Oversight of physicians' conduct by state licensing agencies. Lessons from New York's Libby Zion case.

The unexplained and highly publicized death of an 18-year-old woman in a New York Hospital in 1984 became the focus for debate throughout the country concerning working conditions and supervision of house officers. It also led to charges by the State of New York of gross negligence against her resident physicians. The residents were exonerated of all charges by a review panel with lay and physician representation after testimony of expert witnesses. Although the Commissioner of Health concurred with this verdict, residents were charged with gross negligence by the Board of Regents, a lay panel. Fundamental contrasts in the way the two panels made their judgments supports the importance of peer review in disciplining physicians in matters of medical judgment. Analysis of the actions by New York State against the residents also underscores the importance of other principles in the oversight of physician behavior that are applicable to all jurisdictions: resolution of charges without undo delay, an equitable and consistent standard for the administration of sanctions, and adherence to a clearly defined standard for the level of culpability required for disciplinary action. Both the structure of the review process and its application in this instance led to violations of each of these principles.

Studies of breast cancer and alcohol consumption.

Alcohol consumption as a potential risk factor for breast cancer was examined in a case-control study of 1,467 female breast cancer patients and 10,178 hospital controls. Lean females (Quetelet index less than 22) had elevated unadjusted odds ratios for breast cancer of 2.1, 1.7, and 1.4, associated with consuming less than 5, 5-15, and greater than 15 g of alcohol per day, respectively. However, this pattern is not consistent with a dose-response, and adjustment for a risk profile of confounding factors, including education and occupation (which are strong correlates of age at first pregnancy and parity), reduced these estimates to 1.4, 1.2, and 0.9; none of which differs significantly from 1.0. Among all subgroups, the odds ratios adjusted for pertinent confounders and interactions fluctuated randomly by about 0.9 and showed no consistent trend with increased alcohol consumption. In a second investigation, proportional breast cancer rates were estimated for female veterans diagnosed in Veterans Administration Hospitals during 1970-1982 using 1973-1977 rates for the general population as the standard of comparison. In the VA cohort of females, which had an approximate twofold higher prevalence of alcohol abuse and chronic cigarette smoking, the proportional rates of known alcohol and tobacco-related malignancies were significantly elevated but the rates of breast cancer were not. The standardized proportional morbidity rates of breast cancer for white, black, and all VA females were 0.92, 0.85, and 0.91, respectively. Although these results do not rule out weak associations between breast cancer and alcohol in certain subgroups, neither do they provide any compelling evidence that alcohol has a role in the genesis of this malignancy.

Effect of experimental diabetes on the susceptibility of myelin proteins to proteolysis.

To investigate abnormalities in peripheral nerve myelin in experimental diabetes, we studied the effects of the proteolytic enzymes trypsin and alpha-chymotrypsin on the proteins of this membrane, obtained from the sciatic nerves of normal rats and from animals made diabetic with streptozotocin. The dominant effect of the proteolytic enzymes was to incompletely degrade the major membrane protein (mol. wt. 28,000), with the appearance of new protein (mol. wt. 20,000). Using myelin isolated from the nerves of diabetic animals, the reaction was approximately one-half that of the controls (P less than 0.01) for both enzymes. When, however, the myelin protein affected by trypsin and chymotrypsin was isolated from the membrane and then incubated with the proteolytic enzyme, its proteolysis was complete and took place at the same rate in the diabetic animals and controls. These findings suggest that, in this model of experimental diabetes, there is an alteration in the structure of peripheral nerve myelin that inhibits interaction between the protein in the membrane bilayer and two water soluble proteolytic enzymes. This alteration could not be demonstrated in protein isolated from the membrane, suggesting that the change relates to the interaction of the protein and other components of myelin, rather than to chemical alteration in the protein per se.

Protein kinases associated with peripheral nerve myelin. 1. Phosphorylation of endogenous myelin proteins and exogenous substrates.

When highly purified myelin from rat sciatic nerve was incubated with [gamma-32P]ATP, protein components of the membrane were phosphorylated indicating the presence of both the substrate (receptor protein) and an endogenous kinase in the membrane. Polyacrylamide gel electrophoresis of the phosphorylated membrane proteins followed by scintillation counting of gel slices and autoradiography showed that the polypeptides of molecular weights 28000, 23000 and 19000 were phosphorylated, and 32P from [gamma-32P]ATP having been incorporated into serine residues of the substrate proteins. Phosphorylation of purified myelin was Mg2+-dependent, was optimal at pH 6.5 and was not stimulated by adenosine 3',5'-monophosphate. We found that proteins other than those in myelin, such as phosvitin, casein, protamine and histones, can also act as a substrate for the membrane associated kinase. Muscle protein kinase inhibitor had no effect on the endogenous phosphorylation of myelin proteins or on the phosphorylation of phosvitin by peripheral nerve myelin protein kinase. However, the phosphorylation of histone by peripheral nerve myelin protein kinase was inhibited by the protein kinase inhibitor. After washing the membrane with 150 mM KCl the protein kinase that utilizes histone as substrate was found in the supernatant. In contrast, the endogenous phosphorylation of membrane proteins or the phosphorylation of phosvitin by the membrane associated kinase was not affected by washing. From these findings we conclude that at least two protein kinase systems exist in purified peripheral nerve myelin. One system is not inhibited by muscle kinase inhibitor, is tightly bound to the membrane and utilizes as its receptor proteins either exogenous phosvitin or endogenous membrane proteins. The second system is inhibited by muscle kinase inhibitor, is removable from the membrane and utilizes histones as its receptor proteins.

Decrease in myelin content of rabbit sciatic nerve with aging and diabetes.

Previous studies of the amount of peripheral nerve myelin have been based on histologic examination. In this study, myelin content was measured directly after quantitative isolation from sciatic nerve. There was a decrease in the amount of myelin beginning at nine months, the time of maximal myelin content in normal rabbits, and beginning at six months, the amount was decreased in diabetic as compared with control animals. Composition of myelin isolated from young (age three to four months) and old (age nine to thirteen months) rabbit sciatic nerves was also determined and is similar to that of other species. Although the composition was not affected by diabetes, with aging there was a significant decrease in the amount of cholesterol and an increase in glycolipid.

Metabolism of peripheral nerve myelin in experimental diabetes.

Previous in vitro studies of the metabolism of the peripheral nerve have been based on incorporation of radioactive precursor into components isolated from whole nerve. In this study we have determined incorporation secifically into myelin components of peripheral nerve by isolating myelin after incubating whole nerves with lipid or protein precursors and by determining the specific activity of the components of that membrane. The effect of diabetes on such incorporation was also studied. In the rat, in vitro incorporation of DL-[1-14C]leucine into protein components of myelin was decreased by 30-88% in diabetic animals as compared to controls. The major polypeptide constituent of rat sciatic nerve myelin (mol st 28,000; 58.5% of total mass of proteins) was not labeled in either the diabetic or the control group. In diabetes incorporation rate into a polypeptide of mol wt 23,000, which constitutes 21% of total mass, was approximately one half that of controls. In polypeptides of mol wt 38,000-49,000, which are heavily labeled in normal animals, but constitute only about 5% of total mass of proteins, depression of incorporation was e-en more marked in the diabetics. While these marked differences in incorporation between diabetic and control animals were observed, the amount of protein and its distribution among the constituent polypeptides was the same in both groups. In young rats made diabetic with streptozotocin and young rabbits made diabetic with alloxan, there was a lower rate of incorporation of the lipid precursors, [1-14C]sodium acetate or [3H]water, into myelin components. In older animals of both species incorporation in the controls was considerably lower than in the yount animals, and the effect of diabetes was no longer apparent. In nondiabetic animals, the in vitro addition of insulin (10-7 M) stimulated incorporation of DL-[1-14C]leucine into myelin proteins 1.6-3.1 times that of controls. This stimulation by insulin in vitro was not seen in diabetic animals. In animals in which diabetes had spontaneously recovered, however, incorporation rate in the in vitro experiments approached that of controls and were significantly above that in animals whose diabetes persisted. Since myelin is the palsma membrane of the Schwann cell, these studies provide evidence that the Schwann cell is affected by insulin and that some aspects of the metabolism of myelin are altered in insulin-deficient states.

Myelin from human peripheral nerves. Quantitative and qualitative studies in two age groups.

Myelin in femoral nerve segments obtained at autopsy was isolated quantitatively by a series of discontinuous and continuous flotation procedures. The total amount of myelin isolated from these nerves was expressed as the sum of cholesterol, glycolipid, phospholipid, and protein and averaged 2.6+/-0.4 mg/g in a group aged 60-77 yr compared with 10.8+/-1.9 mg/g of nerve in a group aged 35-58 yr. The lower value in the older group remained apparent whether the myelin content was related to the whole nerve segment, its unit length or weight. This indicates that the decrease is an absolute one, not related to a change with aging in the nonmyelin content of nerve. No qualitative differences in myelin lipids were found between the two groups. Protein content was, however, significantly higher in the older group (34 and 28.7% of the total myelin weight, respectively). The decrease in myelin content with aging, observed by direct measurement in this study, may be the structural counterpart to age related alterations in peripheral nerve function-decreased conduction velocity, and impaired appreciation of vibration.

Studies of brain myelin in the "quaking mouse".

Myelin was isolated from the brains of "quaking" and littermate control animals and its composition was determined. The brains of quaking animals contained approximately one-fourth as much myelin as the control animals. There were qualitative as well as quantitative differences between the myelin from the two groups. By continuous cesium chloride gradient flotation it was shown that the myelin from the quaking animals consisted solely of a band corresponding to the heavier and smaller of the two bands found in normal controls. Cholesterol and glycolipids were lower and phospholipids (mainly phosphatidylcholine) and protein were higher in quaking animals than in controls. Also, phosphatidal-ethanolamine was decreased, and several consistent differences in the fatty acids (both unsubstituted and hydroxy) and aldehydes of the component lipids were found. In general there were smaller amounts of monounsaturated fatty acids in quaking animals. We suggest from these findings that myelin in the quaking mouse has certain compositional similarities with juvenile myelin, but it may be an abnormal type of myelin.

Fatty liver produced by dietary deficiencies: its pathogenesis and potentiation by ethanol.

In a study of the pathogenesis of hepatic fat accumulation under experimental conditions mimicking chronic alcoholism, rats were fed a low-fat diet, deficient in amino acids and choline, containing either ethanol or isocaloric amounts of carbohydrate. Dietary deficiencies alone produced a moderately fatty liver after 24 days. The combination of ethanol and dietary deficiencies resulted in enhanced lipid accumulation, which was apparent after only 11 days. In an investigation of the origin of hepatic triglyceride fatty acids, the experiment was repeated after the adipose lipids had been marked by the feeding of oils containing characteristic fatty acids (linseed oil, containing linolenate, or coconut oil, containing laurate and myristate). In all animals, the fatty acid composition of the hepatic triglycerides differed markedly from that of adipose tissue; it had a larger percentage of endogenously synthesized fatty acids and a five times smaller percentage of the marker fatty acids. In addition, ethanol feeding resulted in a greater retention of the marker fatty acids in the adipose tissue. Thus, the deposition of hepatic triglycerides produced by the feeding of deficient diets is markedly potentiated by ethanol; the triglyceride fatty acids accumulated under these conditions appear to originate, for the most part, not from mobilization of depot fat, but from endogenous synthesis.

Effects of dietary fats on plasma lipids and lipoproteins: an hypothesis for the lipid-lowering effect of unsaturated fatty acids.

Several aspects of the effects of dietary fat on plasma lipids and lipoproteins were investigated in 12 subjects during the long-term feeding of formulas containing 40% of their calories as either saturated or unsaturated fats. The changes in fatty acid composition of plasma lipids, shown previously to occur after prolonged feedings of a dietary fat, required 10-14 days to be complete and were synchronous with the effect of the fat on plasma lipid concentrations. The change in lipid concentration occurred in low but not in high density lipoproteins. The effects on lipid levels of the low density lipoproteins were found to occur with little or no effect on the concentration of the protein moiety of these lipoproteins; as a result, cholesterol- and phospholipid to protein ratios in low density lipoproteins fell during unsaturated fat feeding. The effects of dietary fat on plasma phospholipids were studied in detail: the relative amounts of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine were unaffected by the type of dietary fat. However, the molecular species of phosphatidylcholine were markedly affected. More than 90% of the fatty acids at the alpha-position were saturated during both saturated and unsaturated feedings. In contrast, during unsaturated feedings, linoleate at the beta-position outnumbered oleate by approximately 4:1, whereas during saturated feedings these two types of fatty acids were present in nearly equal amounts.This paper also presents the following hypothesis for the lipid-lowering effect of unsaturated dietary fat: since unsaturated fatty acids occupy a greater area than saturated acids, they alter the spatial configuration of the lipids into which they are incorporated; as a result, fewer lipid molecules can be accommodated by the apoprotein of the low-density lipoproteins (LDL), and thus the lipid content of the lipoprotein is lowered. The experimental findings of this study, while not proving this hypothesis, are consistent with it.