EFFECTS OF CHRONIC EXCESS SALT INGESTION : FURTHER DEMONSTRATION THAT GENETIC FACTORS INFLUENCE THE DEVELOPMENT OF HYPERTENSION: EVIDENCE FROM EXPERIMENTAL HYPERTENSION DUE TO CORTISONE AND TO ADRENAL REGENERATION

Two strains of selectively inbred rats were demonstrated previously to have opposite genetic predisposition to develop hypertension from NaCl ingestion (1, 2), DOCA-NaCl (3), and unilateral renal artery compression without NaCl (3). Using these same strains, similar disparate responses were elicited with two other models for inducing experimental hypertension, namely cortisone and adrenal regeneration. On the basis of these experiences, it is proposed that the genetic substrate will be found to modify significantly the influence of all non-genetic factors considered to play a primary role in the etiology of experimental hypertension. Furthermore, it is suggested that similar genetic and non-genetic factors interact to produce hypertension in man. An hypothesis has been elaborated that is compatible with the experimental data and there is some clinical evidence to support this hypothesis.     

Low Density Lipoprotein: A METABOLIC PATHWAY FOR RETURN OF CHOLESTEROL TO THE SPLANCHNIC BED

The mechanism(s) by which cholesterol returns to the splanchnic bed from peripheral tissues are not well understood. To study this phenomenon in fasting man, lipoproteins were isolated from plasma obtained from hepatic vein and aorta. Cholesterol content of each lipoprotein class was determined and arteriovenous (AV) differences could be calculated for each patient. The results in the first 24 patients indicated splanchnic secretion of very low density lipoprotein cholesterol (mean AV difference - 3 mg/100 ml, P < 0.01), but not significant AV difference for total cholesterol, high density lipoprotein cholesterol, or low density lipoprotein (LDL) B protein. In contrast, for LDL (d 1.006-1.063 g/ml), there was significant uptake of cholesterol across the AV bed +8 mg/100 ml, P < 0.0002). In a further 15 patients, similar samples were obtained and intermediate density lipoprotein isolated at d 1.006-1.019 g/ml and LDL at 1.019-1.063 g/ml. The AV difference previously noted could now be localized to the 1.019-1.063 cholesterol ester moiety (+8 mg/100 ml, P < 0.0005). In the final 14 patients, the LDL cholesterol AV difference was again confirmed and shown to be unrelated to heparin. As well, there was secretion of triglyceride in the hepatic vein LDL. These quantitative data obtained in man raise the possibility that LDL rather than high density lipoprotein transports cholesterol ester to the splanchnic bed.     

Tangier Disease: HIGH DENSITY LIPOPROTEIN DEFICIENCY DUE TO DEFECTIVE METABOLISM OF AN ABNORMAL APOLIPOPROTEIN A-I (APOA-ITANGIER)

Tangier disease is a rare familial disorder characterized by enlarged orange tonsils, transient peripheral neuropathy, hepatosplenomegaly, and lymphadenopathy, as well as striking reductions in plasma high density lipoproteins (HDL) and their major protein constituents, apolipoproteins (apo)A-I and A-II. In order to test the hypothesis that Tangier patients have abnormal apoA-I or apoA-II, the in vitro lipoprotein binding and in vivo metabolic characteristics of these proteins isolated from normal and Tangier plasma, were studied in normal subjects and patients with Tangier disease.     

I. RENAL THRESHOLDS FOR HEMOGLOBIN IN DOGS : DEPRESSION OF THRESHOLD DUE TO FREQUENT HEMOGLOBIN INJECTIONS AND RECOVERY DURING REST PERIODS

We use the term "renal threshold for hemoglobin" to indicate the smallest amount of hemoglobin which given intravenously will effect the appearance of recognizable hemoglobin in the urine. The initial renal threshold level for dog hemoglobin is established by the methods employed at an average value of 155 mg. hemoglobin per kilo body weight with maximal values of 210 and minimal of 124. Repeated daily injections of hemoglobin will depress this initial renal threshold level on the average 46 per cent with maximal values of 110 and minimal values of 60 mg. hemoglobin per kilo body weight. This minimal or depression threshold is relatively constant if the injections are continued. Rest periods without injections cause a return of the renal threshold for hemoglobin toward the initial threshold levels—recovery threshold level. Injections of hemoglobin below the initial threshold level but above the minimal or depression threshold will eventually reduce the renal threshold for hemoglobin to its depression threshold level. We believe the depression threshold or minimal renal threshold level due to repeated hemoglobin injections is a little above the glomerular threshold which we assume is the base line threshold for hemoglobin. Our reasons for this belief in the glomerular threshold are given above and in the other papers of this series.     

V. THE IRON CONTENT OF BLOOD FREE TISSUES AND VISCERA : VARIATIONS DUE TO DIET,ANEMIA AND HEMOGLOBIN INJECTIONS

When hemoglobin is set free in the circulation the kidney plays an important part in the conservation of iron. When the renal threshold is not exceeded by the hemoglobin in the blood there is little or no excess iron deposited in the kidney but when superthreshold doses of blood hemoglobin are given the epithelium of the convoluted tubules accumulates much iron and the iron analyses may show 5 times normal values. The normal dog (140 to 150 per cent hemoglobin) has a large reserve store of iron in the liver, spleen and marrow. Diets may modify this storage of iron in these tissues. To bring conclusive proof relating to the individual diet factors, the reserve store of iron should be depleted by an anemia period of 2 to 3 months. Complete removal of red cells from tissue capillaries is essential for accurate iron assays of fresh tissue. The method described accomplishes this without causing gross tissue edema. The lowest iron content is observed in the pancreas, stomach, jejunum, colon and urinary bladder. These figures average from 1 to 2 mg. iron per 100 gm. fresh tissue. This shows that smooth muscle and mucous membranes contain little iron. Striated muscle (heart, psoas) shows a relatively low iron content but uniform values close to 4 mg. per 100 gm. tissue. Lungs show a considerable fluctuation with low iron values in anemia (3.7 mg.) and higher values in health (6 to 7 mg.). The spleen shows maximal fluctuations and the highest reserve storage of iron per 100 gm. fresh tissue. The spleen iron analyses show low values in anemia (7 to 15 mg.) and wide differences in controls (25 to 50 mg.). With hemoglobin injections the iron storage is conspicuous and iron analyses may run as high as l50 to 175 mg. iron per 100 gm. fresh tissue. Bone marrow of the rib runs in parallel with the spleen as regards iron storage following hemoglobin injections and depletion following anemia periods. The liver because of its weight always contains the main bulk of the iron stored in the blood free tissues of the body. Its store is depleted by anemia even to levels of 4 to 5 mg. iron per 100 gm. fresh tissue. In the normal dog the iron store in the liver averages 25 mg. per 100 gm. tissue. Frequent hemoglobin injections may increase this level to 31 mg. iron per 100 gm. The liver is considered the most active clearing house for iron storage and utilization.     

AN EXPERIMENTAL STUDY OF DIATHERMY : IV. EVIDENCE FOR THE PENETRATION OF HIGH FREQUENCY CURRENTS THROUGH THE LIVING BODY.

The principles governing the passage of high frequency currents through various conductors have been discussed and exemplified in experiments done on both non-living and living bodies. In Part I it was shown: (1) That the current takes the path of least electrical resistance rather than the shortest path; (2) that maximal heating occurs at the point of greatest concentration of the lines of current flow. In a homogeneous medium with parallel electrodes maximal heat production occurs in those portions of the medium adjoining the electrodes and the heat gradient is from without inward. Under these circumstances maximal heating never occurs at the center. In discussing the localization of heat not only the electrical resistance and current concentration, but also the cooling effect, must be considered. In experiments on the dog''s cadaver no evidence of the so called "skin effect" could be demonstrated. This is in contradistinction to the findings of Bettman and Crohn, but the discrepancy is explained on the basis of what we believe to be a technical error in their work. The finding of no "skin effect" is in agreement with the conclusions of Dowse and Iredell, based on both experimental and theoretical considerations. In Part II three types of experiments were performed on the anesthetized dog. The conclusions to be derived from them are these: (1) The heat gradient of the body is reversed during diathermy and heating occurs from without inward; (2) deep heating during diathermy is greater than that which results from the application of local heat to the skin; (3) the lung can be heated by diathermy in spite of simultaneous cooling of the chest wall. These experiments we regard as satisfactory evidence of the passage of the current through the interior of the body.     

THE INFLUENCE OF TETHELIN,AND OF OTHER ALCOHOL-SOLUBLE EXTRACTIVES FROM THE ANTERIOR LOBE OF THE PITUITARY BODY,UPON THE GROWTH OF CARCINOMATA IN RATS

1. The hypodermic administration of tethelin increases markedly the rate of growth of the primary tumor and the tendency to form metastases in rats inoculated with carcinoma, in this, as in other respects, reproducing the action of the whole anterior lobe of the pituitary body. 2. Other alcohol-soluble extractives of the anterior lobe of the pituitary body, with the exception of the lecithin fraction, exert no appreciable effect upon the growth of carcinomata in rats. 3. The lecithin fraction, as in previously reported experiments in which we employed lecithin obtained from eggs, causes evident retardation of the growth of carcinomata in rats.     

阿霉素背根神经节介入治疗带状疱疹后神经痛疗效及影响因素

目的:分析背根神经节阿霉素介入治疗带状疱疹后神经痛(posthepetic neuralgia,PHN)的临床效果及影响因素。方法:随机选择患者65例患者,按随访时间分为短期(<1年)、中期(1~3年)和长期(>3年)三组,影像引导下背根神经节椎旁注射。采用简化疼痛量表(short-form McGill painquestionnaire,SF-MPQ)综合评定治疗效果,并进行定期随诊,评价疼痛程度和睡眠时间及其他不适症状,并分析影响疗效的因素。结果:治疗前SF-MPQ为(21.90±4.98)分,治疗后1周SF-MPQ(9.78±1.35)和随访(6.95±0.97)评分均明显降低,与治疗前比较有显著性差异(P<0.01);增加睡眠时间(3.09±0.29)小时。疗效持久,短、中、远期效果无差异(9.78±1.35、9.66±1.25、9.57±1.31)。结论:背根神经节阿霉素介入治疗PHN效果明显。高龄、病史过长、免疫力低下均影响治疗效果。     

II. BILE CHOLESTEROL : FLUCTUATIONS DUE TO DIET FACTORS,BILE SALT,LIVER INJURY AND HEMOLYSIS

Under uniform diet conditions the normal bile fistula dog will eliminate pretty constant amounts of cholesterol—about 0.5 to 1.0 mg. cholesterol per kilo per 24 hours. Diets rich in cholesterol (egg yolk) will raise the cholesterol output in the bile but compared to the diet intake (1.5 gm. cholesterol) the output increase in the bile is trivial (5–15 mg.). Calves'' brains in the diet are inert. Bile salt alone will raise the cholesterol output in the bile as much and often more than a cholesterol rich diet. Bile salt plus egg yolk plus whole bile give maximal output figures for bile cholesterol—60 mg. per 24 hours. Liver injury (chloroform) decreases both bile salt and cholesterol elimination in the bile. Blood destruction (hydrazine) fails to increase the bile cholesterol output and this eliminates the red cell stroma as an important contributing factor. Certain cholagogues (isatin and decholin) will increase the bile flow but cause no change in cholesterol elimination. The ratio of cholesterol to bile salt in the bile normally is about 1 to 100 but the bile salts are more labile in their fluctuations. The ratio is about reversed in the circulating blood plasma where the cholesterol is high (150–300 mg. per cent) and the bile salt concentration very low. Cholesterol runs so closely parallel to bile salt in the bile that one may feel confident of a physical relationship. In addition there is a suspicion that the bile cholesterol is in some obscure fashion linked with the physiological activity of hepatic epithelium.     

PROTEOSE INTOXICATIONS AND INJURY OF BODY PROTEIN : III. TOXIC PROTEIN CATABOLISM AND ITS INFLUENCE UPON THE NON-PROTEIN NITROGEN PARTITION OF THE BLOOD.

The acute intoxication following an injection of a toxic proteose is usually associated with a large increase (40 per cent or more) in the non-protein nitrogen of the blood. This increase is found chiefly in the blood urea nitrogen, but the amino and peptide nitrogens also may show small increases. The changes observed in the blood non-protein nitrogen are identical with those which follow the feeding of large amounts of meat (8). These facts indicate that the proteose intoxication causes an abnormally rapid autodigestion of tissue proteins, but that the nitrogenous end-products are, in chief part at least, the same that result from normal catabolism of food proteins. There is no evidence that the autolytic products play any part in causing the intoxication. The possibility of such a part and a resultant vicious circle is not excluded, but from the available facts the autolysis appears more as a result rather than cause of the intoxication. It appears possible that in disease or intoxication tissue catabolism may be enormously accelerated and yet yield the end-products of normal protein metabolism.