Abnormal plasma amino acid profiles in patients undergoing bone marrow transplant

Amino acid concentrations in plasma have been measured during total parenteral nutrition in patients undergoing bone marrow transplantation. Profound hyperaminoacidemia was noted in the immediate para-transplant period. The increase was due mainly to high levels of phenylalanine and methionine. During the radiation treatment period these amino acids plus valine, proline, serine and glycine were exceptionally high. Levels of cystine and asparagine tended to be low. The results suggest that infusion of a mixture of amino acids which is lower in phenylalanine and methionine might result in better nitrogen utilization.     

Isolation of leptospires and demonstration of antibodies in human leptospirosis in Madras, India

Among 25 clinically suspected cases of leptospirosis, organisms could be isolated from blood and urine of only 10 cases but demonstrated in 15 cases. Antibody titres at a low level were observed to one or more leptospiral antigens in all 25 cases. Nine of the repeated samples from 12 cases showed a four-fold rise in titre. The highest antibody titres were seen against autumnalis. The predominant clinical picture was of fever, myalgia, conjunctival suffusion and jaundice with renal involvement.     

Comparative multicentre trial of three IUDs inserted immediately following delivery of the placenta

A multinational comparative trial of three IUDs (Copper 7, Lippes loop size D and the Postpartum T) randomly inserted immediately following delivery of the placenta was conducted in six centres. A total of 841 women entered the study. As the predetermined termination indices for expulsions were exceeded at six months the trial was prematurely closed. An excess of expulsions during the first 48 hours following insertion was observed for the Lippes loop compared to the other devices. At six months the expulsion rate for the Lippes loop was significantly higher than that for the Copper 7. In addition, the discontinuation rate for the Lippes loop at 12 months was significantly higher than that for the Copper 7. There were no significant differences in either the expulsion rates or the discontinuation rate at six or twelve months between the postpartum T and the other devices. At 12 months the pregnancy rates with all three devices was high; there were no ectopic pregnancies. Considerable between-centre differences were observed, particularly for expulsion rates. Possible reasons for this are discussed and future research lines are suggested.     

Aminoacid imbalance and malnutrition in liver cirrhosis

The reason branched chain aminoacids are decreased and aromatic aminoacids increased in chronic liver failure is unclear. Branched chain aminoacids are mainly catabolised in muscles, and it is known that protein energy malnutrition may decrease the concentration of these aminoacids in plasma. In this study we have evaluated the nutritional status of a group of cirrhotics and compared it with their plasma aminoacid imbalance. Fourteen patients were considered as well-nourished and nine as malnourished. Plasma levels of branched chain aminoacids were significantly decreased and the phenylalanine increased in the malnourished group. Arm muscle circumference was significantly correlated with branched chain aminoacids. In conclusion our data suggest that malnutrition may contribute to the low levels of these aminoacids in patients with liver cirrhosis.     

Research activity on systemic contraceptive drugs by the U.S. pharmaceutical industry, 1963–1976

The process of drug development and regulation in the U.S. is first reviewed, with special reference to contraceptives. We next summarize recent data on all pharmaceutical innovation in terms of new chemical entities (NCEs) developed by the U.S.-owned pharmaceutical industry from 1963–1976, and then examine the data on all contraceptive NCEs brought to the stage of clinical investigation by the U.S.-owned firms during that period.Of the 956 NCEs studied in man by 39 U.S.-owned firms, 20 NCEs from ten firms were identified as antifertility agents. Of these, 17 had INDs filed, three of the INDs reached NDA submission, and two of the submissions were approved.Since the mid-1960s there has been a decline in the number of antifertility NCEs taken into human testing anywhere in the world and in the number filed as INDs by U.S. firms. Apart from the approved NDAs, there were only two antifertility NCEs with active INDs at the end of 1976.There have been no marked differences between the oral systemic contraceptive NCEs marketed in the U.S. or Britain since 1963. However, taking both countries together, no true NCE has been introduced for systemic contraceptive use since 1968.Although this study shows declining activity in resesarch on contraceptive NCEs by the U.S. industry, thus supporting to some extent Djerassi's prediction of a decade ago, it should be recognized that it does not include complete data on the research activities in this area by the U.S. government or other non-industrial organizations, or on research sponsored by any group on new contraceptive methods other than NCEs.     

Measles in Tanzania: antibody response in children after vaccination and antibody state of mothers and newborns

The antibody response to attenuated live measles vaccines was studied in two groups of 29 (A) and 53 (B) African children. In group A 22 sera and in group B 34 sera showed no pre-immunization haemagglutination inhibition (HI) titres. Vaccination resulted in seroconversion in 64 and 85% of groups A and B, respectively. The difference in antibody response between the two groups could be traced to children in the age group seven to eight months, where seroconversion was absent in 67% of group A children and in 0% of group B children. Antibody levels were studied in 234 mothers and their newborns. In 131 serum pairs the antibody levels of mother and child were similar. 78 (33%) of mothers showed a higher titre and 25 (11%) a lower titre than their babies. All newborns except one and all mothers except one possessed antibody titres above 10. Children in the age groups seven to eight months and nine to ten months showed antibody in 12 and 7%, respectively. Over 90% of these children had not been infected in the first ten months of life.     

Changes in muscle and plasma amino acid metabolism in severe malnutrition--the influence of total parenteral nutrition

The concentrations of free amino acids in muscle and plasma were determined in nine female patients with severe anorexia nervosa before and after 3 to 5 weeks of total parenteral nutrition (TPN). The patients had lost 25 to 42% of their pre-morbid weight. During TPN their weight gain was around 2.5 kg/week. Initially total non-essential amino acids (NEAA) in muscle were decreased 30% compared to controls. The major part of this depletion was due to a 40% reduction in glutamine. After TPN the level of glutamine normalized. Alanine, being normal before TPN, decreased after TPN. Proline and several other non-essential amino acids in muscle were decreased before and after TPN. Total essential amino acids (EAA) in muscle were initially normal and were not significantly affected by TPN. Total NEAA in plasma were decreased at admission and normalized after TPN. Total EAA in plasma, however, were normal both before and after TPN. This study demonstrates that severely malnourished patients with anorexia nervosa have changes in amino acid patterns in both muscle and plasma. These changes were largely, though not completely, reversed after 3 to 5 weeks of TPN.     

Creaming and plasma clearance rate of intravenous fat emulsion in critically ill patients

Intravenous fat emulsion incubated with serum or plasma in vitro may result in the aggregation of fat (creaming). Twenty critically ill patients were tested for in vitro creaming of the fat emulsion Intralipid. An intravenous fat tolerance test was used to determine the plasma clearance rate of Intralipid in each patient. Eleven patients (55%) were found to be creamers. These patients had a higher mean plasma clearance rate of Intralipid than non-creamers (5.73 +/- 0.56 vs. 2.77 +/- 0.37% per min; p < 0.001); however, the rates of both groups were within the range reported in normal healthy subjects. Mean C-reactive protein concentration was significantly higher (p < 0.01), and albumin levels were lower (p < 0.01) in creamers compared to non-creamers. Ionized calcium levels did not differ between the two groups. The results of this study indicate that in vitro creaming is common in acutely ill patients. The clinical significance of creaming is probably minimal since creamers tolerated 50 to 100 g/day of intravenous fat emulsion while receiving total parenteral nutrition. Creaming was uncommon when the fat was mixed with blood in vitro.     

Glucose balance and muscle glycogen during TPN in the early post-operative phase

In order to study how muscle glycogen is influenced by different nutritional regimens in the early post-operative period we took muscle biopsies from 20 patients preoperatively and on the fourth post-operative day after abdominal aortic surgery. Ten patients received 93% of non-protein energy as glucose, 7% as fat (Intralipid) and insulin was given to keep the blood glucose below 10 mmol/l. The remaining patients had 80% of non-protein energy as fat (Intralipid). Amino acids constituting 12 g of nitrogen daily were given to both groups. Daily measurements of gas exchange (oxygen uptake, CO2-production) were performed and from these data glucose balance was calculated as the difference between glucose intake and glucose expenditure. Muscle biopsies were analysed for glycogen, adenosine triphosphate, glucose-6-phosphate, lactate and citrate. We found that it was possible to maintain muscle glycogen stores at pre-operative levels with a glucose-insulin regimen. With the fat regimen there was a 31% decrease in muscle glycogen and two patients had a negative glucose balance despite the fact that 150 g of glucose were given. Average glucose balance throughout the study correlated positively with glucose intake. A significant correlation between glucose on the third day and change in muscle glycogen content was found. Muscle content of adenosine triphosphate, glucose-6-phosphate, lactate and citrate were similar in both groups.     

Actinomyces in the endometrium of IUD users

The colonization of the female genital tract with Actinomyces is closely related to the presence of an IUD in the uterine cavity. This was confirmed in the present study, which shows an Actinomyces frequency of over 3% in users of IUDs, while non-users were free from the opportunistic invader. This frequency was higher with certain types of devices than with others. None of the patients with positive results had pelvic symptoms, but cases of serious infections have been reported in the literature. The length of IUD usage appears to be directly related to the incidence of this colonization. The possible pathogenesis of pelvic actinomycosis is presented; the clinical significance of asymptomatic colonization is discussed.     

Clinical implications of continuous measurement of energy expenditure in mechanically ventilated patients

Energy expenditure was monitored in 20 critically-ill mechanically ventilated patients using the Siemens-Elema Oxygen Consumption Calculator (OCC 980). Energy expenditure was measured continuously over the 24-h period in all patients (altogether, over 2500 patient hours; range 48-288 h). A predicted energy expenditure was calculated for each patient from standard tables for basal metabolic rates modified according to previously published reports on the influence of trauma, infection and elevated body temperature. For all patients combined, the agreement between the predicted and the measured energy expenditure was good. However, in individual patients the measured energy expenditure varied between 48 and 148% of the predicted value. The measured energy expenditure in surviving traumatized and/or septic patients correlated well (95-100%) with the predicted value at the time when weaning off the ventilator could be initiated. On the first day of measurements, the energy expenditure (in % of the predicted value) in the six patients who later died was significantly lower than in surviving patients (84 +/- 6 vs 107 +/- 2%; p < 0.01). Over a 24-h period, energy expenditure, defined as the value noted during a stable 30-40-min period of measurement, varied between 12 and 50% in the individual patients. This study shows that energy expenditure cannot be accurately predicted in the individual patient, that an energy expenditure below predicted values appears to be indicative of a poor prognosis and that short periods of energy expenditure monitoring may fail to reflect 24-h conditions.     

Study of copper,zinc, magnesium and cadmium in ICC patients,parents and siblings

Twenty-seven histopathologically proved cases of Indian childhood cirrhosis (ICC), 13 parents (father and mother) and nine siblings of ICC patients were studied from serum and urinary Cu, Zn, Mg and Cd levels by Atomic Absorption Spectrophotometer (AAS). Milk and drinking water from various sources were analysed for Cu, Zn, Mg and Cd contents, as was milk boiled and stored for up to six hours in various utensils. Serum and urinary Cu excretion were high (P < 0·001) in ICC patients and within normal limits in siblings and parents. In ICC patients most hepatocytes contained multiple, coarse and dark brown orcein staining granules representing Cu associated protein. Serum Zn was low and urinary Zn excretion high in ICC patients (P < 0·001 and P < 0·01 respectively) and within normal limits in siblings and parents. Mg and Cd in serum and urine of ICC patients, siblings and parents were within normal limits. Cu content of milk boiled and stored in peetal (brass) utensils was high and directly related to the duration of storage; there was no change in Cu level in milk boiled and stored in steel and aluminium utensils. Zn, Mg and Cd levels in milk boiled and stored in peetal (brass) utensils remained unchanged. The levels of these elements in drinking water from various sources were also within limits as recommended by WHO 1971. Milk boiled and stored in peetal (brass) utensils seemed to account for increased Cu intake. Excessive Cu intake in ICC should be eliminated by avoiding brass utensils for boiling and storing milk. Some treatment to chelate excess Cu is also warranted.     

Clonal diversity in a single isolate of the malaria parasite Plasmodium falciparum

Clones of an isolate of Plasmodium falciparum from Mae Sod (Thailand) were prepared by a dilution procedure. Some of the parasite cultures thus obtained have been typed for the following characters: (i) electrophoretic variants of three enzymes; (ii) susceptibility to chloroquine and pyrimethamine; (iii) antigen diversities recognized by ten strain-specific monoclonal antibodies; (iv) presence or absence of knobs on infected erythrocytes and (v) two-dimensional PAGE variants of seven proteins. Amongst the clones there was variation involving each of these five characters. At least seven different types of clones were found in ten cultures produced by dilution. The amount of phenotypic variation within a single isolate has thus been shown to be surprisingly great. Variations in drug susceptibility and antigens are considered to be particularly important in view of their relevance to anti-malarial treatments.     

Overestimation of caloric demand in a long-term critically ill patient

This case report deals with a clinical situation in which an alteration in the nutritional regimen based on indirect calorimetric monitoring may have promoted recovery. A 43-year-old man with a history of acute haemorrhagic pancreatitis, intra-abdominal sepsis, and requirements of mechanical ventilation and total parenteral nutrition over 9 weeks was studied metabolically by means of indirect calorimetry in an attempt to interpret his clinical condition, which was characterised by difficulties in weaning off the ventilator, jaundice and muscular wasting. The caloric load was found to be 56% above measured energy expenditure. The respiratory quotient (RQ) was > 1, indicating the presence of lipogenesis. An alteration in the nutritional regimen based on these findings was followed by a decrease in RQ and a rapid improvement in spontaneous breathing and clinical condition. These results suggest that monitoring of gas exchange in the long-term critically ill patient may be of great importance as a means of avoiding detrimental effects of inadequate nutritional therapy.     

Diet, lipoproteins and cholesteryl ester transfer activity in hyperlipidaemic subjects

In order to study the response of cholesteryl ester transfer activity (CETA) to alteration in diet in humans we carried out a longitudinal study in hyperlipidaemic patients. Five subjects, all hyperlipidaemic, were first given a low fat diet for 7 to 15 days and then a diet high in fat for 7 to 21 days. In four out of five patients both diets were low in energy. The plasma lipoprotein levels and CETA were measured daily. All patients responded on the low fat diet by a decrease in total cholesterol and total triglycerides. No response on the high fat diet was noticed except in the patient for whom the high fat diet was also high in energy. In all patients the changes in CETA ran parallel to changes in (VLDL + LDL) cholesterol. It is concluded that diet induced changes in (VLDL + LDL) cholesterol are accompanied by similar changes in CETA in hyperlipidaemic subjects.     

Effect of leucine or ketoleucine on nitrogen metabolism in postoperative patients receiving energy substrate

It has been shown that ketoisocaproate (KIC) spares nitrogen (N) in fasting postoperative patients while leucine does not. The aim of the present study was to determine if KIC when compared with leucine, decreases nitrogen excretion in postoperative patients receiving energy substrate. Thirty patients undergoing gynecological surgery (hysterectomy with or without lymphadenectomy) were randomized to receive for the first 3 postoperative days one of the following I.V. solutions per kilo and per day: 3 g glucose (group A) 3 g glucose + 90 mg Leucine (group B), 3 g glucose + 100 mg ketoleucine (group C). The output of 3 methylhistidine (3 MEH), total nitrogen and creatinine were measured daily. Although muscle protein breakdown measured as 3 MEH/creatinine molar ratio was significantly reduced in group C as compared with A and B, total nitrogen and creatinine did not differ significantly in A, B and C. Thus, the metabolic effects of KIC in postoperative patients are appreciably influenced by glucose infusions and the usefulness of KIC infusions in such patients needs further study.     

Nutritional intake after colorectal surgery: a comparison of a traditional and a new post-operative regimen

The energy and protein intake was studied for 12 days after colorectal surgery in 36 patients. Eighteen patients followed a traditional management with nasogastric suction until bowel movements occurred after which a liquid diet, protective diet and normal food were successively administered. In a subsequent period a new regimen was introduced. Nasogastric suction was not used. Instead, 18 patients received liquid diet from the first post-operative day and normal food, when the patient wanted to eat it. In addition, the nutritional intake was supplemented by protein-enriched refreshing drinks and milk products between the meals. The new regimen was tolerated without discomfort and resulted in a significant increase in protein intake (43 g/day vs. 26 g/day, p<0.001) and energy intake (78% vs. 71% of the basal metabolic rate, p<0.05). The increase was most pronounced in the first 4 days after the operation. Finally, the weight loss was significantly lower on the new regimen (1.8 kg vs. 3.9 kg, p<0.001).     

A comparison of immediate post-operative enteral and parenteral nutrition in patients with gastric carcinoma

Fourteen patients with gastric carcinoma were studied in the first post-operative week following the administration of immediate post-operative nutrition. Eight received Clinifeed ISO^® enteral feed and six received parenteral nutrition (TPN) (Vamin-glucose, dextrose and Intralipid^®). Plasma albumin and transferrin concentrations decreased post-operatively in both groups, but did not differ significantly between the groups. Positive nitrogen balance was achieved on the fifth post-operative day in the enteral group and on the first post-operative day in the TPN group. There were no significant differences in the pre and post-operative weights and anthropometric measurements in either group. One patient in each group developed a subphrenic abscess, six patients in the enteral group experienced nausea and diarrhoea and two of these also vomited. The results indicate that immediate post-operative enteral nutrition is accompanied by a degree of negative nitrogen balance because a 3 day ‘build up’ period is necessary to achieve a full intake and with a higher incidence of minor gastro-intestinal complications which are easily controlled.     

Post-operative substrate utilisation and gas exchange using two different TPN-systems: glucose versus fat

Twenty patients were studied over the first 4 post-operative days following abdominal aortic surgery. Ten patients had 93% of their non-protein energy as glucose and insulin was given to keep blood glucose below 10 mmol/l. The other 10 patients had 80% of non-protein energy as fat (Intralipid). Amino acids corresponding to 12 g of nitrogen were given in both groups. Gas exchange, nitrogen balance, phosphate balance, vanillylmandelic acid (VMA) excretion, 1- and 3-methylhistidine in urine, acute phase proteins, immunoglobulins and albumin were followed. Substrate utilisation was calculated from indirect calorimetry data and nitrogen excretion. Metabolism in the early post-operative phase was found to adapt to the nutrition regimen given even though the composition was extreme either in fat or carbohydrate content. The glucose-insulin regimen had a better nitrogen sparing effect and based on the difference in 3-methylhistidine excretion it is suggested that mainly protein muscle benefitted from this. Regardless of the TPN-regimen given, those patients whose RQ deviated the most from the average in their group had the highest nitrogen excretion. The two groups showed no differences in plasma proteins and catecholamine excretion.     

Muscle and plasma amino acids during semi-starvation in normal subjects: hypocaloric glucose vs. amino acid infusions

Normal subjects were fed hypocaloric amounts of amino acids or glucose for 3 days to separate the effects of these nutrients from those of trauma on muscle and plasma amino acids. Intracellular and plasma levels of Val, Leu and Ile were increased in both groups but were increased to a greater extent when amino acids were infused. Intracellular free glutamine concentration in muscle tissue was not significantly altered. Some of the trauma induced changes in amino acids can be replicated by maintaining normal subjects on hypocaloric amino acids; the decrease in glutamine concentration seen with trauma is not a function of hypocaloric nutrition.