Falciparum malaria cured by quinine followed by sulfadoxine-pyrimethamine. Quinine (at least four doses given at intervals of eight to 12 hours) followed by a single dose of sulfadoxine-pyrimethamine (Fansidar) is the most effective treatment of chloroquine-resistant falciparum malaria. This regimen cured 96% of patients (302 out of 314) with an average initial parasite count of 90 X 10-9/1.


Simplified computer-aided diagnosis of acute abdominal pain. A simplified version of a system for computer-aided diagnosis of acute abdominal pain has been tested by "new" personnel unfamiliar with the previous system. After a two-month learning period the system proved more accurate in its diagnoses than the unaided clinician, and during the first five months of using the system the unaided clinicians' accuracy rose from 73% to 84%. When computer "feedback" was withdrawn the clinicians' diagnostic accuracy reverted towards the previous, "unaided" level. These findings further validate the concept of the computer as a potentially valuable diagnostic aid but indicate that a training period and computer feedback are important factors in its 4 use.


Clinical applications of an automatic data handling system for sexually-transmitted diseases. An automatic data handling system for the storage and evaluation of data from investigations on sexually-transmitted diseases has been developed. Among the clinical applications are epidemiological investigations, evaluation of diagnostic procedures, and evaluation of treatment regimens. One of the main features of the system is its flexibility, which allows the inclusion of an unlimited number of further evaluation programs. After a running-in period of about 3 years, during which time a number of changes were found to be necessary, the method has been found to satisfy medical and data processing requirements.


Miconazole nitrate compared with chlordantoin in the treatment of vaginal candidiasis. In a double-blind study of the treatment of vaginal candidiasis, miconazole nitrate gave a cure-rate of 88 per cent. (29 out of 33) compared with 58 per cent. (21 out of 36) using chlordantoin. Although approximately two-thirds of the patients who responded did so to a 10-day course of treatment, the different rates of cure with these preparations at this stage were not statistically significant. However, when a second course of treatment was given to those women who still had proven candidiasis, the overall cure-rate with miconazole was significantly greater than that with chlordantoin.


Comparison of the treatment of herpes genitalis in men with proflavine photoinactivation, idoxuridine ointment, and normal saline. 36 male patients with genital infection by HSV confirmed by culture were each allocated to one of three treatment groups: (1) Proflavine photoinactivation, (2) 0.5 per cent. idoxuridine ointment (IDU), (3) Normal saline. They were assessed objectively at each attendance by measurement of the lesions with an operating microscope fitted with a measuring grid in one eyepiece. Material for culture for HSV was taken at each visit; the presence of symptoms (pain, discomfort, and irritation) was noted. The areas of lesions in the proflavine photoinactivation group remained larger significantly longer than in the other groups, the healing time was slower, and HSV could be isolated for longer. It is concluded that proflavine photoinactivation is of no greater value than 0.5 per cent. IDU or normal saline in the treatment of genital infection by HSV in the male.


Clinical value of the Treponema pallidum haemagglutination test. In 1,129 patients attending the Department for Sexually Transmitted Diseases, the serum was examined by three screening tests (VDRL slide, RPCF, and TPHA) and twelve cases of syphilis (1 per cent. of patients attenting the clinic) were discovered. Six of these patients were considered to have latent syphilis (5 acquired, 1 congenital) and were detected only by the TPHA; all six cases were confirmed by the FTA-ABS, The TPHA failed to detect three of the remaining six cases (2 primary and 1 very early, the latter in a contact of a patient with primary syphilis). All six cases were, however, detected by the VDRL. In seven cases, the TPHA was positive in the absence of other evidence of present or previous syphilis. In these cases the FTA-ABS was also negative. The clinical application of the TPHA test in the detection of syphilis is discussed.


Single-dose treatment of uncomplicated gonorrhoea in males with minocycline. Minocycline in a single 300 mg. oral dose was given to 103 men with uncomplicated gonorrhoea, of whom 85 were followed-up for at least 2 weeks. The cure rate in the 85 followed was 94.1 per cent. There were no side-effects. Thus minocycline could be considered as an effective and safe alternative to penicillin in the single-dose treatment of uncomplicated gonorrhoea in the male, but at the moment it is too expensive for routine use.


Comparison of oral ampicillin and doxycycline in the treatment of uncomplicated gonorrhoea. An account is given of a computer-processed 1-year study comprising 1,124 patients (625 males and 499 females) with uncomplicated gonorrhoea. Alternate patients were treated with either two oral doses of 1 g. ampicillin 5 hours apart, or 0.3 g. doxycycline in a single oral dose. Ampicillin remained as efficacious as in 1968 to 1970, in both males and females, in whom the failure rates were 1.1 and 1 per cent. respectively. After doxycycline the failure rate was 8.1 per cent. in males, 5.7 per cent. in females, and 7.1 per cent. overall. Ampicillin was significantly better than doxycycline in the treatment of men (P less than 0.001) as well as of women (0.05 greater than P greater than 0.01). 89.7 per cent. (29/29) of the relapses in doxycycline-treated patients occurred in those harbouring strains sensitive to tetracycline. Sensitivity to doxycycline followed the pattern of tetracycline sensitivity. Thus sensitivity tests with these antibiotics provided no practical aid to therapy. The high incidence of nausea and vomiting in patients treated with doxycycline (12 per cent.) makes it inadvisable to increase the dose; instead, multiple doses are necessary to obtain satisfactory results. There were very few adverse reactions to ampicillin; a rash occurred in only three patients (0.5 per cent.). In the group treated with doxycycline, 31.5 per cent. of the patients infected by streptomycin-resistant strains relapsed compared with only 1.8 per cent. of patients infected by streptomycin-sensitive strains. This difference is highly significant (P less than 0.001). Thus the sensitivity of gonococcal strains to streptomycin in vitro may serve as a valuable guide to the likely outcome of treatment with tetracyclines.


The sources and intracerebral distribution of auditory evoked potentials in the alert rhesus monkey. Average auditory evoked potentials (AEP) to click stimuli were recorded from chronically implanted electrodes in alert rhesus monkeys. The cortical sources of each AEP component were identified on the basis of transcortical polarity inversions. The active loci were limited to the supratemporal plane (STP) and to a region within precentral motor cortex. Small and inconstant responses were generated in the lateral superior temporal gyrus and no locally generated activity was detected in frontal granular cortex. The responses from STP were complex, with early components generated mainly within auditory koniocortex and later components in surrounding regions. Each of these components was volume-conducted widely, both above and below the STP, and they projected onto various regions of dorsolateral surface cort(x. The volume-conducted potentials from the STP summed with the potentials generated in motor cortex to produce a complex resultant waveform. Barbiturate anesthesia abolished all but the primary AEP and reduced the volume-conducted projection of this response at the cortical surface. The configuration and intracranial distribution of the monkey AEP were compared to human intracerebral and scalp AEP recordings.


Prophylactic chemotherapy with low-dosage trimethoprim-sulfamethoxazole following acute urinary tract infections in children. The cases of 10 children with acute and recurrent infection of the urinary tract are presented. Their ages were between 7 weeks and 9 years. Five of the children had been previously treated with a combination of sulfisoxazole, ampicillin, mandelamine and nitrofurantion and four of these children had "breakthrough" infections. When trimethoprim-sulfamethoxazole was administered twice weekly no further infections were noted in four of these five patients. The second group of five children were started on trimethoprim-sulfamethoxazole from the start of their infection and treatment was continued twice weekly for 5 to 7 months. No recurrence of infection of the urine has been detected up to the present time. It is concluded that treatment with trimethoprim-sulfamethoxazole initiated at the outset of urinary tract infection and twice weekly is a valuable drug in children, provided the organism responsible for the infection is sensitive to this agent.


Comparison of trimethoprim-sulfamethoxazole with sulfamethoxazole in urinary tract infections of children. The effect of trimethorpim-sulfamethoxazole was compared with that of sulfamethoxazole alone in 26 children with urinary tract infection, randomly assigned according to a double-blind procedure to two equally sized groups. TMX-SMX was found to be superior in rendering the urine culture negative for the 3 months after the start of treatment. Also, over 12-month follow-up period there were fewer recurrences in the patients who received TMP-SMX but here the difference between the two groups did not reach statistical significance.


Trimethorpim-sulfamethoxazole in the treatment of chronic prostatitis. Chronic prostatis is a common condition for which evidence of bacterial etiology is often lacking, possibly because of difficulty in obtaining secretion from the diseased portion of the gland. Aids to diagnosis apart from bacteriologic studies are of little value. It has been shown that trimethoprim reaches high levels in the prostatic fluid and when combined with sulfamethoxazole provides a highly effective antibacterial agent. In a survey of 40 patients with chronic prostatitis treated with TMP-SMX the usefulness of the combination was demonstrated.


Treatment of salmonella carriers with trimethoprim-sulfamethoxazole. One hundred and two patients with salmonellosis were observed, as either acute cases or asymptomatic carriers, over a span of 6 years. Twenty-eight patients were treated with antibiotics only or received no treatment; those in the treated group became negative for the infecting organisms after a mean time of 160 days, as compared with a mean of 52.4 days for those who were not treated. Seventy-four other patients were treated with frimthoprim-sulfamethoxazole (TMP-SMX) as the sole medication or after prior antibiotic therapy. Sixty of these patients (81.1%) were free from Salmonella in the mean time of 19.2 days, whereas 14 failed to respond and the condition cleared spontaneously in a mean time of 134.9 days. The poor response to treatment with TMP-SMX by children 2 years of age and younger is noted. The beneficial effects of treatment with TMP-SMX, as compared with antibiotics or no treatment at all, are examined in the light of the need to protect the public from this potentially dangerous infection.


Treatment of gonorrhea in the male with trimethoprim-sulfamethoxazole using a one- or two-dose regimen. One hundred and eighty-four male patients with uncomplicated gonorrhea were treated in a randomized double-blind trial using two drug regimens. The combinations used were co-trimoxazole (trimethoprim, 80 mg and sulfamethoxazole, 400 mg) and TMP-SDZ (sulfadiazine, 400 mg and trimethoprim, 80 mg). In 43 patients who received eight tablets of co-trimoxazole in a single dose the cure rate was 88%. In the 46 patients who received a second dose of eight tablets 24 hours later the cure rate was 100%. When TMP-SDZ was used according to the same schedule the respective cure rates were 85% (41 patients) and 86% (35 patients). It is suggested that the two-dose regimen with co-trimoxazole is very effective in the treatment of uncomplicated urethral gonorrhea in the male and that the single-dose regimen, although less effective, may well prove adequate in patients defaulting after the initial treatment. At the present time, and with our local conditions, this form of treatment should be reserved for patients sensitive to penicillin or whose infections are resistant to this agent. The attack rate for patients having an episode of gonorrhea in the 12-month period immediately preceding the trial bore a direct relation to the outcome of therapy. It was highest (26%) in the group with an unsatisfactory outcome and lowest(4.3%) in the group with the highest cure rate. No adverse toxic reactions to the drug were recorded.


Trimethoprim-resistant Enterobacteriaceae in urinary tract infection. The incidence of trimethoprim-resistant Enterobacteriaceae has not increased since the introduction of the combination trimethoprim-sulfamethoxazole (TMP-SMX) into the clinical use at our centre in 1973. Using the minimum inhibitory concentration (MIC) as the index of trimethoprim resistance, this ranged from 1.6 to 800 mug/ml; for the majority of isolates it lay between 1.6 and 12.5 mug/ml. About half of these trimethoprim-resistant organisms were sensitive to sulfonamide. In vitro data suggest that organisms resistant to sulfonamide as well as to trimethoprim, where the MIC for the former drug is 3.1 mug/ml or less, will be susceptible to the combination. More resistant organisms, i.e., those for which the MIC of trimethoprim is 6.2 mug/ml or more, often appear quite resistent to the combination. There is no evidence that previous therapy with TMP-SMX is a significant predisposing factor to infection with these organisms, although there is a significant correlation between previous TMP-SMX therapy and infection with organisms with a high level of trimethoprim resistance. Organisms harbouring R-factor resistance or thymine-dependent mutants were not encountered during the course of this study.


In vitro sensitivity of hemophilus influenzae and streptococcus pyogenes to co-trimoxazole. The invitro testing of Hemophilus influenzae and Streptococcus pyogenes for co-trimoxazole sensitivity requires certain "defined" media that have to be free of inhibitory substances. The use of Columbia agar base with Fildes extract for H. influenzae or of blood agar for S. pyogenes may produce "false-resistant" strains. The addition of thymidine phosphorylases in the form of gentlylysed horse blood (2 to 10%) does not remove all inhibitors in those tests, especially where "undefined" agar bases are used, and results in scanty growth of H. influenzae; the addition of more than 2% results in dark plates, making reading of sensitivities difficult. Fildes agar for testing H. influenzae may be made with enriched sheep or horse blood if the proper "defined" agar base is used. The use of Wellcotest or DST (Oxoid) agar is recommended with Fildes extract for H. influenzae or with blood for S. pyogenes for in vitro testing for co-trimoxazole sensitivity. The addition of thymidine phosphorylase in the form of 2% lysed horse blood does not interfere with reading. However, it results in scanty growth of H. influenzae. Proper inoculation of plates is important. The growth on the plates should be light, dense, but not confluent. Heavy growth may render some strains "false-resistant" even when defined media are used. Our results indicate that many of the previously reported resistant strains of H. influenzae and S. pyogenes may have been "false-resistant" because of the use of "undefined" media. We believe that, in view of our results, respiratory infections may be treated with co-trimoxazole until bacteriologic studies prove that this treatment is contraindicated, since H. influenzae and S. pyogenes are usually found sensitive in vitro under proper conditions.


Comparison of ampicillin and trimethoprim-sulfamethoxazole in the short-term treatment of urinary tract infection. Two groups, each of 20 patients, with urinary tract infection were randomly chosen and treated according to a double-blind procedure with either ampicillin, 500 mg, or trimethoprimsulfamethoxazole, either drug being given 4 times daily for 10 days. A number of features of the infections were studied: the occurrence of single or multiple attacks, the presence or absence of complications whether the lower or upper urinary tract was affected, favourably with ampicillin in sterilizing the urine of patients and the bacteria involved. Trimethoprim-sulfamethoxazole was found to compare with multiple and complicated urinary tract infections during a follow-up period of 3 months.


Pharmacokinetics of trimethoprim-sulfamethoxazole in children. The present report extends experience with the use of trimethoprim-sulfamethoxazole (TMP-SMX) in children aged 3 months to 10 years. The regimen was TMP (200 mg)--SMX (1000 mg)/m-2d given in two equal doses. The drug was easily administered, well tolerated and efficacious in the treatment of a variety of infections in 12 children. A steady state had been achieved by the third dose of medication and accumulation of either component during days 1 through 4 did not occur. Serum concentrations of TMP were slightly lower in children aged less than 3 years compared with those aged 3 to 6 years but the differences were small and these results are preliminary. Peak mean serum TMP concentration was highest at day 3 when it reached 1.63 mug/ml. It is concluded that this regimen may be suboptimal for some major parenchymal infections even though the therapeutic result was excellent in most children.


Comparative efficacy of ampicillin and trimethoprim-sulfamethoxazole in otitis media. Seventy-nine children with acute otitis media were the subjects in a study designed to compare the effectiveness of ampicillin and trimethoprim-sulfamethoxazole in this infection. They received either of these two agents according to a double-blind randomized procedure that also took the child's weight into account. No significant difference was found in the clinical outcome between the two treatment regimens. Undesirable side effects from TMP-SMX were notably few.


A comparison of trimethorprim-sulfamethoxazole with sulfamethoxazole alone in infections localized to the kidneys. Ninety patients with urinary tract infections were treated in a randomized double-blind study with either a combination of trimethoprim and sulfamethoxazole (TMP-SMX) or sulfamethoxazole alone (SMX). Thirty of 42 patients treated with TMP-SMX were cured by the time of follow-up compared with 26 of 48 treated with SMX alone. Of the 29 patients infected with SMX-resistent organisms, the combination TMP-SMX cured 12 of 17, whereas SMX alone cured 2 of 12. Of the 61 patients infected with SMX-sensitive organisms, TMP-SMX cured 18 of 25; SMX alone cured 24 of 36. In 50 women the infection was found localized to The upper urinary tract by the use of the Fairley bladder washout technique. TMPsmx cured 16 or 24 of these patients with proved upper tract infections and SMX alone cured 11 of 26. Although none of these differences were significant, TMP-SMX appears to be an effective drug combination for the therapy of proved upper tract infection and is also effective in eradicating sulfonamide-resistant organisms.


Hepatitis B antigen (HBAg) infection in a hemodialysis unit. I. HL-A8 and immune response to HBAg. A total of 28 hemodialysis patients and 23 healthy individuals working in close association with the patients or their blood samples were found to possess either HBAg (22) or anti-HBAg (29). HL-A typing revealed the lack of HL-AB in the group with anti-HBAg, suggesting that the immune response to HBAg may be negatively associated with HL-AB.


Immunotherapy of prostatic carcinoma with bacillus Calmette-Guerin. Seventeen patients with histologically proven adenocarcinoma of the prostate were selected for evaluation of their immunologic competence and therapy with bacillus Calmette-Guérin (BCG). All patients were in stage D. The immune response was explored in two main aspects: cell-mediated and humoral immunity. Delayed skin hypersensitivity reaction with purified protein derivative (PPD), streptokinase-streptodornase (varidase), Candida, mumps antigen, and Trichophyton were tested. Lymphocyte reactivity was measured by in vitro blastogenesis. Serum immunoglobulin levels and serum protein electrophoresis were also measured. The patients were then divided in two groups according to the skin test response to PPD. Group 1 (PPD-positive) consisted of seven patients. Group 2 (PPD-negative) consisted of ten patients. In group 1, two patients were treated with intraprostatic injection of BCG every week in the following doses: 1 cc the first week, 2 cc the second week, 4 cc the third week, and 6 cc the fourth week. The five remaining patients in this group received only 1 cc every week for 4 weeks. The group 2 patients (PPD-negative) were stimulated by oral intake of BCG in an attempt to convert their skin tests to positive. All patients revealed varying degrees of immunodepression. None of the patients in group 2 (stimulated by oral intake of BCG) converted to positive skin tests. Three patients in group 1 treated with BCG showed necrosis of the tumor. The different aspects of immunodepression in this disease are analyzed and correlated to the clinical staging, histologic grading, and response to therapy. The mechanism of BCG action in advanced prostatic carcinoma is discussed.


Comparison of adriamycin (NSC-123127) and the combination of 5-fluorouracil (NSC-19893) and cyclophosphamide (NSC-26271) in advanced prostatic cancer: a preliminary report. A preliminary report on chemotherapy for advanced prostate malignancy is presented. Nine patients have been entered in the study, of which eight are evaluable for tumor response. Of four patients initially treated with adriamycin, only one brief (5-week) objective response was noted in a patient with soft tissue disease. No responses have been seen in four patients treated with the combination of 5-fluorouracil and cyclophosphamide. No responses have been noted in five patients who failed initial treatment and were crossed over to the other treatment. Durg toxicity has been quite acceptable.


Clinical trial of 2-bromo-alpha-ergocryptine (NSC-169774) in human prostatic cancer. An EORTC type I clinical trial of 2-bromo-alpha ergocryptine was performed in patients with prostatic carcinoma in clinical stages III and IV. Evaluating rules of response to the therapy were based on objective criteria. The maximum period of followup was 16 weeks. No objective remissions were observed in 24 patients, and in 13 of these patients, evidence of progression of the disease was apparent during the first 8 weeks of drug administration.


Oral estramustine phosphate (NSC-89199) in the treatment of advanced (stage D) carcinoma of the prostate. Thirty-two patients with stage D carcinoma of the prostate were treated with oral estramustine phosphate at a dose of 15 mg/kg/day from 3 to 15 months. Objective remissions, reduction of greater than 50 percent of measurable lesions such as soft tissue masses, lymph nodes, and prostatic masses, were seen in seven of 32 patients (22 percent response rate). Subjective response, ie, relief of pain, weight gain, sense of well being, snd improved performance status, occurred in all objective responders and in seven other patients with stable disease (15 of 32 patients = 47 percent). No hematologic, hepatic, or renal toxic effects were observed. Transient nausea occurred early in one half of the patients and nausea and vomiting was dose limiting in only two patients. Oral estramustine phosphate is well tolerated and worthy of further clinical use.


The Veterans' Administration Cooperative Urological Research Group studies of carcinoma of the prostate: a review. The Veterans' Administration Cooperative Urological Research Group has conducted three consecutive randomized clinical trials of various treatments for all stages of prostatic carcinoma. Thus far, a total of 3774 patients have been entered into these three main studies. The first study showed that early endocrine treatment of patients with advanced prostatic cancer did not increase overall survival when compared to initial treatment with placebo alone. Diethylstilbestrol, when given in a dose of 5.0 mg/day, was associated with an increased incidence of cardiovascular deaths. In the second study, diethylstilbestrol given in a dose of 1.0 mg/day has been as effective as the 5.0-mg dose in controlling the prostatic carcinoma but has been associated with a lower incidence of cardiovascular deaths. Patients are still being entered into the third study and it is too early to report the findings in detail.


Clinical results with estramustine phosphate (NSC-89199): a comparison of the intravenous and oral preparations. The clinical results with estramustine phosphate in far-advanced carcinoma of the prostate refractory to other treatments are presented. Good clinical results have been achieved in about 40 percent of the 90 patients treated and regression of metastases has occurred in about 20 percent. Estramustine phosphate in the primary treatment of far-advanced carcinoma of the prostate shows very good and promising clinical results. A total of 132 patients were treated.


Serial labeling index determination as a predictor of response in human solid tumors. A rapid method for determining labeling indices in solid tumor specimens, tumor-induced effusions, and tumor-bearing bone marrows was utilized in 116 patients. Of these, 48 patients were studied pre- and postchemotherapy. The magnitude of a significant change in labeling index (LI percent) was determined statistically. Of the 48 patients studied serially, 42 were studied 17 days or less following completion of their chemotherapy. In 26 patients without a significant change in tumor LI percent, there was no subsequent clinical response to chemotherapy. Three additional patients in this group are inevaluable at present. In 11 patients, there was a significant fall in tumor LI percent following chemotherapy. Seven of these had a 50 percent or greater regression of demonstrable disease, one patient had definite tumor effect but the effect was not a partial response and three patients were not evaluable for clinical response. In two patients there was a significant increase in tumor LI percent and the patients had rapid tumor progression and death. Predictions derived from serial study of the LI percent by this method correlate significantly with subsequent behavior of the tumors tested following chemotherapy and may prove clinically useful in making decisions about when or whether to change therapy.


Effect of iodoacetate on the bone marrow immunocompetence of AKR mice. Studies were conducted to determine whether the sulfhydryl inhibitor, sodium iodoacetate, administered to preleukemic AKR mice and to mature C3H mice altered the immunocompetence of their bone marrow. Parameters investigated included the splenic plaque-forming capacity directed to sheep erythrocytes of bone marrow transferred from iodoacetate-treated aanimals to irradiated syngeneic recipients and the mitogenic responsiveness of bone marrow cells from untreated and iodoacetate-treated preleukemic AKR mice to phytohemagglutinin and concanavalin A. The administration of two 0.5-ml doses of 10 mM iodoacetate to preleukemic AKR mice and to C3H mice resulted in a significant increase in bone marrow immunocompetence. Irradiated mice given marrow transplants from iodoacetate-treated syngeneic donors exhibited greater numbers of plaque-forming cells directed against sheep erythrocytes than did recipients of marrow from control animals. This effect was abrogated when the donor marrow was previously treated in vitro with rabbit antimouse brain serum and the complement to remove thymus-derived lymphocytes. The mitogenic responsiveness of marrow cultures from iodoacetate-treated AKR mice to phytohemagglutinin was similar to that observed for control mice, while the response to concanavalin A was decreased. These findings suggest that the administration of iodoacetate potentiated the immunocompetence of bone marrow by affecting thymus-derived cells.


Localization of neuroblastoma in vivo with tumor-specific antibodies. Studies of the mouse C-1300 neuroblastoma were undertaken in order to isolate tumor-specific antibodies and harness them for detection of tumors in vivo. Preliminary investigations demonstrated the strain-growth specificity of the neuroblastoma in A/Jax male mice and established the requirement for tumor viability for successful adoptive passage. Intradermally passaged tumor permitted extended survival of mice so that serum could be sampled at intervals for the presence of tumor-specific antibodies. By means of an indirect radioimmunoassay with glutaraldehyde-fixed identified in the serum of tumor-bearing hosts 6 days after inoculation, with a steady increase in antibody levels observed through Day 22. An eluate in which immunoglobulin G antibodies were identified by immunoelectrophoresis was obtained from purified tumor cells by acid buffer incubation. These antibodies were labeled with 125-I, absorbed with normal tissues, and injected into tumor-bearing mice. A selectively collimated single-probe isotope localization was positioned over the intradermal tumor, while the rest of the animal was shielded with lead. With this device, 125-neuroblastoma eluate was significantly taken up in the neuroblastoma but not in the mouse head or in a reticulum cell sarcoma control. Increasing uptake of MOPC 141 125-I-immunoglobulin G was not observed in either tumor. These studies suggest that the mouse neuroblastoma may provide a source of tumor-specific, antibodies and that, with sensitive monitoring devices, these antibodies may be utilized to localize occult neoplastic tissue in vivo.


Effects of methanol extraction residue and therapeutic irradiation against established isografts and simulated local recurrence of mammary carcinomas. Female BALB/c mice carrying established isografts or simulated local recurrence implants of 2 rapidly growing mammary adenocarcinomas were treated either by injection of the methanol extraction residue (MER) fraction of killed Bacillus Calmette-Guérin organisms (given s.c. or into the tumor) or by focal X-irradiation or by both. None of the modalities of therapy effected cures, but in many instances there was a significant retardation of tumor cevelopment and prolongation of the lives of the mice. Administration of MER alone offered protection in a number of cases but less often than the other forms of treatment. Combined therapy with MER and irradiation was, on the whole, the most successful therapeutic intervention. MER or irradiation administered alone enhanced the neoplastic process only on rare occasions; this appeared to be the case even more infrequently with combined treatment. MER was most likely to be effective alone or in combination when small quantities were used and when only 1 treatment or 1 cycle of combined therapy was given. The therapeutic action of MER was not dependent on direct introduction of the agent into a neoplastic focus; s.c. administration distal to the tumor site was almost always at least as satisfactory as injection directly into the tumor mass and indeed was often more efficacious.


Dietary modifications affecting the mutagenicity of N-nitroso compounds in the host-mediated assay. The effects of various dietary modifications on the mutagenicity of dimethylnitrosamine (DMNA), N-nitrosomorpholine, and N-methyl-N-nitrosourea for Salmonella typhimurium his G-46 in the host-mediated assay were studied. The diets used were:chow, complete semisynthetic, protein-free, and all-casein, in addition to a 24-hr starvation regimen. The mutagenicity of DMNA and N-nitrosomorpholine, which require metabolic activation for their biological activity, was depressed by the complete semisynthetic diet, as compared to the mutagenicity in mice fed the chow diet. DMNA mutagenicity was depressed by the protein-free diet and enhanced by pure casein as compared with the complete semisynthetic diet. N-Nitrosomorpholine mutagenicity was enhanced by starvation, but results with mice fed the protein-free and all-casein diets were ambiguous. N-Methyl-N-nitrosourea, which does not require metabolic activation for its biological activities, responded in an opposite manner to that of DMNA; its mutagenicity was enhanced by the complete semisynthetic and protein-free diets, but was depressed by the all-casein diet.


Secretory component in human mammary carcinoma. Since secretory component is thought to be a normal glandular epithelial cell product, surgical specimens from patients with mammary carcinoma, an epithelial cancer, were studied with antisera to human free secretory component by indirect immunofluorescence microscopy. Normal breast tissue (10 cases) showed fluorescent epithelial cells confined to normal ducts. This was in marked contrast to ubvasive mammary carcinoma (20 cases), which showed intense staining of tumor cells and stromal cells in addition to the normal ductular  epithelium. Metastases in axillary lymph nodes (2 cases) showed intense fluorescence for secretory component, whereas axillary nodes without metastases from 2 patients with breast cancer showed no fluorescence. In both normal and tumor tissue, antiimmunoglobulin A stained only ducts and subepithelial plasma cells, thus establishing that the secretory component in tumor cells was not part of an intact secretory immunoglobulin A molecule. This finding was not restricted to mammary carcinoma, since preliminary studies of colon, lung, and bladder carcinoma also demonstrated tumor cells with cytoplasmic fluorescence for secretory component. In contrast, the tumor cells in 2 cases of sarcoma, a nonepithelial cancer, did not exhibit fluorescence for secretory component.


Vitamin A inhibition of keratinization in rat urinary bladder cancer cell line Nara Bladder Tumor No. 2 in meniscus gradient culture. The Nara Bladder Tumor No. 2 cell line, established from a urinary bladder carcinoma in the Wistar rat, formed keratinizing cells and multicellular pearls in meniscus gradient culture when fed with a medium of 15 or 30% fetal calf serum in Eagle's minimal essential medium. Confluent monolayer cultures were first prepared with the tubes in conventional horizontal position. When cultures were then changed to a vertical position, stratification, piling up, and aggregation of cells were observed in a few days at the aerobic end of the gradient. Keratinization appeared 1 week after the tubes were placed in vertical position. Squamous differentiation proceeded to the formation of keratin pearls, a phenomenon never observed so distinctly and in such abundance in horizontal culture. Supplements of vitamin A, as low as 1 IU/ml, added to the medium did not inhibit piling up or aggregation but did prevent keratinization. Inhibition of keratinization by vitamin A was reversible. After vitamin A was removed from the medium, the cells in the aggregates progressed to keratinization.


Immuno-electron microscopic localization of luteinizing hormone-releasing hormone in the arcuate nuclei and median eminence of the rat. Luteinizing hormone-releasing hormone (LH-RH) was localized in neurons of the arcuate nucleus and median eminence, and in many of the nerve fibres of the median eminence of the rat, by using antisera to synthetic LH-RH with the immunoglobulin-peroxidase technique or by using a soluble peroxidase-antiperoxidase complex at the electron microsc opic level. Many of the arcuate neurons and some of the median eminence neurons contained numerous densely stained granules elsewhere in the cytoplasm. Similar granules, positive for LH-RH, were observed in many nerve profiles around the capillaries of the primary portal plexus of zona palisadica and zona granulosa of the medain eminence, and such profiles may represent the release sites of LH-RH  into the portal vessels. About 20% of the nerve profiles around the primary portal plexus were LH-RH positive and the rest of the nerve profiles were negative. The negative profiles may belong to other hypophysiotropic hormones and/or to catecholaminergic fibers. Some nerve endings at the ventricular surface of the ependymal cells, in contact with the ventricular fluid, were also LH-RH positive. These nerve endings probably release their secretion into the cerebrospinal fluid. There was no staining of the mitochondria, the nuclei or the axonal membranes. Stain of varying intensity was seen in the secretory granules, and within and around the cisternae of the Golgi complex. The stained granules in the cisternae wer pleomorphic. From these observations it was concluded that the LH-RH  is packaged or condensed into granules in the Golgi cisternae.


Regulation of stable RNA synthesis and ppGpp levels in growing cells of Escherichia coli. Under the balanced condition of growth of E. coli cells, no distinct difference is observed in stable RNA and protein synthesis between CP78 (rel+) and CP79 (rel minus), whereas a considerable difference is present in RNA accumulation between NF161 (rel+) and NF162 (rel minus), where NF161 smaller than NF162. The RNA content of NF161 is lower than that of NF162 in four different cultures with different growth rates. These two sets of isogenic pairs of rel+ and rel minus strains are commonly used in the study of rel gene function; however, NF161 is a mutant in the spoT gene whose product may be responsible for the degradation of ppGpp. The basal levels of ppGpp in these four strains growing with three different growth rates were examined: NF161 (rel+ spoT minus) has a much higher content of ppGpp than do other strains. Furthermore, the contents of ppGpp tend to be lower when the above four strains are growing at a faster rate. Thus a close correlation seems to exist between the content of RNA and the basal level of ppGpp under the condition of balanced growth.


Primary role of renal homografts in setting chronic blood pressure levels in rats. The genotype of homograft kidneys plays the primary role in determining chronic blood pressure levels in two strains of rats with opposite genetically controlled propensities for hyptertension. In hypertensive rats from the hypertension-prone (S) strain, a renal homograft from the same strain resulted in a slight rise in blood pressure to a level that was equivalent to that in appropriate uninephrectomized S controls. In contrast, a renal homograft from the hypertension-resistant (R) strain led to a sharp fall in blood pressure in hypertensive S recipients. Opposite results were found when the host came from the R strain: R homografts maintained the same low pressure as that seen in controls, whereas S homografts resulted in hypertension. We concluded that genetically controlled factors operating through the kidney can chronically modify the blood pressure up or down. The central role of the kidney in hypertension is thus further documented.


Changes in myocardial blood flow and S-T segment elevation following coronary artery occlusion in dogs. The relationship between regional blood flow and epicardial S-T segment elevation was studied in 26 open-chest anesthetized dogs with left anterior coronary artery ligations. Changes in myocardial blood flow, measured with 15 plus or minus 5mu (diameter) microspheres labeled with 141-Ce, 85-Sr, and 169-Yb, were correlated with summated S-T segment elevations 15 minutes, 1 hour, and 2 hours after coronary artery occlusion. In normal areas, myocardial blood flow was 113 plus or minus 5 ml/min 100 g- minus 1 and summated S-T segment elevation was 0.3 plus or minus 0.2 mv. Fifteen minutes after coronary artery occlusion in 26 dogs, S-T segment elevation was 5.7 plus or minus 0.7 mv over the center of the infarct and myocardial blood flow was 10 plus or minus 1 ml/min 100 g- minus 1; over the border zone, myocardial blood flow was 63 plus or minus 4 ml/min 100 g- minus 1 and S-T segment elevation was 3.1 plus or minus 0.1 mv. One third of the areas with a myocardial blood flow of 10 ml/min 100 g- minus 1 or less had no S-T segment elevation. In the center and border zones of the infarct in 9 dogs, myocardial blood flow increased from 11 plus or minus 2 and 67 plus or minus 8 ml/min 100 g- minus 1 15 minutes after occlusion to 20 plus or minus 4 and 84 plus or minus 12 ml/min 100 g- minus 1, respectively, 2 hours after coronary artery occlusion. These increases were not associated with a significant reduction in summated S-T segment elevation. The results do not suggest a simple quantitative relationship between epicardial S-T segment elevation and myocardial blood flow following acute coronary artery occlusion.


Mechanism of the serotonin effect on lung transvascular fluid and protein movement in awake sheep. To see how serotonin affects filtration from lung vessels, we measured vascular pressures, lung lymph flow, lung lymph and blood plasma protein concentrations, arterial blood gases, cardiac output, and lung water content in unanesthetized sheep before and during intravenous serotonin infusions and compared serotonin effects with the effects of inflating a balloon in the left atrium in the same sheep. Serotonin caused a dose-related increase in lung lymph flow and a dose-related decrease in lymph-plasma protein concentration ratios. Steady-state 4-hour serotonin infusions at 4 mu-g/kg min-1 caused lymph flow to increase from 5.4 plus or minus 0.7 (SE) ml/hour to 8.3 plus or minus 1.3 ml/hour, lymph-plasma albumin ratios to fall from 0.78 plus or minus 0.05 to 0.72 plus or minus 0.04, lymph-plasma globulin ratios to fall from 0.64 plus or minus to 0.56 plus or minus 0.02, and pulmonary arterial and left atrial pressures to increase by 3 cm H-20 each. Lymph clearance and permeability-surface area products for eight protein fractions ranging from 36 A to 96 A in molecular radius during steady-state serotonin infusion studies were not significantly different from those during steady-state increased pressure studies. Four-hour infusions of serotonin at 4 mu-g/kg/kg min-1 caused a moderate fall in arterial Po-2 and a slight increase in arterial pH but did not affect cardiac output or cause pulmonary edema. We conclude that serotonin increases lung transvascular filtration primarily by increasing the transmural pressure gradient in exchanging vessels rather than by increasing vascular permeability.


Role of the collecting duct in the regulation of sodium balance. A large body of evidence has accumulated which demonstrates that sodium transport in some distal nephron segment is altered in response to changes in extracellular fluid volume. Sodium reabsorption in the loop of Henle and distal tubule is directly related to delivery rate and is not inhibited by volume expansion. In contrast, recent studies have shown that Ringer loading causes a greater natriuretic response than hyperoncotic albumin because of diminished collecting duct sodium transport in the former model. Additional studies in animals with different basal extracellular fluid volumes and in DOCA-escape rats indicate further that the collecting duct is an important regulator of sodium balance. Although the factors that modulate sodium transport in the collecting duct are not clear, it is postulated that the local release of prostaglandins may be of major importance.


Blood pressure regulation in end-stage renal disease and anephric man. The hemodynamic pattern of response to bilateral nephrectomy was studied in 29 patients with end-stage renal disease on maintenance hemodialysis. Four patterns of hemodynamic response were seen. In 12 patients with nonmalignant hypertension, bilateral nephrectomy reduced blood pressure and total peripheral resistance with no effects on cardiac output. In 5 patients with malignant hypertension, bilateral nephrectomy reduced blood pressure, increased cardiac index, and reduced total peripheral resistance more markedly. In these two groups, at equivalent levels of total exchangeable sodium, before and after bilateral nephrectomy, mean arterial pressure and total peripheral resistance were invaribly lower in the absence of renal tissue. In 3 additional patients with nonmalignant hypertension, the decrease in blood pressure after bilateral nephrectomy was delayed from 3 to 12 weeks. When this occurred spontaneously, it was accompanied by a decrease in total peripheral resistance. The fourth hemodynamic pattern was seen in 6 normotensive patients with end-stage renal disease. After bilateral nephrectomy, there were no significant changes in mean arterial pressure, total peripheral resistance, or cardiac output. Salt and water loading failed to elevate blood pressure significantly. Renal transplantation was performed in 3 hypertensive patients before removal of the end-stage kidney. The functioning renal homograft did not result in normal blood pressure as long as the end-stage kidneys remained in place. Removal of the end-stage kidneys significantly decreased mean arterial pressure and total peripheral resistance. In the anephric state, a sharp difference was seen in blood pressure response to salt and water loading between previously normotensive and previously hypertensive patients. Previously hypertensive patients responded with a progressive increase in blood pressure that reached hypertensive levels. Previously normotensive patients failed to elevate their blood pressure significantly. It is concluded that the vasopressor function of the kidney is the most important factor in the pathophysiology of hypertension of end-state renal disease. Expansion of body fluid plays a role, but elevates the blood pressure only in patients who were previously hypertensive. The antihypertensive function of the kidney does not appear to be a major factor in the regulation of blood pressure in end-stage renal disease.


Development and maintenance of renal hypertension in normal and guanethidine sympathectomized rats. The sympathetic nervous system has been postulated to play a role in the maintenance of renal hypertension. Permanent peripheral sympathectomy was performed by treating newborn rats for 21 days with guanethidine. Sympathectomy was confirmed by (1) relative insensitivity to tyramine, (2) lack of responsiveness to renal nerve stimulation, and (3) absence of dopamine-beta-hydroxylase immunofluorescence in renal blood vessels. Placement of a clip on the left renal artery led to the development of two-kidney renal hypertension. No differences were observed between the two-kidney renal hypertensive normal and sympathectomized rats; both had elevated plasma renin activity and vasodepression with angiotensin antagonists which were maintained up to nine weeks. Furthermore, in normal rats chronic beta-adrenergic blockade with propranolol caused no change in the development of the two-kidney renal hypertension. Similarly, no differences were seen in blood pressure, plasma renin activity, or response to antagonists between the one-kidney renal hypertensive (clip plus contralateral nephrectomy) normal and sympathectomized rats. Both showed sustained low renin hypertension up to 12 weeks. The absence of the peripheral sympathetic nervous system did not affect the development or maintenance of hypertension in either model of hypertension.


Cardiovascular regulation by central adrenergic mechanisms and its alteration by hypotensive drugs. Electrical stimulation of the posterior hypothalamus is followed by an immediate increase in sympathetic nerve activity and rise in blood pressure. Destruction of hypothalamic adrenergic structures by local unilateral injection of 6-hydroxydopamine into the posterior hypothalamus reduced the blood pressure rise in response to stimulation of the lesioned side. This and numerous other findings indicate an involvement of central adrenergic neurons in the mediation of an increase of sympathetic nerve activity caused by hypothalamic stimulation. However, central adrenergic neurons do not seem to be an integral part of the sympathoexcitatory pathways originating in the posterior hypothalamus but rather facilitate their activation: after almost complete norepinephrine depletion produced by combined treatment with reserpine and alpha-methl-p-tyrosine, hypothalamic stimulation was still followed by an increase in spontaneous sympathetic nerve activity. Stimulation of an alpha-adrenoceptive site, probably located in the lower brain stem, mimics an activation of the baroreceptor reflex. The hypotensive drug, clonidine, stimulates this alpha-adrenoceptive site. In low doses clonidine facilitates the activation of the reflex, and in high doses this drug induces a state which closely resembles a pronounced activation of the reflex. Experiments following depletion of norepinephrine suggest that the central part of the baroreceptor reflex arc does not contain adrenergic neurons. However, these findings are compatible with the view that some neurons within the reflex arc are supplied with alpha-adrenoceptors. For the present it cannot be stated with certainty whether these alpha-adrenoceptors possess an innervation by adrenergic neurons projecting onto the reflex arc. In favor of such an innervation are the obsevations that alpha-methyldopa has its site of action in the lower brain stem and that the integrity of central adrenergic neurons is essential for its hypotensive effect. It seems that two central adrenergic systems exist with opposing effects on cardiovascular control. These are an excitatory hypothalamic and an inhibitory bulbar adrenergic system. Partial destruction of central adrenergic neurons by intraventricularly injected 6-hydroxydopamine prevents the development of DOCA/NaCl, renal, and neurogenic hypertension and alters the pattern of blood pressure rise in spontaneously hypertensive rats. Impairment of central adrenergic function or imbalance of the two central adrenergic mechanisms may represent a trigger mechanism for the initiation of hypertension.


Effect of salt depletion and propranolol on blood pressure and plasma renin activity in various forms of hypertension. The effect of propranolol therapy on the mean arterial pressure (MAP) and plasma renin activity (PRA) was studied in three groups of hypertensive patients who were also treated with saliuretics. Group A: In 14 patients with essential hypertension on chlorthalidone treatment, an additional daily dose of 640 mg propranolol for two months led to a significant reduction of the MAP (from 124 to 105 mm Hg) and PRA (from 5.3 to 2.0 ng AI/ml/hr standing). There was no correlation between MAP reduction and either the original levels or change in PRA. Group B: In 14 patients with essential hypertension and 5 with renal artery stenosis studied on a fixed salt intake, the plasma and extracellular volumes, PRA, and blood pressures were recorded before and after three days of diuretic induced salt depletion and, with maintenance of the depleted state, after three days of propranolol. Salt depletion resulted in a decrease in MAP from 132 to 128 mm Hg (NS), and PRA increased from 3.4 to 22.3 ng AI/ml/hr (P less than 0.01). There was no correlation between change in MAP and PRA control values, PRA change, or any of the volume parameters. Addition of propranolol was followed by a rapid MAP decrease to 111 mm Hg (P less than 0.01), and the PRA dropped to a mean of 8.5 (P less than 0.01). No correlation was found between change in MAP and change in PRA. The patients with renal artery stenosis did not differ in their reactions from those with essential hypertension. Group C: In five patients with moderate renal failure and normal to expanded 82-Br distribution volume, propranolol lowered MAP by 10% and lowered the PRA in all five. Salt depletion by furosemide to 82-Br volumes below normal resulted in a 10% decrease of MAP and a marked rise in PRA. In this state propranolol was followed by a further MAP reduction of 18% and a decrease in PRA. There was no quantitative relationship between MAP and PRA change during either of the treatment regimes. It is concluded that in various forms of hypertension, the blood pressure can be effectively lowered by combining diuretics and propranolol regardless of the pretreatment PRA level.


Pharmacological effects of alpha-methyldopa, alpha-methylnorepinephrine, and octopamine on rat arteriolar, arterial, and terminal vascular smooth. Experiments on rat mesenteric arterioles, metarterioles, and aortae demonstrate that although alpha-methylnorepinephrine is much less potent in inducing contraction than epinephrine on all three blood vessel types, it is either equivalent or only one and a half to two times less potent than the natural postganglionic neurotransmitter, norepinephrine, on these blood vessels. Furthermore, alpha-methylnorepinephrine is equivalent to norepinephrine in its ability to induce maximal contractile responses on rat arterioles, metarterioles, and aortae. Systemic administration of alpha-methyldopa to rats for 15 days shifted the log dose-response curves for all three catecholamines, but not vasopressin or potassium chloride, to the right of all three blood vessel types; the maximal contractile responses to these amines were, however, not affected by chronic treatment with alpha-methyldopa. In addition, acute, intra-arterial administration of 500 mg/kg of alpha-methyldopa was found not only to induce mesenteric arteriolar vasodilatation gradually but also to depress arteriolar reponsiveness to catecholamines. In view of these direct findings, it is difficult to accept the hypothesis that alpha-methyldopa induces hypotension via formation of a "false" postganglionic neurotransmitter substance, namely, alpha-methylnorepinephrine. The present findings suggest that alpha-methyldopa may exert some of its anti-hypertensive action, at least in the rat, by (1) depressing arteriolar responsiveness to circulating and released catecholamines and (2) some unknown direct action on peripheral vascular muscle. In addition, the present study indicates that octopamine is (1) between 60 and 15,000 times less potent than norepinephrine on rat arterioles and metarterioles and (2) incapable of eliciting more than a 40% occlusion of these terminal vessels. It is suggested that such data support the concept that octopamine, in contrast to alpha-methylnorepinephrine, could serve as a false adrenergic neurotransmitter agent and thus account for part or all of the hypotensive action of monoamine oxidase inhibitors like pargyline. The use of complete dose-response curves, several different adrenergic compounds (i.e., epinephrine, norepinephrine, alpha-methylnorepinephrine, octopamine, phenylephrine, and dopamine), and different rat blood vessels supports the concept that adrenergic molecules containing a catecholamine nucleus and a beta-hydroxyl group elicit the most potent constrictor responses from peripheral blood vessels. In addition, the data suggest that the structure-activity relationships for catecholamines and their analogs on terminal vascular smooth muscle are probably different from those for arterial smooth muscle.


Partial versus complete control of blood pressure in the prevention of hypertensive complications. The data from the Veterans Administration Cooperative Study on Antihypertensive Agents Prevention of Morbidity Trial were reviewed from the point of view of the importance of normalizing the blood pressure in preventing cardiovascular complications. The treated group of patients was subdivided into three subgroups on the basis of the diastolic blood pressures recorded at the fourth month after randomization as follows: subgroup A, the poorly controlled patients whose diastolic blood pressures were 90 mm Hg or higher, an intermediate subgroup B with diatolic levels of 81 to 89 mm Hg, and subgroup C, the best controlled patients, all of whom exhibited diastolic blood pressures of 80 mm Hg or less. While the incidence of morbid events was slightly higher in subgroup A than in the other subgroups, the differences were not statistically significant. On the other hand, the incidence of morbid events in subgroup A was significantly lower (P less than 0.05) than in the untreated control patients (14.9% in subgroup A vs. 28.9% in the control group). While normalization of blood pressure is a desirable goal of treatment, even partial reduction appears to exert significant therapeutic benefit.


Return of elevated blood pressure after withdrawal of antihypertensive drugs. The rate at which arterial pressure rises after discontinuing active treatment was investigated in a group of 86 hypertensive patients who received treatment with hydrochlorothiazide, reserpine and hydralazine for two years or longer and whose diastolic pressures averaged below 96 mm Hg for the last year of treatment. Sixty patients were assigned double-blind to placebos and 26 were continued on active drugs. Forty-two of the placebo group of patients were removed over an 18 month follow-up because of return of elevated blood pressures, 39 being removed in the first six months. Six patients in the placebo group and none in the treated group were removed because of morbid events. Nine or 15% of the placebo patients remained normotensive. The rate of rise in arterial pressure in the placebo group appeared to be related directly to the height of the pressure prior to initiation of active treatment and inversely to the age of the patients. Serum uric acid fell significantly while serum potassium rose significantly after active treatment was discontinued. The glucose tolerance test changed slightly in a direction toward normal while serum creatinine showed no significant change.


Radionuclide angiocardiography. Improved diagnosis and quantitation of left-to-right shunts using area ratio techniques in children. A comparison of several reported methods for detection and quantitation of left-to-right shunts by radionuclides was performed in 50 children. Count ratio (C2/C1) techniques were compared with the exponential extrapolation and gamma function area ratio techniques. C2/C1 ratios accurately detected shunts and could reliably separate shunts from normals, but there was a high rate of false positives in children with valvular heart disease. The area ratio methods provided more accurate shunt quantitation and a better separation of patients with valvular heart disease than did the C2/C1 ratio. The gamma function method showed a higher correlation with oximetry than the exponential method, but the difference was not statistically significant. For accurate shunt quantitation and a reliable separation of patients with valvular heart disease from those with shunts, area ratio calculations are preferable to the C2/C1 ratio.


Diagnostic techniques: closed biopsy of bone. Closed biopsy of bone has proven to be a useful and accurate method of establishing the diagnosis of certain primary and secondary bone tumors, infections, and metabolic disorders. The use of a Craig needle for biopsy has simplified this technique and has provided the orthopedic surgeon with an excellent diagnostic tool.


Bone scanning: principles, technique and interpretation. Bone scanning is most useful in the detection of bone metastases. The recent introduction of new radiopharmaceuticals and instrumentation has reduced the time needed to perform the study and its relative cost, while increasing the usefulness of the study in detecting roentgenographically occult diseases. Metastatic disease is used as the pathophysiologic model for understanding the principles of bone scanning. When a tumor invades bone, in addition to causing bone destruction, it also causes reactive bone formation or repair. It is here that radioisotopes are of considerable value, since some radionuclides are incorporated into the hydroxyapatite crystals of reactive bone. Bone repair is described as occurring in three phases. In Phase I, the roentgenogram shows no change in bone density, but the scan is abnormal. In Phase II, both scintigraphic and roentgenographic abnormalities increase, and in Phase III, when the osteoid has calcified completely, the roentgenogram shows radiodensities and the scan appears almost normal. Fewer than 5 per cent of patients have a normal scan in the presence of an abnormal roentgenogram. Presently, most bone scans are performed with phosphate compounds labeled with -99m-Tc. In the past, 85-Sr, 87M-Sr, and 18-F were more broadly used. Scanning may be performed on either a rectilinear scanner or a scintophoto (gamma) camera. Areas which are abnormal on bone scan should be interpreted with current roentgenograms in the light of clinical findings.


The detection of venous thrombosis.

The detection of venous thrombosis. It is imperative that the orthopedic surgeon recognize the magnitude of the problem of thromboembolic disease. It is the most common complication of trauma or surgical procedures. Because the clinical signs and symptoms of deep venous thrombosis are so variable, and since pulmonary embolism is often the first sign of deep venous thrombosis, we must continue to refine our techniques for screening and diagnosis. The 125-I fibrinogen localization of propagating venous thrombi in the legs is a very promising and sensitive screening procedure. With refinements, the Doppler effect flowmeter and impedance phlebography may prove to be valuable screening techniques. Venography is still one of the most effective procedures in detecting venous thrombi and remains the standard of detection. The search must continue for better methods of prevention, diagnosis, and treatment.


Minimal internal fixation of tibial fractures. Flexible wire and small pins cause minimal disturbance of osseous blood supply, and introduce minimal foreign material into the wound. Supplemental support by a plaster cast or by traction is required, but the external support can generally be discontinued  early for joint mobilization. Several simple auxillary fixation devices extend the usefulness of wire fixation. Removal of metal is not required. Many common fractures of the tibia are amenable to this method of minimal internal fixation. In the diaphysis, long oblique fractures are the most suitable for this application; the firmness of their fixation by cerclage is augmented by muscle pull. Rotation is effectively controlled by a plate which is L-shaped in cross section, and is held in position by cerclage. In the metaphysis, articular fractures of the knee and ankle are securely fixed by a flattened loop of wire and two washers (wire-washer set), supplemented sometimes by pins or hand-made staples. Two pins alone provide excellent fixation of the medial malleolus. A single pin, or a single wire loop through drill holes, may be sufficient to impart stability to an unstable tibial fracture. A key-type graft of iliac bone, maintained by crossed wire loops through cortical drill holes, is effective in the tibial diaphysis. Autogenous iliac cancellous chips provide minimal and effective internal fixation for an infected ununited fracture of the tibia. The surgical instrument most important for making wire fixation highly successful is a tightener-twister which protects wire loops from excessive strain during application, and permits twisting at a predetermined and therefore reproducible tension. Other special and ordinary instruments are valuable assets.


Electrodiagnosis in orthopedic surgery.

Electrodiagnosis in orthopedic surgery. The electromyogram is gaining importance as a diagnostic tool in the clinical practice of orthopedic surgery. Its uses in the area of kinesiology will undoubtedly be further developed in the future in ways which can be standardized and made available to the practicing orthopedist to improve the results of muscle and tendon surgery and the design of surgical procedures. It should be noted that in either case electromyograms can be utilized to give a great deal of valuable information concerning the competence of the motor unit, the functioning mass of muscle fibers and the phasic relationships of muscle groups. Its value in diagnosis, however, depends directly upon the care with which it is performed, the patience of the electromyographer in sampling an adequate quantity of muscle mass to be certain that nothing has been overlooked and, above all, the specificity of the orthopedic surgeon in delineating exactly what information he wishes to obtain, so that the performance of the electromyogram can be confirmed and aimed directly at producing answers to the questions he is asking. In this regard, the electromyogram is in no sense a screening test or a catchall which the orthopedic surgeon can substitute for a careful clinical evaluation.


Fractures of tibial plateaus.  A review of the literature. Tibial plateau fractures, common injuries in the middle-aged, often result from falls or vehicular accidents.  The wide spectrum of fracture patterns can be theoretically related to the sequential application of bending (valgus/varus) and compression forces.  End-results of 599 fractures in 13 different studies were compared by fracture pattern using a clear-cut fracture classification.  Minimally displaced (less than 5-10 mm displacement) fractures average 85-90 per cent acceptable end-results.  Associated soft tissue lesions include frequent meniscal (50% of cases) and ligamentous (10-30%) injuries.  Vascular and nerve injuries are most unusual: non-union is not reported.  A diagnostic and therapeutic approach is outlined.  The assessment of bony and/or ligamentous instability is stressed.  Reduction is required in most displaced fractures: open reduction and rigid internal fixation with ample bone grafting is suggested in displaced local depression fractures and other unstable fracture types refractory to closed reduction.  Operative repair of ruptured ligaments seems indicated.  Early knee motion is important in all fractures.  In unstable fractures angular alignment must be maintained (rigid internal fixation, skeletal traction, or bracing) during early motion.  Quadriceps rehabilitation must be vigorous.  Weight-bearing should be deferred for at least three months.  The cast brace is useful in unicondylar fractures.


Pathologic-anatomical findings and cerebral localization in stereotactic treatment of extrapyramidal motor disturbances in multiple sclerosis. Two postmortem case of multiple sclerosis treated by sterotactic operations for the intention shaking of limbs, trunk, and head, and for the action myoclonus are analyzed to determine the location of the substrate of myoclonic and ballistic movements, the location of the coagulations for relief of these movements, and whether fresh demyelinating foci are elicited by intracerebral interventions. In the first case of a clinically typical multiple sclerosis, the foci responsible for the severe action myoclonus and intention ataxia of the trunk are demyelinations in the right and left red nucleus resulting in nerve cell damage and loss and an almost complete destruction of myelinated fibers. The restricted foci in the white matter of the cerebellum which do not involve the cerebellar nuclei are not extensive enough or old enough to be the cause of the action myoclonus but may, perhaps, sustain the pathogenesis. - In the second case of cerebral palsy and combined multiple sclerosis (detected post mortem), the combination of the severe damage of putamen and caudate nucleus by status marmoratus and the extensive nerve cell and fiber damage due to demyelinating foci in the substantia nigra are probably the substrate of the jactitation and intention myoclonus of the left limbs. The stereotactic coagulation of the dentatothalamic and pallidothalamic fibers in the base of V. o.p. and V.o.a. at the point where they pass through the zona incerta (location confirmed post mortem) resulted in a nearly complete relief of hyperkinetic movements. In the first case, fresh demyelinating foci are present in both hemispheres with stereotactic interventions; these foci are located, amongother places, around the coagulation and the electrode track. In the second case, post mortem serial brain sections demonstrate that stereotactic operations even in subacute multiple sclerosis can be carried out without eliciting any exacerbation of demyelination foci. Therefore, the danger exists that stereotactic intervention in cases of multiple sclerosis may precipitate fresh demyelinating foci. As our clinical experience [Riechert and Richter, 1972a, b] indicates, however, this occurred in markedly less than 10% of the cases.


Permeability changes in the blood-brain barrier: causes and consequences. 1. Generalized changes in blood-brain barrier (BBB) permeability are accompanied by extravasation of plasma proteins; thus, they are readily studied with protein markers or protein-dye complexes. Selective changes in permeability involve alterations in BBB transport systems; they are best studied with techniques which detect the qualitative hallmarks of carrier-mediated transport, namely saturation, competition, and stereospecificity. 2. Quantitative assessments of the selective permeability of the BBB can be made from the saturation data expressed in terms of Michaelis-Menten kinetics. The advantages of the latter are twofold: (a) alterations elicited by modified barrier affinity (Km) can be distinguished from alterations in carrier capacity (Vmax); (b) the relative rates of flux of a metabolite across the BBB can be placed in the perspective of cerebral metabolism. Kinetic data on transport processes in the BBB are obtained by either constant infusion or single injection techniques. Results obtained with both methodologies have been comparable. 3. Independent transport systems for glucose, neutral amino acids, basic amino acids, and monocarboxylic acids have been identified in the BBB. The description of these transport systems in kinetic terms provides a background of information on intact mechanisms to which altered transport can be compared. 4. Experimental evidence indicates that the availability of key metabolic substrates, such as glucose or essential amino acids, may be rate-limiting in cerebral metabolism. A working hypothesis was developed that the consequences of a selective change in barrier permeability to one or more of these essential substrates are directly related to altered rates of reaction in substrate-limited pathways, e.g., cerebral protein or neuro-transmitter biosynthesis. 5. Toxicological causes of generalized changes in BBB permeability include hypertonic solutions, organic solvents, surface-active agents, enzymes, and heavy metals. Some agents, e.g., mercury or hypertonic urea, induce selective changes in BBB transport at doses much lower than those required for nonspecific barrier break-down. Subtle changes in transport of metabolic substrates may remain unrecognized unless specifically investigated, yet may have profound consequences on brain metabolism. 6. Pathological processes can also induce selective changes in BBB permeability. Such changes often temporally precede the more generalized alterations in permeability that can occur during pathogenesis. For example, in brain edema due to an ischemic infarct, glucose transport increases during the early cytotoxic phase, whereas generalized changes are not detected until the later vasogenic phase.


X inactivation, differentiation, and DNA methylation. A model based on DNA methylation is proposed to explain the initiation and maintenance of mammalian X inactivation and certain aspects of other permanent events in eukaryotic cell differentiation. A key feature of the model is the proposal of sequence-specific DNA methylases that methylate unmethylated sites with great difficulty but easily methylate half-methylated sites. Although such enzymes have not yet been detected in eukaryotes, they are known in bacteria. An argument is presented, based on recent data on DNA-binding proteins, that DNA methylation should affect the binding of regulatory proteins. In support of the model, short reviews are included covering both mammalian X inactivation and bacterial restriction and modification enzymes.


The synaptonemal complex and the spindle plaque during meiosis in yeast. Meiosis in Saccharomyces cerevisiae proceeds principally in the same manner as in other Ascomycetes. Leptotene is characterized by unpaired lateral components and pachytene by the presence of extensive synaptonemal complexes. The synaptonemal complex has the same dimensions and is similar in structure to those described for other organisms. Chromosome counts can now be made by reconstructing the synaptonemal complexes. Diplotene nuclei consistently contain a single polycomplex. The behaviour, doubling and the fine structure of the spindle plaque provide additional markers for the different stages of meiosis.


Lampbrush-type chromosomes in the primary nucleus of the green alga Acetabularia mediterranea. Structures with a lampbruch-chromosome-like morphology are described in the nucleoplasm of primary nuclei of the green alga, Acetabularia mediterranea, by light and electron microscopy in sections of cells fixed in situ and in spread preparations of isolated nuclear components. These chromosomes reveal typical loops (up to 20 micronm long), chromomere-like nodules (1-2 micronm in diameter), and 2-4 micronm large axial globules. Associations of some of these chromosomes with nucleolar structures and with the nuclear envelope are also recognized. The light microscopically identified loops are correlated with distinct fibrillogranular structures observed in the thin sections and with the very long matrix units seen in the spread preparations. The similarity of these structures to the lampbrush chromosomes of various animal cell types, all exclusively stages of meiotic prophase, is discussed as well as the possible relation of the appearance of lampbrush chromosomes to a defined phase of the vegatative growth of this alga.


Investigation of cellular interaction and deployment in the early mammalian embryo using interspecific chimaeras between the rat and mouse. Mammalian chimaeras can be produced experimentally by aggregating early embryos or by injecting cells into them.  They have been used to study several aspects of early development.  However, lack of a genetic marker enabling unequivocal identification of all cells of either genotype in situ has frustrated full exploitation of the experimental possibilities offered by these organisms.  Hence interspecific chimaeras have been produced between rat and mouse embryos in which cells of the two species can be identified in sectioned embryos by immune fluorescence.  These chimaeric embryos have been used to study differentiation of the trophoblast and inner cell mass, and the deployment of cells during morphogenesis.  Preliminary results suggest that the two tissues are determined by the blastocyst stage, and that the trophoblast forms part of the extra-embryonic membranes originally presumed to be derived from the inner cell mass.  Also, rat inner cell mass cells can induce mitosis in mouse trophoblast.  Futhermore, the distribution of rat cells in implanted embryos suggests that the embryo may grow in a coherent clonal manner from a very early stage.  Very recently, chimaerism has been induced by transplanting single rat cells, which may allow a more critical analysis of morphogenesis and determination than was possible hitherto.  An obvious question raised by crossing the species barrier is the extent to which results may be applicable to normal development.  Adverse effects of immunological interaction between the mouse uterine foster-mother and fetal rat cells, and sorting out of cells according to species, are two of the problems that might complicate interpretation of these experiments.


[Autologous renal transplantation for renovascular hypertension (author's transl)]. Renovascular hypertension was diagnosed in a 20-year-old man as being due to bilateral renal-artery stenoses and infrarenal aortic coarctation. Reconstruction of the renal arterial supply by vein graft and aortorenal bypass failed to reduce the hypertension. But after bilateral autotransplantation of the kidneys into the iliac fossa and a dacron lay-on graft over the coarcted region the arterial blood pressure returned to normal. Pre-operative measurement of plasma-renin concentration in renal vein blood and the patient's age are essential factors in deciding on reconstructive surgery of a stenosed renal artery.


[Anterior pituitary regulation of testicular function in the elderly (author's transl)]. Pituitary gonadotrophin regulation was examined with the LH-RH test in 15 men (aged between 55 and 90 years), five of them aged between 71 and 90 years. Compared to normal mature males, the plasma testosterone in these subjects was reduced or was in the lower range of normal, while basal LH levels were increased in half the cases. However, basal FSH values were increased in three only. In most of these subjects with increased basal values of LH, the LH-RH stimulation caused a paradoxical temporary reduction in LH release which did not occur with FSH. This paradoxical response also did not occur when basal LH values were normal.


[Improving bacteriological diagnosis by using culture medium during transport of specimens (author's transl)]. It is well known that long transport diminishes the chances of isolating causative micro- organisms, especially from swabs. In a trial, in which beta-haemolytic streptococci were kept for 24-hours at room temperature, culturing failed even if more than one million bacteria had been placed on the swab. Culture medium consisting of agar with 0.5% human albumin made it possible to isolate beta-haemolytic streptococci even after transport and with a count of less than a hundred micro-organisms per swab. The use of selective nutrient media may be necessary because of the sometimes marked multiplication during transport when there are mixed organisms. The nutrient medium was used during six small epidemics of scarlet fever in Freiburg and proved superior to the usual dry swab. In parallel studies of patients and contacts the causative beta-haemolytic streptococcus was isolated three times as often.


[Studies on heat generation by drills of various abrasion grade]. By means of our own measuring method, drilling tests were performed at a test block made of silicate cement using rose-head and fissure burs as well as diamond-stones with different feed.  The temperature increases only within a limited range of wear and tear, it does not increase rectilinearly but stepwise, mainly influenced by two heat values, the shearing and the friction heat.  Having reached the temperature maximum, further drilling or further wear and tear only prolong drilling time.  The danger of damaging the pulp is primarily dependent on the feed and less on wear and tear, as was shown by the tests with the rose head burs.  Only when the feed is rising, the worn-out driller further increases a rise in temperature.


[Prosthetics and prevention of periodontal diseases]. This paper gives a survey of the present knowledge regarding prosthetical treatment under the aspects of preventing periodontal disease.  This survey is based on the German publications mainly of the past ten years.  In the beginning, the prevention of periodontal disease is weighed against the requirements of caries prophylaxis.  Then the requirements of periodontal hygiene are described that are inevitable for the beginning of treatment as well as for the dentures themselves.  The marginal periodontium that is in contact with the margin of the crown is generally regarded as an area of minor resistance, therefore particular attention should be given to this point of contact.  Construction of removable, partial dentures for partially edentulous jaws is also discussed in detail.  Final conclusions show that our knowledge in this specific field has been broadened.


[Economic value in the therapy of edentulous masticatory system]. In the present paper it is tried to analyze the economic value of prosthetical treatment of edentulous jaws which has to be performed from the physiological and gnathological viewpoints.  After defining the therapeutical objective and after  standardizing case histories, and medical examinations as well as therapy, well-known individual methodological measures are described which are indispensable for achieving the therapeutical aim.  Analysis of therapy, definition of therapeutical objective and standardization of case histories, medical examination, therapy, and methodological individual measures can be used for--rationalizing working procedures in the dental office, --evaluating new methods, --evaluating full dentures, --further elaborating ill-defined methodological steps, --investigating ill-defined therapeutical measures.


[Marker-evidence for documentation and evaluation of findings and treatment in fractures of the facial skull]. A special form is presented by means of which clinical findings and therapy of fractures of the visceral cranium are documented in such a way that the data can be fed into a computer and be evaluated.  Like similar forms for cheilognathopalatoschisis and tumors of the jaw and face area the present form is meant for a special field or specific problems and is not to replace the traditional case history.


[A new substituted benzamide with neuroleptic effects: lin 14 18 or sultopride]. After the research about Sulpiride, a new substituted benzamide has been studied. Although it was characterized by modest pharmacological effects in the neuroleptic identification tests, LIN 1418 turned out to have very interesting therapeutic properties. A study conducted with 50 cases, 30 of which were submitted a systematic pluridisciplinary control, leads to provisory conclusions as follows: 1) its psychotropic effects are powerful and constant; 2) its prevailing action is antipsychotic and desinhibiting altogether; 3) while LIN 1418 appears as successful with all psychoses, whether acute or chronic, up to now, the quality of its results in many chronic psychoses seems to be particularly remarkable; 4) its side-effects are those of most neuroleptics: its extrapyramidal symptoms being all the more obvious as the patient's "passivity" is less important.


[Situation of sultopride among present-day neuroleptics]. The authors report preliminary clinical investigations about sultopride, a new substituted benzamid, related to sulpiride. The drug was administered to thirty-nine hospitalized psychotic patients. A very powerful and constant efficacy of sultopride was observed in 11 manic and hypomanic typical syndroms: excitation was controlled between the first and third day, with oral doses of 1,200-1,800 mg. But thymical inversion was observed in 8 cases (3 light anxious states and 5 typical melancholic syndroms). Besides, interesting improvements were obtained in atypical excitation disorders, chronic hallucinatory delusions, acute oniric and confusional states, schizophrenia and chronic alcoholism. Side-effects were frequent: extrapyramidal syndroms, often requiring antiparkinsonian correctors, somnolence, asthenia, and above all (in 30 percent of cases) psychical side-effects, consisting in depressive and anxious modifications of mood, even apart from manic-melancholic psychosis. This psychotropic depressive effect appears as very interesting theoretically, and justifies further enquiry.


[Comparison of clinical effects of delta-9-tetrahydrocannabinol with the classic effects of hashish]. Moreau de Tours's classical studies about haschisch had pointed out to a rich symptomatology: visual and auditive hallucinations preceded by the "primordial effect": "the dissociation of ideas". This delirious state was assimilated to dream. Modern studies, conducted with Delta-9-THC, in healthy voluntaries, again suggest the comparison or even the identity of the modifications caused by cannabis with sleep and dream. 10 mg of Delta-9-THC was absorbed in sesame oil by the voluntaries, and all of them presented disturbances of their vigilance, changes of their mood, now with euphoris and now with dysphoria, and slight psycho-sensorial alterations. The voluntaries EEG showed important and specific individual reactivity. Three subjects presented an arousal tendency, three other a greater towards sleep. Slight morphological changes have appeared, such as desynchronised periods, rapid shifts between I A, I B, II stages of sleep or an hypovariable I B stage of sedation with period of occular movements resembling to REM-stage.


[Sulpiride and drug addiction].

[Sulpiride and drug addiction]. The authors carried on their study as presented in Tunis Congress of Psychiatry and Neurology. The results of the administration of Sulpiride with drug-addicts are still difficult to evaluate, because none of the patients are hospitalized and there is no possibility to know the precise doses absorbed by the patients. An improvement is however obvious with patients who spontaneously come to ask for more. They generally present polytoxicomania and use haschisch, opium-derivatives, amphetamines and usually L.S.D. Two recent observations summarize the action of Sulpiride: 1. --A fit of acute depersonnalisation in a young lady was suppressed within eight days with the administration of 1 g p.o. of Sulpiride a day. Recovery without relapse. 2. --An old drug-addict would shoot himself i.v. with at least 1 g of Sulpiride whenever he wanted to stop his intoxication periods. He did not feel any "flash" but only could thus obtain a "soft" withdrawal without need syndrome. Neither dependence, nor serious side-effects were observed.


[Clinical study of a new agent correcting the syndrome of neuroleptic impregnation in acute psychotic states]. The correcting action of tropatepine hydrochloride upon the extrapyramidal effects induced by neuroleptics has been studied in 32 acute psychotic states. A satisfying result has been obtained with daily doses of 10 to 20 mg in 30 cases (excellent results: 20, good results: 10 patients). The action upon dyskinetic crises is particularly good and quickly obtained, avoiding a recourse to an i.m. corrector in 7 cases out of 8. The akineto-hypertonic syndrome has been efficiently corrected in 18 cases out of 23. The hyperkinetic manifestations (akathisia, tasikinesia) reacted favourably in 8 cases out of 11, dysarthria in 7 cases out of 11. The lessening of tremor was less satisfying (8 cases out of 15); same thing for the dryness of the mouth (7 cases out of 16) and disorder of visual accomodation (6 cases out of 12). The clinical tolerance was excellent. With the used doses, we found neither inconvenient atropinic effect, nor disorder of the vigilance, nor pharmacodependence. The one daily administration of a 10 mg tablet turned out to be sufficient in 19 cases. This possibility of only one administration a day appeared to us as a great advantage.


[A French experience with methadone].

[A French experience with methadone]. Methadone chlorhydrate has been administred to opiate addicts either for a short period with a decreasing dosage as a withdrawal cure, or for longterm treatments as a basis of a maintenance program. The analysis of precise clinical criteria regarding the socio-professional states, the family-life, the general health and the psychopathological diagnosis, allows an evaluation of the success of the cure and of its elective indications. The study of the personnality of the drug-addicts shows the importance of this factor in the potential success of a methadone cure. Urinary biological controls are regularly performed. This limitations and promises of this treatment discussed form a basis of a year's experience.


Beta-N-acetylhexosaminidase active on dermatan sulfate. The dodecasaccharide obtained by treating dermatan sulfate with testicular hyaluronidase, chondroitinase AC, and beta-glucuronidase was incubated with diluted, normal human serum at pH 4.5 or 7.0 followed by chondro-4-sulfatase at pH 7.0. Analyses of the reaction products indicate release of hexosamine but not further degradation of the substrate. It is concluded that normal human serum possesses an exo-beta-N-acetylhexosaminidase active on dermatan sulfate.


Vagal role and pacemaker indication in hypersensitive carotid sinus reflex. The effect of carotid sinus pressure (CSP) on sinus rate was studied in 24 patients with sinoatrial pauses below 3 sec (control) and 23 patients with sinoatrial pauses above 3 sec (hypersensitive carotid sinus reflex equal to (HCSR). For registration of P waves, intraatrial electrograms were used. CSP was applied several times before and after atropine. Patients with HCSR showed inconstant response to CSP. The maximal result was considered diagnostic. No difference in the lengths of sinoatrial pauses was found between patients without dizziness or syncopes in the presence of HCSR and patients with dizziness that proved clinically to be based on the existence of HCSR. It was concluded that CSP-induced asystole can serve neither as a differential diagnostic criterion nor as an indication for pacemaker application. Sick sinus syndrome, and thereby dysfunction of the sinus node, were excluded by rapid atrial stimulation. Patients with HCSR showed overall higher age, slower resting heart rate before and after atropine and less atropine response during CSP compared to control. Hypersensitivity of the carotid sinus reflex was interpreted as a part of the physiological augmentation of vagal tone in elderly people.


Insulin biosynthesis and secretion.

Insulin biosynthesis and secretion. Studies are presented which support the concept that a cell membrane localized glucoreceptor system is involved in the insulin secretory response to glucose and that the specific stimulation of insulin synthesis by glucose reflects effects at both the transcriptional and posttranscriptional level. After 48 hours of fasting the insulin secretory response to glucose is markedly reduced. This reduction is overcome by 24 hours of refeeding carbohydrate, but notprotein or fat, and is blocked by refeeding in the presence of an inhibitor of RNA synthesis. Although these studies clearly demonstrate an inducible glucoreceptor system, they do not permit conclusions regarding either its composition or location in the beta-cell. Phloridzin, a glycoside with a high affinity for glucose-carrier systems in plama membranes, stimulated basal insulin secretion sixfold. A large number of plant lectins were tested for ability to stimulate insulin release from isolated islets, and only mushroom lectin did so. The lectin concentration producing half-maximal hormone releaseis 3 x 10-7, a value in good agreement with the dissociation constant forlectin binding. Glucose stimulated insulin sythesis in isolated rat islets was determined to be partially inhibited by actinomycin D. The posttranscriptional effect was determined to be increased initiation of total islet mRNAas well as proinsulin mRNA. To futher quantitate the effect of glucose on proinsulin mRNA, immunoprecipitation of proinsulin synthesizing polysomes was accomplished. It appeared that proinsulin is synthesized on a mRNA accommodating six to eight ribosomes, and the size of the proinsulin mRNA is 10-11 S on sucrose gradients. This unexpectedly large size of the proinsulin mRNA is discussed.


Mitochondrial ATP-Pi exchange complex and the site of uncoupling of oxidative phosphorylation. Five enzyme complexes, which are concerned with electron transport and oxidative phosphorylation, have been isolated from beef heart mitochondria. Enzyme complexes I, II, III and IV are the electron transfer complexes discovered in 1961. Complex V is an energy-conserving complex. It catalyzes ATP-Pi exchange and ATP hydrolysis. The exchange reaction is sensitive to uncouplers, rutamycin, valinomycin plus K-+, dicyclorexylcarboditmide, arsenate, azide, and adenylyl imidodiphosphate. It is also specific for ATP; ITP, GTP and UTP are essentially ineffective. Studies with the photoaffinity labeling uncoupler, 2-azido-4-nitrophenol (NPA), have shown that the mitochondrial uncoupler-binding sites are located exclusively in complex V. Complexes I, III and IV, which carry the three coupling sites of the respiratory chain, had negligible capacity for the binding of NPA, whereas the uncoupler-binding capacity of complex V appeared to be increased two- to threefold as compared to mitochondria. Complexes I, II, III, IV and V are obtained from the same batch of mitochondria by a simple fractionation procedure, which employs cholate, deoxycholate, ammonium acetate and ammonium sulfate. Studies with NPA have shown that mitochondria contain per milligram protein about 0.6 nmole of uniformly reacting uncoupler binding site. All of the uncouplers tested appeared to interact competitively with this site. Photoaffinity labeling with tritiated NPA has shown that a major portion of NPA binds to a polypeptide of molecular weight between 26,000 and 30,000. Other studies on the mechanism of uncoupling have shown that picrate is a membrane-impermeable uncoupler. It cannot uncouple mitochondria. However, it is an effective uncoupler of ATP synthesis and ATP-induced transhydrogenation or reverse electron transfer when used in conjunction with sonicated submitochondrial particles, which have an inside-out orientation of the inner membrane with respect to the medium. In these particles, picrate binds to the same uncoupler-binding site as NPA and other uncouplers. However, unlike the membrane-permeable uncouplers, picrate is a poor protonophore. It has a very small effect on the proton permeability of phosphorylating submitochondrial vesicles, even at two to three times the concentration needed for complete uncoupling. The increase in the proton permeability of submitochondrial vesicles caused by such high concentrations of picrate (500 mum) can be achieved with approximately 5 mum 2,4-dinitrophenol. At this concentration, dinitrophenol results in only about 20% uncoupling.


Macrophage-lymphocyte interaction and antigen recognition. The functional and morphologic aspects of immunologically relevant macrophage-lymphocyte interaction have been characterized in inbred guinea pigs. Antigen-dependent initiation of in vitro DNA synthesis in lymphocytes taken from animals previously immunized with that antigen has been shown to be macrophage dependent. Expression of this in vitro correlate of in vivo established cellular immunity requires that antigen is initially bound to macrophages antecedent to any interaction with the specific lymphocyte. In view of the failure of supernatants from macrophages briefly exposed to antigen to initiate DNA synthesis in immune lymphocytes and the critical density requirements for lymphocyte proliferation, it is reasonable to assume that a direct physical interaction occurs between the antigen-bearing macrophage and lymphocyte. Using an in vitro assay of lymphocyte binding to macrophage monolayers, we have characterized what appear to be sequential events in macrophage-lymphocyte interaction. The initial event is an antigen-independent interaction between macrophage and lymphocyte whose characteristics are rapid reversibility, species but not strain specificity, and dependence on macrophage metabolism. If macrophages bear antigen for which a given lymphocyte possesses a specific receptor, then a second nonreversible antigen-dependent stabilization of binding occurs. This latter step requires tht macrophage and lymphocyte be histocompatible. These observations parallel functional studies of the histocompatibility dependence of macrophage-associated antigen initiation of lymphocyte DNA synthesis in guinea pigs. A model sequence of the physical events correlating with functional macrophage-lymphocyte interaction is proposed.


Luteinizing hormone-releasing hormone in the treatment of anovultory infertility. Fifteen infertile, anovulatory women, ages 20 to 37, were treated with synthetic luteinizing hormone-releasing hormone (LH-RH) to stimulate follicular maturation and/or ovulation. Thirteen of the patients had been treated unsuccessfully with other therapeutic regimens. To obtain follicular maturation, LH-RH was given intramuscularly in daily doses of 25 mu-g for 7 days and 50 mu-g for the next 7 days, or 100 mu-g for 3 days and 150 mu-g for the next 3 days. Both regimens were begun on the 4th day of a spontaneous or induced cycle. Follicular maturation (evaluated by the cervical mucus scale) occurred in three of seven cycles treated withe the first regimen and three of five treated with the second regimen. To induce ovulation, LH-RH was given in intravenous infusion (50 to 500 mu-g), intramuscularly (100 mu-g), or in a combination of both methods. The drug was administered after follicular maturation with LH-RH, clomiphene citrate, or human menopausal gonadotropin had been achieved; it was also given during four cycles in which spontaneous follicular maturation had occurred. Ovulation occurred in 10 of 25 treated cycles. Five pregnancies resulted, three in the first post-treatment cycle.


Anti-luteinizing (LH)-releasing activity of several analogues of LH-releasing hormone. The anti-LH-releasing activity of several analogues of LH-RH was tested by 2-hour infusion in ovariectomized, estrogen-progesterone-pretreated rats and in immature male rats. [Leu3]LH-RH, [Leu3, desGly10]-LH-RH ethylamide, [desHis2, Leu3,desGly10]-LH-RH ethylamide, [Gly2, Leu3,desGly10]-LH-RH ethylamide, [Leu1, desGly10]-LH-RH ethylamides, [desHis2,D-Ala6,desGly10]-LH-RH ethylamide, [desHis2,Leu3,D-Ala6, desGly10]-LH-RH ethylamide, and [D-pGlu1,desGly10]-LH-RH ethylamide, and and [D-pGlu1,desHis2,desGly10]-LH-RH ethylamide showed some anti-LH-releasing activity, but never completely inhibited the increase in serum LH in response to LH-RH. No significant differences were found among the analogues tested and [desHis2,desGly10]-LH-RH ethylamide, and inhibitory potency was not improved with those peptides containing D-alanine in position 6 of the chain. None of the analogues tested, including [desHis2,desGly10]-LH-RH ethylamide, was able to block the LH-RH-induced FSH release in these systems.