Robert J. Levine

Synergism Between Gold and Restraint for Rapid Production of Stress Ulcers in Rats.

Discussion and conclusion This method offers several significant advantages over those described previously. The simplicity of the technique permits an experienced operator to immobilize an animal in approximately 30 to 45 seconds. Only 2 hours are required to produce lesions, offering further saving of time. Apparently this rapid production of lesions represents a synergistic effect of the dual stresses employed. We believe that the mode of restraint also contributes to the improved results obtained. This method obviates additional environmental variables that may be difficult to control, e.g., increased temperature, as with plaster of paris immobilization (5); pain, as with nailing the paws to a board (1); or ingestion of sharp metal fragments, as with wire screen immobilization(3). Furthermore, use of the plastic box permits immobilization in a relatively uniform volume. Bonfils and Lambling, on the basis of studies in a large series of animals, described a linear inverse relationship between incidence of lesions and restraint volume(6). It was our experience that when restraint volume was decreased below a critical point, mortality rates rose sharply; furthermore, it was difficult to identify this critical point. The technique described here rarely results in death of the rat.

Inhibition of histamine synthesis in the rat by α-hydrazino analog of histidine and 4-bromo-3-hydroxy benzyloxyamine☆

Abstract Inhibitors of either specific or nonspecific histidine decarboxylase, or both, were studied in vitro and in vivo . Alpha-hydrazine analog of histidine (αHH) and 4-bromo-3-hydroxy benzyloxyamine (NSD-1055) were found to be potent inhibitors of the specific enzyme, while α-methyldopa and α-methyldopa-hydrazine had little activity. The latter two compounds as well as NSD-1055 were potent inhibitors of the nonspecific decarboxylase. Only αHH and NSD-1055 altered histamine levels in vivo . Administration of these compounds to female rats resulted in decreased levels of histamine in heart (30%), stomach (50%), and urine (45%) but did not alter histamine levels in peritoneal mast cells. Animals whose tissue histamine levels had been partially depleted by pretreatment with compound 48 80 showed little or no further lowering on administration of the histidine decarboxylase inhibitors. Administration of NSD-1055 to germ-free animals produced effects on tissue histamine similar to those in normal animals and decreased already low urinary histamine levels even further. The data suggest that histamine exists in rat tissues in at least three metabolic pools and that its synthesis in vivo is catalyzed primarily by the specific decarboxylase. Because of an apparent lack of toxicity, αHH should be a valuable research tool and warrants study as a potential therapeutic agent.

Children as Research Subjects

In 1975 the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the National Commission) began its studies of the ethics and regulation of research involving children as subjects. In its report, Research Involving Children, published in 1977, the National Commission presented its recommendations for the ethical conduct of research involving children [22]. These recommendations formed the basis of federal regulations that were proposed in 1978 [21] and promulgated in final form in 1983 [19].

Tyrosine Metabolism in Patients with Liver Disease

Plasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis. Tyrosine tolerance tests in patients with cirrhosis were characterized by larger than normal increments in tyrosine levels and by delayed returns toward fasting levels. The results of phenylalanine conversion tests were abnormal in approximately one-half of patients with either hepatitis or biliary obstruction and four-fifths of patients with cirrhosis. Abnormalities were characterized by elevated fasting plasma tyrosine levels, or small and delayed increments in tyrosine levels, or both. Abnormal phenylalanine conversion test results in patients with cirrhosis did not correlate closely with any clinical feature of cirrhosis or with the results of any standard liver function test; there was positive correlation only with abnormal ammonia tolerance, a test of portalsystemic shunting. Tests of tyrosine metabolism do not appear to be useful for routine clinical assessment of liver function. Tyrosine tolerance tests and phenylalanine conversion tests done for purposes of diagnosis of other diseases may yield misleading results in patients with liver disease.

A sensitive and specific assay for histidine decarboxylase activity.

Abstract A method for assay of histidine decarboxylase activity is described; it is based upon using as substrate 14C-histidine labeled in the carboxyl carbon and trapping in hydroxide of hyamine the 14CO2 evolved during incubation. This procedure may be applied to assay of histidine decarboxylase activity in individual tissue specimens after gel-filtration chromatography of homogenates. For illustrative purposes assays of gastric tissue homogenates are presented. Among the advantages offered by this technique over those previously reported are simplicity, specificity, sensitivity, and the capability of expressing enzyme activity in terms of total histamine formed per unit of original tissue. Histidine decarboxylases from fetal rat tissue and from gastric tissue were found to be stereospecific for l -histidine and not inhibited by high concentrations of histamine. Data are presented that suggest the presence of an unidentified soluble inhibitor of histidine decarboxylase in gastric tissue.

Informed Consent: Some Challenges to the Universal Validity of the Western Model

This paper presents first an account of informed consent as it is envisioned and ethically grounded in the Western world. Next there is a discussion of why the Western model is unsuitable in much of the remainder of the world where the concept of “person” differs substantially from that of Western societies. This is followed by some comments on the current controversy on whether ethical standards should be regarded as universally applicable or, rather, whether some degree of ethical and cultural relativism is to be regarded as legitimate. After providing preliminary responses to some questions posed by the Conference Programme Committee, the paper concludes with a proposal for a procedural approach to the resolution of problems with informed consent.

Adolescents as research subjects without permission of their parents or guardians: ethical considerations.

This paper is presented in five sections: I. The first is an overview of current ethical standards for all research involving children relating them to the recommendations of the National Commission for the Protection of Human Subjects (hereafter called The National Commission). II. The second section reviews the exceptions from the general requirements of the regulations for children permitted for some research involving adolescents. This section demonstrates that current regulations may be interpreted to permit the conduct without parents or guardians permission of much more research involving adolescents than is currently being done. This point notwithstanding I recommend that such interpretations should not be implemented without first having the relevant policies reviewed by an authoritative agency such as The National Commission. III. This section explains why I consider this an appropriate time to reconsider national policies regarding research involving adolescents. Current policies reflect the attitude of the time in which they were written--that research is both dangerous to and exploitative of persons particularly those who are vulnerable. They do not reflect the recent changes in the publics perception that participation in research is often beneficial particularly for some vulnerable populations and their individual members. IV. This section is an appraisal of the Guidelines for Adolescent Participation in Research proposed by The Adolescent Scientific Committee of the Pediatric AIDS Clinical Trials Group. The availability of this document affords a valuable opportunity to evaluate a carefully thought out comprehensive proposal. V. The final section presents my recommendations for guidelines for the conduct of research involving mature minors without permission of their parents or guardians. (excerpt)

Fatal dysnatraemia caused by elective colonoscopy

Colonoscopy can cause fatal dysnatraemia, and plasma sodium should always be checked after the procedure

Measurement of urinary epinephrine in screening for pheochromocytoma in multiple endocrine neoplasia type II

Abstract A sensitive screening test for the pheochromocytoma component of multiple endocrine neoplasia type II (MEN-II), comparable to the calcitonin radioimmunoassay for medullary carcinoma of the thyroid (MCT), has been lacking. A large family with MEN-II was screened for pheochromocytoma measuring 24 hour urinary catecholamines as norepinephrine and epinephrine fractions. Pheochromocytomas have been confirmed at surgery in six family members and at autopsy in one. All seven have had associated MCT. In an additional six family members, MCT only has been detected. In five of the six patients treated surgically, the urinary epinephrine fraction was either the dominant or sole abnormality, and an epinephrine level above 20 μ/24 hours, by itself, was diagnostic of a pheochromocytoma. An increased urinary epinephrine fraction appears to be a characteristic feature of the pheochromocytoma of MEN-II, and measurement of this fraction is a sensitive and reliable screening test in afflicted families.

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) ls 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 he determined by chance? We conclude that problems of justice arise not only hecause of the vulnerability of patients in VA hospitals hut also hecause 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 he made more just through various modifications in design. We also conclude that the gact of randomization should be disclosed in any situation in which it might materialiy affect the prospective subjects decision, and that the values and preferences of the subjects should he 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 loeus 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.