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Guinea pig liver mitochondria 40–70 per cent depleted of magnesium are three times more sensitive to phenethylbiguanide inhibition of state 3 respiration than are comparable controls. Similar results are obtained whether the depletion is accomplished by the divalent cation ionophore A23187 or by incubation with inorganic phosphate. In contrast to controls, inhibition in Mg-depleted mitochondria is competitively reversed by Mg 2+ . These phenomena are observed with NAD + -linked substrates, stimulated by either ADP or Ca 2+ , but not with succinate. The Mg-depleted mitochondria can be restored to the normal degree of phenethylbiguanide sensitivity by incubation with high levels of Mg 2+ followed by washing. As in controls, phenethylbiguanide inhibition in Mg-repleted mitochondria is not reversed by Mg 2+ . These results suggest a dual action of Mg 2+ : (1) a structural role of bound magnesium which regulates the activity of cation transporters, and (2) competition between Mg 2+ in solution and guanidinium derivatives for a cation carrier.

Excerpt To the editor: The data from Schneider and associates' (1) long experience with radiation-induced thyroid carcinoma validate the theoretical results we obtained using decision analysis (2),...

Seven episodes of severe ketoacidosis in six nondiabetic patients were recognized at this hospital within an eighteen month period. All were women; one pregnant patient experienced two episodes at twenty-eight and thirty-two weeks' gestation. All patients admitted to heavy chronic alcohol intake and drinking binges. On admission, these patients were conscious and alert. Mean values were 143 mg./100 ml. for plasma glucose and 7.25 for arterial pH. Plasma bicarbonate was depressed with a mean anion gap of 18. Beta-hydroxybutyrate/acetoacetate ratio averaged 5.2. All patients had liver function abnormalities. Mean serum immunoreactive insulin was low, 5μU./ml. (n=2), while cortisol was markedly elevated at 76.5μg. per cent (n=3); mean growth hormone level was 14.1 ng./ml. (n=3). Free fatty acid concentration, measured on admission in one episode, was 1,945 mEq./L. Therapy with glucose, saline, and minimal amounts of alkali led to prompt recovery. Circulating levels of cortisol, insulin and growth hormone were measured serially in one patient during recovery; they quickly returned to normal. The dissociation of severe ketosis from glycosuria and hyperglycemia in these patients raises important questions concerning coupling of ketogenesis to gluconeogenesis. The striking preponderance of women, including one pregnant patient, reported with this condition also suggests a possible role for ovarian and placental hormones in its pathogenesis; fetal drain on carbohydrate reserves may further contribute to the tendency to ketosis. Alcoholic ketoacidosis may be relatively common, since we saw one case of this syndrome for about every four of diabetic ketoacidosis during this period.

Clinical librarian services provide highly specific, case-related medical literature searches in a manner that permits the information obtained to influence ongoing case management. We have measured the impact of such services on actual case management and on diagnostic thinking in a random sample of 50 searches over five months provided to house officers on medical and pediatric services of a university hospital. Patient management was affected in 20% of cases, and diagnostic thinking was influenced in an even higher percentage of instances. In comparison with information generated by other ancillary services such as clinical laboratories, clinical librarian services appear to be highly effective at an acceptable cost. Since the information generated by such searches may often result in further cost savings to patients, the potential overall efficiency of such services may be great.

This decision analysis compares two currently recommended management strategies for adults at increased risk for thyroid carcinoma due to childhood upper body irradiation who present without palpable thyroid nodularity: 1) scan-surgery: initially thyroid scan every patient, then perform subtotal thyroidectomy for each patient with single or multiple scan defects; and 2) no scan reexamine: do not scan initially, but reexamine at least every 2 yr, reserving surgery for those in whom palpable nodularity later develops. When surgical morbidity and mortality are taken into account, the expected utility of the no scan reexamine strategy slightly outweighs that of scan-surgery; this preference is maintained in several sensitivity analyses, unless more than 80% of occult cancers progress to palpable size. Moreover, the financial costs of universal scanning coupled with surgery are considerably greater. The no scan-reexamine approach, therefore, deserves serious consideration as the preferred strategy. Since the expected utilities of the two strategies are nearly equal, however, patient attitudes toward risk should be given particular weight in choosing management.

Publisher Summary The frequency and great biological importance of divalent metal binding sites on proteins makes them of particular interest as the object of affinity labeling studies. Organic cations of many types interact with metal ion sites in biological materials; the binding of amidine and guanidinium compounds at these sites has been extensively studied. The chapter examines the principles involved in this affinity labeling technique to mitochondria by using a more hydrophobie derivative, 4-phenyl-3,5-dimethylpyrazole-1-carboxyamidine. It details the preparation reagents, preparation of affinity-labeled Pyruvate Kinase, and characterization of 4-Phenyl-3,5-Dimethylpyrazole-1-carboxamidine (PDMPA) as a Potential Affinity Label for Mitochondria. The chapter concludes that several unlabeled guanidinium compounds, including butylbiguanide, phenethylbiguanide, and phenethylguanidine, have been tested as potential binding competitors, hence protective ligands, but none are effective, nor is Ca2+ competitive. Conversely, unlabeled PDMPA does not compete for the nonenergized binding of 45Ca2+. 22.

FIFTY years have passed since the introduction of insulin into medicine. It is not widely known that guanidine derivatives were first used in the therapy of diabetes at about the same time, and that the effects of guanidine in a biologic system were first described nearly 100 years ago.1 Over the years, a wide variety of guanidine derivatives have become important investigational tools, as well as major therapeutic agents. Table 1 shows some of these compounds and the extensive range of their activities and uses. It is tempting to conclude that the common structural feature, the guanidine residue, confers no more specificity . . .

Pyruvate kinase (EC 2.7.1.40) is inhibited by phenethylbiguanide. The kinetics of inhibition are competitive between biguanide and divalent, but not monovalent, metal cation activators of the enzyme; biguanide inhibition thus resembles inhibition by Ca ++ . Alteration of either the polar or nonpolar portion of the phenethylbiguanide molecule quantitatively reduces its effectiveness as an inhibitor of pyruvate kinase, but the kinetics of inhibition remain qualitatively unchanged. Measurements of [ 3 H]phenethylbiguanide binding to the enzyme indicate the presence of a single class of about 12 binding sites per enzyme molecule; binding characteristics are not significantly different in the presence of either monovalent or divalent metal cations. Studies with 45 Ca ++ and 54 Mn ++ demonstrate about 4 metal binding sites per enzyme molecule; phenethylbiguanide displaces these metal cations from the enzyme. Studies with several enzymes, dependent upon divalent metal cations, of both metal-bridge and substrate-bridge classes fail to show significant inhibition except at much higher phenethylbiguanide concentrations.

It is unacceptable in this “information age” for medical information to remain in its current neglected and disorderly state. The concept of the informationist—a professional who will retrieve, syn...

Reference 34 should read : 34. SCHAFER, G., Abstracts of Communications Presented at the Meeting of the Federation of European Biochemical Societies, 6th Meeting, Madrid, 1969, Abstract 967. We suggest that subscribers photocopy these corrections and insert the photocopies at the appropriate places where the article to be correctcd originally appeared. Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.

Excerpt The syndrome of mixed gonadal dysgenesis (MCD), in which the gonads are a testis and an undifferentiated "streak," provides a junction point among true hermaphroditism (testis plus ovary), ...