High volume intraperitoneal chemotherapy ("belly bath") for ovarian cancer. Pharmacologic basis and early results.

The currently accepted therapies for ovarian cancer have produced only limited numbers of extended complete remissions in advanced-stage disease. Studies of high-volume intraperitoneal chemotherapy have been initiated to define the toxicology, pharmacokinetics, and the therapeutic effectiveness of this treatment modality. This technique has been virtually ignored until recently, because little success has been achieved with it except in one study (Rutledge, 1966), in which large intraperitoneal fluid volumes were used. The general lack of success probably reflects inadequate attention to physiologic and pharmacologic principles of drug distribution and absorption in a space as large as the peritoneal cavity. Biomedical engineers, pharmacologists, and clinicians at the NCI have cooperated in the development of a rational chemotherapy for ovarian cancer. Following mathematical pharmacokinetic modeling and toxicologic studies in rat, a Phase I clinical trial of intraperitoneal methotrexate administered in large volumes of dialysis fluid was initiated. Results in three patients confirm the practicality of this approach, and further investigation is warranted.


Chemotherapy in the management of extramedullary plasmacytoma.

The results of chemotherapy in 24 patients with extramedullary plasmacytoma are reported. Complete regressions, including disappearance of monoclonal paraprotein and healing of bone lesions, were seen in 12 of 20 (60%) patients with disseminated disease. Extramedullary plasmacytoma responds better to chemotherapy than myeloma, and treatment should be pursued with vigour until all signs of disease have disappeared. Sensitivity to single-agent chemotherapy may vary, and if treatment fails with one agent, others should be tried.


Preliminary results of chemo-radiotherapy followed or not by active immunotherapy of stage III and IV lymphosarcoma and reticulosarcoma. Correlation of the results with WHO categorisation.

We treated 101 patients with advanced (stage III and IV) lymphosarcoma and reticulosarcoma at first presentation of the disease or in relapse according to a protocol combining initial chemotherapy, complementary radiotherapy on icebergs, supplementary chemotherapy, and, finally, active immunotherapy. The overall complete remission rate was about 79% for lymphosarcoma and 73% for reticulosarcoma. About 50% of the patients were still in remission in each of the two diseases at 2 years; 60% of lymphosarcoma and 44% of reticulosarcoma patients achieved 2-year survival. This study shows the prognostic value of the WHO classification for lymphosarcoma and reticulosarcoma: the prognosis of prolymphocytic (centrofollicular) lymphosarcoma is far better than that of the lymphoblastic type, which is in turn better than that of the very poor prognosis of the immunoblastic type. The prognosis of reticulosarcoma is intermediate between that of the best-prognosis and that of the poorest-prognosis type of lymphosarcoma.


Cytostatic-associated vomiting effectively inhibited by domperidone (R 33 812).

The effect of domperidone on vomiting due to cytostatic treatment was studied during a double-blind trial involving 41 patients. One group received the sequence domperidone-placebo and the other the reverse sequence during two consecutive courses of cytostatic therapy (chlormethine alone or in combination with other cytostatics). Domperidone 2 mg/ml or the placebo was injected IV 1 h before the start of the cytostatic treatment. A similar injection was given 4 h later. Presence, duration, and incidence of nausea and vomiting before, during, and after the peak period (period from the second up to and including the sixth hour after cytostatic injection) were measured. With respect to vomiting, domperidone was significantly superior to placebo concerning duration and effect before and after the peak period in both sequences. There was no difference during the peak period. With respect to nausea, domperidone was superior to placebo concerning duration and effect during the peak period in the placebo-domperidone sequence. No difference was observed in the reverse order. A significant superiority of domperidone was noted before the peak period.


High-dose methotrexate with citrovorum factor rescue in non-small-cell lung cancer.

Nineteen patients with non-small-cell carcinoma of the lung were treated with high-dose methotrexate and leucovorin rescue. Two partial responses (10.5%) were observed, lasting 13 and 17 weeks. Toxicity was acceptable. It is concluded that the occasional benefit of high-dose methotrexate with leucovorin rescue at this dose and according to the schedule described for these patients does not warrant further study.


Preliminary results of a phase II trial of aclacinomycin in acute leukaemia and lymphosarcoma. An oncostatic anthracyclin that is rarely cardiotoxic and induces no alopecia.

A phase II trial of which preliminary results are available for 22 patients indicates that aclacinomycin applied in a continuous modality induced complete and partial remission in four of nine patients with acute lymphoid leukaemia that was resistant to all previously available drugs, and in four of eight patients with stage V lymphosarcoma (leukaemic). Bone-marrow toxicity was the major side-effect. Only one patient of 20 suffered from cardiac toxicity; no one had alopoecia. This very low incidence of myocardial lesions and the absence of hair loss had been predicted, respectively, by our electron microscope study of the myocardium and the light electron microscope study of the skin of golden hamsters [7], a test that detects frequent severe myocardium and skin toxicities for adriamycin and some anthracyclin analogues such as detorubicin, which was found to be toxic in a high percentage of patients in a clinical trial conducted by the E.O.R.T.C. Clinical Screening Group [8].


Instantaneous blood flow responses to positive end-expiratory pressure with spontaneous ventilation.

Variable hemodynamic responses to positive end-expiratory pressure (PEEP) with spontaneous ventilation have been reported. To clarify these responses, 15 awake patients were studied using a catheter-tip velocity transducer to record phasic aortic root blood flow continuously before, during and after PEEP (10 cm H2O) applied with a face mask. Central blood volume and effective ventricular filling pressures were measured. Phasic pulmonary artery blood flow was also simultaneously recorded in three of these patients. PEEP produced an acute aortic blood flow reduction, detected within one respiratory cycle. Stroke volume decreased 12%, and since heart rate was unchanged, cardiac output also declined (p less than 0.05). Inspiratory-to-expiratory aortic flow changes were less during PEEP. In contrast, inspiratory-to-expiratory pulmonary artery flow alterations were exaggerated due to a marked flow decline during expiration. Central blood volume and effective left ventricular filling pressure decreased 9% and 19%, respectively (p less than 0.05 in all patients). The decrease in pulmonary artery flow was associated with a decrease in central blood volume in the three patients in whom pulmonary flow was measured. PEEP promptly reduces cardiac output during spontaneous ventilation, related to a decrease in pulmonary flow in expiration.


Enzyme immunoassay of estrogen-like substances in plasma, with polyethylene glycol as precipitant.

We devised an enzyme immunoassay for plasma estrogen-like substances in pregnancy, using estriol covalently linked to horseradish peroxidase. Free and bound steroid were separated by use of polyethylene glycol reagent. The assay satisfies the normal criteria of specificity and precision. Results obtained by radioimmunoassay and enzyme immunoassay agreed well. Our assay is particularly applicable in smaller clinical laboratories to routine determination of plasma estriol in pregnancy.


Evaluation of automated enzyme immunoassays for five anticonvulsants and theophylline adapted to a centrifugal analyzer.

We report a clinical evaluation of the enzyme immunoassay (EMIT) performed with the GEMSAEC centrifugal analyzer as compared to gas-liquid and liquid chromatography for anticonvulsant drugs and theophylline, respectively. A good correlation was obtained for all drugs, although some difficulties were experienced with one lot of reagent for ethosuximide. The analyzer has an economic advantage if many samples are being analyzed for few drugs in each sample.


Determination of valproic acid (di-N-propyl acetic acid) in plasma by gas-liquid chromatography with pre-column butylation.

A gas-liquid chromatographic procedure for the determination of the anti-convulsant drug valproic acid in plasma or serum is described. Valproic acid is extracted from acidified plasma (or serum) into toluene containing octanoic acid as the internal standard. The toluene layer is back extracted with a methanolic solution of tetramethylammonium hydroxide; an aliquot of the methanolic layer is mixed after phase separation with N,N-dimethylacetamide and 1-iodobutane. After centrifugation the clear supernatant (which is stable for at least 24 h) is analysed by gas-liquid chromatography, on a 3% OV17 column. The procedure is rapid and sensitive, and the back-extraction step with methanolic tetramethylammonium hydroxide results in clean chromatogram obtained from blank plasma. Sample volumes of 50 microliter suffice for the determination of therapeutic levels of VPA.


Sensitive radioimmunoassay for somatostatin using N-[125I]-Tyr-somatostatin as labelled antigen.

A sensitive radioimmunoassay for somatostatin using N-[125I]-Tyr-somatostatin is described and compared with that using [125I]-Tyr1-somatostatin. The minimum detectable amount of somatostatin using N-[125I]-Tyr-somatostatin as tracer was 0.1 to 0.5 pg, which is approximately 10-fold lower than the lower detection limit of the RIA using [125I]-Tyr1-somatostatin. Moreover, it was found that the shelf-life of N[125I]Tyr-somatostatin was prolonged in comparison with labelled Tyr1-somatostatin. Human pancreatic and gastric extracts displayed immunological similarity to synthetic somatostatin tetradecapeptide.


Chromosome 8 abnormalities as components of neoplastic and hematologic disorders.

Publications involving patients with any abnormality of chromosome 8 have been reviewed in detail. For the time period involved, a total of 277 cases were found, including 74 instances of congenital aneuploidy, 130 instances of acquired aneuploidy, 38 instances of congenital rearrangements, and 35 instances of acquired rearrangements. A total of 170 cases of neoplastic and hematologic disorders were included; three were associated with congenital aneuploidy, two with congenital rearrangements, and the remaining 165 with acquired aberrations. The specific disorders ranged from sideroblastic anemia through chronic and acute leukemia to solid tumors. There appears to be a definite, though non-specific correlation between congenital or acquired chromosome 8 abnormalities and the development of certain types of neoplastic growth.


Widespread IgE-mediated hypersensitivity in Northern Sudan to the chironomid Cladotanytarsus lewisi ('green nimitti').

Hypersensitivity to Chironomidae (non-biting midges) has been a problem in Northern Sudan since about 1927 and is probably due to the working of dams which have produced lake-like conditions on parts of the Blue and main Niles where breeding has evidently increased. Studies were undertaken to determine whether this hypersensitivity is mediated by IgE. Sixteen Sudanese, with bronchial asthma associated with exposure to the chironomid, Cladotanytarsus lewisi ('green nimitti'), were investigated. All patients gave a positive immediate-type skin reaction to an extract of the midge and the majority had markedly elevated concentrations of circulating IgE. Serum from all patients passively sensitized human lung fragments in vitro for the release of histamine and slow-reacting substance of anaphylaxis by the 'nimitti' antigen. This tissue-sensitizing activity could be removed by immunoabsorption with an anti-IgE. These results indicate that this widespread and important hypersensitivity in the Sudan is IgE-mediated and thus may potentially be treated by desensitization.


Detection of circulating immune complexes in alcoholic liver disease.

Sera of twenty-five patients with alcoholic liver disease and forty normal control sera were screened for circulating immune complexes by means of the anti-antibody neutralization test and by Raji-cell membrane immunofluorescence assay. IgG-containing immune complexes were detected in thirteen out of twenty-five patients with alcoholic liver diseases and in one out of forty normal individuals; in addition, IgA-containing complexes were demonstrated in seven out of thirteen sera positive for IgG complexes. The presence of immune complexes was restricted to alcoholic hepatitis and active cirrhosis, thus indicating a relationship with disease severity.


The role of macrophages in the lymphoproliferative response to Mycobacterium leprae in vitro.

Peripheral blood lymphocytes from patients suffering from lepromatous leprosy do not normally react in vitro to stimulation by Mycobacterium leprae antigens. In contrast, we found that T cells from non-responding patients in combination with macrophages from responding patients or healthy contacts did respond well to M. leprae. Conversely, T cells from responding patients or healthy contacts in combinations with macrophages from non-responding patients failed to respond. It seems, therefore, that the lack of response normally observed in in vitro tests using cells from lepromatous leprosy patients is due to a failure of their macrophages to present M. leprae antigens in an immunogenic form.


Effect of cyclophosphamide treatment on the course of Mycobacterium lepraemurium infection and development of delayed-type hypersensitivity reactions in C57B1 and BALB/c mice.

Pre-treatment of Mycobacterium lepraemurium susceptible, BALB/c, and resistant, C57Bl, mice with cyclophosphamide markedly altered the development of delayed hypersensitivity during footpad infections with this organism. A tuberculin-type response demonstrated by untreated C57Bl mice was significantly intensified after week 3 in cyclophosphamide-pre-treated mice although this response had returned to normal levels by week 8. A Jones-Mote-type response demonstrated throughout experiments by untreated BALB/c mice was considerably increased in magnitude by week 3 in cyclophosphamide-pre-treated mice. By week 6 this response had become considerably protracted and was of the tuberculin-type. By week 8 however this response had started to diminish and by week 12 cyclophosphamide-treated and untreated BALB/c mice produced similar Jones-Mote-type responses when skin-tested. Cyclophosphamide pre-treatment had no effect on the growth of M. lepraemurium in C57Bl mice over 12 weeks. In BALB/c mice however cyclophosphamide-pre-treated mice demonstrated considerable resistance to infection at weeks 8 and 10 after infection but not thereafter. Whereas the magnitude of the delayed hypersensitivity response in C57Bl mice could not be correlated with resistance such a relationship could be demonstrated in BALB/c mice.


Loss of circulating T lymphocytes with normal levels of B and 'null' lymphocytes in Thai adults with malaria.

Peripheral blood mononuclear cells from forty-nine Thai adults infected with either Plasmodium falciparum or Plasmodium vivax were examined in order to determine the percentage of T, B, and Fc-receptor-bearing cells present. In comparison to healthy  controls, both the percentage and concentration of peripheral T cells were decreased in the malaria-infected individuals as assessed by formation of rosettes with sheep red blood cells. The percentage of peripheral B cells was increased but their concentration was unchanged, as assessed by two techniques: the presence of surface immunoglobulin and the presence of a complement receptor. Both the percentage and concentration of lymphocytes bearing Fc receptors were unchanged in infected individuals. Finally, calculation of the changes in 'null' cells (defined either as non-T, non-B lymphocytes or as non-T, non-B, non Fc-receptor-bearing lymphocytes) revealed an increase in the 'null' cell percentage but a decrease in the absolute number of 'null' cells. These data indicate that in adult Thai patients naturally infected with malaria, there is a real loss of circulating T lymphocytes with no real change in B, Fc-receptor-bearing, or 'null' lymphocytes.


Active T and EA-rosette-forming cells in human cadaver renal allograft recipients.

Active T(AT) and EA-rosette-forming cells (RFC) were determined in seventeen haemodialysis patients and twenty-two renal allograft recipients to correlate these estimates with the clinical outcome of renal allografts. Either AT- or EA-RFC or both were found to be elevated during the period of rejection crisis. Assays for AT- and EA-RFC were found to be complementary suggesting that they may be detecting two different types of rejection crises. Thus, determination of AT- and EA-RFC in the peripheral blood may prove to be useful in the routine immunological monitoring of renal allograft recipients.


The combined use of antilymphocyte serum and cyclophosphamide to suppress renal allograft rejection in the rat.

Cyclophosphamide and antilymphocyte serum (ALS) were compared for their ability to suppress renal allograft rejection in the rat. These two agents were chosen since they are generally considered to act on different arms of the immune response, and might therefore complement each other's action. Dose response studies showed that both agents could suppress rejection completely. There were no differences in their ability to suppress the lymphocytotoxic antibody response to the graft and the histological patterns of rejection were similar. There was no evidence that cyclo-phosphamide was more effective in suppressing vascular lesions. The doses of both agents which suppressed the lymphocytotoxic antibody response were substantially lower than those required to suppress graft rejection. When suboptimal doses of the two agents were administered together, the combinations were found to be additive and not synergistic.


Effects of isosorbide dinitrate on pulmonary hypertension in chronic obstructive pulmonary disease.

Eighteen patients with chronic obstructive pulmonary disease with pulmonary hypertension were studied to assess the hemodynamic response to acute oxygen administration and to oral isosorbide dinitrate (ISDN). All 18 patients had baseline hemodynamic measurements and hemodynamic measurements during low-flow nasal oxygen. Following a second baseline measurement, patients received either oral ISDN (11 patients) or placebo (7 patients) in a randomized, double-blind protocol. Heart rate decreased with oxygen administration but there were no other significant hemodynamic changes. With oral ISDN, there was a significant fall in pulmonary artery and brachial artery pressure. Cardiac output, right atrial pressure, pulmonary wedge pressure, and pulmonary vascular resistance all fell but not significantly. We conclude that oral ISDN is effective in reducing pulmonary hypertension in patients with chronic obstructive pulmonary disease.


gamma-Carboxyglutamate excretion and warfarin therapy.

The urinary excretion of gamma-carboxyglutamic acid (Gla), the amino acid involved in the vitamin K-dependent calcium binding of prothrombin and clotting factors VII, IX, and X, was studied in warfarin-anticoagulated patients. An isotope dilution procedure was developed for the measurement of free urinary Gla with the use of prior anion-exchange chromatography to separate and concentrate the free Gla from whole urine and subsequent automated amino acid analysis. Eight subjects on stable warfarin anticoagulant therapy and 11 comparable control subjects with normal coagulation were examined. Urinary Gla excretion was reduced in patients on warfarin anticoagulant therapy (p = 0.001) and the urinary Gla level correlated (r = -0.73, p = 0.001) with plasma prothrombin time. It is concluded that decreased urinary Gla in warfarin-treated patients is related to coagulation status and may be a clinically useful parameter.


Pirprofen and aspirin in the treatment of rheumatoid arthritis.

Pirprofen (800 mg/day) or aspirin (3,600 mg/day) was administered in double-blind fashion for up to one year to 40 adult outpatients with rheumatoid arthritis, after a short, single-blind placebo period. There were no statistically significant differences in efficacy between pirprofen and aspirin, as evidenced by patient opinion, observer opinion, grip strength, walking time, number of tender joints, number of swollen joints, or erythrocyte sedimentation rate. Clinically significant pain of gastrointestinal origin occurred in an equal number of patients from each group. Audiologic evaluation revealed 3 pirprofen-treated patients and 5 aspirin-treated patients in whom sensorineural hearing loss progressed during therapy and required either discontinuation or reduction of drug dosage. Ophthalmologic evaluation disclosed a high prevalence of lesions, the most common being decreased visual acuity and cataracts not explained by previous antiarthritic therapy. The high prevalence of audiologic and ophthalmologic pathology reported in the literature in patients with rheumatoid arthritis makes it difficult to establish in our study whether pirprofen or aspirin affected these organ systems.


Terminating a trial -- the ethical problem.

A comparative clinical trial will often lead to the conclusion that one regimen is clearly better than another. Should the estimated difference in the regimens be large and precisely determined, continuation of the trial would constitute abuse of the participants. Some earlier proposals for ethical decision making on continuing a trial are shown to be unsatisfactory, and a more general framework for dealing with the problem is proposed.


Terminating a long-term clinical trial.

Long-term trials often include more than one active treatment group. These may be discontinued independently if found ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet anouther kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.


Problems of university-based scientists associated with clinical trials.

University faculty members who participate in clinical trials face a number of difficulties in connection with this association. Publication opportunities are often limited, and individual scholarship is difficult to express and evaluate within the context of a cooperative trial. Merit increases, promotion, and the award of tenure will usually require evidence of scholarly achievement outside the trial setting. For this reason, it seems inadvisable to recommend that a young investigator devote a major portion of his scholarly and research time to such an activity. A possible exception may be a full-time appointment for 1 to 2 years. Nonetheless, cooperative clinical trials are an important investigative tool and they should continue to be associated with academic centers. If appropriate administrative arrangements can be made, it should be possible to solve the academic problems of the young investigator associated with such trials.


Effective clinical trials investigators and adequate incentives.

Because of the importance of randomized controlled trials in medical research and development, the most competent and qualified individuals from a variety of medical specialties are needed as investigators for these trials. Such people must be highly dedicated to the improvement of human health and they must also be cooperative and able to work in the highly disciplined atmosphere that such a trial demands. In order that the trial investigators be persons of high caliber, certain incentives must be guaranteed, such as recognition of one's contributions to the trial itself, publications, and opportunities to present study results at various meetings. University and medical school policies on promotion and tenure need to be reassessed bearing in mind the complexity of achieving optimal recognition of the individuals investigator's contributions to a clinical trial.


Publications and promotions for the clinical investigator.

If cooperative clinical trials are to compete with other types of clinical research for the attention of physician investigators, they must offer rewards in the form of publication credits and academic recognition. Large-scale multi-institutional clinical trials provide less opportunity for authorship than individual or small-group research. This problem cannot be solved by attempts to multiply publications unnecessarily or to blur the meaning of authorship. Only those who contribute significantly to the design and interpretation of an experiment should be designated as authors; journals should be prepared to recognize all those who meet that test. Increased opportunities for authorship can be provided if the National Institutes of Health (NIH) encourage small-scale clinical trials carried out by individual investigators. Academic recognition of the clinical investigator in increasing and would be greatly strengthened by an NIH policy of greater support for this kind of research.


Recruitment in the Coronary Drug Project and the Aspirin Myocardial Infarction Study.

Both the Coronary Drug Project (CDP) and the Aspirin Myocardial Infarction Study (AMIS) were successfully able to recruit adequate members of postmyocardial infarction patients to long-term multicenter clinical trials in the secondary prevention of coronary heart disease. Aggressive efforts to achieve the recruitment within an acceptable time limit were found to be neccessary. A direct approach to the general public via the mass media and painstaking search of hospital records proved to be the most effective methods. Referral from physicians was not an effective way to recruit participants for the most part. Both the general public and the medical profession are generally supportive of this type of research.


Recruitment for the Coronary Primary Prevention Trial.

A preliminary account of some aspects of recruitment for the Coronary Primary Prevention Trial is provided. Extension of recruitment sources to include various forms of community screening resulted in more rapid acquisition of potential participants than was possible when recruitment was restricted to the more traditional sources of physician and laboratory referral. Extended recruitment was supported by augmented data feedback and by the development of the job of recruitment coordinator at each participating clinic. The identification of delays in reaching the maximal recruitment rate from particular sources points to the need for detailed planning of a recruitment campaign before large-scale clinical trials are begun.


Recruitment for the National Cooperative Gallstone Study.

The National Cooperative Gallstone Study (NCGS) recruitment experience is reported, and the factors determining recruitment performance at a center are evaluated. Recruitment performance was grouped into four major areas: coordinating center, protocol, patient population, and treatment center. At the treatment centers, no relationship was found between performance and the prior experience of the clinic staff in clinical trials or expertise in gallstone research, lack of institutional support was not initially apparent, and ancillary studies did not appear to stimulate performance. Neither the population density nor the annual rate of cholecystectomy were predictive of the monthly rate of patient randomization. After the initial biopsy study and in the major study, changes in eligibility criteria and procedural requirements were followed by an augmented randomization rate. No significant correlation was found between the rating given to a center at the time of selection and the subsequent randomization rate. In conclusion, the criteria used by the NCGS for treatment center selection were inadequate to predict subsequent performance.


Patient recruitment: other examples of recruitment problems and solutions.

Plans to recruit patients for a clinical trial must begin early and must utilize a variety of workable techniques if patients are to be acquired at an acceptable rate. Publicity campaigns must be directed toward winning the confidence and good will of the public and of interested physicians.


Quality assurance of clinical data: diagnostic standardization.

Diagnostic standardization requires substantial effort, including detailed specification of procedures in a written protocol and training of examiners in such procedures. Success is neither automatic nor assured. It is essential to monitor performance through replicate examinations and/or computation of examiner variance. When examiner variance exceeds permissible limits, consideration should be given to discarding the data.


Quality assurance of clinical data: internal monitoring: patient and study management at the clinic.

Adquate methods to assure the quality of data collected at the clinic need to be developed. A full understanding of the limitations of physicians as information processors and reasonable performance expectations for physicians during peak information periods will result in concentrated planning for patient visits and will limit the data that must be collected at the clinic. It is mandatory for each clinical research project that protocol treatment take into account the question of variable provider follow-up versus constant provider follow-up. It is also imperative that all clinical research providers receive special training, testing, and follow-up evaluation. The prime responsibility for the overall conduct of clinical research rests with the principal investigator. A monitoring tool that should be more fully used is the informed patient.


Aspects of clinic monitoring in large-scale multiclinic trials.

Monitoring the implementation of large-scale and the adherence of clinical centers to a common protocol should be an integral part of the study design and a primary responsibility of the coordinating center for the study. There are four basic concepts in external clinic monitoring: (1) the maintenance of open lines of communication between all study facilities, (2) "responsibility and accountability" for study implementation and for the integrity of the data, (3) evaluation of clinic operations, and (4) analysis of data quality. A monitoring scheme consisting of regular telephone calls to the screening centers. periodic visits to the screening centers, and continuing review of the data collected can be effectively used by the coordinating center.


Some ethical considerations in clinical trials.

The ethical norms established in various codes and regulations are inadequate to resolve some of the ethical problems presented by clinical trials. They are stated too vaguely to provide unequivocal answers to many specific questions. In order to remedy this situation, many commentators have proposed the development of more specific and complex regulations. We propose that a more fruitful approach would be to examine the ethical principles underlying the norms and to apply these principles to the specific problems. We apply this approach to two questions: (1) Is it ethical to select subjects for a randomized clinical trial (RCT) exclusively from Veterans Administration (VA) hospitals? (2) In the conduct of a RCT is it necessary to disclose the fact that therapy will be determined by chance? We conclude that problems of justice arise not only because of the vulnerability of patients in VA hospitals but also because of the loss of the physician-patient relationship in an RCT. However, the use of patients in a VA hospital is not always unjust; in most cases such use can be made more just through various modifications in design. We also conclude that the fact of randomization should be disclosed in any situation in which it might materially affect the prospective subject's decision, and that the values and preferences of the subjects should be taken into account in determining what information might be material. This work is only a preliminary step toward analyzing ethical issues in clinical trials. While some would challenge our conclusions, we hope that our methods will facilitate clarity about the locus of disagreement in current controversies and about the value questions that must be answered in order to set an ethical context for the conduct of clinical trials.


Problems in publication of clinical trial methodology.

The literature on analgesic testing in man reveals a series of informational gaps. These include a failure to document the occurrence of "trials that failed", the problems associated with recruiting patients and in dealing with dropouts, the relative advantages and disadvantages of different methods of assessing relief from pain, the importance of baseline variables, and the utility of global and comparative judgments by patients. A trial is described in which only 100 subjects of a total of over 8,000 patients theoretically available for study proved suitable. Significant differences between consenters and nonconsenters and selection factors that are used in choosing an experimental population have implications for the generalization of a study. Such conclusions have been largely ignored both in and out of the scientific literature.


Communications: Should mechanisms be established for sharing among clinical trial investigators experiences in handling problems in design, execution, and analysis? Methodology: the case for improved communications.

Despite their long history, the number that are in operation now, and the current level of expenditures on them, clinical trials have not been the focus of sufficient methodologic research. The paucity of metholologic explorations is further aggravated by the constraints on communications regarding methodology. Those individuals working in the area of clinical trials need to establish some professional identity with the field. Methodology in the areas of design and management of clinical trials needs to be stimulated, perhaps through special requests for applications (RFAs) and requests for proposals (RFPs). Communications could be improved by the establishments of a professional society, the development of an appropriate journal, and establishment of national training and information centers for clinical trials.


Retrieving information on clinical methodology.

Evidence derived from several simple searchers of the literature suggests that one interested in identifying papers which discuss the methodologies of clinical trials will have reasonable success. However, the retrieval of a meaningful methodologic duscussion of any actual trial is unlikely because very little of this information has been published. Some suggestions to remedy this deficiency are given.


The relative roles of surgery and radiotherapy in the management of soft tissue sarcomas of adults. A personal appraisal.

The literature of the last 25 years pertaining to the treatment of sarcomas of the soft somatic tissues by surgery and radiotherapy, both separately and in combination, has been reviewed. Surgery alone, if it is to be successful in an appreciable proportion of cases, must be radical. There is a growing body of evidence which suggests that less-than-radical surgery in combination with postoperative radiotherapy may give results equal or superior to those of radical surgery alone. There is need for a multicentre controlled clinical trial to compare the results of the two modes of treatment.


Online literature retrieval in poison control.

Modern bibliographic databases include an increasing number of substantial abstracts, as well as other features which contribute to their becoming useful additional tools in poison control. This paper is a contribution to the assessment of their respective value in providing rapid and up-to-date information about toxic effects of drugs and chemicals, as well as about the therapy of poisoning. The main systems compared are Excerpta Medica, Scisearch, and Toxline.


Reception of acupuncture by the scientific community: from scorn to a degree of interest.

This article presents a comprehensive review of the clinical phenomenon of acupuncture. The historical development of this technique, in China, in other parts of Asia, and in the West is discussed. Contemporary advances in acupuncture applications, such as in anesthesia and in the treatment of drug addiction are reviewed. Up-to-date material regarding current physiological theories of acupuncture's mechanism is included. Acupuncture is seen as presenting of challenge to the scientific community which is moving from a posture of scorn to justifiable interest.


Comparative trial of co-trimoxazole and tetracycline in the treatment of lower respiratory tract infection.

One hundred and twenty-six adult patients with acute lower respiratory infection were studied in a double-blind trial. One group was treated with co-trimoxazole (480 mg trimethoprim and 2400 mg sulphamethoxazole) per day and the other group with tetracycline 2 g per day. The results showed that co-trimoxazole was significantly more effective than tetracycline as judged by clinical improvement, and the reduction in sputum volume and purulence. No haematological abnormalities were observed, but the incidence of side-effects, though mostly mild, was higher in the group of patients on tetracycline than in the co-trimoxazole group. The results of this study strongly suggest that co-trimoxazole may be a useful and reliable drug in the treatment and control of acute lower respiratory tract infection in the developing countries.


A double-blind, crossover trial of mefenamic acid, sulindac and flurbiprofen in rheumatoid arthritis.

A double-blind crossover trial was carried out in 24 patients to compare the effects of mefenamic acid, flurbiprofen, sulindac and placebo. Each drug was given for 2 weeks, the treatment sequence being randomized. Daily doses were 1500 mg mefenamic acid, 150 mg flurbiprofen or 150 mg sulindac. All of the active drugs were significantly superior to placebo in terms of pain score, patients' assessment, articular index of joint tenderness, and duration and severity of morning stiffness. There was improvement in grip strength compared with placebo, but the differences were not statistically significant with sulindac. There was slight reduction  in joint circumference but this was only statistically significant in the right hand with flurbiprofen and sulindac. No significant  differences were found in technetium uptake in knee joints. The three drugs appeared to be equally effective and tolerated, and no significant differences were noted.


A comparative study of haloperidol and diazepam in the treatment of anxiety.

In a single-blind study in general practice, 60 patients with anxiety neuroses were randomly allocated to receive either 0.5 mg haloperidol twice daily or 2 mg diazepam 3-times daily for 6 weeks. Eighteen patients (6 on haloperidol and 12 on diazepam) were excluded from the analysis of efficacy. On the Hamilton Rating Scale both haloperidol and diazepam reduced the anxiety and depression scores. The investigator's assessment of 14 anxiety symptoms and signs indicated that haloperidol produced significantly (p=0.05) greater symptomatic improvement than diazepam after 4 and 6 weeks of treatment, and the patients' overall response was also significantly (p less than 0.005) greater with haloperidol. After 6 weeks, 93% of patients felt 'better' or 'much better' on haloperidol, compared with 83% on diazepam. A few, minor side-effects were reported, slightly fewer on haloperidol than on diazepam. In the parameters tested in this study, haloperidol has been shown to be more effective than diazepam in the treatment of anxiety neuroses and appears to provide significantly better overall symptomatic relief and to be more acceptable to patients than diazepam.


Cefuroxime in the treatment of lower respiratory tract infection.

Cefuroxime is a new parenteral antibiotic with a wider spectrum of activity than earlier cephalosporins and is particularly active against Haemophilus influenzae, including strains resistant to ampicillin due to beta-lactamase production. From 18 centres, 274 patients suffering with 275 infections were treated with cefuroxime sodium using the standard regimen of 750 mg 8-hourly by intramuscular injection. The clinical results showed a 90% success rate in the patients with bronchopneumonia (105), 91% in patients with post-operative pneumonia (74), and 89% in the patients with acute exacerbations of chronic bronchitis (96). Renal function was closely monitored during therapy, and no adverse changes attributable to cefuroxime therapy were seen in any patient, including those who also received frusemide. Two patients (0.7%) developed a rash, although 8 penicillin-allergic patients were treated without incident. From these studies, it can be concluded that 750 mg cefuroxime 8-hourly is effective in the treatment of lower respiratory tract infections. It is suggested that the attributes of this antibiotic may offer several advantages over existing therapies.


Efficacy of bufexamac cream versus betamethasone valerate cream in contact dermatitis: a double-blind trial.

A double-blind controlled study was carried out in 72 patients with atopic or contact dermatitis, who were randomly allocated to receive treatment with either 5% bufexamac, 0.1% betamethasone valerate or placebo creams. Patients applied the cream twice daily for 2 weeks. Assessments of the degree of severity of inflammation, induration, lichenification, crusts, scaling, and pruritus were made before and after treatment. The results showed that both active preparations were equally effective in improving the skin condition in the majority of the patients. In younger patients, however, the improvement with betamethasone valerate appeared to be somewhat better than that with bufexamac, particularly in relation to pruritus.


A comparison of salbutamol and ritodrine when used to inhibit premature labour complicated by ante-partum haemorrhage.

A retrospective study was carried out in 26 patients in premature labour complicated by antepartum haemorrhage. Patients treated with the beta-adrenergic agonists, salbutamol or ritodrine, continued the pregnancy longer, had smaller subsequent blood losses, and delivered infants in better condition than patients no so treated. There was little difference between the effectiveness of either beta-adrenergic agonist.


Mezlocillin in gonorrhoea: a pilot study.

A pilot study was carried out in 50 patients with uncomplicated, untreated gonorrhoea to asses the effectiveness of mezlocillin, a new semi-synthetic penicillin. Patients received a single intravenous injection of 2 g mezlocillin and were followed-up for periods up to 101 days. Four patients defaulted immediately. Clinical and bacteriological findings showed that only 1 of the 46 patients followed-up had failed to respond to treatment, indicating a cure rate of 97.8%. Five (10.8%) male patients had developed post-gonococcal urethritis when seen 3 weeks or later in the follow-up period.


Indoprofen versus ibuprofen in osteoarthrosis: a short-term, double-blind, crossover trial.

A double-blind, crossover, short-term clinical trial was carried out in osteoarthrosis to compare the activity of two non-steroidal anti-inflammatory drugs. Twenty-four patients were given orally, in sequence, 600 mg indoprofen daily and 1200 mg ibuprofen daily, or vice-versa, for 1 week with no interval between treatment periods. Pain, quality of sleep, and overall effectiveness were recorded at the end of each week by inviting patients to express a score on a simple rating scale. Finally, patients were asked to express a preference for one treatment or the other. Significant improvement was observed in all parameters following treatment with both drugs. The distribution of score differences between indoprofen and ibuprofen was in favour of the former in all measurements; statistical analysis, however, demonstrated a significant superiority of indoprofen only for pain elicited by passive motion. The patients' preferences were also in favour of indoprofen, though not attaining statistical significance. Indoprofen was well tolerated, and no side-effects were observed. While on treatment with ibuprofen, 1 patient had to be withdrawn from the study because of gastric intolerance and 2 further patients had transient skin rashes.


Pimozide in acute schizophrenia: a pilot study.

Pimozide was used in a pilot study to treat 10 patients with frank symptoms of acute schizophrenia. Eight patients appeared to respond favourably to doses ranging from 12 to 40 mg daily. Two of the patients responded within 1 week and all 8 within 5 weeks. It was possible to discharge all 8 patients from hospital within this time period. It is concluded that oral pimozide is an effective treatment for the whole range of symptoms accompanying acute schizophrenia. Brief representative case histories are presented, and dosage recommendations for the effective treatment of acute schizophrenia with pimozide are discussed.


Vascular and lymphatic tumors in infancy, childhood and adulthood: challenge of diagnosis and treatment.

The essential features of the major benign and malignant vascular tumors affecting infants, children and adults have been presented. Major emphasis has been placed upon the classification and treatment of hemangiomas, although malignant vascular tumors are discussed, and extensive and selected references are cited. The classification system of hemangiomas presented in this monograph is based upon the clinical prognosis of the angioma. The principles of treatment for hemangiomas based upon our clinical classification are discussed and may be summarized as follows: 1. The diagnostic features and prognosis vary with the variety of the angioma. 2. Spontaneous regression occurs only with juvenile hemangiomas, and the major involution occurs before age 5. 3. Patients with rapidly growing capillary cavernous hemangiomas should be treated with steroids. 4. Treatment modalities that increase scarring of the surface epithelium are contraindicated. 5. Intradermal and cirsoid angiomas do not spontaneously regress. 6. Congenital A-V fistulas require aggressive surgery. 7. The ultimate deformity resulting from angiomas may be greatly reduced by plastic surgical techniques. 8. Radiation therapy is never indicated for the treatment of hemangiomas. 9. The psychologic impact of the congenital deformity on patients is generally more detrimental than comparable postsurgical or traumatic deformities.


Sex steroid control of intermale fighting in mice.

The data presented here are based on over 700 mice and employed over 13,000 injections. The results obtained provide good evidence that the influences of sex steroids on fighting motivation in aggressive mice are discrete from the somatic influences of these hormones. Further, it seems possible that some of the effects of naturally occurring endogenous androgens in the mouse are consequent upon local neural aromatization of these compounds to estrogenic metabolites, before they exert an influence on aggressive motivation. It seems possible that this is a physiological effect as well as a consequence of pharmacological influence, as the doses of steroid employed in this present study are quite low. However, this model of hormone action cannot be the entire story, as 5 alpha DHT is behaviorally effective even though its A ring cannot be aromatized. Aggressive mice seem useful behavioral models for these effects. These studies indicate some of the likely sources of variability in the literature, as well as providing a number of considerations for clinical behavior therapy. They also indicate some of the features of steroid hormones (such as an aromatized A ring; the presence of a hydroxyl group at position 19; the influence of alpha hydroxyl groups, etc.) which may change the behavioral and somatic influences of these compounds.


Micromethod for chromosome preparations from Chinese hamster lymphocytes.

Chromosome preparations from Chinese hamster lymphocytes were made by culturing for 2 to 6 days 50,000 to 800,000 lymphocytes in flat-bottomed Cooke microtiter plates in 0.1 or 0.2 ml Roswell Park Memorial Institute-1640 medium (RPMI-1640) supplemented with 5--40 microliters PHA/ml, 20% fetal calf serum (FCS), and 40 microns 2-mercaptoethanol. Depending on blood volume and cell concentrations used, it was possible to obtain up to 1400 well-spread metaphases from one venepuncture.


Endotracheally administered antibiotics for gram-negative bronchopneumonia.

Sisomicin or a placebo was administered endotracheally to two groups of 18 and 20 unconscious patients, respectively, who had tracheostomies or endotracheal tubes in place and developed a severe gram-negative broncho-pneumonia. In addition, the patients received systemically a combination of sisomicin and carbenicillin. A favorable clinical response was obtained in 14 (77 percent) of the 18 patients who were treated with sisomicin and in nine (45 percent) of the 20 patients who received the placebo (P less than 0.05). Endotracheal therapy with sisomicin was well tolerated and resulted in high levels of sisomicin and in elevated bactericidal activity within the bronchial secretions. Endotracheally administered amino-glycosides might be an important adjunct to systemically administered antibiotics in the management of severe gram-negative bronchopneumonia.


The concentration of tobramycin in bronchial secretions.

Fifteen noninfected patients received three consecutive doses of tobramycin (1.7 mg/kg intramuscularly). Serum and bronchial secretions were obtained during bronchoscopy. Microbiologic assay demonstrated that bronchial secretions containing tobramycin produced inappropriately small zone sizes when compared with serum. Also, it was shown that bronchial secretions frequently do achieve therapeutic concentrations of tobramycin at this dosage level and route of administration.


[Catheter dilatation of arterial stenosis after renal transplantation (author's transl)].

Post-anastomotic arterial stenosis after renal transplantation requires active intervention in order to save the transplant. As an alternative to a taxing surgical reoperation selective transluminal catheter dilatation was performed in one case and severe stenosis was removed. Rapid normalisation of blood pressure and recovery of excretory function should encourage further such therapeutic attempts in stenoses in these high-risk patients.


[Kinetics and load distribution of supported free-end prostheses. IV. Effect of the saddle curvature on the saddle resp. abutment kinetics and the load distribution in prosthesis beds without abutments].

The influence of the saddle curvature on abutment tooth kinetics and abutment tooth stress was studied with unilateral rigid and movable free-end saddle dentures. The results showed that, independent of the length of the saddle and/or of the saddle curvature, considerable horizontal and vertical extrusive abutment tooth stress is present in addition to vertical intrusive abutment tooth stress. The saddle kinetics are basically influenced by the form of the saddle. The kinetics cannot be altered appreciably because of the mechanical characteristics of the connecting elements; it can only be surpressed at the cost of increased pier stress.


Treatment of intrabony defects.

New attachment of periodontal tissues can be obtained following surgical treatment of intrabony pockets. To day flap procedures with complete surgical opening to the defect and removal of all soft material from the intrabony lesion often followed by bone transplantation constitute the accepted approach to obtain a new connective tissue attachment. However, since the epithelium of elevated full thickness flaps are well preserved, the placement of these flaps adjacent to the treated areas facilitate the migration of epithelium into the defects. In a search for means to retard epithelial proliferation into the defects, disintegration of epithelium of free gingival grafts within the first days following transplantation might possibly be utilized in new attachment attempts. It has been demonstrated in three-wall intrabony defects in monkeys and in humans, that if the intrabony defect is covered with a free transplantat following a split flap procedure the epithelial migration into the defect will be delayed. This procedure resulted in a greater amount of new attachment when compared with traditional flap surgery and less residual pockets. The succes of new attachment procedures is directly related to the abscense of plaque in the area where regeneration takes place. Without absolute plaque control a further loss of attachment can be seen.


[Healing of a spongiosa graft in the periodontal pocket (animal experimental study)].

Healing of cancellous bone grafts taken from the iliac crest which were implanted in alveolar bone pockets were followed with polychromatic sequence marking in animal experiments using beagle dogs. Healing of the cancellous bone graft is unproblematic only in the case of one- and two-walled defects. A periodontal fissure of normal width, but perforated by ankyloses, formed within seven weeks. The fissures are considerably more pronounced when the dentin is denuded than when the cement layer has been preserved.


[Experimental studies on a periodically reproducible radiologic interpretation in bone transplantations].

A method of radiologic evaluation using a semiautomatic image analysis device was developed which permits a two-dimensional analysis of bony changes in time intervals. The objective reproducibility of the evaluation was determined in a control group of four patients without signs of periodontal changes. The standard deviation was 7%. The statistical analysis of the subjective range of radiologic interpretation showed a standard deviation of 9.1%. This method of radiologic evaluation was applied to control examinations of 20 patients with bone grafts. It was possible to carry out a percent and an absolute evaluation of the bony changes in time intervals.


[Intensive drug therapy of the marginal periodontium].

Two composite pastes composed of iodoformglycerin-tween 80 and tribromphenol-bismuth-glycerin were examined using the results of microbiologic studies. Because of their broad antimicrobial spectrum and their easy application, both pastes are suitable for primary control of bacteria in periodontal pockets, particularly when the complete picture of an inflammation is present. The application period for the therapeutic use of corticosteroids should be limited. In addition to freedom from pain, initially slight tissue damage may worsen considerably with prolonged use of these pastes.


[Persistency and resistance of streptococci isolated from periodontal pockets].

Intradermal injection of cell walls or cell wall constituents (Peptidoglycane) of Streptococcus sanguis II in experimental animals caused a similarly severe inflammatory reaction as with Streptococcus A. The three "viridans" species of streptococci proved to be resistant to complement (active serum) as well as to lysozyme and were superior to Streptococcus A in their capacity for resistance to another type of muralytic enzyme isolated from Streptomyces albus. The new acylureido penicillins (Mezlocillin, Azlocillin) had an almost equally inhibitory effect on the growth of the various species of bacteria. The "viridans" and beta-haemolytic types of streptococci which induce a chemotactic reaction in vitro were about equally rapidly and effectively killed in the phagocytes (granulocytes, monocytes) isolated from a patient.


Therapeutic electrical stimulation. The transistorized placebo?

(1) Electrical stimulation therapy for patients suffering with labile signs and symptoms, and these include all varieties of acute and chronic pains, seizures and spasticity, has come into fashion and gone, and come again with each new technological advance for the past two hundred years. (2) A proportion of patients with chronic disease have their suffering made worse if they feel deprived of the latest therapy and may be relieved if they are given it in the right circumstances. In this group the relief will usually be temporary and the limited supply of such reactors will promote the cycle of fashion. In a group of 126 patients with chronic pain associated with organic disease who were offered transcutaneous stimulation, only 23 (18%) continued to use it one year after they started. (3) The cycling of therapeutic fashion is assisted not only because relief is often temporary, but also by the difficulty in establishing the normal range of variability from which significant change can be assessed and by the uncertain relationship between signs and symptoms and for the functions of daily living. For these reasons there is an inevitable tendency to temporary over-optimism and it seems impossible to counter this by the execution of a satisfactory clinical trial, since the patient cannot be "blind" and a significant variable is the enthusiasm with which a therapy is surrounded. (4) Electrical stimulation by cutaneous devices or implants can give much benefit to some patients in whom other methods have failed and there are indications, not only from anecdote and clinical impression but also now from experimental physiology, that it may benefit by mechanisms of interaction at the first sensory synapse. It is, however, an over-simplification to regard any therapy as either strictly physiological or simply fraudulent. Like other so-called placebos, physical methods of therapy can presumably act on hormonal systems associated with stress and the experience of pain.


Perturbation of hormone storage and release induced by cyproheptadine in rat pancreatic islets in vitro.

The effects of cyproheptadine (CPH) added in vitro were studied in rat pancreatic islets maintained in culture medium. CPH added over 6 days resulted in either an increase (5 X 10(-7) M CPH) or a marked, but reversible decrease (5 X 10(-5 M) in insulin content of islets when related to that of controls. At both concentrations, however, total recoverable insulin from islets, cells detached from islets, and medium was decreased relative to control cultures. The increased insulin content observed after 6 days with 5 X 10(-7) M CPH may be explained by the partial inhibition of insulin release, preventing the normally occurring early drop in insulin content of control islets. The decreased total recoverable insulin in the culture system with 5 X 10(-5) M CPH (17% of the initial insulin content of the islets placed into the CPH-containing culture medium) was not acounted for by the combined effects of insulin degradation in the culture medium and inhibition of insulin biosynthesis. Together and by exclusion these data suggest increased insulin degradation within beta-cells as a result of exposure to 5 X 10(-5) M CPH. Since increased intracellular insulin degradation was not found at 5 X 10(-7) M CPH, the data suggest that only severe inhibition of insulin release (5 X 10(-5) M CPH) increases intracellular insulin degradation. CPH added in vitro irreversibly decreased islet glucagon content; the data suggest that these effects are due to alterations in the physical properties of the peripheral cell layers of isolated islets. Studies with 5 X 10(-5) M CPH on the biosynthesis of insulin immunoreactive material failed to link the appearance of flocculent material in dilated cisternae of the rough endoplasmic reticulum (observed by electron microscopy) with accumulation of an immunoreactive biosynthetic precursor for insulin.


Endogenous opioids participate in the regulation of the hypothalamus-pituitary-luteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone.

Two narcotic antagonists, naloxone and naltrexone, significantly elevated serum LH levels in male rats within minutes after their sc injection. The peak increase in serum LH occurred 20 min after the injection. Naloxone increased LH levels up to a dose of 1 mg/kg, after which no further increases were found. A dose of 0.35 mg/kg produced a half-maximal response. The exogenous opioid morphine blocked the increase in LH produced by naloxone in a dose-dependent fashion, suggesting that the specific receptor-blocking effects of the antagonist could account for its enhancement of serum LH levels. The locus of action of naloxone within the hypothalamic-pituitary-LH axis appeared to be at the level of the hypothalamus since the drug had no effect on LHRH-stimulated release of LH by the anterior pituitary and did not block dihydrotestosterone's suppression of pituitary LH release in vitro. Naloxone also prevented testosterone's negative feedback inhibition of serum LH in the castrated male rat. The results of these studies suggest that endogenous opioids exist in brain tissue which normally inhibit activity in the hypothalamic-pituitary-LH axis and participate in the androgen-dependent feedback control of LH elaboration by this axis.


Starvation diabetes in the rat: onset, recovery, and specificity of reduced responsiveness of pancreatic beta-cells.

A 24-h starvation markedly diminished the stimulant action of 8 mM glucose on insulin secretion from isolated perifused rat islets of Langerhans. The response to a supramaximal glucose stimulus (27.5 mM) remained normal, but prolonged fasting (48 or more) also reduced its efficacy. Refeeding of 24-h fasted animals resulted in complete restoration of glucose sensitivity within 24 h. The responses to glyceraldehyde (2 mM) and alpha-ketoisocaproate (8 mM) at concentrations which elicit approximately half-maximal stimulation were unaltered by a 24-h fast, while that to a half-maximally effective dose of mannose (15 mM) was decreased. Theophylline (5 mM) could not normalize the reduced secretory response to glucose seen in this state. The islets' ability to metabolize glucose, using various in vitro pretreatment protocols and different incubation times, was not affected by a 24-h fast. Mannose and glyceraldehyde metabolism were also unaltered. Prolonged fasting (48 h) reduced glucose metabolism by 25% at both 8 and 27.5 mM. The acute adaptive changes in islet sensitivity to moderate glucose and mannose concentrations during short term fasting (24 h) cannot be explained by an altered usage of the added hexoses.


An investigation of the conformational properties of ribosomes using N-ethylmaleimide as a probe.

The reactivity of ribosomal proteins towards N-ethylmaleimide has been examined in a variety of ribosome and ribosomal subunit preparations from Escherichia coli. The data show that samples which would be regarded as equivalent operationally can differ significantly in conformation, as judged by reactivity, depending on the method of preparation. The washing of ribosomes with high concentrations of salt has a particularly dramatic effect on protein reactivity. The implications of these results for our understanding of ribosome conformation and for the further study of conformation by chemical reactivity are discussed.


Messenger RNA of the large subunit of ribulose-1,5-bisphosphate carboxylase from Chlamydomonas reinhardi. Isolation and properties.

Polysomes specifically synthesizing the large subunit of ribulose-1,5-bisphosphate carboxylase were isolated from Chlamydomonas reinhardi cells by the indirect immunoprecipitation method. Electrophoretic analysis showed that the immunoprecipitated polysomes were of chloroplast origin. The mRNA coding for the large subunit which was purified from immunoprecipitated polysomes migrated at the 19-S position on sucrose density gradients, and its molecular weight was estimated to be 7.3 x 10(5) by acid-urea/agarose gel electrophoresis. The mRNA was translated in vivo with a cell-free protein-synthesizing system derived from Escherichia coli to give full-length large-subunit polypeptides.


Yeast tRNA Leu UAG. Purification, properties and determination of the nucleotide sequence by radioactive derivative methods.

A second major species of leucine tRNA, tRNA Leu UAG (formerly designated tRNA Leu CUA) was purified from baker's yeast in a three-step procedure entailing BD-cellulose chromatography in the presence and absence of Mg2+ and Sephadex G-100 gel filtration. Results of aminoacylation and partial RNase T1 digestion experiments showed that this tRNA retains a native conformation under conditions that denature yeast tRNA Leu m5CAA (tRNA3 Leu). The primary structure of baker's yeast tRNA Leu UAG was elucidated by application of sensitive radioactive isotope derivative ("postlabeling") methods. Complete RNase T1 and A and partial RNase U2 fragments, prepared from non-radioactive tRNA and 5'-half and 3'-half molecules, were separated by two-dimensional polyethyleneimine-cellulose anion-exchange thin-layer chromatography and isolated by a novel micropreparative procedure affording high yields of these compounds in sufficient purity for subsequent tritium derivative analysis. Base composition and sequence of oligonucleotides were analyzed by tritium derivative methods. Molar ratios of the fragments were determined from the radioactivity of 3H-labeled nucleoside trialcohols in combination with base analysis. 2'-O-Methylated guanosine was characterized using the [gamma-32P]ATP/polynucleotide kinase reaction. The analysis of classical complete and partial RNase digests by the tritium derivative methods yielded the complete nucleotide sequence of the tRNA. A total of about 20 A260 units of the RNA was used for analysis, i.e. considerably less material than required for conventional spectrophotometric analysis. A different sequencing approach, consisting of a combination of "readout sequencing" with tritium sequencing of complete RNase T1 and A fragments, was applied to the 3'-half molecule. The 3'-half molecule was labeled with 32P at its 5' terminus, partially degraded with RNase T1, U2, and Phy1 and with alkali, and subjected to polyacrylamide gel electrophoresis. The sequence was read off the gel on the basis of cleavage patterns and size of the fragments. While the readout procedure provided only the positions of A, U, C, and G residues in the chain, additional information from tritium derivative analysis was utilized to define the positions of the modified nucleosides. The readout sequencing procedure was found to require less than 0.01 A260 unit of RNA and the analysis of the complete fragments about 6 A260 units. Interesting structural features of tRNA Leu UAG are (a) the location of unique, leucine tRNA iso-acceptor-specific sequences next to U-8, a constant nucleotide participating in synthetase recognition, (b) the occurrence of 1-methyladenosine in the T loop, a modification not present in the structurally related tRNA Leu m5CAA, and (c) the unusual presence of an unmodified uridine in the first position of the anticodon, which may be related to the unusual coding properties reported for this tRNA.


Studies on the multi-enzyme complex of yeast fatty-acid synthetase. Reversible dissociation and isolation of two polypeptide chains.

1. The multi-enzyme complex of fatty acid synthetase, Mr 2300,000, was dissociated by acylation with dimethyl maleic anhydride under conditions which lead to an acylation of about 30% of the epsilon amino groups of lysine. The complete dissociation into the subunits alpha and beta is demonstrated by analytical ultracentrifugation as well as disc gel electrophoresis. 2. This dissociation is reversible. Hydrolysis of the resulting protein dicarboxylic acid monoamides under mildly acidic conditions leads to the unmodified subunits, which can be reconstituted to form a complex displaying about 60% of the original activity. 3. The subunits were isolated by sucrose-density-gradient centrifugation and studied for the different partial enzyme activities involved in long-chain fatty acid synthesis: malonyl, palmitoyl and acetyl transferase, enoyl reductase and dehydratase were shown to be exclusive functions of the beta chains of the complex, confirming a pentafunctional role of this subunit.


The kinetics of Schiff-base formation during reconstitution of D-serine apodehydratase from Escherichia coli with pyridoxal 5'-phosphate.

Schiff base formation during reconstitution of D-serine dehydratase (Escherichia coli) from its apoenzyme and pyridoxal 5'-phosphate (pyridoxal-P) has been studied by rapid kinetic techniques using absorbance changes at 436 nm. Three distinct reaction phases have been observed. The first is a very rapid change during which pyridoxal-P is initially bound to the apoenzyme. This step has an equilibrium constant of 1500 M-1 and a forward reaction rate of the order of 2.6 x 10(6) M-1 s-1. The second phase shows a first-order rate constant with a value dependent on pyridoxal-P and corresponds to a first-order step with a forward rate constant of 3.04 s-1 interacting with the initial equilibrium. The final phase is a slow first-order reaction, the rate constant of which is approximately 0.01 s-1 and is independent of pyridoxal-P concentration. The active pyridoxal species has been shown to be the free pyridoxal-P as opposed to hemiacetal or hemimercaptal forms.


Ribosomal translocation assayed by the matrix-bound poly(uridylic acid) column technique.

The system of translation of cellulose-bound poly(uridylic acid) by Escherichia coli ribosomes has been used for preparation of pre-translocation state ribosomes in columns. Translocation has been induced by passing the elongation factor G (EF-G) with GTP or its non-cleavable analog (guanosine 5'-[beta, gamma-methylene]triphosphate) through the column. A method for quantitative comparison of translocation rates, and thus of effectiveness of translocation-inducing factors, has been proposed. The method is based on an analysis of the profile of deacylated tRNA elution resulting from translocation in the column. The determination of the rate and amount of translocation has been done under different ionic conditions. It has been found that the Mg2+ concentration is a decisive factor of translocation in vitro: at high Mg2+ (30 mM) EF-G cannot induce translocation, and lowering the Mg2+ concentration (to 10 mM) is required for EF-G to become effective. Sufficiently low Mg2+ (3 mM) itself has proved to induce fast and complete translocation, without EF-G.


The 'DNA-membrane complex' of Escherichia coli B/r. Its composition and properties and the fate of nascent and genome DNA during DNA synthesis.

The composition and properties of 'DNA-membrane complex' of Escherichia coli B/r have been investigated. The 'complexes' contain most of the DNA and membrane of the cells, and about 50% and 25% of the RNA and protein respectively. The properties of DNA synthesized by the 'complexes' are described and the process is concluded to be largely mediated through polymerase I. Nascent DNA synthesized by the 'DNA-membrane complexes' was of two main classes, one of molecular weight around 600,000--800,000 and the other of higher molecular weight. Polynucleotide ligase activity was not detectable. The onset of synthesis coincided with the dissociation of at least 70% of the genome DNA and all of the nascent DNA from the 'complexes' and was concomitant with the action of a nuclease on parental DNA. This nuclease activity was not ATP-dependent.


Consecutive study of early CPAP-application in hyaline membrane disease.

Continuous positive airways pressure (CPAP) has been applied with a face-chamber in 74 infants with hyaline membrane disease (HMD) before 10 h of age. The total survival rate was 91% and the complication rate of pneumothorax was low (5%). The incidence of long term developmental and neurological sequelae was also low (4%). Among the 19 surviving very low birth-weight (VLBW) infants below 1501 g, only one has shown neurological sequelae at follow-up examinations after 18 months to 3 years of age. The incidence of cerebellar hemorrhage was not higher in infants treated with the CPAP face chamber than in infants not receiving assisted ventilation. Bronchopulmonary dysplasia did not occur in any infant treated with CPAP face chamber only. The main advantages with the face chamber technique are: no disturbance of glottis function, no mucosal damage and tube obstruction, or sudden pressure drops, as seen with other modes of CPAP application. The face chamber technique is suitable for early application of CPAP in infants with HMD as it is efficient, without hazards, and easily applied.


Absorption of digoxin in severe right heart failure.

The absorption of digoxin has been investigated in 8 patients before and after successful treatment of severe right heart failure. 3H-digoxin 0.1 mg as a solution, and un-labelled digoxin 0.25 mg as a tablet, were given to fasted patients. Blood samples were taken at various time intervals up to 120 hours and urine was collected over the same period. The concentrations of labelled digoxin in plasma and urine were measured in a liquid scintillation counter, unlabelled digoxin was estimated by radioimmunoassay, and various pharmacokinetic parameters were calculated. There was no significant difference in the plasma concentration curves in severe right heart failure and after its successful treatment, nor did any of the calculated pharmacokinetic parameters change significantly. Therefore, inhibition of the absorption of digoxin appears unlikely. In an additional study to estimate absolute bioavailability two different groups of patients in severe right heart failure were given 3H-digoxin 0.1 mg or unlabelled digoxin 0.25 mg i.v. and the pharmacokinetic parameters were compared with those from the previous study. The bioavailability of the 3H-digoxin solution and of the digoxin tablet were in the same range as values previously published for healthy volunteers, and patients both with and without cardiac failure.


Disposition of guanethidine during chronic oral therapy.

The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuous of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.


Anti-peroxidase antibody-secreting hybrid lines. I. Identification, cloning and cell characterization.

Anti-peroxidase antibody (Ab)-secreting hybrids have been produced by fusion of peroxidase (PO)-immunized mouse lymph node cells and immunoglobulin (Ig)-secreting P3-X63-Ag8 (X63) myeloma cells. Identification of Ab-secreting hybrids can be performed as early as day 5 after cell fusion by the hemolytic plaque assay. Immediately after identification, hybrids were directly isolated, by means of a micropipette, into Terasaki microchambers containing nutrient medium and a thymocyte filler layer. The yield of secreting hybrids is improved by using this procedure. All the cells of the PO 772 C2 clone show the same ultrastructural pattern and immunocytological properties; they are proplasmocytes, as are the parental X63 cells; they present intracisternae Ab and show no Ig or Fc receptors at the cell surface. Over 90% of viable PO 772 C2 cells form specific plaques. Isoelectric focusing and sodium dodecyl sulfate polyacrylamide gel electrophoresis show that the cells of this clone secrete Ab; the secreted Ig are formed with chi and gamma 1 chains from the parental X63 cells and specific L and H chains from the lymphoid parent. These biological investigations demonstrate the relative stability of the PO 772 C2 clone secreting anti-peroxidase antibody.


Maturation of B lymphocytes. II. Sequential appearance of increasing IgM and IgD in the adult bone marrow.

The relationship between surface IgM (sIgM) and surface IgD (sIgD) was examined on small lymphocytes in the adult murine bone marrow or prepubertal spleen. Cells were sorted on the basis of different sIgM levels by a fluorescence-activated cell sorter (FACS) and relabeled for sIgD or total sIg by a sandwich technique using 125I-labeled protein A and radioautography. For detecting sIgD, an anti-delta allotype reagent was used in congenic mice. Cells lacking sIgM in the bone marrow or spleen were also found to be sIgD-; thus, sIgD appeared only in the presence of sIgM. Weak sIgM-bearing cells in the bone marrow also had no sIgD indicating that sIgD appeared only after the acquisition of a significant level of sIgM. Subsequently, the incidence of sIgD+ cells increased in fractions showing increasing sIgM levels indicating the acquisition of new sIgD by "sIgM only" cells with increasing maturation levels in the bone marrow. In marrow lymphoid cells expressing both Ig isotypes, sIgM and sIgD levels increased in parallel, possibly with increasing maturation level. In the spleen, the incidence of sIgD+ cells among various cell fractions showing different sIgM levels was found constant. However, spleen cells bearing both receptors, showed a small increase in the sIgD level with increasing sIgM level.


The immune response of CBA/N mice and their F1 hybrids to 2,4,6-trinitrophenylated (TNP) antigens. I. Analysis of the response to TNP-coupled lipopolysaccharide in vivo and at the clonal level.

Plaque-forming cell (PFC) responses to 2,4,6-trinitrophenylated lipopolysaccharide (TNP-LPS) were studied in normal and immunodeficient mice. In vivo immunizations with TNP-LPS showed a 25--50% reduction in PFC responses in CBA/N mice and their (CBA/N X BALB/c)F1(NBF1) male hybrids with an X-linked immune defect of B lymphocyte differentiation. A detailed clonal analysis of the reduced responses to TNP-LPS revealed that CBA/N and NBF1 male mice with the X-linked genetic defect have fewer precursor B cells engaged in the response to TNP-LPS than the control mice. The reduction in precursor cell numbers affects selectively B cells secreting high avidity anti-TNP antibodies as determined by PFC inhibition studies.


Reactivity of monoclonal anti-melanoma antibodies with melanoma cells freshly isolated from primary and metastatic melanoma.

Human melanoma cells, freshly obtained from nine primary and metastatic melanoma cases, were tested for binding of monoclonal anti-melanoma antibodies produced in vitro by hybridoma clones. Monoclonal anti-melanoma antibodies bind to melanoma cells but do not react with nonmalignant cells obtained from the same patients or with cells obtained from giant hairy nevus. These results confirm the existence of tumor-specific antigens. Binding of monoclonal antibodies to melanoma cells of several origins, primary or metastatic, from different patients suggests the existence of tumor antigens shared by human melanoma cells. The binding pattern of different antibodies to various cells also predicts the existence of more than one tumor-specific antigenic determinant on melanoma cells.


Purification with monoclonal antibody of a predominant leukocyte-common antigen and glycoprotein from rat thymocytes.

A leukocyte-common (L-C) antigen which can be dominant as an immunogen in rabbit anti-rat thoracic duct lymphocyte serum has been purified from rat thymocytes. Initially, an antigenic fragment of 100,000 apparent mol. wt. was prepared at 400 to 900-fold purification by lentil lectin affinity chromatography and gel filtration in deoxycholate. Mice were then immunized with this fraction, and a hybrid myeloma cell line secreting antibody to the L-C antigen was prepared by cell fusion. This antibody was used for affinity chromatography and gave pure L-C antigen at 1400-fold purification compared with thymocytes. The L-C antigen is a major membrane glyco-protein of rat thymocytes and has an apparent mol. wt. of 150,000 as determined by electrophoresis on polyacrylamide gels in sodium dodecyl sulfate. The antigen constitutes one of the three thymocyte glycoproteins which stain intensely for carbohydrate with periodic acid Schiff stain. It is present on greater than 95% of thymocytes, bone marrow cells and thoracic duct lymphocytes.


Comparison of effects of prostaglandins E2 and I2 on rat renal vascular resistance.

Effects of PGE2 and PGI2 on renal vascular resistance (RVR) were compared in anesthetized rats. Renal blood flow and systemic blood pressure were measured before and during infusion of PGE2 (2--2 microgram/min) or PGI2 (1--5 microgram/min) into the aorta just proximal to the renal arteries. Both prostaglandins significantly decreased blood pressure and renal blood flow, but effects on RVR were dissimilar. At low doses, PGI2 reduced RVR in 8 of 10 rats; PGE2 increased it in 5 of 7. At higher doses, PGE2 increased RVR in all rats; during PGI2 infusion RVR did not significantly exceed control at any dose. We conclude that, in the intact rat, PGE2 increases RVR either directly or through potentiation of other constrictor stimuli, while PGI2 tends to reduce RVR and diminish the renal response to other constrictor stimuli. PGI2 is the only prostaglandin found to decrease RVR in the rat.


Effect of catecholamine-receptor stimulating agents on blood pressure after local application in the nucleus tractus solitarii of the medulla oblongata.

The effect of various catecholamines and alpha-mimetics, given by microinjection in the A2-region of the nucleus tractus solitarii (NTS), on blood pressure was investigated in anesthetized male rats. A dose-dependent decrease of blood pressure and heart rate was induced by adrenaline as the most effective drug, followed by noradrenaline, dopamine, alpha-methylnoradrenaline and octopamine. Ablation of the rostral or caudal part of the NTS, or removal of the area postrema did not diminish the effect of alpha-methylnoradrenaline. Higher doses of noradrenaline and alpha-methylnoradrenaline caused an initial rise of blood pressure, while the blood pressure lowering effect of noradrenaline was diminished, and that of alpha-methylnoradrenaline and dopamine delayed. Isoprenaline and the (+)-stereoisomers of noradrenaline and alpha-methylnoradrenaline were ineffective. The hypotensive effect of dopamine was not prevented by systemic injection of the dopamine beta-hydroxylase inhibitor FLA 63. Prior application of haloperidol, yohimbine and phentolamine antagonized the hypotensive response to dopamine and alpha-methylnoradrenaline. Application of peripherally effective alpha-mimetics into the A2-region had no or little effect, while high doses increased blood pressure. Tyramine and clonidine caused some decrease of blood pressure. Clonidine also decreased blood pressure when it was applied in the area of the locus coeruleus. Application of isoprenaline in the locus coeruleus also decreased blood pressure while in contrast adrenaline, noradrenaline, dopamine and alpha-methylnoradrenaline increased blood pressure. The present data suggest that the catecholaminergic receptors in the A2-region of the NTS differ from the classic vascular alpha-receptor and that the NTS also may contain structures which can antagonize the decrease in blood pressure.


Experimental studies of schistosomal pigment from Schistosoma japonicum.

The schistosomal and malarial pigments were distinguishable before and after extraction from the host liver. Presence of iron in both pigments was ascertained by the elemental X-ray analysis. Histochemically, however, schistosomal pigment was similar to that of malarial pigment.


An adrenergic participation subserving a positive inotropism and chonotropism of prostacyclin on isolated rat atria.

The effects of prostacyclin (PGI2) on the contractile frequency and on the isometric developed tension of spontaneously beating or paced isolated rat atria were explored. PGI2 enhanced frequency and contractile tension, both effects being blocked by the presence of propranolol, or following a pretreatment with 6-OHDopamine.


Different marrow cell number requirements for the haemopoietic colony formation and the curve of the W/Wv anemia.

The lowest cell number in the normal marrow transplant, which allows the cure of W/Wv anemia was found to be between 10(4) and 10(5). This exceeds by several times the lowest cell number necessary for the haemopoietic colony formation. Therefore, either the colony forming cell is not the haemopoietic stem cell but rather its progeny, or this cell requires an aid from some other cells to exert is activity.


Precoital single doses of delta9-tetrahydrocannabinol block ovulation in the rabbit.

delta9-Tetrahydrocannabinol (delta9-THC) inhibits pituitary gonadotropin secretion in castrated rhesus monkeys. Also, delta9-THC blocks the ovulatory reflux in rabbits. We report now the dose-response relationship of precoital single doses of delta9-THC on luteinizing hormone (LH) release and ovulation in the rabbit. Forty-five female rabbits in estrous were divided into nine groups of five animals. Groups 1 to 5 received a single intramuscular dose of delta9-THC (5,2.5, 1.25, 0.612, and 0.306 mg/kg, respectively) 2 hours before mating; animals of group 6 received vehicle only. In animals of groups 7 and 8 ovulation was induced with 100 IU of human chorionic gonadotropic (hCG), given intravenously 2 hours after the administration of delta9-THC (5 mg/kg) or vehicle. Rabbit luteinizing hormone (rLH) was measured in plasma 90 to 120 minutes after coitus or hCG administration. After the injection of 5 mg of delta9-THC, luteinizing hormone-releasing factor (LH-RF) (20 microgram intravenously) was administered to the animals of group 9. All animals of groups 6, 7, and 8 ovulated. A dose-response curve was observed in the animals treated with delta9-THC and natural mating. Whereas none of the animals treated with 5 or 2.5 mg/kg ovulated, one of the group treated with 1.25 mg/kg, two of the group treated with 0.612 mg/kg, and all treated with 0.312 mg/kg ovulated. Ovulations correlated with postcoital levels of rLH. All animals of group 9 ovulated, indicating that the site of action of delta9-THC is suprapituitary, probably hypothalamic.


[Gonadotropin releasing activity of different regions of rat brain and the probability of presence of a factor which inhibits it in the suprachiasmatic region].

The amount of gonadotropin-releasing hormone (Gn--RH) was measured in the preoptic area and in some parts of hypothalamus by radioimmunoassay. Maximal level was found in the median eminence next followed by that in the portions containing n. arquatus or retrochiasmatic area. The preoptic area contained less Gn--RH. The quantity of Gn--RH was negligible in the suprachiasmatic area. If tested in both supra- and retrochiasmatic areas simultaneously the amount of Gn--RH was much lower than in the retrochiasmatic area alone. Existence of inhibiting or inactivating factor in the suprachiasmatic fragment is suggested. The amount of Gn--RH was small in hypothalamic areas including n. paraventricularis, n. supraopticus, mamillary bodies. From among all the fragments tested the pineal body showed the lowest Gn--RH. There was no correlation between the serum LH concentration and the amount of Gn--RH in any investigated area except the preoptic one.


[Effect of hypothalamic lHRH (luliberin) on the electrical activity of isolated rat heart].

Decelerating effect of LH--RH upon the frequency of contraction of the rat isolated perfused heart was revealed. The neurohormone was also shown to change the heart electrical activity causing elongation of the systole due to an increase in repolarization period. Simultaneous application of LH--RH and norepinephrine to the rat isolated perfused heart did not alter the frequency of contractions. The LH--RH seems to take part in the regulation of the myocardium excitability by means of its effect on the membrane permeability for monovalent cations.


The Teledyne Articulator System 154 as applied to complete denture construction.

A practical articulator, the Teledyne System 154, has been described. It acceptably simulates mandibular movement. Also, it can be used within the economic limitations of an average dental practice. Mechanical limitations of this articulator do exist and must be kept in mind when using this articulator. A fully adjustable articulator satisfies all components of occlusion. However, the registration of the condylar path and the adjustment of such an articulator are complicated, and most dentists do not believe that such complicated articulators are necessary. The choice of articulators depends upon the precision with which the dentist wishes to work and his preference in the handling quality of the instrument.


[Paraproteins in dermatological patients (author's transl)].

Report on paraprotein-cases in a dermatological totality of patients during a six years period. Among 860 seras we found 22 cases with paraproteins. Except IgE-paraprotein all other paraproteinclasses were found in their natural multidy. In 2 cases we saw Bence-Jones-protein, in an other case a very rare combination of IgD-paraprotein with Amyloidosis cutis nodularis atrophicans Gottron. Diseases with sure or probable autoimmune background, i.e. diseases of the vessels with a possible dependence from cold and malignant tumours were on the top of paraproteinemia. 4 of 22 patients died during a 3 years' period after detection of paraprotein. Common clinical and paraclinical signs and symptoms of paraproteinoses are collected in a special table.


Pemphigus foliaceus in a patient with rheumatoid arthritis and Sjögren's syndrome. A case report.

A 74-year-old male patient with rheumatoid arthritis and Sjögren's syndrome developed pemphigus foliaceus. Clinically healthy skin tissue revealed a fluorescent band of IgM along the basal membrane and an intercellular deposit of C3 and IgG in the deepest areas of the epidermis. Similar investigations of diseased skin revealed no deposits of IgM, and C3 and IgG were spread over a large area of the epidermis, though following the same pattern. In sero-positive rheumatoid patients with and without vasculitis, C3 and IgM are frequently found in small dermal vessels immediately below the epidermis in apparently normal skin. The fluorescent band of IgM along the basal membrane is thought to be an expression of the patient's rheumatoid arthritis, in spite of the fact that this IgM site is not typically associated with rheumatoid arthritis. The change in the pattern of deposition is thought to be due to pemphigus foliaceus.


Low allergenicity of triclosan. Predictive testing in guinea pigs and in humans.

Allergic predictive testing with triclosan (Irgasan DP 300) has been carried out in guinea pigs and in humans in order to evaluate its potential allergenic properties. Triclosan, an antimicrobial agent increasingly used in the cosmetic industry (concentration 0.5%) has recently appeared on the market at a higher concentration (3%) in association with flumethasone pivalate as an antimicrobial and antimycotic cream (Logamel). The results of predictive tests for allergy in guinea pigs (1 of 20 positive) and in humans (none of 20 positive) indicate that the sensitization index of triclosan is very low, which is in good accord with some reports from the literature. These underline the rarity of cases of allergic contact dermatitis to triclosan considering its widespread use in the cosmetic industry.


Changes in obstetric anaesthesia in the last twenty-five years.

The last twenty-five years have provided a continuing success story in the achievement of satisfactory obstetric analgesia. Maternal mortality and morbidity from general anaesthesia has not decreased substantially. Mothers still run the same risk of inhalational pneumonitis and are even more likely to suffer the distressing experience of awareness. It must, however, be admitted that general anaesthesia for child-birth has brought increasing benefits to the new born during the last twenty-five years.


The clinical management of the aspiration of gastric contents.

The management of the aspiration of gastric contents is considered under five different headings - clearance of the airway, the problem of oxygenation, the use of steroids, the possible use of prophylactic antibiotics and the general measures applicable to the care of any seriously ill patient. An illustrative case report is presented.


Can aminophylline reduce the need for oral corticosteroids?

Fifteen patients with long-standing chronic obstructive airways disease, who had received oral prednisolone for at least one year with objective and subjective response were included in the study. Attempts to reduce or withdraw steroids had been made unsuccessfully on at least two occasions in all cases. Phyllocontin Continus tablets were given at a dose of 225 mg in the morning and 450 mg at night for a 33-week period. One patient was withdrawn after 8 weeks due to side-effects. Four patients had their oral prednisolone withdrawn entirely and a further seven had a beneficial reduction without adverse effect on FEV1 or VC. The average reduction in daily dosage of steroids was from 10 mg to 4.97 mg (p less than 0.001) with an associated rise in mean FEV1 of 1.69 to 1.92 litres.


Subjective and objective changes noted by patients with bronchial asthma taking slow-release aminophylline.

The authors describe a placebo controlled trial of a slow-release form of aminophylline in a total of twenty asthmatic patients. The data resulting from this work confirmed the fact that the aminophylline is a bronchodilator which improves mean peak flow rate and reduces the intake of beta-agonist drugs in the majority of asthmatic patients.


An evaluation of a controlled-release aminophylline tablet (Phyllocontin Continus) as a concomitant therapy in patients receiving salbutamol.

In a double-blind crossover trial on forty chronic bronchitics Phyllocontin Continus tablets were shown to produce a greater improvement in objective lung function tests than Ventolin tablets. A combination of Ventolin tablets and Phyllocontin tablets were found to produce a greater effect than either drug alone. Changes in objective measurements were not paralleled by the patients' subjective opinions.


Effect of slow-release oral aminophylline on circadian variation in airflow obstruction in asthmatics.

The effect of an oral slow-release aminophylline preparation (Phyllocontin Continus tablets) in preventing early morning reduction in airway calibre was measured in two groups of asthmatic patients; Group I consisted of eight stable asthmatics whose main complaint was nocturnal wheeziness, and Group II comprised four severe asthmatics studied during the period of recovery from an acute exacerbation of asthma. In both groups the effect on one second forced expired volume (FEV1) of two 225 mg tablets of Phyllocontin was compared with that of two placebo tablets on two successive nights in a double-blind trial. On the nights when the placebo preparation was administered both groups of patients showed a marked fall in FEV1. Administration of the active aminophylline preparation prevented this reduction in airway calibre in the Group I patients but had no effect on the fall in FEV1 in the Group II patients. A possible explanation for the observed difference in response between the two groups may have been variation in bioavailability of aminophylline in the two clinical situations.


A double-blind trial of oral aminophylline (Phyllocontin Continus tablets) in airflow obstruction: preliminary communication.

Twenty-two patients with reversible airflow obstruction were entered into a double-blind crossover trial of Phyllocontin Continus tablets and placebo to assess the additional benefit of the controlled-release aminophylline preparation when added to the patients' medication. Most patients were taking inhaled or oral steroids in addition to inhaled beta-sympathomimetics throughout the trial. The dosage of Phyllocontin tablets was adjusted in a pre-trial study to provide serum theophylline levels in the accepted therapeutic range of 10--20 mg/l. In the seventeen patients who completed the 8-week study a small, but significant, increase in both the patients' own recordings of PEFR and weekly clinic measurements of FEV1 was seen whilst on the active drug. Ten patients had improvement in FEV1 greater than 200 ml. Eleven patients recorded subjective improvement on the active drug and five out of ten patients who used inhaled beta-sympathomimetics p.r.n. showed a reduction in their usage of greater than 10%. Side-effects were reported by twelve patients.


Additive interaction of aminophylline and salbutamol in asthma: an in vivo study using dose-response curves.

Dose-response curves to intravenous salbutamol were constructed after injection of saline or aminophylline in a group of ten asthmatic patients. The shape of the salbutamol dose-response curve was not altered by aminophylline pre-treatment--it is therefore argued that the drugs are additive but not synergistic on the basis of this preliminary study.


Preliminary experience with controlled-release aminophylline in asthmatic children: salivary levels and peak flow following a single dose.

Preliminary experience of a controlled-release aminophylline tablet in twenty-five asthmatic children has been gained by measuring salivary theophylline levels and peak flow after a single dose (11 mg/kg). The results were compared with an oral theophylline preparation. Mean salivary levels remained elevated at eight hours following ingestion of controlled-release aminophylline, at which time 58% of the children continued to show an improvement in peak flow. Individual children showed a wide variation in salivary levels and respiratory response. It is recommended that theophylline levels should be monitored in the saliva to ensure maximum benefit from the drug.