum cholesterol was measured at several time intervals for a period of 7 weeks. Computer analysis of the data indicated that the turnover of cholesterol could best be fitted by a three-pool model. In pool 1, colestipol HC1 caused a significant increase in production rate (10.09 to 15.96 mg/day) and the excretion rate constant (0.53 to 0.79 day-1) of cholesterol without significantly altering the size of the pool or serum cholesterol concentrations. These results are compatible with an agent capable of binding bile acids in the rat but do not cause a decrease of the sterol pool because of an adequate compensatory increase in cholesterol biosynthesis. Neomycin SO4 caused a significant reduction in serum cholesterol (9%) without altering turnover parameters and apparently exerts its hypocholesterolemia by some mechanism other than bile acid sequestration.


Radical scavenging reactions of alpha-tocopherol. II. The reaction with some alkyl radicals. alpha-Tocopherol was reacted with some alkyl radicals (ethyl, n-propyl, iso-propyl, n-butyl, and sec-butyl radical) to study its radical scavenging reactivity. The two types of products (alkyl ethers of alpha-tocopherol and cyclohexadienones) were obtained on treatment of each radial. These structures were determined by the spectral analysis. It was observed that alpha-tocopherol is very sensitive to the alkyl racidals and that the yields of the cyclohexadienones are decreased and that of the alkyl ethers are not much varied with an increase of carbon numbers of the alkyl radicals.


Effect of dietary vitamin E on expiration of pentane and ethane by the rat. An analytical method for the measurement of hydrocarbon gases in the breath of rats is described. The method was used to follow the expiration in rat breath of in vivo formed scission products of hydroperoxides. The major products are pentane from the linoleic acid family and ethane from the linolenic acid family. Rats were fed 0, 11 or 40 i.u. vitamin E acetate/kg diet for 7 wk starting at age 21 days. Data obtained by gas chromatographic analysis of breath samples were analyzed by the Mann-Whitney nonparametric U-test. This statistical analysis showed that pentane evolved by the group of rats not supplemented with vitamin E was significantly higher during the period 1-7 wk than that evolved by either of the two supplemented groups of rats. Ethane from the nonsupplemented group was significantly higher than that from the group supplemented with 40 i.u. vitamin E/kg of diet by 5 wk, and significantly high than both supplemented groups by 6 wk. By 7 wk, pentane production was tenfold greater in the non-supplemented group, and ethane was about twofold greater. There was no significant difference between the groups supplemented with 11 and 40 i.u. vitamin E/kg diet for either ethane or pentane. This new technique, which measures scission products from in vivo lipid peroxidation, promises to be useful for application to many experimental areas where lipid peroxidation is expected or known to occur.


The phytanic acid content of the lipids of bovine tissues and milk. In three steers which were given grass silage for six months, the content of phytanic acid (i.e. 3,7,11,15-tetramethyl-hexadecanoic acid) in plasma lipid increased to about 8% of the total fatty acids, whereas after this time the proportion in the total fatty acids of liver and heart lipids was about 1%, and only 0.1% in those of kidney lipids; the acid was present in trace amounts in adipose-tissue triglycerides and was apparently absent from brain lipids. In eight lactating cows which were given grass silage for about 3 months, the content of phytanic acid in the total long chain fatty acids of milk and of plasma was 0.7% and 13%, respectively. In the plasma lipids of both steers and lactating cows, phytanic acid constituted a substantial proportion of the total fatty acids of the triglycerides and phospholipids; the acid was present in lowest proportion in the cholesteryl esters.


1-Docosanol and other long chain primary alcohols in developing rat brain. Long chain alcohols were detected in developing rat brain at ages ranging from 5 to 40 days. They were at their highest level of 0.0109% of the total lipids at the age of 10 days and decreased to 0.0036% at the age of 40 days. They consited mainly of hexadecanol, octadecanol, octadecenol, eicosanol, docosanol, and tetracosanol. The fact that substantial amounts of fatty alcohols having more than 20 carbon atoms were present in myelinating rat brain indicated a chain length specificity in their utilization for 0'alkyl and 0'alk-1-enyl glycerolipid biosynthesis.


Linoleic acid amides: effect on cholesteremia and atherosclerosis. Several of a series of linoleic acid amides have been reported to inhibit cholesterol-induced atherosclerosis in rabbits. The three amides which have been studied to the greatest extent are (in order of increasing activity) N-cyclohexyl linoleamide (AC23), N(alpha methylbenzyl) linoleamide (AC223), and N[aplha-phenyl-beta-(p-tolyl)ethyl] linoeamide (AC 485).                                                                               We have found AC223 to inhibit cholesterol absorption in rats and to slightly inhibit exogenous but not endogenous cholesteremia in rabbits. In a fiber-free diet, AC223 reduces serum cholesterol and liver triglyceride levels. Rats were also fed a basal semipurified diet with and without AC223. Fecal excretion of labeled exogenous (as [ (14)C] cholesterol) or endogenous (as [14 C] mevalonolactone) steroid was 44 and 43% higher in drug treated groups. The mechanism of hypocholesteremic action of the linoleamides appears to involve inhibition of cholesterol absorption.


Gemcadiol: a new antilipemic drug, a clinical trial. Nineteen patients with type II, III, IV, or V hyperlipoproteinemia received gemcadiol (2,2,9,9,-tetramethyl-1,10-decanediol) in daily doses between 1.2 and 2 g. The patients were hospitalized for dose titration and then followed as outpatients on appropriate doses of gemcadiol. In Type II hyperlipoproteinemia, serum cholesterol was lowered by an average of 24%. The serum triglycerides in Type IV hyperlipoproteinemia decreased by an average of 51%. Serum uric acid was not altered. There were no changes of subjective feelings or of clinical or laboratory findings, including creatine phosphokinase. This study indicates that gemcadiol is an effective antilipemic agent that is very well tolerated.


Diet and cholesteremia.

Diet and cholesteremia. The statistical correlation between elevated serum cholesterol levels and increased risk of coronary heart disease has channeled thinking towards regarding dietary fat and cholesterol as the principal causes of hypercholesteremia. Since 1909 there have been a number of changes in nutrient availability in the United States. Protein availability is unchanged but the ratio of animal to vegetable protein rose from 1.06 in 1909 to 2.37 in 1972. Fat availability has risen by 26% with the ratio of animal to vegetable fat falling from 4.88 in 1909 to 1.64 in 1972. A review of available data indicates that amount and type of protein may affect cholesteremia and atherosclerosis in experimental animals. Soy protein is less cholesteremic than casein but the extent of difference can be affected by the type of carbohydrate. In a semipurified, cholesterol-free diet, saturated fat exerts an atherogenic effect but unsaturated fat does not. No atherogenicity is evident when saturated fat is added to laboratory ration. In the semipurified diet, fructose is more atherogenic than glucose, and casein is more atherogenic then soy protein. The latter difference can be virtually eliminated if alfalfa replaces cellulose as the dietary fiber. The data suggest that all elements of the diet interact and can affect cholesteremia and atherosclerosis. These effects must be considered in the planning of dietary intervention trials.


Maximum lipid reduction by partial ileal bypass: a test of the lipid-atherosclerosis hypothesis. Atherosclerosis is the process responsible for our national epidemic of coronary heart disease. A primary and proven atherosclerotic risk factor is the plasma cholesterol concentration. Yet, proof that a reduction in plasma cholesterol level results in a reduction in the incidence or severity of atherosclerosis and atherosclerotic cardiovascular disease still requires conclusive documentation. The controversial methods of operation and inconclusive results of concluded first and second generation trials are reviewed. These data clearly demonstrate that a definitive test of the lipid hypothesis has not been reported. Evidence is presented to show that the partial ileal bypass operation most nearly fulfills the six features of an "ideal" lipid lowering trial modality: maximum effectiveness (50% cholesterol reduction); known mechanism of action; no response "escape" or "rebound"; obligatory effect without patient cooperation; minimal side effects; and relative safety. The basic design and protocol of the National Heart and Lung Institute Program on Surgical Control of the Hyperlipidemias, a secondary intervention trial using a combination of diet therapy and partial ileal bypass surgery, are outlined.


FDA considerations regarding new hypolipidemic agents. Food and Drug Administration policy being considered for new marketed hypolipidemic agents includes: long-term safety to be demonstrated in postmarketing studies; evidence of clinical effectiveness to be demonstrated within a specified time period. Effectiveness is to be judged by one or more of the following: reduction in xanthomata, reduction atherosclerotic plaque, reduction in morbidity of coronary artery disease or peripheral and cerebral atherosclerosis, and reduction in mortality. Randomized double blind trials are deemed necessary.


2-Aminoethylphosphonic acid metabolism in the rat. Time course studies of the incorporation of radioactive 2-aminoethylphosphonic acid (AEP) into the tissues of rats demonstrated that maximum incorporation into the liver lipids occurred within 12 to 30 hr after injection, compared to 2 to 3 hr for the incorporation of phosphorylethanolamine. Little incorporation of AEP was observed in the other tissues investigated (heart, lung, spleen, adipose, kidney). The AEP was incorporated to the greatest extent into 1,2-diacylglyceryl-aminoethylphosphonate (diacylglyceryl-AEP), the phosphonate analogue of phosphatidylethanolamine, with some incorporation into the lyso derivative. Diacylglycerol-AEP apparently was not further metabolized by the rat; no methylation of diacylglyceryl-AEP to phosphonolecithin was observed. Subcellular fractionation was performed on the livers of rats who received (3)H-AEP 12,30,36, and 48 hr prior to sacrifice. The greatest amount of radioactivity was recovered in the soluble fractions. Lipid extraction was performed on the subcellular fractions, and most of the radioactivity present in the lipids was found in the microsomal fraction, with the next highest recovery in the mitochondrial and nuclear fractions


Preparation of specifically dideuterated octadecanoates and oxooctadecanoates. Sixteen methyl gem dideuterooctadecanoates with two deuterium atoms at positions 2- to 17- and seven oxo esters, 8-oxooctadecanoate-5,5-d(2), 8-oxooctadecanoate-11, 11-d(2), 11-oxooctadecanoate-8,8-d(2), 11-oxooctadecanoate-14,14-d(2), 12-oxooctadecanoate-9,9-d(2), 7-oxooctadecanoate-10,10-d(2) and 13-oxooctadecanoate-16,16-d(2) with two deuteriums on the carbon gamma to the oxo group, have been synthesized. Two prinicipal methods of introducing deuterium were used: preparation of 2,2-dideutero acids by exchange with deuterium oxide followed by chain extension giving dideuteroxooctadecanoates, which were then reduced, as tosylhydrazones, with sodium cyanoborohydride to dideuterooctadecanoates and stepwise introduction by reduction of oxooctadecanoates with sodium borodeuteride, formation of tosylate or mesylate, reduction with lithium aluminum deuteride to tetradeuterooctadecanol and oxidation to dideuterooctadecanoic acid.


Autoxidation of methyl linoleate. Separation and analysis of isomeric mixtures of methyl linoleate hydroperoxides and methyl hydroxylinoleates. The mixture of conjugated diene hyperperoxide isomers obtained from autoxidation of methyl linoleate was separated by high performance liquid chromatography (HPLC). Four major isomers were obtained from adsorption chromatography and identified as the 9 and 13 positional isomers having the trans-trans and cis-trans configurations. The latter geometrical isomers have the trans double bond adjacent to the hydroperoxide group. The hydroxy compounds (methyl hydroxylinoleates) obtained from the hydroperoxides by NaBH4 reduction were similarly separated but with improved resolution. This is the first instance of the complete separation of these compounds and provides a rapid method for their analysis. Unlike adsorption chromatography, reversed-phase chromatography separates the mixtures only according to the geometrical isomerism of the double bonds and not according to the position of the hydroxy or hydroperoxide function.


Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.


Transient bacteremia and endocarditis prophylaxis. A review. Transient, usually asymptomatic bacteremia occurs in a wide variety of procedures and manipulations, particularly those associated with mucous membrane trauma. It may also occur with such daily functions as tooth brushing and bowel movements. These brief bacteremias are especially common in tooth extraction and other dental procedures. Although numerical risk is uncertain, these bacteremias can occasionally give rise to infective endocarditis in the susceptible patient. While no proof exists that antibiotics given prior to procedures causing bacteremia prevent endocarditis in humans, experimental evidence in rabbits supports their use. Therefore, in situations where bacteremia is highly predictable, it would seem wise to administer prophylactic antimicrobials. Procedures in the susceptible host where prophylactic antibiotics seem prudent include dental manipulations and urinary tract instrumentation. Whether patients with acquired valvular or congenital heart disease who are to undergo abdominal surgical procedures should routinely receive prophylactic antibiotics is unclear. However, until the incidence of transient bacteremia associated with various abdominal procedures is further defined, endocarditis-prone patients should probably receive prophylaxis. Furthermore, patients with prosthetic valves who are subjected to upper gastrointestinal endoscopy, sigmoidoscopy, liver biopsy, or barium enema should also probably have antibiotic pretreatment. For dental procedures and for upper gastrointestinal endoscopy in patients with prosthetic valves, a combination of penicillin and streptomycin or vancomycin alone is recommended. For urinary tract instrumentation in all patients and for sigmoidoscopy, liver biopsy, or barium enema in patients with prosthetic valves, prophylaxis should be with ampicillin and gentamicin or vancomycin and gentamicin.


Aspects of the absorption of oral L-thyroxine in normal man. Using a double isotope method, the optimal conditions for the absorption of an L-thyroxine (L-T4) preparation were examined. In particular, the influence of food intake on L-T4 absorption was examined. As distinct from the unfavorable results hitherto obtained with L-T4 lactase mixtures, a tablet similar to a commercial 100 mug L-T4 lactose preparation showed good absorptionof 70.6% +/- 12.9% SD. In the fasting state, the L-T4 absorption of both preparations was significantly better (p less than 0.001) than with simultaneous food intake: 79.3% +/- 7.2% SD versus 63.9% +/- 10.5% SD. The calculated absorption of a 3-mg L-T4 dose in a lactose preparation used in testing thyroid suppressibility was significantly lower (p less than 0.001) than the absorption of a smaller L-T4 dose, and the absorption in the fasting state was again signifiantly (; less than 0.01) higher compared to that with simultaneous food intake: 52.6% +/- 4.3% SD versus 43.9% +/- 5.4% SD. The possibility of retention in the liver in the case of a large 3-mg L-T4 dose is indicated. The data suggest that with L-thyroxine medication simultaneous food intake should be avoided.


Diabetes induced by a high fructose diet. Long-term fructose feeding to the genetically selected albino rat resulted in the development of diabetes mellitus and diffuse glomerulosclerosis. Siblings of these animals that were starch fed did not develop the metabolic impairments nor did they develop diabetic microangiopathy. These results are similar to those observed following sucrose feeding to these genetically selected animals. Hence, fructose feeding is not different than that of sucrose in producing diabetes and diabetic angiopathy.


Insulin and glucagon relationship during aging in man. To determine if the glucoregulatory hormones, insulin and glucagon, are altered with aging inman, 44 healthy volunteers, 22-81 yr of age, were evaluted by measurement of basal levels of glucose, insulin, and glucagon in relationship to their fat mass. In addition, the secretory capacities of the alpha and beta cells were assessed by measurement of the amounts of glucagon and insulin released after intravenous administration of glucose and arginine, respectively. Although no significant differences in weight could be distinguished longitudinally, the percentage adiposity was found to increase with age. Basal concentrations of glucose, glucagon, and insulin were not appreciably altered as a function of advancing years. After intravenous glucose, the glucose disappearance rate (Kg) was significantly slower in the elderly in comparison with the young, yet no differences in glucose-induced release were found. Similarly, insulin responses after arginine infusion between young and old were indistinguishable. The release of glucagon in response to arginine infusion was not perceptibly altered during aging. Thus, despite a decline in Kg with advanging age in this healthy population, gross changes in insulin and glucagon release were not apparent. We infer from bese data that decreased carbohydrate tolerance accompanying aging in some populations may be due to factors other than abnormalities in secretion of insulin and glucagon.


Abnormal glucose tolerance in beta-thalassemia major. The question of whether iron overload causes glucose intolerance was studied in a group of 26 multiply transfused homozygous beta thalassemics. Of the 26, 13 (50%) had some abnormality in their oral glucose tolerance test, 5 fitting criteria for definite diabetes. Glucose intolerance correlated significantly with number of transfusions received and with age of the subjects, while a positive family history for diabetes was more common in the subjects with glucose intolerance. These data and a chart review of four deceased thalassemics with overt diabetes are consistent with the following conclusions: (1) glucose intolerance is common in multiply transfused thalassemics; (2) the incidence of abnormal glucose tolerance correlates with the number of transfusions received and the age of the subject; (3) a family history of diabetes may predisose multiply transfused thalassemics to glucose intolerance.


Influence of physiologic hyperglucagonemia on urinary glucose, nitrogen, and electrolyte excretion in diabetes. To evaluate the effect of physiologic hyperglucagonemia on nitrogen and glucose metabolism and on urinary electrolyte excretion, pancreatic glucagon was administered as a continuous 3-day infusion to three adult-onset non-insulin-dependent diabetics and two insulin-treated juvenile diabetics while on a constant dietary intake. The glucagon infusion resulted in increases in plasma glucagon which were 4-6 fold greater than control values. Despite prolonged hyperglucagonemia, urinary glucose excretion was unchanged. Similarly, urinary urea nitrogen and total nitrogen excretion were not altered by glucagon administration. Urinary sodium tended to rise, albeit not significantly (p less than .01), on the first infusion day, but later declined to control values despite increasing plasma glucagon concentrations. Urinary chloride, potassium, calcium, phosphorus excretion remained unchanged. We conclude that continuous physiologic increments in plasma glucagon do not enhance glycosuria or increase protein catabolism and ureagenesis in diabetes when insulin is available. The augmented protein catabolism and glucogenesis that accompany diabetic ketoacidosis cannot be explained primarily on the basis of hyperglucagonemia.


Laboratory animals exhibiting obesity and diabetes syndromes. Spontaneous hyperglycemia, hyperinsulinemia and obesity are common features for at least one period of the lifetime in some strains of mice. Both genetic and environmental factors are involved in the pathogenesis of the diabetes-like syndrome, making these strains excellent models for studies in both obesity and diabetes-like states. The metabolic peculiarities can be due to a dominant gene, as for the yellow obese, or a single recessive gene, as in the obese and the diabetes mouse; or they can be of polygenic origin, as for the KK and the NZO mouse. However, the severity of the metabolic disorder is due to the interaction of the mutant genes iwth modifiers in the bat genes themselves. Studies on the pathophysiology and biochemistry of these animals have revealed interstrain differences, different patterns of development of the metabolic disorder, and different degrees of severity of the diabetes-like syndrome. Although the primary causes of the syndrome remain unclear in some strains, an involvement of hypothalamic feeding centers has been implicated.


Effect of dichloroacetate on gluconeogenesis in isolated rat hepatocytes. The effect of dichloroacetate on rates of gluconeogenesis was studied in isolated parenchymal cells obtained from the livers of normal fasted rats. Dichloroacetate significantly inhibited glucose formation from endogenous substrates and from added precursors (e.g., lactate, pyruvate, or glycerate) which enter the gluconeogenic pathway prior to the level of glyceraldehyde-3-phosphate dehydrogenase (GPDH). In contrast, dichloroacetate did not significantly affect glucose synthesis from precursors (e.g., fructose, or glycerol) which enter beyond the GPDH-catalyzed step. Lactate production from fructose of glycerol was unaffected by dichloroacetate. Inhibition of gluconeogenesis occurred regardless of the apparent effects of dichloroacetate on the redox state of the cytosol. Dichloroacetate produced variable effects on the lactate-pyruvate substate pair, while it consistently produced a more oxidized state in the beta-hydroxybutyrate--acetoacetate couple. Unlike uncoupling agents, dichloroacetate reduced glucose synthesis without stimulating respiration or altering total adenine nucleotide levels or ATP/ADP ratios. Dichloroacetate did not affect the metabolism of lactate or pyruvate to CO2 or glycogen. It did, however, significantly inhibit conversion by the cells of added lactate to pyruvate and glucose or of added pyruvate to lactate and glucose.


The effects of two dietary fiber supplements on gastrointestinal transit, stool weight and frequency, and bacterial flora, and fecal bile acids in normal subjects. The effect of dietary supplements of sugar-cane fiber (bagasse), on stool weight, solids, and water content were studied in normal ambulant volunteers over a 9-mo period; a second inpatient study was done with bran supplements. The addition on 10.5 g of bagasse containing 5.1 g of crude fiber to a normal diet containing 3.7 g of crude dietary fiber daily raised the mean fecal weight from 88.3 +/- 6.4 g to 139.7 +/- 10.2 g/day (p less than 0.005). There was also a significant rise in fecal solids and fecal water, although the percentage of water in the stools remained unchanged. Bagasse supplements accelerated gastrointestinal transit when measured by the carmine marker technique. Radiopaque "shapes" showed a trend toward more rapid transit with bagasse supplements. Daily supplements of 39 g of wheat bran or 10.5 g of bagasse increased the total daily excretion of fecal bacteria, but there were no changes in bacteria excreted per gram of feces. The composition of the bacterial flora showed no change. There was increased excretion of fecal acid sterols on the bagasse supplement, but this failed to occur with bran. No changes attributable to fiber supplements occurred in the plasma triglycerides or cholesterol. Future work may define specific dietary fiber supplements for different therapeutic purposes. One fiber may be used as a bulk expander in diverticular disease and another as a hypocholesteremic fiber.


Effects of short-term clofibrate administration on glucose tolerance and insulin secretion in patients with chemical diabetes or hypertriglyceridemia. The effect of 1-wk administration of clofibrate on plasma glucose and insulin (IRI) before and during oral glucose tolerance tests (OGTT), as well as on serum lipids, uric acid, growth hormone (GH), and cortisol, were evaluated in 18 nondiabetic patients with hypertriglyceridemia and in 28 patients with chemical diabetes. Fasting plasma glucose, OGTT-glucose, and IRI areas were significantly decreased in both groups of patients, though the effects on glucose metabolism were much more marked in diabetics; 30-min IRI relative increase was unchanged; fasting plasma IRI was reduced in diabetics only. Glucose utilization during insulin tolerance tests carried out in 6 diabetics was significantly enhanced after treatment. Serum triglycerides (TG) and cholesterol (Chol) were significantly decreased in both groups of patients, as were serum free fatty acids and uric acid in diabetics; plasma GH and cortisol did not change. Significant correlations were found in diabetics between the postclofibrate decrease in OGTT-glucose area and the following: pretreatment values of serum Chol (r + 0.42, p less than 0.05) and of 30-min IRI absolute and relative increase (r + 0.44 and + 0.38, respectively, p less than 0.05); postclofibrate decreases in serum TG (r + 0.40, p less than 0.05), in fasting plasma glucose (r + 0.73, p less than 0.001), and in OGTT-IRI area (r + 0.57, p less than 0.01). These data suggest that the improvement in glucose metabolism observed during short-term clofibrate administration may be due to increased insulin sensitivity.


Carbohydrate metabolism in pregnancy. XIV. Relationships between circulating glucagon, insulin, glucose and amino acids in response to a "mixed meal" in late pregnancy. Gestational influences upon the changes in circulating glucose, amino acids, insulin, and glucagon after the ingestion of a "mixed meal" containing carbohydrate (50 g), protein (25 g), and fat (10 g) were examined. Nine subjects were tested during weeks 30-40 of gestation and again 6--8 wk postpartum. The "mixed meal" elicited greater and more prolonged increases in plasma glucose anterpartum, whereas the increments in total serum amino acids were blunted at all time points. In the face of greater glycemic but lesser aminogenic stimulation, the integrated increase in plasma insulin was 60% greater antepartum than post partum, whereas the increment in glucagon was not significantly altered. Thus, integrated insulin/glucagon response was increased during antepartum studies. The insulin preponderance following alimentary challenge with mixed nutrients would suggest that the anabolism of ingested amino acids is "facilitated" during late human pregnancy.


Studies on hepatic glucose cycles in normal and methylprednisolone-treated dogs. In unanesthetized normal and methylprednisolone (MP)-treated dogs the rate of appearance of glucose was measured simultaneously with 2-3H (RA2 = hepatic glucose output), 6-3H (Ra6 = hepatic glucose production), and 14C-glucose (U) (RaC) as tracers (primed constant rate infusion). The substrate ("futile") cycle of glucose (SC: gl in equilibrium gl-6-P) was obtained from Ra2 - Ra6, and Ra6 -RaC gave the recycling (RC) of radiocarbons. In normal dogs SC and RC represented 13% and 11% of Ra6, respectively. MP increased SC almost eightfold without altering RC. Infusion of glucagon (increased breakdown of glycogen, inhibition of glycogen synthetase) or mannoheptulose (inhibition of glucokinase) as well as exercise increased SC. MP greatly potentiated the effect causing SC to rise to 20 times the normal baseline. In both groups there was a direct correlation between Ra6 and SC. Glucose infusion did not alter SC in the controls, but increased it in the MP-treated dogs by suppressing Ra6 more than Ra2. It is suggested that the multifunctional character of gl-6-Pase is at least partly responsible for the glucose substrate cycle, using gl-6-P as one of the phosphate donors: gl-6-P + 3H-gl in equilibrium 3H-gl-6-P+gl. The activity of this enzyme is greatly elevated by the glucocorticoid, and it can be further enhanced by increasing the availability of gl-6-P by raising Ra6.