Pathology of subacute bitterweed (Hymenoxys odorata) poisoning in sheep. Subacute bitterweed (Hymenoxys odorata) poisoning was produced in sheep by force feeding them ground plant material (1 gm/kg/day) for 15 days. Five sheep died and two became moribund and were killed at the end of the experiment. The forestomach and abomasum were severely congested and occasionally eroded on the mucosal surface. There was an accumulation of edematous fluids along the rumino-reticular folds and ruminal sulci. Gaseous and fluid distension of the forestomachs, abomasum and cecum was a consistent finding. The gall bladder was greatly distended and occasionally the mucosa was sprinkled with petechiae. The most common finding was severe glomerulonephrosis characterized by proteinaceous casts, swollen and degenerated glomerular tufts and degeneration and necrosis in the inner renal cortex and outer medulla. Mild to moderate toxic hepatosis, characterized by vacuolar degeneration of hepatocytes primarily around the central vein, was consistent.


Biochemical genetics of MN.

Biochemical genetics of MN. Quantitative hemagglutination studies of the MN-hemizygous (M/-) patient and his family reported by German et al. are given together with data on the electrophoretic mobility of their red cells. These results, and those obtained on the cells of a donor of the MU phenotype (MU=M+N-S-s-U+); Mu=M+N-S-s-U), demonstrate a series of shortcomings in the current 'precursor transferase' theory of the biochemical genetics of MN antigens. Another theory is proposed, according to which the effects of the MN genes take place exclusively in the protein part of the glycopeptide. The MN proteins would carry acceptor sites for the antigenic oligosaccharides which are put together by enzymes genetically independent of MN. In M glycoproteins, the acceptor sites are close to each other, in doublets, while in N they are all separate. This model is shown to apply successfully to several difficult problems in MN.


Some sex- and age-dependent correlations in acute viral hepatitis. HBsAg was found to be present in 28.7% of 1980 sera from acute viral hepatitis (AVH) patients tested by immunodiffusion and counterimmunoelectrophoresis. The incidence of HBsAg-positive AVH cases was lower in female subjects aged 10-19 years. The follow up of SGPT, bilirubinemia and thymol turbidity kinetics in 473 of the patients revealed some HBsAg-dependent differences. Such differences oscillated more markedly in adults than in children and were less obvious in women. The possible involvement of certain individual factors in the determinism of hepatitis B virus infection and of its further evolution is suggested.


The influence of modifications in the potency of smallpox vaccines on the immunological reactivity of the organism. The possible influence of shipment and storage conditions upon the potency of smallpox vaccines was investigated by testing the direct effect of vaccine potency on the type of cutaneous reaction and on the level of serum antibodies. Vaccine no. 1--freshly prepared, shipped and stored at +4 degrees C--proved to be more potent than vaccine no. 2, at the limit of its efficiency, shipped and maintained under usual conditions. To maintain the initial potency of smallpox vaccines it is recommended either to improve the shipment and storage conditions, or to use a lyophilized vaccine.


Autoimmune haemolytic anaemia with the unusual combination of both IgM and IgG autoantibodies. Two patients with autoimmune haemolytic anaemia of no obvious aetiology are presented. Both cases had IgM autoantibodies which were cold agglutinins with anti-I specificity and were complement binding. Both cases also had IgG autoantibodies which were incomplete, of wide thermal range and also had anti-I specificity, but were not complement binding. The red cells of both patients were coated with C4/C3d and IgG.


Association between HLA and red cell antigens. IV. Further studies of haemagglutinins in cytotoxic HLA antisera. Cytotoxic HLA antisera of various specificities were examined on the AutoAnalyzer against red blood cells (RBC) from a great number of HLA-typed donors. HLA-associated haemagglutinins of different specificities were demonstrated. In cytotoxic anti-HLA-A9 and anti-HLA-A10, as well as in anti-HLA-B12, anti-HLA-Bw15 and anti-HLA-B17 sera, haemagglutinins of apparently corresponding specificities were found. This indicates that several HAL antigens may be present on RBC, but they are demonstrable only on RBC from a limited number of donors who possess the corresponding antigens on their white cells. Some antigens, like HLA-A28 and HLA-B7, are relatively strong RBC antigens, whereas others, like HLA-B12 or HLA-Bw15 seem to be much weaker. In cytotoxic anti-HLA-A1 and anti-HLA-B13 sera, no corresponding haemagglutinins were demonstrated. However, haemagglutinins of anti-HLA-B7 specificity were shown to be present in two cytotoxic anti HLA-A1 and three anti-HLA-B13 sera. No cytotoxic anti-HLA-B7 was found in these sera. Cross-reacting antibodies also seem to be frequent amoung HLA associated haemagglutinins.


[Organization of laboratories in the German Democratic Republic]. The effectivity of the clinical medicine becomes increasingly dependent on the efficiency of medico-experimental subjects, to which belong pathological chemistry and clinical biochemistry as well as haematology. The scientifically proved increasing demands made on the laboratories concern the quality of the results of investigations, constantly increasing numbers of investigations as well as a considerable enlargement of the investigation programmes. Adequate developments of workman are not to be expected. The requirements are to be met by the increase of the working productivity, for which a good organisation of work the use of mechanisation and automatisation means for the elaboration of large series of investigations are the prerequisite. A high degree of centralisation ascertains the effectivity of the adequate investments. Exceeding the ascertained foundations for a project of organisation of the laboratory work in the GDR in the next time still various problems must be solved which especially influence the organisation. Among others they concern the necessary investigation programme for the general practitioner in an out-patient practice, moreover the establishment of investigation programmes for several levels of care, the necessary quality (precision and exactness) of the results of investigations, the suitableness of stripe tests and the influence of preanalytic factors and especially of the biorhythmics on the findings of investigations. The tendencies described are accompanied by the danger that the reciprocities between clinic and laboratory becoming increasingly more necessary for the interpretation and classification of laboratory findings into the symptom complex become rather loose. Therefore, it will be one of the most important tasks of future to develop together reorganisation and collaboration.


[Central accounting as a model of laboratory diagnosis]. From the experiences in the field of scientific organisation of the last years results a laboratory-diagnostic model with an automatic laboratory, a district laboratory and larger central units, so-called coordination laboratories which work together with about 10 to 20 laboratories and guarantee an up-to-date diagnostic spectre for the whole territory. Apart from the increasing investigation frequency, a constant dilatation of the diagnostic spectre and improved quality control of structural conditions must be taken into consideration. The constructed model which demands the collaboration of all institutions meets these critical problems. A central balancing should also extend to the personal and technical apparative capacity. Apart from this the system is to be extended by further automation in the sense of a machine activity with improvement by control and regulation processes. An electronic data processing improves the functional capacity only when the analytic data processing has achieved a high level. The cooperation in the field of laboratory diagnostics is not only a task in scientific organisation, but in the same way also scientific problems are solved together. The requirements increasing in qualitative and quantitative respect may optimally be fulfilled only by the two partners, clinic and laboratory. With increasing independence the laboratories should in scientific and organizational respect remain a place of meeting for laboratory scientist and physician.


[Standard methods in a hematologic laboratory--a prerequisite for an optimal diagnosis]. State of scientific knowledge and economic prerequisites determined the selection of the optimum methods for the necessary parameters in standardizing haematologic methods. Concerning the methods of counting, measuring and staining in the haematologic laboratory, we have to do above all with so-called conventional methods with an expenditure of work considerable in most cases. In the single steps necessary for obtaining a laboratory result the physician in a clinic or outpatient department essentially participates particularly in such cases when EDTA venous blood is applied. It is especially referred to the advantage of EDTA venous blood for taking blood samples for haematologic parameters compared with the taking of capillary blood which has a high rate of error. Apart from the common efforts of physicians in clinics or out-patient departments and laboratory physicians to obtain reliable results of the findings, the use of an improved technique (particle counters, dilutor, automatic picture analysis among others) as well as further proceedings of standardization (dye for panoptic staining and others) will achieve this aim.


[Perspectives of clinical biochemistry in hepatology]. In a survey the trend of the biochemical investigations in hepatology is analysed. Together with the histologic diagnosis the function of the liver parenchyma must be determined, in which cases tolerance tests which do not only determine the function of the liver parenchyma, but also the changed functions of other organs are of importance. On the basis of own findings is shown that the ammonia metabolism in patients with hepatic encephalopathy is also disturbed in musculature. In the serum of patients with decompensated liver cirrhosis a factor could be isolated which apart from the inhibition of the utilisation of glucose has also another metabolic effect. In future we might expect an intensified search for such active metabolites. Investigations concerning the salicylaemia in patients with liver cirrhosis and experimental findings about changes of the O-demethylase activity in the fatty degeneration of the liver show the great significance of the pharmacokinetic analyses in the clinical hepatology.


Epidemioligical particularities of influenza outbreaks in a town of Romania during 1975. Results are presented of the complex epidemiological influenza surveillance in a large town of Romania during 1975. The comprehensive and unitary methodology including systematic laboratory, clinical and epidemiological investigations supplied data on the influenza type A outbreak recorded during the first term of 1975. The factors of importance for epidemiological prognosis -- seroepidemiological indicators of the immunological profile of the population according to age groups, serodiagnostic and virological investigation clinically diagnosed influenza cases, complex epidemiological surveys in representative foci, study of the antigenic structure of the influenza strains isolated -- are outlined. The importance of a continuous, complex influenza surveillance for the differential orientation of prophylaxis and control steps is emphasized.


[Laboratory diagnosis of liver and biliary tract disease]. Of a greater number of biochemical tests in hepatobiliary diseases by means of methematico-statistical methods (calculation of specificity and sensitiveness, variance analysis, discrimination analysis with following discrimination experiments) the parameters should be established which in a step programme with multivariate observation and non-discriminated approach give the best possible information. The recognition of patients with liver diseases (preliminary diagnostics) is at nearly 94% possible with a scale comprising GOT, AAP, some relevant clinical data (touch findings, jaundice, hepatic skin signs) and the hepatitis B-antigen. In non-discriminated approach according to our findings the following scale should not be trangressed: GPT, GOT (compare preliminary diagnostics), LAP, AP, AAP (compare preliminary diagnostics), cholesterol, TTT, bilirubin, beta-GC. As to aimed questionings the bromsulphalein test belongs to the enlarged basic scale.


[Spontaneous hypoglycemia].

[Spontaneous hypoglycemia]. On the basis of a survey is attempted to describe mode of development, symptomatology, individual forms and the different possibilities of therapy of the spontaneous hypoglycaemias. A particularly broad range was devoted to the cerebral sequelae, since in these cases--according to our experience--on account of simulation of neurologico-psychiatric symptoms at the soonest wrong diagnoses are to be expected. Furthermore, it is attempted to classify the hypoglycemias according to their development, in which cases their incompleteness was evident from the very beginning. The individual forms of appearance are treated according their to significance. Out of the inducible hypoglycaemias a particular attention is devoted to the forms caused by insulin and oral antidiabetics, since these most frequently participate in the development. Finally the author inquires into diagnostic measures for recognition of special forms of hypoglycaemia. In this place the diagnostics of hyperinsulinism conditioned by adenomatosis or tumours of other kinds is of particular importance. Finally conservative and operative possibilities of the therapy of these tumours are discussed,whereby the only recently tested treatment with streptotocin is mentioned.


Familial medullary carcinoma of the thyroid through 3 generations. A family with high genetic penetrance of medullary carcinoma of the thyroid was reported. Seven proven (6 patients and one autopsy case) and 2 probable cases of medullary carcinoma were present in 25 members through 3 generations. An endogemy had intervened in the prior generation of these cases. Preliminary results in clinicopathological examinations of 7 proven cases were as follows; clinically, all of the cases showed B type blood group. Glycosuria was found in 2 cases, and diarrhea in one case. Serum thyrocalcitonin being estimated in two cases showed high levels. The autopsy cases coexisted with medullary carcinoma of the thyroid and pheochromocytoma of the right adrenal. Pathologically, the majority of tumors occurred in both thyroid lobes, and were present from the middle to upper portion of the thyroid. The tumor showed a variety of histological features even in the same tumor. In the tumor cell, numerous membrane-limited granules were seen with an electron microscope. Amyloid was demonstrated only in the tumor tissue.


Primary leiomyosarcoma arising in the trunk of pulmonary artery: a case report and review of literature. An autopsy case of a 46-year-old woman with primary leiomyosarcoma arising in the pulmonary artery is presented. This case is the first description in Japan and the 10th in the world literature as leiomyosarcoma in this part of the body. An electronmicroscopic observation of the postmortem material was useful to conform the histologic diagnosis, in addition to some kinds of staining method of histologic section.


Fine structural study of annulate lamellae complexes in human tumors. Specific intracytoplasmic organelles, annulate lamellae and radial cisternae, have been studied in several human tumours. Annulate lamellae are observed in all cases of leiomyoma, leiomyosarcoma, rhabdomyosarcoma and malignant melanoma, whereas radial cisternae are only found in a case of leiomyosarcoma. Annulate lamellae are characterized by stacks of parallel arrayed long cisternae showing alternative arrangement of annuli and sacs. Some of these cisternae are connected directly with rough-surfaced endoplasmic reticulum and there is continuity with the lumen and membrane. Radial cisternae are mainly composed of two structures: numerous short cisternae, which are a variant of annulate lamellae, and numerous spherical particles derived from the cisternae. The cisternae are arranged parallel or radially around particles measuring up to 1100 A in diameter. These particles consisting of an amorphous high electron dense material without distinct limiting membrane are organized in groups and vary in number. There is no evidence of a direct relationship between these structures and viral infection.


Experimental rat choriocarcinoma: an electron microscopic study. Experimental choriocarcinomas of the rat were studied with electron microscopy and compared with the ultrastructure of rat trophoblasts at mid-and late-gestational stage. The choriocarcinoma numbered m-803 contained abundant cytoplasmic organellae and was quite similar to the trophospongial cell at late-gestational stage. The M-801 closely resembled the trophospongial cell at mid-gestational stage. The m-673, which has 3-beta-ol dehydrogenase enzyme system, could not be studied sufficiently inspite of the examination of more than 30 blocks of epon embedded specimen, because of the degeneration and necrosis occurring in the specimens.


Establishment and characteristics of a human pancreatic cancer cell line (HCG-25). A floating cell line (HCG-25) was established from the metastatic ascitic fluid of a human pancreatic adenocarcinoma of ductal cell origin. The cell line was characterized by the growth in suspension with a doubling time of 15.6 hr, a high cloning efficiency in soft agar and a modal chromosome number of 72. Electron microscopic examination revealed terminal bars in a small number of cells. Production of mucin and immunoglobulins and phagocytosis were not demonstrated. Heterotransplantation of the cells produced tumors, being undifferentiated carcinoma histologically. These characteristics mentioned above confirm that HGC-25 cell line is a human pancreatic cancer cell line.


Pulmonary changes in congenital heart disease of childhood: histometrical and histological studies. One hundred and fifty lungs from the cases below 15 years of age with various congenital heart diseases and 80 controls were used for histometrical and histological studies. Cases with congenital heart disease were divided into two groups of the increased and the decreased pulmonary blood flow. In the former group, the thickness of the pulmonary arterial media was the same as that of controls in the neonatal period, and through the wall thickness gradually decreased in a pattern seen in controls, the thickness was constantly larger than that of controls. In some cases, the media increased gradually within 6 months after birth. Pneumonia and massive pulmonary hemorrhage were seen in a higher incidence in autopsy cases. Pneumonia in younger infants was histologically characteristic and possibly more correlated to their death. In the latter group, most of the cases were with the thinner medias of the pulmonary arteries. Massive pulmonary hemorrhage was not common in the latter group.


[Electron microscopic and histochemical study of the rat adrenal cortex treated with aminoglutethimide (Elipten, CIBA) and its reparative process]. Aminoglutethimide blocks the conversion of free cholesterin to delta5-pregnenolone. It's effects on the fasciculata cells were studied electron microscopically in Wistar rats fed with this chemical for a maximum of seven days. The animals surviving after this treatment were also examined to follow the process of restoration from the damage. Four to seven days the initiation of the feeding, the mitochondria were enlarged, variously deformed and contained intramitochondrial vacuoles. The lipid droplets were increased in size. Three to four days after withdrawal of aminoglutethimide, so-called "intramitochondrial mitochondria" appeared. The picture suggesting division of the mitochondrial matrx was also occasionally encountered. These features suggested formation of new mitochondria from preexisting mitochondria. The mitochondria resumed their normal shape and appearance starting about ten days after withdrawal of aminoglutethimide. The electron microscopic histochemical method demonstrated tubular crystals of digitonin-cholesterol in the intramitochondrial vacoles as well as in the lipid droplets 4 days after the initiation of the feeding. The withdrawal of aminoglutethimide was followed with disappearance of these crystals from the sites of deposition.


Mesenchymal chondrosarcoma--a case report with an ultrastructural study and review of Japanese literatures. A case of mesenchymal chondrosarcoma occurring in the left maxilla of a 30-year-old Japanese male was reported. Electron microscopic observation confirmed transition of undifferentiated cells to chondrocytes and calcification in similar manner as previously described with physiological processes. Matrix vesicles were thought to be the cytoplasmic products of tumor chondrocytes. Electron-dense finely granular deposits resembling the organic matrix of cartilagenous calcification were seen within the intercellular matrix. Matrix vesicles were also closely related to these deposits. Japanese cases of this rare tumor were reviewed and 8 cases, including the present case as 6th among them, were accepted. Clinical characteristics were similar to those of a series reported by SALVADOR et al.


Hypomagnesaemia and muscle electrolytes and metabolites. Ten patients, aged 39-61 years, with hypomagnesaemia due to chronic alcoholism (7 cases) or malabsorption (3 cases), have been investigated by assessing the maximum isometric voluntary contraction force (MVC) of the quadriceps femoris muscle (7 cases), laboratory screening (9 cases) and estimating the electrolyte and metabolite content of biopsy specimens from the quadriceps femoris muscle. The MVC ranged from 0.5 to 34 kp and was significantly lower than in 12 apparently healthy normomagnesaemic controls (p is less than 0.001). The results of the laboratory screening, apart from a significant lowering of the serum magnesium concentration (p is less than 0.01), were mainly within the range of normal values, apart from signs of liver damage, such as an elevated activity of S-OCT (3 cases), alkaline phosphatease(3 cases), S-ALAT (1 case) and an elevation of bilirubin and blood ammonia (2 cases). Low serum iron-binding capacity occurred in 4 cases, a finding reported in protein-calorie malnutrition. Muscle magnesium content was significantly lower than in healthy controls (p is less than 0.001). Muslce sodium and chloride contents were significantly increased (p is less than 0.05). Total H2O content and the extracellular H2O content were both significantly increased (p is less than 0.05). Pyruvate and lactate values were within the normal range. The apparent equilibrium constant for creatine kinase differed significantly ( is less than 0.01). ATP values were within the normal range, but there were slight decreases for ADP (p is less than 0.05) and creatine phosphate ( is less than 0.01), whcih is of interest in view of the lowering of the MVC and the diminished capacity for sustained muscular effort in hypomagnesaemic patients reported earlier.


Kaliuretic effect of L-dopa treatment in parkinsonian patients. Hypokalemia, sometimes severe, was observed in some L-dopa-treated parkinsonian patients. The influence of L-dopa on the renal excretion of potassium was studied in 3 patients with hypokalemia and in 5 normokalemic patients by determination of renal plasma flow, glomerular filtration rate, plasma concentration of potassium and sodium as well as urinary excretion of potassium, sodium and aldosterone. L-Dopa intake was found to cause an increased excretion of potassium, and sometimes also of sodium, in the hypokalemic but not in the normokalemic patients. This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor. It is not known why this effect occurred in some individuals but not in others, but our results indicate a correlation between aldosterone production and this renal effect of L-dopa.


Prediction of cardiovascular deaths and non-fatal reinfarctions after myocardial infarction. The present study concerns the development and validation of a logistic multivariate prognostic function in patients followed for two years after myocardial infarction. The patients studied constituted at least 90% of all cases in a total community--the City of Göteborg, Sweden. Using a multivariate logistic function with 7 variables, based on 30 cardiovascular deaths during two years after discharge from hospital among 292 men with first infarction, breathlessness at onset of symptoms of infarction, SGOT quartile, left heart failure, relative heart size, atrial fibrillation, a history of hypertension, and AV block recorded during the hospital phase were the most important variables. The first five of these variables made significant contributions (p less than 0.01) to the predictive power. The predictive capacity was confirmed in an independent series of 195 men with first infarction, among whom 17 cardiovascular deaths occurred. Around 60% of the total cardiovascular mortality was concentrated in the highest risk quintile. Deaths from non-cardiovascular causes were predicted less efficiently. Non-fatal recurrences could not be predicted by the present model. Thus, the function can predict the excess risk of mortality but not the excess risk of reinfarction during two years among men after an initial myocardial infarction.


Auricular catecholamine content in ischaemic heart disease. The noradrenaline (NA) content (mean +/- S.D.) of tissue samples from the right atrial appendage in 19 patients with ischaemic heart disease (IHD) was 2.81 +/- 0.94 microng/g and in 7 patients with valvular heart disease (VHD) 2.79 +/- 1.12 microng/g. In 10 patients with uncomplicated atrial septal defect (ASD) the NA content was 1.64 +/- 0.32 microng/g and in 11 patients with congestive heart failure (CHF) 0.75 +/- 0.41 microng/g. The difference in NA content between the IHD group and the ASD and CHF groups is significant (p is less than 0.001). Small amounts of adrenaline and dopamine were found in all groups. There was no significant correlation between auricular NA content and either systemic diastolic blood pressure. The relatively high level of NA in the IHD group is assumed to be a contributory factor in the intracellular metabolic as well as in the systemic changes typical of ischaemia and infarction.


The prognosis in Ebstein's disease of the heart. Long-term follow-up of 22 patients. A follow-up study of 22 patients with Ebstein's anomaly has been performed. Nine patients died 1-21 years (mean 9) after the initial admission while the 13 patients alive at the end of the observation period had been followed for 5-26 years (mean 15). Clinical, ECG, radiological, and haemodynamic features were analyzed with reference to their prognostic significance. The presence or absence of cyanosis due to right-to-left shunt through an atrial septal defect (ASD) distinguished best between a good and poor prognosis. Right-sided heart failure and dyspnoea at rest, often associated with palpitations, precordial pains and syncopes, were grave prognostic findings. After the initial signs of heart failure there was a rapid deterioration, death ensuing within a few years. Operation with insertion of a prosthetic valve (and closure of the ASD) should be seriously considered at the appearance of heart failure.


Low threshold endocaridal electrodes for permanent cardiac pacing. Comparison between one large and two small surface electrodes. Three different electrodes, i.e. conventional large and small surface endocardial electrodes and a new large contact area-small active surface electrode, have been compared with respect to their stimulation thresholds for cardiac pacing in 94 patients with 96 electrodes. Both capacitor discharge and constant current pulses were used for the measurements. The average 2 msec impulse threshold for the 47 mm(2) electrode reached its maximum on the 14th postoperative day and was 3.6+/-1.4 V and 4.4+/-1.8 mA. One month after insertion, the threshold was 3.2+/-1.4 V and 3.9+/-1.7 mA. Corresponding values after one month for the 6 mm(2) electrode were 2.0+/-1.0 V and 1.7+/-0.9 mA and for the new electrode 1.7+/-0.9 V and 1.4+/-0.8 mA. Thresholds increased by about 20% when the impulse duration was diminished from 2 to 0.5 msec. The new large area-small active surface electrode offers advantages of significantly smaller increases in stimulation thresholds during the first month after insertion and good attachment to the endocardium.


Renin-dependent hypertension in patients with unilateral kidney disease not caused by renal artery stenosis. The practical value of renin secretion studies in hypertension associated with unilateral kidney disease, other than renal artery stenosis, has not been documented. This study, comprising 19 patients of this kind, disclosed three who had an abnormal renin secretion from the diseased kidney. The level of peripheral renin under basal conditions, and the change from this level as a result of provocation of renin secretion, were used to evaluate the importance of an arteriovenous renin gradient in the diseased kidney. The three patients were the only ones to become normotensive when the diseased kidney was removed in seven of the cases studied. When nephrectomy is considered in severe hypertension with unilateral kidney disease, there is a place for renin secretion studies, but a screening procedure is advisable. Measuring peripheral renin under basal conditions and after provocation of renin secretion, should reveal whether the renin-angiotensin system might be playing a part in maintaining the high BP. The finding of diminishing kidney function in many of the patients, despite good BP control, emphasizes the importance of sparing kidney function whenever possible.


Albumin metabolism and gastrointestinal loss of protein in chronic renal failure. The catabolism of albumin labelled with 125I has been studied in 10 patients with advanced renal failure and in 5 with nephrotic syndrome. In 10 patients the gastrointestinal protein loss was studied simultaneously by determing the faecal excretion during 7 days of 51Cr after i.v. administration of 51Cr-labelled chromic chloride. The results were related to a control group in which 12 subjects were studied with respect to albumin catabolism and 17 with respect to the gastrointestinal protein losses. The results showed that: 1) In the two patient groups the means for serum albumin concnetration and the intravascular albumin pool, expressed as g or g/kg b.wt., were significantly decreased compared with those of the control group. 2) The two patient groups had an increased extravascular albumin pool as well as an elevated ration between extra- and intravascular pools. 3) The mean albumin catabolic rate was not increased in the renal insufficiency group, expressed as a percentage of the intravascular pool/24 h or as g/24 h. In the patients with nephrotic syndrome, however, it was significantly increased. 4) The renal insufficiency group had a mean cumulative 51Cr excretion during 7 days of 1.6+/- 0.80% of the given dose, the control group 0.63+/- 0.30%. This difference is highly significant. The patients with nephrotic syndrome did not differ from the control group.


Effect of sodium loading and exercise on renal haemodynamics and urinary sodium excretion in young patients with essential hypertension before and during propranolol treatment. The effects on renal plasma flow (RPF) and glomerular filtration rate (GFR) of an i.v. sodium load and exercise have been measured in 14 young patients with essential hypertension before and after 3-4 months' treatment with propranolol as well as in 10 normotensive control subjects. In the untreated hypertensive patients, RPF and GFR were significantly reduced during sodium loading and exercise. After propranolol treatment, RPF and GFR were unaffected by sodium loading but decreased during exercise. In the normotensive control group, GFR and RPF were unchanged during sodium loading; RPF decreased during exercise, wherease GFR was not significantly reduced. RPF was significantly lower in the untreated hypertensive patients than in the normotensive control subjects during sodium loading and exercise. Propranolol treatment induced a significant reduction of BP and heart rate. RPF and GFR were not altered by propranolol treatment during sodium loading. During exercise, however, RPF was significantly lower after treatment than before. Urinary sodium excretion during sodium loading was significantly higher in the hypertensive patients than in the control subjects and decreased significantly during propranolol treatment. The reason for the abnormal reduction in renal haemodynamics during sodium loading in patients with essential hypertension is not clarified, but may possibly be related to functional or structural alterations in the renal vascular bed. The lower RPF during exercise after treatment with propranolol is most likely caused by an inhibition of the cardiac output induced by beta-adrenergic blockade. It is conceivable that the reduced urinary sodium excretion during propranolol treatment is attributable to the reduction of BP.


The significance of AV block I in asymptomatic young men. Variability, some anthropometric data, orthostatic test reaction and physical work capacity. Twenty-nine young men with AV block I (P-R interval greater than 0.22 sec), without any history of heart disease, have been compared with 112 randomly selected healthy men of the same age. In 24 subjects who were free from concomitant ECG changes the P-R interval was normalized during orthostatic test and/or physical exercise. This group did not differ from the controls regarding anthropometric data and physical work capacity except for a higher heart rate at rest, thus suggesting that in these subjects an occurrence of AV block I has no pathological significance. However, it cannot be excluded that the block is a sequela, for instance, to myocarditis. Three subjects with AV block I and inverted T waves in the precordial leads and two subjects with unchanged P-R intervals to increased sympathetic tone had on average a smaller body size, a higher HR and systolic BP in recumbent position and smaller blood volumes.


Prolonged monosymptomatic fever due to Yersinia enterocolitica. A previously healthy 14-year-old girl showed monosymptomatic hectic fever for over 3 weeks with negative clinical findings. Extensive laboratory investigation revealed only elevated ESR and a high titer of agglutinating antibodies against Yersinia enterocolitica, serotype 0-3. These abnormalities disappeared upon tetracycline therapy, after which she remained in excellent health. This unusual manifestation of yersiniosis, which was of unknown source, demonstrates that Yersinia infection should be considered in patients with prolonged febrile illnesses of obscure etiology.


[Obesity in childhood, seen by the pediatrician (author's transl)]. Presently, obesity is beginning more and more in early childhood. This is one of negative factors of civilization. Author describes biochemical properties and the sequelae of obesity (high morbidity and mortality). The role of psychic resp. educational factors is stressed. A program of a fasting cure in a childrens clinic is dealt with.


[Ovarian cycle and school-notes (scores) (author's transl)]. Girls 14 to 16 years of age, menstruating regularly and with a stabile cycle, were tested every school-day by a dictation in their slovakian language. Mistakes were counted and analysed statistically. The girls were interviewed about their cycle. Their capacity to write down the text correctly was different in the four phases of the cycle (P less than 0,001). Most mistakes were made in the premenstrual phase,  results were found in the four days of the menstruum. Divided in terziles according to their capacity, the girls of the best terzile had their optimum in the postmenstrual phase, whereas the girls in the medium and in the lower tezile had their optimum during the menstruation.


[A questionnaire for parents on school difficulties of their children (author's transl)]. A questionnaire for parents is proposed in order to get information about load and stress and resulting difficulties in pupils. The authors are analysing their questions and giving proof of the usefullness of this questionnaire.


[Psychological problems in children living with parents suffering from traumatic lesions of the vertebral column (author's transl)]. After trauma of the vertebral column and the neuromuscular consequences in one of the parents, children must experience many changes in the life of the family. They tend to react by psychosomatical symptoms as f.i. Anorexy, Colitis mucosa, Enuresis nocturna, Emesis a.s.o. Child guidance in such a case is urgently needed, as the author shows in two case reports.


Factors affecting the 5 year survival rate of men following acute coronary heart disease. A total of 213 male patients who survived an initial episode of acute coronary inusfficiency or myocardial infarction for 28 days have been followed for 5 years. The effect of age, weight, severity of infarction diastolic blood pressure, serum cholesterol, and cigarette smoking at the time of the initial attack on postinfarction morbidity and death was examined. Only severity of infarction adversely influenced the long-term mortality rate; none of the factors studied was related to subsequent morbidity. The effect of subsequent cigarette smoking on morbidity and death was noted over the 5 year period. Smoking did not affect subsequent morbidity but there was an increased death rate among those who continued to smoke. This effect of smoking was independent of the severity of infarction. Improved long-term survival may be predicted for patients who stop or markedly reduce cigarette smoking.


The role of serial echocardiography in the evaluation and differential diagnosis of pericardial disease. Echocardiography is an established method for the diagnosis of pericardial effusion. Echographic findings in fibroadhesive disease have also been described. The interpretation of a changing serial echogram during the clinical course of pericardial disease has not been established. Sixteen patients with echographic evidence of pericardial effusion were followed with serial echographic studies. In seven, surgical or autopsy correlation was obtained. Because of the serial changes noted we undertook a study in dogs to clarify the problem of variability in intensity of sound reflected from the pericardial space. Three open-chested dogs were studied with rapid sequence surface echograms as blood introduced into the pericardial space was converted from the unclotted to the clotted state. In all three dogs blood clooting increased the intensity or sound reflected from the pericardial space. Our study of two patients with fibroadhesive pericardial disease documents serial changes in echoes from the pericardium and pericardial space accompanying the clinical evolution of the disease process, and suggests a method for avoiding the commonly encountered difficulty in proper identification of the pericardial and epicardial echoes. Our preliminary studies suggest that serial echograms should play an important role in the management of patients with pericardial effusion; further surgical/pathological correlations are required.


Echocardiographic criteria of the diagnosis of mitral-semilunar valve continuity. A prospective echocardiographic study of 39 healthy adults with no history of heart disease was conducted to investigate the relationship between the anterior mitral valve leaflet (AMVL) and the posterior aortic root (PAR). The difference between the echocardiographic depth of the AMVL and the depth of the PAR with respect to the chest wall (CW) echoes was measured from both the third and fourth intercostal spaces in both the supine and left lateral positions. The results indicate that there were no statistically significant differences between the two depths in three of four measuring position postures. However, the best correlation between the depth of the AMVL had the PAR was obtained in the fourth ICS supine position. The echocardiographic difference between the CS-PAR and the CW-AMVL was less than or equal to 8 mm. in 90 per cent and less than or equal to 10 mm. in 97 per cent of our subjects in the fourth ICS. In the third intercostal space in the left lateral position, however, there was a statistically significant (P less than 0.01) difference in the two dimensions. In an individual subject, in any of the four possible positions, however, there were differences of up to 14 mm. in the two depths. The AMVL was found to be echocardiographically continuous with the PAR in all cases. An understanding of the normal AMVL-PAR relationship is becoming increasingly important, especially in regard to the application of echocardiography to the diagnosis of congenital heart disease, such as tetralogy of Fallot, double-outlet right ventricle, and transportation of the great vessels and of mitral regurgitation.


Inhibition of a ventricular synchronous pacemaker. Noncompetitive ventricular synchronous pacemakers (VVT) have been available since 1965. Most presently available and earlier models have a single, fixed pulse-to-pulse interval divided into a total refractory period of 350 to 400 msec., followed by a sensitive period. During the refractory period the pacemaker will not respond to QSR complexes or electrical signals, but a pacer stimulus will be produced during the sensitive period. The generator cannot be inhibited under any circumstances. The Cordis Omni-Sctocor has a refractory period and two sensitive periods, during one of which the generator is inhibited. Unlike other ventricular synchronous pacers, the Omni-Ectocor is capable of inhibition by single or  multiple  ventricular or other signals, of slowing or increase of the stimulus formation rate which depends on the timing of the premature ventricular contractions, and of inhibition by a run of ventricular tachycardia or by electromagnetic interference. The rate of interference producing these effects is a function of the automatic rate to which the generator is programmed. All of these factors must be considered for proper interpretation of the ECG.


Acute hemodynamic effects of an alpha- and beta-receptor blocking agent (AH 5158) on the systemic and pulmonary circulation at rest and during exercise in hypertensive patients. The acute hemodynamic effects of 50 mg. of the alpha- and beta-receptor blocking agent AH 5158, administered intravenously, on the systemic and pulmonary circulation were studied in 13 hypertensive patients at rest in the supine and erect positions, and during exercise, with right heart and brachial artery catheterization. AH 5158 induced a significant fall of systemic blooc pressures under all conditions, whereas the pulmonary systolic and mean pressures were lower at rest and unaltered during exercise. The left ventricular filling pressure largely remained unchanged. Blood pressure was lowered predominantly by a reduction in systemic vascular resistance together with a reduction in cardiac output. These effects were particularly pronounced in the erect position and during exercise. Cardiac output was lowered solely by the reduction of heart rate; stroke volume was unchanged or even increased. The arterial-mixed venous oxygen difference increased in the erect position and during exercise. The pattern of AH 5158-induced hemodynamic adaptation comprising a reduction of both vascular resistance and cardiac output, without evidence of significant negative inotropic action, offers a novel basis for treating hypertension with a single drug. Its pharmacological and hemodynamic profile suggests considerable potential in the treatment of hypertensive patients.


Echocardiographic evaluation of septal motion in patients with artificial pacemakers: vectorcardiographic correlations. Twenty-one patients with transvenous endocardial right ventricular pacemakers and one patient with epicardial right ventricular pacemaker inducing artificial left bundle branch block (LBBB) were studied with echocardiographic and vectorcardiographic techniques. Sixteen patients were found to have an initial very active posterior motion of the interventricular septum occurring within 70 msec. (range, 40 to 100 msec.) of the pacemaker artefact followed by posterior movement during the ejection period (Pattern A). Eighteen of 20 patients with clinical LBBB serving as a control group showed a dynamic posterior motion occurring within 40 msec. of the onset of QRS and preceding anterior (paradoxical) motion of the septum during ejection. In four patients, following the initial brief posterior septal movement, there was flat or anterior movement of the septum during the ejection period (Patern B). Two patients had myocardial infarction and one had atrial septal defect and epicardial right ventricular pacemaker. Only in two patients the initial brief posterior septal motion was not recorded before moving posteriorly during the ejection period (Pattern C). The different patterns of septal motion found in patients with artificial LBBB and in those with natural LBBB could be explained by differences in activation of the heart, as shown by vectorcardiography. Echocardiographic septal evaluation of patients with artificial pacemakers could have diagnostic implications in suggesting possible underlying complicating cardiac abnormalities.


Precordial ST-segment mapping 3. Stability of maps in the early phase of acute myocardial infarction. To evaluate the stability of precordial ST-segment mapping techniques in assessing ischemic myocardial injury, we studied 28 patients with acute anterior myocardial infarction using a 49-lead electrocardiographic system (1 mV. = 10 mm.). The sum of ST elevations in millimeters was taken as an index of ischemic injury, and remained stable in two consecutive maps made approximately one hour apart (65.8 +/- 8.4 vs. 63.8 +/- 8.7 mm.). The number of sites showing ST elevation larger than or equal to one mm. was taken as an index of extent of injury, and showed a small but statistically significant decline (23.9 +/- 4.5 vs. 22.3 +/- 4.2 mm.) during the same time interval. Blood pressure and heart rate remained stable. Changes in the map were observed in five patients, but could be explained in four by abrupt alterations in clinical status. In one patient no explanation for alterations in the map was apparent. We conclude that precordial ST segment maps are usually stable in the early stages of anterior myocardial infarction, but should be used to evaluate interventions only with careful clinical monitoring, and with the knowledge that occasional unexplained variations do occur.


Hemodynamics of supine bicycle exercise in "normal" children. Sixty children age 5 to 16 years with normal or nearly normal hearts performed submaximal and maximal supine bicycle exercise. Submaximal cardiac output was linearly correlated with work load (r = 0.80). After 2 minutes' exercise cardiac output was over 90 per cent of the value for 6 minutes' exercise. Maximal cardiac index was 10.1 +/- 1.8 for boys and 8.6 +/- 1.8 L. per minute per square meter for girls. Stroke volume was highest during the recovery period after maximal exercise. Pulmonary artery PO2 fell to 24 mm. Hg, oxygen saturation to 33 per cent, and pH to 7.21. During maximal exercise mean pulmonary artery pressure was 24 +/- 5 mm. Hg and mean brachial artery pressure was 113 +/- 8. There were no major differences between children aged 5 to 9 years of age and those 10 to 16 years, except for higher hemoglobin values in postpubertal children.


Transposition of the great arteries, primum atrial septal defect, azygos continuation of the inferior vena cava, bilateral superior venae cavae and dextrocardia with centrally placed liver. Successful surgical correction of transposition of the great arteries in a nine-year-old girl with dextrocardia, primum atrial septal defect, bilateral venae cavae, and azygos continuation of inferior vena cava is reported. The patient was cooled on cardiopulmonary bypass and the operation performed under circulatory arrest at 19 degrees C. nasopharyngeal temperature. The problems of diagnosis and management are discussed.


Lactose malabsorption in adult Vietnamese. Because of the traditional "nonmilking" attitude in Vietnam, a high incidence of lactose malabsorption would be expected in Vietnamese. However, confirming data are not available, and for this reason 31 adult Vietnamese were studied by obtaining diet histories and performing oral lactose tolerance tests. Twenty-three had drunk from one glass of milk a month to three glasses a day as adutls in Vietnam, and eight had noted milk-related symptoms. Since arrival in the United States, 30 had drunk milk and six had experienced symptoms. All 31 adult Vietnamese tested had flat lactose tolerance tests, signifying lactose malabsorption, with 20 subjects having symptoms during or after the tests.


Lactose malabsorption in Mexican-American adults. Lactose malabsorption was determined in 277 Mexican-American (MA) and 142 Anglo-American (AA) adults aged 18 to 94 years old, and correlated with nutrient intake assessed from 24-hr dietary recalls, as well as with milk and dairy product consumption. Lactose malabsorption occurred in 144 of 277 (53%) MA and 21 of 142 (15%) AA. Analysis of dietary questionnaires revealed no differences between lactose absorbers and malabsorbers within each ethnic group in their consumption of protein, calories, riboflavin, vitamin A, or calcium. Vitamin A, calcium, and riboflavin intake was greater in AA than in MA subjects. Milk and dairy product consumption was the same in lactose absorbers and malabsorbers in both ethnic groups. Nearly 60% of MA malabsorbers and 24% of AA malabsorbers recognized experiencing symptoms after milk ingestion. Although group differences in milk consumption on the basis of lactose absorption status are not apparent, individual lactose malabsorbers may alter milk ingestion in response to lactose-induced symptoms. Lactose malabsorption occurs in over half of MA adults and may in some individuals present a clinically relevant problem.


Interaction between dietary carbohydrates and intestinal disaccharidases in experimental diarrhea. The effects of carbohydrate intake on jejunal disaccharidases in rats with chronic mannitol-induced, osmotic diarrhea were studied. Weanling rats were force-fed 5 ml/100 g of body weight of water of 20% mannitol (w/v 1300 mOsm) daily for up to 14 days. Diets containing 70% of either starch, sucrose, glucose, or 20% lactose with 50% starch were fed ad libitum. Mannitol-fed rats had increased water intake and diarrhea. They gained weight, but less than controls. The levels of intestinal disaccharidases in mannitol-fed rats were related to dietary carbohydrate intake. Seven days of mannitol treatment led to lactase and sucrase deficiencies in rats fed starch whereas jejunal maltase and alkaline phosphatase were unchanged. Deficiencies in lactase and maltase but not in sucrase were induced when rats were fed a sucrose diet, while a decrease only in sucrase occurred in rats fed a lactose-starch diet. Rats with mannitol-induced diarrhea fed a glucose diet had reduced levels of all disaccharidases. The changes in intestinal disaccharidases were not associated with alterations in the number of epithelial cells or ultrastructural abnormalities. 3H-thymidine incorporation into DNA following 7 days of mannitol treatment was similar to water-fed controls. Absorptive epithelial cells were not damaged and the microvilli were normal in height and appearance. These data suggest that the levels of specific disaccharidases show and enhanced dependence upon the corresponding dietary substrates during diarrhea induced by an osmotic load.


Effect of dietary egg on serum cholesterol and triglyceride of human males. One hundred fourteen male volunteers (mean age 44.6 years) consumed one whole egg daily in their customary diets for 3 months. Their final serum cholesterol (SCHOL) and triglycerides (STG) levels were compared with their initial levels on customary free choice diets and also with their levels after a 3-month elimination of dietary whole eggs. All subjects had previously confirmed normal serum lipid levels and no history of heart disease. Four-day food records were kept during both experimental dietary periods. A Latin square design allowed analysis for seasonal effects on lipid levels. No significant change in mean SCHOL on either diet was found; there was a seasonal effect on mean STG. Significant linear associations of fat intake and of energy intake were found. There was no significant association of dietary cholesterol intake with either SCHOL or STG.


Racial differences in nitrogen content of nails among adolescents. Ectodermal derivatives provide a readily accessible means of chemically evaluating body protein composition. Therefore, it has been postulated that the analysis of nail nitrogen content may reflect recent nutritional status. Assessment of nail nitrogen content has been previously reported in a small group of neonates and school children. The present study was undertaken to determine if standards for nail nitrogen content could be established for adolescents which could then be used in the assessment of protein nutritional status. Nail clippings were obtained from 118 economically indigent urban black youth, 10 black and 39 white subjects from wealthy suburban communities in the New York area, and 10 poor white-Indian adolescents residing within a barrio in Lima, Peru. Nail samples were analyzed for protein content using the micro Kjeldahl technique. Mean nail nitrogen content for wealthy suburban and impoverished urban black youth was 136 and 137 mg N/g of nail, respectively. Values for poor Peruvian white-Indian and affluent suburban white adolescents were 142 and 141 mg N/g of nail, respectively. The differences between ethnic groups were significant using t test analysis at a P value of less than 0.001. No differences, however, were found between either wealthy and poor of the same racial background or when the data were analyzed by gender. These results suggest that differences in nail nitrogen content are at least in part a reflection of ethnicity. These racial differences must be considered in assessing nutritional status by nail nitrogen analysis.


Breast milk composition in Ethiopian and Swedish mothers. IV. Milk lipases. The (potential) activities of the two lipases in human milk were determined in breast milk samples collected from Ethiopian and Swedish mothers. The major lipase in human milk is dependent on bile salts for activity and probably participates in intestinal digestion of milk lipids in the newborn. The level of this lipase in the milk did not change with time after parturition, but differed between the groups so that it was higher in the privileged Ethopian mothers than in the nonprivileged Ethiopian mothers, who in turn had a higher level than the Swedish mothers. The other lipase is a serum-stimulated lipase (lipoprotein lipase). The level of this lipase varied between samples from different mothers as well as between different samples from the same mother. It tended to be lower in samples obtained at 4 to 5 days after parturition (Swedish mothers) than in later samples. There were in this case no significant differences between nonprivileged and privileged Ethiopian mothers or between them and Swedish mothers.


A potential diagnostic method for food allergy: clinical application and immunogenicity evaluation of an elemental diet. The use of a simple, hypoallergenic elemental diet would appear well suited for diagnosing food allergy. Vivonex was used in 21 patients (5 to 40 years old) suspected of food allergy or those who had failed to respond to the usual management of inhalant allergy. To study immunogenicity, five New Zealand rabbits were immunized with Vivonex, milk, and egg and were evaluated for the production of precipitin and passive cutaneous anaphylactic antibodies, the latter was evaluated in three Hartley guinea pigs. The clinical study was conducted over a 2- to 3-week period with evaluation of symptom and medication scores, physical examination, and hematological and biochemical measurements made before and after the Vivonex trial, which was a minimum of 1 week. No consistent, significant improvement of allergic manifestations were seen while patients received Vivonex. On the other hand, there were no serious side effects noted either clinically or by laboratory measurements, although four patients discontinued the study because of Vivonex palatibility. Vivonex was not immunogenic by either the precipitin reaction or passive cutaneous anaphylactic response. Although Vivonex did not prove helpful in these severe, refractory allergic individuals, we were encouraged by its safety and acceptance in the outpatient setting. Further studies in young allergic children who are more likely to have clear-cut food sensitivity are being planned.


Supplementation with vitamin E in hyperlipidemic patients treated with diet and clofibrate. Effects on serum lipoprotein concentrations, plasma fatty acid composition and adipose tissue lipoprotein lipase activity. Twelve hyperlipidemic patients on long term treatment with a lipid lowering diet enriched in polyunsaturated fatty acids and with clofibrate were supplemented with vitamin E (400 mg/day). The effect on serum lipoprotein concentration, plasma lipid fatty acid composition, and adipose tissue lipoprotein lipase activity was studied. No additional lipid-lowering effect was registered during a treatment period of 4 months. A slight increase in total serum cholesterol concentration and in high density lipoprotein concentration was probably attributable to seasonal variations in serum lipoprotein concentrations. No major changes of fatty acid composition in plasma cholesteryl esters or triglycerides were recorded. However, an increased relative amount of arachidonic acid and a reduced amount of palmitic acid in the plasma phospholipids after 2 months was possibly caused by the vitamin E therapy.


Influence of histidine administration on zinc metabolism in the rat. The influence of intravenous and oral histidine administration on zinc metabolism in the rat has been investigated. Acute studies: histidine (250 mg/hr) was given by constant intravenous infusion to rats with paired control animals receiving diluent alone. During the hour preceding histidine the urinary zinc excretion averaged 0.435 +/- 0.37 (SE) microng/hr. During the hours of histidine infusion the urinary zinc excretion averaged 7.58 +/- 0.97, 20.21 +/- 2.07, and 16.78 +/- 1.90 microng/hr. These values were all higher than the prehistidine infusion value and higher than in the rats receiving diluent alone. Plasma zinc at the end of the infusion was 76 +/- 5 microng/100 ml compared to control levels of 110 +/- 9 microng/100 ml, P less than 0.001. Chronic studies: histidine (500 mg/day) was given by gavage for 43 days to rats. Urinary zinc excretion in histidine treated rats was 3 to 6 times that of controls throughout the study. Despite this there was no difference in the plasma, testicular, or kidney zinc content. No histological lesions of zinc deficiency were noted in the esophagus. In conclusion, histidine increased urinary excretion in the rats whether administered orally or parenterally. Evidence for zinc deficiency, however, was not apparent after 43 days of histidine administration.


Zinc absorption through skin: correction of zinc deficiency in the rat. The therapeutic effect of topical administration of zinc was tested in pregnant rats consuming a diet deficient in the element. Four groups of rats were fed a zinc-deficient diet for 24 hr. Half of the animals were treated during this period with a topical application of oil saturated with zinc chloride, for the full 24 hr in one group, and for the last 8 hr in the other. In the two remaining groups, oil without zinc chloride was applied under the same conditions as described above, and in all cases oral ingestion of the supplement was prevented. At the end of the 24-hr period, the animals were killed and plasma zinc was determined. An additional group of animals consuming a diet adequate in zinc was killed without any treatment to provide control values of normal plasma zinc. Rats consuming the deficient diet and without topical zinc supplementation had plasma zinc values significantly lower than all other groups after 24 hr. Animals receiving zinc supplementation for 8 hr had plasma levels similar to those of the control group fed an adequate zinc diet and significantly higher than those of rats that received no zinc application to the skin. In animals in which zinc was applied for 24 hr, plasma zinc values were significantly higher than in any other group, including normal controls. The results indicate that percutaneous transport of zinc may be of sufficient magnitude to be clinically significant and that topical application of this element may be useful in cases of dietary zinc deficiency or diseases producing a zinc deficiency state.


Iron absorption from Southeast Asian diets. II. Role of various factors that might explain low absorption. Previously reported levels of iron absorption from common Southeast Asian meals composed of rice, vegetables, and spices were too low to be consistent with the known prevalence of iron deficiency. In the present paper the cause of the low absorption was systematically sought. Variables investigated comprised methodological errors, factors in the diet such as certain foodstuffs, or contaminants inhibiting the absorption and characteristics of the subjects accompanied by malabsorption of dietary iron. The latter was excluded by comparing the absorption from both wheat rolls and a composit rice meal in Thai and Swedish women using the absorption of a small dose of ferrous ascorbate as a common basis of comparison. Two main factors were identified as causing the low absorption in the previous studies: the homogenization of the labeled meals before serving and the use of rice flour instead of rice. Iron absorption from nonhomogenized meals of identical composition as studied previously was many times higher (on an average 0.16 mg) and was consistent with the actual prevalence of iron deficiency in lower socioeconomic groups of Thais mainly consuming the simple meals studied. Recent modifications of the method to measure nonheme iron absorption from composite meals have thus not only made the determination simpler but also more accurate.


Phosphorus metabolism in potassium-deficient rats. Hypophosphatemia as a consequence of potassium deficiency has been reported sporadically. Most cases have been complicated by other factors which might lead to decreased serum phosphorus levels. Therefore, the serum phosphorus in this study was measured in Sprague-Dawley rats with nutritionally induced potassium deficiency. Severe potassium depletion was manifested by hypokalemia (2.4 mEq/liter versus 3.9 mEq/liter in controls) and decreased muscle potassium content. Statistically significant hypophosphatemia did not develop, although decreased muscle phosphorus content was observed. Therefore, hypophosphatemia is not a regular accompaniment of severe potassium deficiency in the rat.


Prediction of body density and lean body weight in females 25 to 37 years old. Sixty-one physically inactive females (ages 25 to 37 years) underwent hydrostatic weighing to determine body density (Db). A series of anthropometric measures were also obtained and were used to develop multiple regression equations for the prediction of (Db) and lean body weight (LBW). The anthropometric variables were also used to determine the prediction accuracy of several previously published regression equations. Mean Db was 1.0405 +/- 0.0131 g/ml, relative fat, 25.1 +/- 5.55%, and LBW, 42.14 +/- 4.64 KG. Percentage of body fat was calculated from Db using the formula of Brozek er al. (Am. N.Y. Acad. Med. 110: 113, 1963). Higher correlations were obtained between actual and predicted LBW (R = 0.66 to 0.82). The best regression equation was found to be one using a combination of body weight, one skinfold, and four circumferences. When selected multiple regression equations developed by other authors were used to predict the Db and LBW of the present subjects, the actual values were both over- and underestimated, and correlations between measured and predicted values were lower. It was concluded that even though the body composition of these women was similar to that of college-age women, different regression equations are needed for accurately predicting their Db and LBW.


Oxygen consumption in the azotemic rat.

Oxygen consumption in the azotemic rat. To test the hypothesis that basal energy expenditure may be abnormal in azotemia, oxygen consumption was studied in partially nephrectomized, azotemic male Sprague-Dawley rats and sham operated control rats 10, 16, and 31 days after surgery. Observed decreased oxygen consumption in the azotemic group was related to their decreased body weight. There was no significant difference in oxygen consumption between groups when oxygen consumption values were related to weight.75.


Comparison of the nutritional status of pregnant adolescents with adult pregnant women. III. Maternal protein and calorie intake and weight gain in relation to size of infant at birth. Factors influencing the outcome of pregnancy were studied in 98 women, ages 12 to 32, divied into four age groups. A significantly higher weight gain was recorded for the youngest age group and the lowest gain for the oldest age group. The amount of weight gained was a function of length of gestation, but was not influenced by calorie intake of the mother. Neither was there significant correlation between protein and calorie intake of the mother and the infant's birth weight. Mean calorie intakes averaged below and mean protein intakes above the 1974 RDA. About 10% of the infants weighed less than 2,500 g and no single factor could be identified as the cause of low birth weight.


Failure of histidine supplementation to improve anemia in chronic dialysis patients. Failure of histidien supplementation to improve anemia in chronic dialysis patients was seen in six patients after a study period of 8 weeks. Serum amino acid levels were elevated to normal by supplementation with 1 g of oral histidine/day in all patients. There was no significant change in serum iron or transferrin levels, hematocrit, or red cell mass in five of the six patients. Histidine supplementation may raise serum amino acid levels, but does not cause any increase in red cell mass or improve the anemia in patients on chronic dialysis who are ingesting adequate dietary protein.


Anthropometric and maturation measurements of children, ages 5 to 14 years, in a biracial community--the Bogalusa Heart Study. An epidemiological survey of anthropometric and maturation variables was conducted on 3,524 children from the biracial community of Bogalusa, Louisiana. These children, representing 93% of the population, were examined during the school year September 1973 through May 1974. Black boys differed slightly from white boys in height and weight; black girls were taller and heavier than white girls. The black children had longer upper arm lengths and smaller upper arm circumferences than the white children. The median ponderosity (weight divided by the cubed height) decreased with increasing heigth for the four race-sex groups, and a skewed distribution of ponderosity indicated an excess of heavy children among the tall. Based on the Tanner criteria for grading secondary sex characteristics, maturation occurred earlier in the more ponderous girls, although such was not the case for boys. Whereas the Tanner secondary sex characteristics appeared earlier in black girls, white girls reported menarche earlier. The racial and sexual differences known to exist in triceps skinfold were observed for this population. No statistically significant difference was observed overall for height and weight between children within this one community and those of the National Health Examination Survey. However, Bogalusa girls at the 95th percentile were heavier after age 11 than girls of the United States. Also, there was a tendency for white girls in this community to report reaching menarche at an earlier age than black girls, which contrasts slightly with the national sample.


Weight fluctuations after immunization in a rural preschool child community. After inoculations with diphtheria, pertussis, tetanus (DPT), smallpox Bacillus Calmette-Guèrin (BCG), polio, and DPT + polio vaccine preparations, weight-for-age fluctuations were monitored in over 470 rural preschool children and compared to those in nonvaccinated control children matched for age, weight-for-age, season and year of immunization, and village affiliation. It was found that children immunized with live agents (BCG, smallpox, polio, DPT + polio) who also were below 6 months of age suffered statistically significant reductions in their weight-for-age compared to matched nonimmunized controls. Children inoculated with polio or smallpox who also were below 80% of the Harvard weight-for-age median experienced a larger decrease in their nutritional levels than those above, with correction for age distribution. It is suggested that in the developing world immunizations with live agents to children below 6 months of age should be given only if the infectious illness in which immunization is provided poses a real threat to health, or if vaccination coverage of children above 6 months of age would subsequently be difficult to achieve.


Pancreatic and salivary amylase activity in undernourished Colombian children. Amylase activities were quantitated in secretions of marginally and severely malnourished Colombian children. In young children with a mean age of 21 months, the relative pancreatic and salivary amylase isozyme activities of urine were significantly changed in marginally malnourished children compared to normal children. There was a relative increase in salivary and decrease in pancreatic amylase activity in the undernourished children and total amylase activity was somewhat decreased. Amylase activity in saliva and tears was significantly lower in these malnourished children. Older children who were more severely malnourished had significantly lower amylase activity in their sera and tears. Thus marginal and severe malnutrition affects the production of amylase by the pancreas and salivary glands of young children distinctly. It significantly suppresses amylase activity in tears, saliva, and serum.


Necrotizing sialometaplasia: a source of confusion with carcinoma of the palate. Necrotizing sialometaplasia is a self-healing nonneoplastic disease of the hard and soft palate characterized by one or two deeply excavating ulcers. Histologically, there is necrosis of the mucous cells of the minor salivary gland tissue with partial replacement by squamous epithelium. The deeply situated squamous epithelium intermixed with mucous cells may lead to the erroneous diagnosis of squamous carcinoma or mucoepidermoid carcinoma. The confinement of cytologically benign squamous epithelium to the pre-existing lobular pattern of the salivary gland should permit an accurate histologic diagnosis by biopsy and avert further surgical intervention.


Ovarian thecal metaplasia in adrenal glands. Wedge-shaped microscopic nodules resembling ovarian stroma or theca were found in the adrenal cortices of 14 women. Thirteen of the women were postmenopausal and one had ovarian stromal hyperplasia. The lesions were frequently multiple and bilateral and were almost always located just beneath the adrenal capsule. These nodules probably represent metaplasia of embryologically competent cells in the adrenal cortex or capsule which become transformed into ovarian tissue under the influence of unopposed pituitary gonadotropin during or after menopause. Support for this theory is found in (1) studies of human embryos that demonstrate the intimate anatomic development of ovary and adrenal gland, (2) experimental studies of mice that had morphologically similar, functional adrenal nodules following bilateral oophorectomy at birth, and (3) reports of certain human adrenal tumors. It is not known whether these nodules have functional significance in the human female.


Ultrastructure of lymphoid interstitial pneumonia: virus-like particles in bronchiolar epithelium of a patient with Sjögren's syndrome. Ultrastructural studies of an open lung biopsy of a patient who had lymphoid interstitial pneumonia, Sjögren's syndrome, and a highly elevated level of immunoglobulin M in the serum disclosed the presence in bronchiolar epithelium of numerous round electron-dense particles 70-120 nm in diameter. These were closely reminiscent of the oncogenic type-A viral particles associated with tumors of laboratory and wild mice. In the inflammatory infiltrate the morphology of some small lymphocytes was suggestive of germinative activity, although no germinal centers were found. Plasma cells, which were numerous in the vicinity of the bronchiolar epithelium, contained varying amounts of electron-dense material, probably immunoglobulin, which was also deposited in the irregulary thickened epithelial basal lamina. The observations support the theory that viral infection may be the stimulus to the immunologic abnormalities observed in patients with lymphoid interstitial pneumonia and Sjögren's syndrome.


Acute myelofibrosis: a report of three cases. This report describes three cases of an atypical variant of agnogenic myeloid metaplasia characterized by pancytopenia, high peripheral blast cell count, lack of significant splenomegaly or tear-drop poikilocytosis, and diffuse marrow fibrosis with an abnormal proliferation of megakaryocytes. It is suggested that these cases represent an acute variant of agnogenic myeloid metaplasia that is distinct from either the terminal blastic transformation of myelofibrosis or acute granulocytic leukemia.


Platelet factor 4 activity and thromboembolic episodes. Platelet factor 4 activity was evaluated in 323 patients who had various diseases. High incidences (30% or more) of elevated levels of platelet factor 4 were found in patients with recent myocardial infarctions, recent episodes of thromboembolism, hepatic diseases, and low platelet counts. Three of the four patients who had prosthetic heart valves had markedly elevated platelet factor 4 activities. It appears that elevation of platelet factor 4 activity is associated with a high platelet turnover such as is seen in intravascular coagulation or thromboembolism. Determination of platelet factor 4 activity may be a valuable laboratory tool for the diagnosis of thromboembolism.


Development and description of the "random duplicates" method of quality control for a hematology laboratory. Calibration of laboratory apparatus is not sufficient to ensure accurate results. Application of the "random duplicates" method to the measurement of hemoglobin estimations and leukocyte counts by the Coulter Model S revealed unsuspected deficiencies in the laboratory operation. The resultant changes led to a significant improvement in the quality of work performed.


Pooled normal values, a useful technic.

Pooled normal values, a useful technic. Few laboratories determine their normal values, because of the work involved. This study attempted to see whether a group of laboratories, each contributing a portion of the samples, could pool their information to yield data applicable to the whole group. Each of 20 VA Hospital laboratories obtained approximately 20 fasting early morning specimens from healthy men, aged 20-29 years, during a four-week period. Routine chemistry examinations (16) were performed on Technicon AutoAnalyzers (12/60, 6/60, and AAII), and model S Coulter Counters were used for five hematology tests (381 values for each constituent). Within-day, day-to-day, and interlaboratory variance were determined in parallel-method variability studies. The data showed: (1) it is valid to pool normal values from different laboratories when non-random variables have been eliminated; (2) non-random variables can be identified by increased interlaboratory variance, whether differences such as methods and equipment are obvious or not; (3) normal values so derived agree well with those from large series performed in single laboratories.


Rheumatoid esophageal disease.

Rheumatoid esophageal disease. Esophageal diameters were measured in the roentgenogram in 43 patients with rheumatoid arthritis and in 43 healthy subjects matched by sex and age. The incidence of esophageal dilatation in rheumatoid patients was significantly higher than that of healthy subjects (P LESS THAN 0.01). Higher incidence of esophageal dilatation was seen in groups with pulmonary fibrosis and with subcutaneous nodules (P less than 0.01, P less than 0.05 respectively). An orderly relationship between the incidence of esophageal dilatation and the grades of RA test, stage of joint x-ray, or duration of disease were shown. These results suggest the existence of "rheumatoid esophageal disease".


Mass gastric examinations of prisoners at Miyagi Prison in Japan. Mass examinations of the stomach were carried out on 79 convicts over 40 years of age confined in the Miyagi Prison, Japan. Of the 79 subjects, 11.9% were found to need detailed examination of the stomach which disclosed gastric polyp in one case and scar from gastric ulceration in one. None was found to have carcinoma of the stomach. Complaints of symptoms were obviously more frequent with the convicts as compared with a control group. There was not, however, a significant depression in efficiency of this group examination by photofluorography, as compared with the usual gastric mass examination on general inhabitants.


Association of carcinoma with congenital cystic conditions of the liver and bile ducts. Reported cases of carcinoma arising in association with congenital cystic conditions of the liver and bile ducts are tabulated with respect to the specific type of congenital abnormality. The occurrence of carcinoma in solitary nonparasitic cysts of the liver or as a complication of polycystic liver disease is distinctly rare. Carcinoma will arise with a frequency of approximately 1% in congenital hepatic fibrosis, 4% in choledochal cyst and 7% in congenital cystic dilatation of the intrahepatic bile ducts. Those congenital conditions exposing the epithelium to the bile directly are at greater risk for the development of malignancy. Carcinoma in this clinical setting occurs several decades earlier than otherwise expected.


Relationship between the morphologic appearance of pancreatic calculi and pancreatic function in chronic calcifying pancreatitis. The relationship between the two types of pancreatic calculi and their clinical pictures was studied in seven cases of diffuse minute calculi and 12 cases of large calculi. In the large calculi cases, the cause was often unknown, the calculi tended to be localized in the head and body and disturbances in pancreatic exocrine and endocrine functions were frequently found to be mild. In the diffuse minute calculi cases, alcohol ingestion was apparently responsible, the calculi tended to be distributed not only over the head and body but also over the tail and the pancreatic exocrine and endocrine function were markedly decreased with repetition of acute exacerbation. Consequently, the two types were clearly distinguished, indicating marked differences in pathophysiological process; they cannot be regarded as a single disease entity.


Effects of duodenal alkalinization on pancreatic secretion. Effects of duodenal alkalinization on pancreatic secretion were evaluated in seven dogs including two antrectomized dogs with chronic duodenal fistulas. Continuous intravenous injection of secretin or secretin plus CCK PZ was administered as a stimulus for the pancreatic secretion. Intraduodenal infusion of alkaline solutions such as pancreatic juice (pH 8.6), bile (pH 8.1), bicarbonate solution (160 mEq./I., pH 8.6) and TRIS buffer solution (0.3 M, pH 9.5) caused a moderate increase in protein output and a modest or no increase in flow but no change in bicarbonate output. During infusion of pancreatic juice, varied doses of secretin (0, 0.015, 0.03, 0.06 u./kg./min.), or secretin (0.03 u./kg./min.) plus CCK-PZ (0.05 u./kg./min.) were administered intravenously. For example, under the stimulation of secretin (0.03), flow increased modestly (17.7%), an increase which was of statistical significance. Protein output also showed a significant increase of 35.7%. There was, however, no response of the pancreas to the infusion of pancreatic juice when the gland was stimulated by secretin plus CCK-PZ. Antrectomy did not alter the effect of alkaline intraduodenal infusions on pancreatic secretion.


Villous tumors of the duodenum.

Villous tumors of the duodenum. Villous tumors of the duodenum are extremely rare, only 41 cases having been described in the world literature. Modes of presentation were: gastrointestinal bleeding (11 cases); obstructive jaundice (9 cases); duodenal obstruction (10 cases); vague abdominal discomfort (8 cases) and as an incidental finding on barium study of the upper gastrointestinal tract (2 cases) or at autopsy (1 case). Twelve of the 42 cases were associated with invasive adenocarcinoma. These were confined to patients over 50 years of age. Benign tumors should be treated with local excision while in those harboring adenocarcinoma pancreaticoduodenectomy is the treatment of choice. Endoscopy and biopsy should assume a major role in attempting to obtain an accurate preoperative diagnosis. Caution is advised in that the superficial portions of the tumor may appear benign while deeper portions may contain invasive adenocarcinoma. An additional case with a bizarre presentation is described and the literature reviewed.


Erythema ab igne, a sign of pancreatic disease. Patients with abdominal pain resulting from pancreatitis are often misdiagnosed initially. There are no pathognomonic physical signs to implicate the pancreas as a source of chronic abdominal discomfort. Four patients seen consecutively (and one studied retrospectively) illustrate that erythema ab igne of the abdomen or low back may be a sign of pancreatitis. These patients had used heat on their abdomens or backs in attempts to relieve the pain. Using heat in this manner is common among patients with undiagnosed pancreatitis; the heat enhances the appearance of the erythema ab igne. The presence of pigmentation is a sign of organicity which should lead the physician to investigate the pancreas as a source of the patient's pain.


Lymphatic cysts of the retroperitoneal space. Could epiploplasty be the method of choice? Lymphatic cysts of the retroperitoneal space among the rarest abdominal tumors. A very small number, usually single case reports, has been reported in the international literature. Symptoms vary according to the tumor size but usually are minimal so that they are discovered by chance, either during an ordinary abdominal examination or because the patient complains of discomfort due to the pressure of the cyst on adjacent organs and tissues. Surgical intervention is the only treatment. Total cystectomy with the treatment of choice is seldom feasible, because of technical difficulty. A case of a huge retroperitoneal lymphatic cyst is reported. Epiploplasty with drainage is proposed as a new method of surgical treatment.


Pharmacokinetics in renal disease.

Pharmacokinetics in renal disease. The physiologic perturbations associated with renal disease can have a pronounced effect on the kinetics of elimination of drugs and their metabolites from the body. Drugs are ordinarily cleared from the body by a number of routes, each of which can be characterized by a clearance value. The sum of these clearances (renal, hepatic, etc.) is the total or body clearance which is inversely proportional to the steady-state plasma concentration produced by a given drug dosage regimen. The quantitative contribution of each route of elimination to the metabolic fate of a drug is proportional to the clearance value of that route relative to the body clearance. As a first approximation, the reduction in the renal clearance of a drug caused by renal disease is proportional to the reduction in the renal clearance of creatinine. The metabolic (biotransformation) clearance of many extensively plasma protein bound drugs is proportional to their free fraction (ratio of concentrations of free to total drug) in plasma. Since severe renal disease causes a reduction in the plasma protein binding of many drugs, the metabolic clearance of such drugs will be increased. The contribution of hemodialysis to the total clearance of a drug depends on the magnitude of the clearance obtained by hemodialysis relative to the magnitude of the body clearance of the drug on a day between dialyses. To compensate for the increased elimination of a drug during hemodialysis, the dosing rate (i.e., the dose per unit of time) must be increased by the factor (hemodialysis clearance and body clearance):body clearance, where body clearance is that during a day between dialyses. Further dosage compensation may be needed if body clearance is increased during hemodialysis due to decreased plasma protein binding of the drug. Under certain conditions, an increased accumulation of pharmacologically active drug metabolites during renal failure becomes a matter of serious concern.


The binding of drugs to plasma proteins and the interpretation of measurements of plasma concentrations of drugs in patients with poor renal function. The intensity of a drug's action is related to its concentration in plasma water. Since the analytical methods for determining concentrations of drugs in plasma measure this as well as the drug bound to plasma proteins, evaluation of the binding of drugs to plasma proteins is needed for proper interpretation of drug level measurements. Anionic drugs have decreased binding in plasma from patients with renal failure. With some, such as phenytoin, a reduction is required in the levels usually considered "therapeutic" for uremic patients. Basic drugs may have normal or decreased binding. Propranolol, quinidine and tricyclic antidepressants are drugs in this class that have normal binding and that do not require changes in the plasma levels usually considered "therapeutic" for these patients.


Drug distribution in renal failure.

Drug distribution in renal failure. Plasma protein binding of many drugs is impaired in patients with renal disease. This often results in a larger apparent volume of distribution and a larger clearance of the drug compared to that observed in patients with normal renal function. Hence, renal disease can also influence the pharmacokinetics of drugs that are eliminated from the body by biotransformation rather than by renal excretion, Repetitive administration of a given dose of a drug that is eliminated from the body by nonrenal mechanisms may result in considerably lower steady-state concentrations of total drug in the plasma of patients with renal disease than in that of patients with normal renal function. On the other hand, in the absence of liver disease, the average steady-state serum concentration of free (unbound) drug is likely to be the same in both groups of patients. For this reason, it is probably not necessary to change the usual daily dose of a drug that is eliminated from the body by nonrenal mechanisms when it is given to a patient with renal disease. However, such drugs should be administered in divided doses to minimize adverse effects.


Principles of dialysis and dialysis of drugs. Consideration of the interactions of drugs and dialysis must include an understanding of the mechanisms of transport during dialysis, i.e., diffusion, ultrafiltration and membrane-protein binding effects. Clearance is a function of molecular size, blood and dialysate flow, membrane area and permeability, and dialyzer support geometry. Protein binding and hematocrit decrease the in vivo clearances in comparison to those measured in vitro with aqueous solutions. The effect on the serum half-life is also determined by the distribution space and clearance by other routes. Other factors such as metabolic alterations of dialysis can affect pharmacologic activity, and the clinical response is the end product of many determinants. Numerous drugs are effectively removed by hemodialysis or at a slower rate by peritoneal dialysis, which occasionally allows considerable influx. The influence of intestinal contents on elimination rates by peritoneal dialysis is unknown. Peritoneal dialysis can be influenced considerably by vasoactive drugs.


The biotransformation of drugs in renal failure. Studies of the rates of elimination of drugs normally biotransformed in man have been carried out in uremic patients. Drug oxidations are normal or accelerated. Reduction is slowed. Glucuronide and glycine conjugations are normal whereas acetylation may be normal or slowed. Many hydrolyses are slowed. Thus, the usual dosages of metabolized drugs may have to be altered to properly individualize therapy for patients with renal failure.


Active drug metabolites and renal failure. Drugs that are administered to man may be biotransformed to yield metabolites that are pharmacologically active. These metabolites may accumulate in patients with end-stage renal disease if renal excretion is a major elimination pathway for the metabolite. This is true even if the active metabolite is a minor metabolite of the parent drug as long as the minor metabolite is not further biotransformed but is mainly excreted in the urine. Minor metabolite accumulation may also occur if it is further biotransformed by a pathway that is inhibited in uremia. Some clinical consequences of accumulation of the active drug metabolites of procainamide, meperidine, clofibrate, allopurinol, sulfadiazine and nitrofurantoin in patients with renal failure are discussed. The high incidence of adverse drug reactions seen in renal failure may be explained, in part, by the accumulation of active drug metabolites. Examples of active drug metabolites that do not accumulate in patients with renal failure because of further biotransformations are also included.


Renal tubular handling of drugs.

Renal tubular handling of drugs. The renal excretion of drugs is a vectorial quantity, the resultant of physiologic mechanisms that have directional orientation and magnitude. Magnitude is limited by a variety of extrarenal factors including plasma protein binding and the volume of the total body water. The contributions of the glomeruli and tubules to excretion varies with age. This fact has clinical relevance, especially in newborn children and older patients. Although protein binding reduces the amount of a drug that can be filtered, it usually does not alter the rate of proximal tubular secretion of charged organic molecules. Reabsorption of the filtered fluid from tubular lumens creates concentration gradients favoring the reabsorption of drugs, but the movement of drug molecules out of luminal fluid is hindered by the formation of polar drug metabolites in the liver. Although there are only a few examples in the literature, it is probable that many drugs are reabsorbed by a carrier-mediated process located in the proximal tubules. A major difference exists between the renal handling of chlormerodrin, a neutral mercurial, and of mersalyl, an acidic mercurial. Chlormerodrin is reabsorbed (as a complex with cysteine) by a carrier-mediated process; mersalyl is secreted by one of the organic anion transport systems.


Development of mechanisms for drug excretion. Renal excretion of many drugs is less in the newborn than what would be predicted in terms of body weight. This is due, in part, to low renal blood flow and glomerular filtration rate during the immediate newborn period. In the first weeks to months of postnatal life, renal vascular resistance decreases and blood flow increases. Subsequently, the glomerular filtration rate increases. During this time, drug elimination may also be affected by qualitative and quantitative differences in binding of drugs to plasma proteins. In addition, drug elimination may be prolonged due to an immature ability in the newborn to transport or metabolize drugs in the kidney. Recent evidence demonstrated that drugs administered pre- or postnatally may alter the rate of renal excretion of drugs in the newborn. Such effects are of great concern to the clinician and underscore the importance of monitoring drug blood levels in these patients. From another perspective, the ability to stimulate drug excretion has been used as a tool to study basic renal physiology. Quantitative patterns of development coupled with the use of substrate stimulation provided evidence for at least three transport systems for organic anions in the proximal tubule. Similar technics provided preliminary data linking drug metabolism and organic anion transport in the proximal tubule, whereas an obligatory, rate-limiting role for ligandin in anion transport could not be established.


Pharmacology of the renal circulation.

Pharmacology of the renal circulation. The circulatory response of the kidney to drugs is conditioned by a variety of factors, such as basal vascular tone, dietary sodium and structural changes in the renal vasculature which accompany aging and disease. In addition, any drug which affects systemic arterial pressure will activate renal autoregulatory processes, which are superimposed upon the direct effects of the drug on the renal circulation. Renal autoregulation in addition to passive pressure effects probably accounts for the relative constancy of renal blood flow during the administration of renal vasodilators such as nitroprusside, diazoxide and minoxidil. Renal vasodilators which have minor effects on systemic arterial pressure, such as dopamine and glucagon, increase renal blood flow. These effects have been employed clinically in low cardiac output states. A variety of drugs affect the renal circulation by modifying the effects of endogenous vasoactive substances. The mechanisms of action include: receptor blockade; ex, adrenergic and Ag  II-mediated vasoconstriction: enhanced production by the administration of biochemical precursors; ex, arachidonic acid and I-dopa: inhibition of endogenous production; ex, prostaglandin synthetase inhibitors: and inhibition of breakdown of endogenous substances; ex, converting enzyme inhibition. The effect of each of these interventions will depend in part upon the rate of endogenous production of the relevant vasoactive material. The administration of diuretics affects renal blood flow in individually distinctive ways, the mechanisms of which have been only partially elucidated.


Adverse drug effects in relation to renal function. The relationship between acute drug toxicity, diagnosed in the clinical setting, and renal function is estimated for 67 commonly used drugs. Fewer than expected numbers of drugs showed higher rates of toxicity in the presence of an elevated blood urea nitrogen level on admission. For those whose toxicity did correlate positively with an elevated blood urea nitrogen level, detailed study of the relationship, taking into account other important variables, is indicated.


Molecular basis for several drug-induced nephropathies. A recent clinical advance has been the discovery that many drug-induced hepatic diseases result from the metabolic activation of chemically stable drugs to potent alkylating agents by the liver. In addition to the liver, however, the kidney also contains active enzyme systems capable of metabolically activating drugs and other chemicals. For this reason a systematic investigation of the possible role of metabolic activation in the pathogenesis of several drug-induced renal diseases has been undertaken. These laboratory results are reviewed in the light of the clinical spectrum of the renal injuries, and possible therapeutic implications of these new findings are briefly discussed. The potential use of these models of nephrotoxicity to probe a variety of physiologic and pathophysiologic mechanisms of renal function are noted.


Combined seminar on the use of drugs in renal failure: narcotics, psychotherapeutic agents, antiarrhythmics, antihypertensives, sorbents, vitamin D and its analogues, anabolic hormones and nutritional supplements. The use of drugs in the treatment of patients with renal failure requires a knowledge of excretion, biotransformation and pharmacologic activity of metabolites. Narcotics, analgesics, psychotherapeutic agents, drugs affecting the heart and ciruclation, various sorbents, resins and gels, anabolic hormones and nutritional supplements are among the more frequently used drugs for patients with end-stage renal disease. Indications and dosages of these drugs must be modified for patients with renal failure, and mechanisms of their biotransformation must be studied. This combined seminar presents the participants' studies and analyses of the problems surrounding the use of these various pharmacologic agents.


Drug administration in renal failure.

Drug administration in renal failure. Renal failure impairs urinary excretion of drugs and may also modify drug action by alternations in protein binding, distribution, biotransformation and, possibly, by retention of active metabolites. Dialysis adds another variable by altering the blood levels of those drugs soluble in plasma water and therefore available for diffusion or ultrafiltration. Renal insufficiency clearly modifies decisions about the choice and dose of a wide variety of drugs. Although data are accumulating at a rapid rate, available information about the use of drugs in patients with kidney disease is rather limited. The following is a summary of recent information on the use of a variety of drugs frequently utilized in patients with impaired renal function. The guidelines presented here are not absolute, but they are intended to be practical and reasonable, based on current information for adult patients of average size with kidney disease.