Failure to detect circulating DNA--anti-DNA complexes by four radioimmunological methods in patients with systemic lupus erythematosus.

The presence of DNA-anti-DNA complexes in sera from patients with systemic lupus erythematosus (SLE) was investigated by two new radioimmunoassays (RIA) developed for this purpose and by measuring the C1q and DNA binding activity of serum before and after treatment with DNAse. Two direct RIA developed in this study were based on the reactivity of [3H]actinomycin D ([3H]ACT-D) or solid-phase methylated bovine serum albumin (mBSA) with DNA-anti-DNA complexes. DNA-anti-DNA complexes prepared in vitro could be efficiently detected at various antigen--antibody ratios by these two RIA. Increased levels of circulating immune complexes as indicated by the C1q binding test were found in 52% of SLE sera. However, the frequency of specific DNA-anti-DNA complexes detected in SLE sera was very low. Only 6% of sera exhibited an increased value deviating by more than three s.d. from the normal mean when tested with the [3H]ACT-D binding RIA or the solidphase mBSA RIA. On the other hand, there was no significant difference in the serum C1q or DNA binding activity after treatment with DNAse. These results suggest that DNA-anti-DNA complexes do not occur frequently in circulating blood and represent only a very small portion of the immune complexes detected in serum from patients with SLE.


Sex steroid hormones and circulating IgE levels.

The possible influence of sex steroid hormones on circulating IgE levels in general and IgE anti-Candida antibodies in particular was studied by quantification of plasma levels of progesterone, estradiol and IgE (total and anti-Candida-specific) in females during the follicular and luteal phases of the menstrual cycle, and during pregnancy. IgE levels during the follicular and luteal phases were not significantly different, although the mean values for the luteal phase were slightly lower. This trend was apparent in daily samples from two normal females during one menstrual cycle. During pregnancy, when the levels of circulating sex steroids were high, IgE levels were only slightly higher than in the follicular and luteal phases. In men and in gonadal dysgenetics, circulating progesterone levels were similar to those of women during the follicular phase (i.e., lower than in the luteal phase or in pregnancy), but the IgE levels were not different. The apparently low levels of IgE during the luteal phase may therefore be due to physiological factors other than fluctuations in the sex steroid hormones. From the present studies, it is apparent that sex steroid hormones have little or no effect on humoral IgE levels, in marked contrast to previously described correlations for other immunoglobulins, especially anti-Candida antibodies.


Sperm agglutinins in seminal plasma and serum after vasectomy: correlation between immunological and clinical findings.

The development of sperm agglutinins in serum and seminal plasma in relation to vasectomy was studied in forty-seven men by testing samples taken before vasectomy and on five occasions during the first year after vasectomy. Thirty additional patients were tested only 1 year after vasectomy. One year after vasectomy, sperm agglutinins in the serum in titres from 4 to about 4000 had developed in 62% of the entire group, while antibodies in the seminal fluid detectable by the gelatin agglutination test were present in only 4% of the group, and apart from on unusual case the titres were low here (either 4 or 8). Analysis of the modes of agglutination revealed changing patterns in several patients during the observation period, with a predominance of tail agglutinins after 1 year. In some cases, mixed agglutination was seen with serum but pure tail-to-tail  agglutination with seminal plasma. The total number of spermatozoa in a pre-vasectomy ejaculate was found to be correlated with an early immune response and with the titre values after 1 year. The group of patients in whom agglutinins had developed 1 year after vasectomy were found to have significantly larger nodules at the sites of operation than those without sperm agglutinins.


Suppression of DNA synthesis by Con A-activated human lymphocytes: Stimulation by con A bound to non-T cells unless removed after activation.

The capacity of human peripheral blood lymphocytes to suppress DNA synthesis of other lymphocytes was studied in an assay consisting of two steps: firstly, activation by Con A during 24 hr followed by alpha-methylglucoside and mitomycin treatment; secondly, incubation of these Con A-activated 'suppressor' cells with autologous responder cells and stimulants, or incubation with allogeneic responder cells. The results were compared with cells similarly treated but not incubated with Con A. If alpha-methylglucoside treatment is omitted, stimulation of T and non-T cells occurs by Con A bound to the Con A-activated cells. Con A is especially bound to non-T lymphocytes and even gives a T cell-independent proliferation of non-T cells without differentiation to plasma cells. With alpha-methylglucoside treatment, 'suppressor' cells, activated by high Con A concentrations, are able to suppress DNA synthesis of autologous lymphocytes stimulated by allogeneic cells or soluble antigens to about 50%. In a one-way MLC, in which the cell suspension containing the suppressor cells is also used as a stimulator cell suspension, a similar suppression was observed. Suppression of DNA synthesis was correlated with suppression of proliferation without evidence of cytotoxicity.


Selection of medical or surgical treatment of endometriosis.

The use of the culdoscope and now the laparoscope has made the accurate diagnosis of endometriosis possible so that each case can be clinically staged. A suggested staging of endometriosis similar to that used for carcinoma of the cervix, i.e., consisting of four stages, is proposed. Surgical or hormonal treatment, or a combination of both, can be chosen on the basis of the stage of the disease. Success of therapy can be determined and compared to results of other investigators using the same staging or classification. The choice and extent of surgical treatment, stage for stage, is discussed. The several hormonal regimens, progestins alone, progestins plus estrogen or danazol, are outlined. Previously reported results in the treatment of endometriosis demonstrated a close correlation between stage of disease and percentage of patients who conceive.


Release by vasopression of E-type prostaglandins from the rate kidney.

1. In order to test whether the release of E-type prostaglandins from the kidney by various vasoconstrictor stimuli is related specifically to adrenoreceptor activation, we have compared release of prostaglandin E-like material from perfused rat kidneys during infusion of noradrenaline or vasopressin. 2. Concentrations of noradrenaline or vasopressin that produced comparable rises in renal perfusion pressure also released comparable amounts of prostaglandin E-like material. This effect was abolished by infusion of an inhibitor of prostaglandin synthesis into the kidney. 3. We conclude that liberation of E-type prostaglandins during renal vasoconstriction is probably related to the activation of intrarenal smooth muscle and odes not involve any specific hormonal receptor. Stimulation of release of prostaglandin E may explain certain reported renal actions of vasopressin.


Effect of propranolol on blood pressure and renin in renal hypertension in the rat.

1. Propranolol was administered to groups of mature rats before and during the development of renal hypertension induced by ligation of the aorta between the renal arteries. 2. At a dose 10 mumol (3 mg) of propranolol/kg, administered by intraperitoneal injection, the onset and severity of hypertension were not affected, although plasma renin concentration was significantly lower than in the untreated hypertensive rats in the first 5 days after the operation. 3. With 200 mumol (60 mg) of propranolol/kg, administered in the drinking water, peak blood pressure 5 days after aortic ligation was lower than in the untreated control rats, but plasma renin concentration was no lower than with the smaller dose. 4. The development of severe hypertension despite reduction in plasma renin concentration on the low dose of propranolol suggests the participation of renal vasopressor factors other than renin in this model. 5. A higher dose of propranolol reduced the rise in plasma concentration to an equal extent but the rise of blood pressure at 5 days was also reduced, which supports this concept.


Blood pressure control in end-stage renal disease in man: indirect evidence of a complex pathogenic mechanism besides renin or blood volume.

1. In twenty-three uraemic patients on regular dialysis, plasma renin activity and blood volume were measured before and after a single dialysis. Three groups were identified; the first had a low or normal plasma renin activity and a high or normal blood volume, the second had a high plasma renin activity and a low blood volume and the third had both variables above normal. 2. In spite of these differences, diastolic blood pressure before and after dialysis was the same in the three groups and multiple regression analyses failed to demonstrate any dependence of blood pressure on plasma renin activity, blood volume or body weight taken separately or together. 3. We conclude that other factors besides plasma renin activity and blood volume are important in maintaining arterial hypertension in terminal renal failure.


Natriuresis in rats acutely depleted of chloride.

1. Acute chloride depletion, without sodium depletion, was produced in rats by a single exchange peritoneal dialysis against sodium bicarbonate solution. Blood volume was restored after dialysis by infusion of salt-free albumin, and exogenous deoxycorticosterone and antidiuretic hormone were given. 2. Clearance studies in the period (3 h) after dialysis revealed no difference in the glomerular filtration rate or in the filtered sodium load between experimental and control rats but urinary sodium concentrations and absolute and fractional sodium excretion were significantly higher in the chloride-depleted group. 3. There was also a significant kaliuresis, increased urinary flow rate and diminished free water reabsorption. Urinary bicarbonate excretion increased to a variable degree but the major rise in anion excretion was 'unmeasured' (Na+ + K+ - [Cl- + HCO3- + PO4(3-)]). 4. It is postulated that chloride depletion imposes limitations on sodium reabsorption in the ascending limb of the loop of Henle.


Oestrogen-associated disease of the renal microcirculation.

The effect of oestrogen-containing compounds on platelet factor 3, platelet life span, renal platelet localization and the fibrinolytic activity of forearm venous blood has been studied in eleven women with the renal vascular abnormalities of the loin pain and haematuria syndrome. The results were compared with those obtained in twenty-nine healthy female volunteer subjects. 2. Platelet factor 3 (PF3) availability was found to be increased in patients with the loin pain and haematuria syndrome during normal menstrual cycles. Oestrogens produced an increase in PF3 availability in both patients and control subjects. 3. Platelet life span was shortened and the index of renal platelet localization increased when patients with the loin pain and haematuria syndrome received oestrogens. No change in platelet kinetics was found in the healthy control subjects receiving oestrogens. 4. The fibrinolytic activity of forearm venous blood, both at rest and after venous occlusion, was increased in the healthy control subjects in response to oestrogens. No such response was seen in the patients with the loin pain and haematuria syndrome. 5. It is suggested that the change in platelet function may be causally related to the intrarenal vascular abnormalities. 6. The possible role of oestrogens in causing these disturbances or unmasking pre-existing abnormalities of platelet function or fibrinolysis is discussed.


Evidence for renal control of urinary excretion of bile acids and bile acid sulphates in the cholestatic syndrome.

1. The bile acids and bile acid sulphates in the urine, serum and bile of eight cholestatic patients were studied quantitatively by gasliquid chromatography and gas-liquid chromoatography/mass spectrometry. 2. The primary bile acids (cholic acid and chenodeoxycholic acid) comprised on average 94% of the total bile acids in bile, 70% in the serum and 64% in urine. 3. The percentage composition of bile acids in bile was relatively constant and was not influenced by the degree of cholestasis. In contrast, in the serum only the primary bile acids were increased, the concentrations of the secondary bile acids (deoxycholic acid and lithocholic acid) and the minor bile acids remaining constant. 4. The data do not support the hypothesis that monohydroxy bile acids accumulate in cholestasis and are related to the pathogenesis of this syndrome. 5. The pattern of bile acid urinary excretion was similar to that in the serum. But in one patient, 3alpha, 7beta, 12alpha-trihydroxy-5beta-cholan-24-oic acid was a principal urinary bile acid, although very low concentrations of the compound were found in that patient's serum, suggesting that some of the minor bile acids in urine may originate by epimerization in the kidney. 6. In bile only a small proportion of the bile acids was sulphated (range 2.1-4.6%) and in serum the degree of sulphation was very variable (9-50%). However, in urine, sulphate esters accounted for a large proportion of the total bile acids (33-72%). 7. The output of bile acid sulphate in the urine was related to the urine total bile acid output but the serum concentration of bile acid sulphate remained relatively constant. Consequently, in contrast to the non-sulphated bile acids, whose renal clearance was relatively constant, the renal clearance of sulphated bile acids was directly related to the urine total bile acid output. This finding is inconsistent with the earlier hypothesis that their predominance in urine was due to a high renal clearance. It may indicate renal synthesis of some of the bile acid sulphates in the urine and/or inhibition of active renal tubular reabsorption of sulphated bile acids by non-sulphated bile acids.


Biosynthesis of folate polyglutamate in the rat with different tracers.

1. The recent suggestions that folate polyglutamate biosynthesis demonstrated in vivo with [3'5'9(n)-3H]folic acid is due to exchange and cannot be achieved with [2(-14)C]folic acid has been demonstrated to be untrue. 2. The compounds formed with both types of radioactive tracer have been shown to be folate polyglutamates from their elution position from precalibrated ion-exchange columns and their susceptibility to hydrolysis by a gamma-carboxypeptidase (conjugase) from human sera. 3. By the use of the methods involving [2(-14)C]folic acid, reported by others to give only folate monoglutamates, we have been able to demonstrate clearly the presence of folate polyglutamates.


The analysis of decay curves.

1. The limitations inherent in the conventional treatment of glucose decay curves as first-order rate systems are described. 2. The conventionally derived K value is a rate constant and should not be confused with a rate. 3. First-order systems are described by this rate constant and the initial concentration of substance studied. They cannot be described by either factor alone. 4. Two parallel curves cannot both result from first-order systems. 5. If K is conventionally calculated for two parallel curves, then the value obtained for the upper curve must be smaller than the value for the lower.


Routine patch testing with cadmium chloride.

During a 22-month period, 2.0% cadmium chloride in distilled water was included in our routine patch test series. Twenty-five of 1502 eczema patients showed reactions (1.7%), but none had any relevant history. At serial dilution test only one patient reacted to 1.0% cadmium; all the other dilutions applied gave negative reactions. Analysis by atomic absorption spectrophotometry of the cadmium chloride used for patch testing showed that it contained less than 1 microgram/g of chromium, copper, cobalt and nickel. The conclusion is that no certain case of contact allergy to cadmium chloride has been revealed. An experimental study using the guinea pig maximization test is in progress.


Sensitivity to a flame retardant, Tris(2,3-dibromopropyl)phosphate (Firemaster LVT 23 P).

Tris(2,3-dibromoprophyl) phosphate (TDB P) is marketed under many different trade names as a flame retardant, used in clothing and home furnishings. DTB P is chemically related to tricresylphosphate (TCP) and triphenylphosphate (TPP) used as plasticizers in plastics and lacquers. The International Contact Dermatitis Research Group (ICDRG) in 1976 examined the incidence of sensitization to TDB P and found two positives among 1103 patients. One of these two cases is reported here in detail. It concerns a woman, aged 56, with spectacle frame dermatitis. The spectacle frame did not contain TDB P and sensitization with another phosphate ester is assumed.


Turpentine-induced hypersensitivity to peppermint oil.

After a dental operation a former laboratory technician was referred to our clinic because of swelling of his tongue, lips, and gingival mucosa. Patch testing with the ICDRG standard test battery gave positive reactions to colophony, balsam of Peru, and turpentine peroxides. Further patch testing revealed hypersensitivity to peppermint oil (an ingredient of several dental preparations) due to the sensitizing properties of three ingredients: alpha-pinene, limonene, and phellandrene. These compounds also occur in turpentine oil, a substance used in the patient's laboratory.


Multiple concomitant positive patch test reactions.

Thirty-five patients who showed 90 one plus (+) patch test reactions to 28 patch test chemicals at Day 2 (D2) were retested to the chemicals at D7. On retesting, 60% (54/90) reactions were positive but 42% (38/90) were negative at D9, suggesting that false positive patch test reactions were common when more than one positive reaction was obtained by concomitant patch testing. On retesting, the total % positivity was reduced from 344 to 241 suggesting that the true index of sensitivity was falsely exaggerated by concomitant testing.


Allergic contact dermatitis: Sex differences.

Using the repeated insult test, Jordan & King (1977) observed that contact sensitization was more readily induced in females than in males. We reviewed data obtained by maximization testing of 185 test substances of which 73 were allergenic. The overall male-female sensitization rates were respectively 9.9 and 9.2%. Only with the weakest allergens (sensitizing one or two subjects of a 25-member panel) was there a possibility of female predominance in that there were twice as many panels having only female reactors as males exclusively. In these instances, the test agents were mainly fragrances. We have concluded that sex differences, in the prevalence of sensitization to particular substances, reflect past exposure and are not due to sex differences.


Allergic contact dermatitis from fluocortolone, flucocortolone pivalate and fluocortolone caproate.

Two patients with contact allergy to Ultralan preparations are reported. Each Ultralan preparation contains two of three related fluocortolone derivatives. The first patient reacted to all three derivatives. The second patient reacted to flucortolone and when retested 4 months later also to fluocortolone pivalate but ot to flucortolone caproate. The negative reaction to fluocortolone pivalate at the first examination was probably false negative due to a low test concentration. In order to avoid false negative patch test reactions the fluorinated steroids should possibly be applied in concentrations higher than 1%. No cross sensitivity to the other steroids for topical use was found.


Chromosomes of Peromyscus (rodentia, cricetidae). VI. The genomic size.

In the genus Peromyscus cells of all species contain 48 chromosomes; however, the fundamental number varies from 56 (P. Crinitus, P. boylei) to 96 (P. eremicus). In some cases biarmed chromosomes are the result of pericentric inversions, while in others they are the result of addition of large amounts of constitutive heterochromatin. Flow microfluorometric DNA-per-cell determinations demonstrated that in some species (P. eremicus) the genome is increased by 36% over the amount of DNA found in most mammalian species. Studies of unique karyotypes with increased amounts of DNA added as constitutive heterochromatin may ultimately help in the elucidation of the mechanisms involved in karyotype evolution and speciation.


Karyologic studies on hybrids between Asian, Ceylonese, and Oceanian type black rats, with a note on an XO female occuring in the F2 generation.

F1 hybrids between the Asian type (2n=42) and Ceylonese type black rats (2n=40) invariably showed 41 chromosomes, while those between the Oceanian type (2n=38) and the Ceylonese type usually showed 39 chromosomes. Twelve F2 hybrids (three litters) were obtained only from the latter combination. Among them, the karyotypes of nine rats were successfully analyzed. They were segregated into the Oceanian type (three rats) and the F1 type (six rats). No Ceylonese type was obtained. From the results of fertility testing in F1 hybrids between these three variants, the Oceanian type is assumed to be more closely related to the Ceylonese type than the Asian type. This coincided well with the results of karyotypic evolution of these geographic variants. Among the nine F2 hybrids examined, one female consistently showed 37 chromosomes with one X chromosome. This XO female appeared to be a normal female and to have been a sporadic natural occurrence.


Assignment of the genes for human beta-glucuronidase and mitochondrial malate dehydrogenase to the region pter leads to q22 of chromosome 7.

In human fibroblast cultures derived from adults, clones of cells with a common chromosome rearrangement have been widely reported. Cells derived from one of these clones have been used in hybridization experiments using mouse cells to localize the genes for beta-glucuronidase and mitochondrial malate dehydrogenase on human chromosome 7. The results of this study indicate that the genes for these isozymes are located on the region pter leads to q22 of human chromosome 7.


Chromosome replication patterns in an established cell line (CHO).

The chromosome replication patterns of the established cell line CHO have been examined and compared with those of normal primary Chinese hamster cells, using the BudR-Hoechst fluorescence technique developed by LATT (1973). The results of this study indicate that the majority of CHO chromosomes replicate normally. There are four clear-cut exceptions to this rule, three of which are most easily explained as undetected or misinterpreted structural rearrangements ot the CHO genome. Several other regions may also replicate differently in CHO and normal primary Chinese hamster cells, but uncertainties in the technique do not allow us to confirm this.


The abstract and the concrete, the disciplinary and the interdisciplinary approach in the teaching of physiological sciences.

It is the author's thesis that the knowledge imparted in universities is being increasingly fragmented into a multitude of disciplines, which results in graduates who are trained to perform very limited functions and hence are impeded from developing their full potential. He refers to the position of the physiological sciences in the medical school curriculum and emphasizes the importance of moving from the concrete to the abstract and then back to the concrete in the study of these sciences. He discusses the need to change the institutional structure of the university in order to move away from this "disciplinary" approach to the imparting of knowledge. He feels that a change of this kind should be based on analysis, from a historical and interdisciplinary standpoint, of the concrete problems that arise in every part of society.


[The teaching of internal medicine in the forming of the physician].

This paper was presented as a working document to the Second Meeting of the PAHO/WHO Program of Textbooks for the Integrated Teaching of Internal Medicine and its Specialties (Washington, D.C., 13-18 December 1976). The need to place the medical student in his environment from the first as an active member of the health team is stressed, and several considerations about the usual obstacles to this proposal are advanced. Reference is made to the subject of curricular integration as related to the length of medical studies and to the traditional use of the hospital in the teaching of internal medicine. The second part of the document reports on the results of the PAHO survey on how internal medicine is taught in Latin America, in which 84 faculties and schools in 15 countries of the Region participated.


Progesterone receptor in human endometrium of leiomyoma uteri.

This study was designed to examine whether 8S protein as progesterone receptor exists in the human endometrium which has been primed with estrogen. The kinetic study showed that 8S-progesterone binding was specific with Kd of 2.0 X 10(-9) M. 5S-progesterone binding was inhibited competitively by cortisol. The study of ligand specificity also showed that progesterone and its related steroids had much stronger affinity for 8S component than for 5S component. Therefore, 5S protein may be CBG. Progesterone-8S protein binding was easily dissociated during the 5-20% sucrose gradient centrifugation, but such a protein from which progesterone had been dissociated could be sedimented at 8S region. Glycerol could stabilize progesterone-8S protein binding. These results indicate the existence of 8S protein as a progesterone receptor under the low salt medium in the estrogen primed human endometrium.


Further studies on gonadotropin-inhibiting substances excreted in human urine.

Partial separtion of human urinary substances which have properties to suppress the ovulation induced by PMS and HCG in mice was attempted by gel filtration on Sephadex G-100 and ultrafiltration using the Amicon Diaflo membranes UM-2 and UM-10. In addition to a thermostable inhibitor which has a molecular weight more than 10,000, the presence of heat-labile inhibitor with a molecular weight less than 1,000 was newly demonstrated.


Insulin releasing activity of gastrointestinal glucagon-like immunoreactive materials in perfused rat pancreas.

Insulin-releasing activity of porcine gastrointestinal glucagon-like immunoreactive materials purified by affinity chromatography was examined in the perfused rat pancreas. When glucose concentration of the perfusate was raised from 60 to 100 mg/dl, augmented insulin release was observed. The mean incremental area of immunoreactive insulin (sigma delta IRI) during the first 10 min thus observed was 19.07 +/- 3.76 ng/10 min. Pancreatic glucagon and the extract from the gastric fundus showed the enhancement of insulin release in this system when they were added to the perfusate at the rate of 100 ng/min for 5 min; delta IRI were 41.92 +/- 8.47 and 71.70 +/- 18.09 ng/10 min, respectively, which were significantly higher than that of 100 mg/dl of glucose alone. However, no significant difference in the insulinogenic activity was noticed between the extracts from the small intestine and the control. These results suggest that the extract from the gastric fundus has insulinogenic activity similar to that of pancreatic glucagon.


A screening test to detect HGH-antibodies in pituitary dwarfs treated with HGH preparation by the radio-immunoassay with double antibody technique.

Sixty-four blood samples, obtained from 25 pituitary dwarfs treated with KABIHGH preparation, were checked for serum HGH concentration by a double antibody radioimmunoassay and for antibodies against HGH by the method of propylethyleneglycol separation. Antibodies to HGH were detected in the samples whose HGH concentration was falsely estimated to be more than 5 ng/ml, but not in those whose HGH concentration was 5 ng/ml or less. The measurement of HGH concentration by a double antibody technique in the serum obtained from pituitary dwarfs 3-4 days after the last injection can be used to screen the presence of antibodies to HGH peparation used.


Intraphypothalamic implants of testosterone or dihydrotestosterone in neonatal female rats with reference to induction of sterility.

Implants of paraffin micropellets containing about 5 microgram 5 alpha-dihydrotestosterone (DHT) into the hypothalamus of 5-day-old female rats were without effect on the sexual differentiation of the brain. By contrast, approximately the same amount of testosterone propionate (TP) given as subcutaneous or intrahypothalamic micropellets masculinized the female brain. In the light of these results as well as the author's previous findings that an antiestrogen implanted into the hypothalamus of neonatal female rats failed to block masculinization by subcutaneous injection of TP, the possibility cannot be excluded that testosterone is capable of masculinizing the brain of neonatal females without being converted into estrogens.


Stimulation of immunoreactive somatostatin release from hypothalamic synaptosomes by high (K+) and dopamine.

Effects of high (K+) and dopamine on the release of immunoreactive somatostatin from isolated hypothalamic synaptosomes were studied in rats. High (K+) (60 mM) and dopamine (10(-6) M) in the incubation media stimulated the release of immunoreactive somatostatin and the former effect was completely abolished by the removal of Ca++ from the media. These suggest that hypothalamic somatostatinergic synaptosomes preserved at least one of the important basic properties of secretory cells. Although it is of interest to note that dopamine stimulated the release of somatostatin. Its physiological significance awaits further studies.


The effect of nacom (L-dopa and L-carbidopa) on growth hormone secretion in 75 patients with short stature.

The stimulatory effect of Nacom (250 mg L-Dopa and 25 mg L-Carbidopa) on the HGH secretion was evaluated in 75 short stature patients. The number of blood samples was restricted to only three (0, 45 and 90 min). 63 patients reached adequate HGH concentrations after the ingestion of 1 tablet Nacom (84%). Somatotropin levels increased from 2.08 (Sx 0.28) to a maximal HGH value of 14.22 (Sx 0.87) ng/ml. When the stimulatory effect of Nacom was compared with the standard method of arginine infusion in children with normal stature the arginine test was not superior to the Nacom-test. The Nacom-test appears to be a simple and reliable screening method for HGH deficiency, particularly in outpatients.


Thrombocyte functions, thrombelastograms and fibrinogen of healthy children in different age groups.

Platelet counts, adhesiveness, aggregation and spreading capacity, as well as the thrombopoiesis index, thrombelastogram and fibrinogen were examined in 74 healthy children aged from 2 to 14 years. Sex-linked differences were only found in the thrombopoiesis index. Age-linked differences showed in practically all the parameters, especially in the platelet counts, fibrinogen and thrombelastograms.


Insulin secretion in children with growth retardation.

The effect of tolbutamide administration on insulin secretion was studied in 69 children with growth retardation. Diminished insulin secretion was found in all the patients, compared to the control group. This insulin deficit was most evident in patients with isolated, total GH deficiency and least evident in children with idiopathic short stature. Intermediate values were found in dwarfism due to isolated, partial GH deficiency. These results favour the hypothesis that hypoinsulinism contributes to the somatotropin deficiency in causing growth retardation.


Organic aciduria in hypoxic premature newborns simulating an inborn error of metabolism.

A very unusual pattern of organic acid excretion was established in the urine of two premature newborns with severe respiratory distress and cerebral haemorrhages. By combined gas chromatography/mass spectrometry the following acids were identified: lactic acid, alpha-hydroxy-butyric acid, beta-hydroxy-butyric acid, alpha-hydroxy-isovaleric acid, and p-hydroxy-phenyllactic acid. Calculation of the concentration revealed an excessive excretion of lactic acid and also very high excretion of the other acids. A postmortem blood sample from one of the patients revealed a comparable pattern. The abnormal urinary organic acid excretion pattern was most probably caused by severe tissue hypoxia.


The activities of alanine aminopeptidase, leucine aminopeptidase, proline dipeptidase and prolyl dipeptidase in the mucosa of the small intestine. Investigations on normal children and patients with the malabsorption syndrome.

Alanine aminopeptidase (EC 3.4.11.2), leucine aminopeptidase (EC 3.4.11.1), proline dipeptidase (EC 3.4.13.9), and prolyl dipeptidase (EC 3.4.13.8) have been investigated in small intestinal mucosa homogenates of normal children and children suffering from different degrees of villous damage. The activities of proline dipeptidase and prolyl dipeptidase could be shown to be significantly decreased in cases of subtotal and total villous atrophy, whereas the activities of alanine aminopeptidase and leucine aminopeptidase were not influenced. The results are discussed in view of the subcellular distribution of these enzymes.


Haemorrhagic diathesis as a possible early sign of hereditary fructose intolerance.

An infant girl three weeks of age with the leading symptom of skin haemorrhages is presented. On further investigation, the signs of severe hepatic damage with hypofibrinogenaemia and prothrombin complex impairment, and renal tubular dysfunction were disclosed. All these pathological symptoms, which were reversed on fructose free diet, were caused by hereditary fructose intolerance.


Capillary-venous hematocrit differences in newborn infants. I. Relationship to blood volume, peripheral blood flow, and acid base parameters.

Venous and capillary hematocrit, acid base values, and circulatory parameters were measured simultaneously in 92 newborn infants within six hours of birth. Gestational age ranged from 26 to 41 weeks. The capillary/venous hematocrit ratio (Hctc/Hctv) was greater than 1.00 in 89 infants. We found significant inverse correlations between Hctc/Hctv and several parameters, such as pH (r = -0.82), standard bicarbonate (r = -0.73), systolic blood pressure (r = -0.51), and peripheral blood flow (r = -0.70). Most of the infants with a Hctc/Hctv of 1.20 and above had red cell mass values of less than 35 ml/kg. However, blood volume apparently did not influence the Hctc/Hctv. Gestational age appeared to affect Hctc/Hctv only before 30 weeks, when compared with the Hctc/Hctv of term infants. Our results indicate that disturbed circulation, and in particular, disturbed microcirculation is involved in the development of high Hctc/Hctv ratios. We strongly advise that hematocrits obtained by skin prick from a sick newborn infant should not be relied on as they may give misleading information on oxygen carrying capacity to vital organs.


Effect of partial devascularization on the blood flow distribution in the cat stomach.

Partial devascularization of the stomach was performed in cats anesthetized with pentobarbital. Gastric blood flow distribution and cardiac output were determined by means of the microsphere distribution technique. Blood flow was determined before and 30 min after the partial devascularization. Devascularization of the lesser curvature caused a significant decrease in the mucosal and muscularis blood flow at the lesser curvature. After devascularization of the greater curvature, localized reduction in mucosal and muscularis blood flow occurred at the greater curvature. In the sham-operated animals the muscularis blood flow was significantly higher than in the nonoperated animals.


Pressure-induced ischemia. I. An experimental model for intravital microscopic studies in hamster cheek pouch.

A model to study pressure-induced ischemia by intravital microscopy is presented. A hamster cheek pouch is prepared to get a single layer of epithelium, together with vessels and connective tissue. Pressure, which can be varied, is transmitted to the tissue by a pressure chamber with a rubber membrane. Microcirculatory reactions may be studied while the pressure is applied, when the pressure is released and as the tissue is regaining circulation. The local environment is controlled by irrigating the test tissue with a solution approximating the composition of interstitial fluid. Local oxygen and carbon dioxide tensions are controlled. There is a marked difference in restoration of blood flow to the tissue after 2- and 4-hour ischemia. After 2-hour ischemia the tissue regained circulation rapidly. Microbleedings developed during the postpressure observation time. After 4-hour ischemia, on the other hand, the tissue regained circulation slowly and only in one third of the microvessels. Extensive white blood cells sticking to the vessel walls were seen indicating endothelial damage. In the 4-hour experiments there were very few microbleedings compared to the 2-hour experiments.


Mortality and fertility control.

The authors present a continuation of the thesis suggesting that the most rational procedure for regulating fertility is a perfectly safe, even though not completely effective, contraceptive method combined with safe methods for terminating pregnancy when the contraceptive fails. This analysis demonstrates that, compared with the risk of death from pregnancy and childbirth, major reversible methods of fertility control--the pill, IUDs, condoms, and diaphragms--and abortion are associated with very low levels of mortality. The exception to this statement is pill use after age 40 by women who smoke. This analysis also confirms the very low mortality associated with using the condom and diaphragm with early induced abortion as a backup to terminate pregnancies resulting from contraceptive failures.


Medical supervision for contraception: too little or too much?

The need to provide medical supervision in contraceptive services is reviewed in the context of the situation existing in developing nations. The author contends that less rather than more medical supervision can be justified if one compares the relatively low incidence of complications from modern contraception with the inordinately high maternal death rates from pregnancy and its complications in these same countries.


The risk of post-pill amenorrhea: a preliminary report from the Menstruation and Reproduction History Research Program.

Menstrual cycle lengths prior to and after oral contraceptive use were prospectively recorded for 245 women. In this preliminary study, a difference in the distributions in the pre- and post-pill cycle lengths was observed. An increase of 5 days in the medial cycle length occurred after oral contraceptive use had been discontinued. Although there was an approximately twofold relative risk of amenorrhea of 90 days' duration or more after discontinuing pill use, the differences in the rates of amenorrhea between the pre-pill and post-pill cycles were not statistically significant.


Live tumors and oral contraceptives.

Data on 78 cases of benign hepatic neoplasia among women with a history of oral contraceptive (OC) use are analyzed. Data for the study were collected by the Liver Tumor Registry of the University of California Irvine Medical Center. Factors considered in the analyses include the patient's age and duration of OC therapy, histopathology of the tumors, and their symptoms, findings, and prognosis. The pathogenesis and treatment of the tumors are also discussed.


Experience with medroxyprogesterone acetate (Depo-Provera) as an injectable contraceptive.

Depo-Provera injections appear to be a safe and effective alternative for women who cannot tolerate the estrogenic side effects associated with oral contraceptives or the pain and bleeding associated with IUDs. However, women considering the method should be fully aware of the possible risks: (a) inability to withdraw the drug promptly in the event of a serious reaction, (b) disruption of menstrual patterns, and (c) delayed return of fertility after discontinuing therapy. Some women may consider the required trip to the doctor every 3 months an additional disadvantage. For women in developing countries where anemia and nutritional problems are prevalent, Depo-Provera has additional advantages in relation to IUDs and OCs: it causes less bleeding than IUDs or OCs and, unlike oral contraceptives, it does not suppress vitamin levels (4-8). Since it requires a trip to the doctor every 3 months, it also provides a better opportunity for medical supervision and care. For postpartum women who which to breastfeed their babies, Depo-Provera has the additional advantage of causing no adverse effect on lactation (1, 2, 13, 14, 16, 18, 19, 25, 32, 36).


The benefits and risks of IUD use.

Next to combination oral contraceptives (OCs), intrauterine contraceptive devices (IUDs) are the most effect form of contraception available. IUDs require only one-time motivation, cause no systemic metabolic effects, and do not depend on continued action of the user for effectiveness. Risks, side effects and complications of this method, including expulsion, perforation pain, bleeding and infection, are reviewed.


Side effects of intrauterine devices.

Problems in determining and quantifying side effects of intrauterine device (IUD) use are reviewed. The types and incidences of major side effects are discussed, as well as methods of treatment. The author concludes that IUD use remains a safe and effective method of family planning.


Vasectomy: benefits versus risks.

The benefits and risks of modern vasectomy are presented, including a discussion of precautions and contraindications, the incidence of specific complications and suggestions for minimizing them, and the incidence of and reasons for procedure failures. Long-term side effects, including psychological sequelae, are also discussed.


An evaluation of studies concerning reproduction after first trimester induced abortion.

This report gives an estimate of the United States population at risk of fertility complications after legally induced abortion. It also includes a review of the published literature concerning long-term effects of abortion, such as secondary infertility, ectopic pregnancy, and adverse pregnancy complications.


The risk of dying from legal abortion in the United States, 1972-1975.

Data gathered by the Center for Disease Control (CDC) through epidemiologic surveillance of deaths associated with legal abortions performed from 1972 through 1975 are analyzed by the type of procedure and the gestational age of the patients. Analysis shows that deaths increase at higher gestational ages and that the risk of death from abortion is highest with hysterotomy and hysterectomy and lowest with suction curettage. Second trimester instillation procedures are associated with higher rates of mortality than first trimester curettage procedures, even when dilatation and evacuation at 13-15 weeks' gestation is included as a curettage procedure. A case history of a patient who died as a result of legal abortion demonstrates that while legal abortion is a safe surgical procedure, some of the deaths that still occur can be prevented.


Menstrual regulation: risks and "abuses".

The definitions, methods, and techniques of menstrual regulation (MR) are presented. The risks and abuses of performing MR by vacuum aspiration to terminate pregnancies of less than 7 menstrual weeks are reviewed.


Methods of midtrimester abortion: which is safest?

In the United States, the three principal methods of abortion for patients at 13 or more menstrual weeks' gestation are intraamniotic instillation of saline or prostaglandin F2alpha (PGF2alpha) and dilatation and evacuation (D&E). The relative safety of these methods, however, has not been established. This report compares the three methods using data on 17467 abortions collected by the Joint Program for the Study of Abortion under the auspices of the Center for Disease Control (JPSA/CDC). Abortion by D&E was found to be significantly safer than abortion by saline instillatin (p less than 0.001), and abortion by saline instillation was significantly safer than by PGF2alpha (p less than 0.01). Moreover, midtrimester D&E is both safe and practical; it is a direct and rapid procedure which can be performed on an outpatient basis. Although PGF2alpha accelerated the time required for abortion, it also significantly increased serious morbidity.


Risks and benefits of postmenopausal exogenous estrogen.

Cyclically administered estrogen helps prevent and treat vasomotor symptoms and atrophic changes in the genitourinary tracts of postmenopausal women. Administering exogenous estrogen may also help prevent postmenopausal bone loss and help treat severe postmenopausal osteoporosis. Although recent studies have indicated an association between estrogen replacement therapy and endometrial carcinoma, a true cause-and-effect relationship has not been established. Thus, estrogen replacement therapy should be administered carefully, considering the risk/benefit ration for each individual, and should use the smallest dose necessary to achieve the desired effect. If irregular bleeding occurs before or during estrogen administration, a complete gynecologic examination (including a histologic examination of the endometrium) is mandatory.


Pathophysiology of hypotension in patients with fulminant hepatic failure.

Studies on the incidence and pathophysiology of hypotension in fulminant hepatic failure showed that 82 out of 94 patients developed arterial hypotension with a systolic blood pressure of less than 80 mmHg. Such episodes accounted for 16% of the total time spent in grade IV coma. Factors such as haemorrhage, cardiac or respiratory abnormalities, extracorporeal perfusion, or hypotension which occurred during the terminal stages of the illness, could be implicated for only 40% of this time, leaving 60% as unexplained. Further investigation of these unexplained factors showed that peripheral vasodilatation rather than primary heart failure was responsible, and in all but three patients construction of ventricular function curves showed a normal ventricular response to volume expansion with a corresponding increase in blood pressure. A small, but significant, slowing of the heart rate occurred during these periods of unexplained hypotension. This, together with the association that was found between the occurrence of hypotension and cerebral oedema with coning, suggests that central vasomotor depression may be important in its pathogenesis.


Clinical study of liver blood flow in man measured by 133Xe clearance after portal vein injection.

During the course of a clinical trial to assess the value of adjuvant liver perfusion of 5-fluorouracil after surgery for colorectal cancer, liver blood flow was measured in 14 patients. Access to the portal circulation was achieved by dilatation and cannulation of the obliterated umbilical vein. The clearance from the liver of a bolus of 133Xe was monitored using a gamma-ray camera so that blood flow from different areas of the liver could be calculated. The clearance curve of 133Xe was a double exponential of which the initial fast component accounted for a consistently high proportion of the total clearance. The perfusion studies have shown wide differences in blood flow to the various areas of the liver in the same patient, in addition to a wide variation in perfusion rate between the 14 patients. This technique of quantitative estimations of liver blood flow to different areas of the liver may have importance in planning operative procedures and understanding the haemodynamic mechanisms involved in liver disease.


Qualitative and quantitative evaluation of internal anal sphincter function in the newborn.

One-hundred-and-one normal neonates were examined manometrically in the first day of life to assess anorectal function. In order to overcome some of the difficulties in subjective interpretation of results, the stimuli used and the response pattern seen in the anal canal were measured. In the unstimulated state, all subjects demonstrated rhythmical changes in anal canal tone. Mean maximal intraluminal pressure in the anal canal decreased significantly after 10 hours of age and after the first meconium stool. Only five out of the 101 examined on the first day of life had an abnormal manometric response. It is significant that none of these had passed meconium at the time of examination, and that all had a normal response pattern at the age of 28 hours. In 20 of these babies the sensitivity of the rectoanal reflex was measured and found to be significantly increased on the third day of life compared with the first. The quantitative changes in anorectal reflex function in the newborn, are thought to be related to the state of physiological ;constipation' which exists in utero and in the early neonatal period. The results indicate that a normal response pattern can be obtained in healthy babies after the first day of life. Consequently, anorectal manometry will be meaningful as a diagnostic method thereafter in the neonatal period. Further, it is suggested that measurement of the stimulus and the response will add useful information and reduce subjective error in interpretation of results.


Policy of local excision for early cancer of the colorectum.

A policy of local excision or total biopsy for early cancer of the colorectum, when this is technically possible, has been described. This is based on thorough histological examination of the excised specimen with special reference to the completeness of surgical excision, the depth of spread of the cancer into the bowel wall, and the histological grade of malignancy. The results of this policy in 119 patients treated by local excision only have been studied. There have been 10 recurrences but only five of these are regarded as policy failures. Because of these good results it is suggested that the policy as described should be regarded as an established alternative to partial colectomy, anterior resection, and abdominoperineal excision in carefully selected patients.


Giant sigmoid diverticulum: clinical and radiological features.

Two case reports of giant sigmoid diverticulum associated with diverticular disease of the sigmoid colon are presented. The clinical and radiological features of 30 similar cases found in the literature are reviewed. Our two cases represent the largest recorded diverticulum and the oldest recorded patient with this condition.


Changes in the plasma clearance and protein binding of carbenoxolone with age, and their possible relationship with adverse drug effects.

Comparison by equilibrium dialysis of plasma protein binding sites for carbenoxolone in people under 40 years of age and in people over 65 years of age showed that the number of binding sites was reduced in the elderly and that this fall was associated with a reduction in plasma albumin levels. Although carbenoxolone has some aldosterone-like effects, these properties could not be shown to be due to displacement of aldosterone from its protein binding sites by competitive protein binding of carbenoxolone. Single doses of carbenoxolone were found to be removed considerably more slowly from the plasma of elderly individuals than from the young. The results of these three series of experiments suggest that the side-effects of carbenoxolone in the elderly may in part be caused by reduced protein binding, leaving more free drug in the active unbound form, and in part by reduced hepatic clearance mechanisms.


Failure of glucagon to influence ion transport across human jejunal and ileal mucosa in vitro.

Glucagon (90 to 880 pg.ml-1) failed to influence electrical activity or fluxes of sodium and chloride across human jejunal and ileal mucosa in vitro. These results suggest that the intestinal secretion and diarrhoea produced in vivo in man during intravenous infusion of glucagon may be produced by changes in motility and blood flow and not directly by activating an ion secretory mechanism as is the case in cholera.


A comparison of the binding specificities of lectins from Ulex europaeus and Lotus tetragonolobus.

The L-fucose-binding lectins present in the seeds of Ulex europaeus and Lotus tetragonolobus have been isolated by affinity chromatography. The binding specificities of the lectins were compared by hemagglutination inhibition analysis. The lectins behaved similarly with respect to a variety of synthetic saccharides. D-Fucose derivatives were inactive as inhibitors. In general, the alpha -L-fucopyranosyl derivatives were better inhibitors than the beta-L-fucopyranosyl derivatives. Aromatic aglycones increased the inhibitory activity of the saccharides with p-nitrophenyl-alpha-L-fucopyranoside being one of the best inhibitors. The major difference between the two lectins was the observation that the Ulex lectin required higher concentrations of saccharides to bring about complete inhibition of hemagglutination than did the Lotus lectin.


Selective transport of an oligomeric IgA into canine saliva.

Evidence is presented which shows that an oligomeric IgA myeloma protein possessing J-chain but lacking secretory component, is selectively transferred from serum into canine saliva. The data also demonstrate that 125I-label remains with the IgA during the transfer process. These data interpreted in the light of findings in humans support the concept that the oligomeric form of IgA, devoid of secretory component, is required to achieve selective transport.


Lipolysis in brown adipose tissue of cold- and heat-acclimated hamsters.

Rates of release of free fatty acids (FFA) and glycerol to the incubation medium by brown adipose tissue (BAT) slices isolated from heat-acclimated (H), cold-acclimated (C), and control (N) hamsters in the absence or presence of epinephrine (E) were studied. Rates of FFA and glycerol release by tissue slices isolated from H and N animals were similar. In tissue slices isolated from C animals rate of release of FFA and glycerol was three times as high. Addition of E to the incubation medium (200 microgram/ml) had no effect on the rate of FFA and glycerol release of slices from C animals, but tripled the rates of slices from N, resulting in similar values for the two groups. In slices from H animals the rate of release was lower than in the other two groups, increasing only 1.5-fold. Pretreatment of N animals with triiodothyronine (T3; 0.8 microgram/100 g daily for 7 days) doubled the rates of FFA and glycerol release. Addition of E to the medium affected both pretreated and nontreated slices similarly. Two possible mechanisms by which temperature acclimation controls the lipolytic rate of BAT are suggested by 1) the concentration of specific enzymes and 2) cellular metabolites and hormones which activate existing systems. It seems that both operate in temperature-acclimated hamsters.


Influence of arterial hypoxia on cardiac and coronary dynamics in the conscious sinoaortic-denervated dog.

Arterial hypoxia was produced in 10 conscious, chronically instrumented, tracheostomized dogs by allowing them to breathe 7.5% O2 in N2 for 10 min. Hypoxia (Pao2 = 28 +/- 0.7 (SE) Torr) caused significant increases in coronary blood flow (+196%), left ventricular dP/dt max (+60%), aortic blood flow (+48%), heart rate (+50%), and left ventricular systolic (+12%) and aortic (+10%) pressures. Left ventricular end-diastolic pressure and stroke volume were unchanged, while systemic (-30%) and coronary diastolic (-66%) vascular resistances declined significantly. When equivalent levels of arterial hypoxia were produced in four of these dogs after chronic sinoaortic denervation, the coronary, cardiac, and systemic hemodynamic responses were not significantly different, with the exception that the small arterial pressure response was abolished. Thus the peripheral chemoreflexes are not essential for the normal coronary vasodilator and cardiac adjustments to occur during hypoxia in the conscious dog. The data support the hypothesis that a large part of the cardiac adjustments to hypoxia is initiated outside the sinoaortic reflexogenic zones, probably within the central nervous system.


Insulin and glucose responses during bed rest with isotonic and isometric exercise.

The effects of daily intensive isotonic (68% maximum oxygen uptake (VO2 max)) and isometric (21% maximum extension force) leg exercise on plasma insulin and glucose responses to an oral glucose tolerance test (OGTT) during 14-day bed-rest (BR) periods were investigated in seven young healthy men. The OGTT was given during ambulatory control and on day 10 of the no-exercise, isotonic, and isometric exercise BR periods during the 15-wk study. The subjects were placed on a controlled diet (mean +/- SD = 344 +/- 34 g CHO/day and 3,073 +/- 155 (SD) kcal/day) starting 10 days before each BR period. During BR, basal plasma glucose concentration remained unchanged with no exercise, but increased (P less than 0.05) to 87-89 mg/100 ml with both exercise regimens on day 2, and then fell slightly below control levels on day 13. The fall of glucose content (-11 to -15%) during BR was independent of the exercise regimen and was an adjustment for the loss of plasma vol. The intensity of the response of insulin and glucose to the OGTT (integrated area under the curves) was inversely proportional to the total daily energy expenditure during BR; i.e., the largest response with no exercise, then isometric, isotonic, and ambulatory exercise. It was estimated that at least 1,020 kcal/day must be provided by supplemental exercise to restore the hyperinsulinemia to control levels.


Response of prepubertal girls and college women to work in the heat.

Five prepubertal females and five college women, matched for aerobic power, walked on a treadmill at approximately 30% VO2 max for two 50-min periods in three environments: 1) 28 degrees C, 45% rh, 2) 35 degrees C, 65% rh, and 3) 48 degrees C, 10% rh. In the mild heat (28 degrees C) both groups were able to work 100 min with no discomfort. At 35 and 48 degrees C tolerance time for the prepubertal subjects averaged 84.4 and 37.0 min, respectively; for adults, 100 and 75.0 min. At all temperatures the girls had higher heart rates and a lower stroke index, and finished the walks with a higher rectal temperature. There were no differences between groups in cardiac index, mean skin temperature, forearm blood flow, or percent loss in body weight. The proportion of the thermal load dissipated by the two groups was similar but the route for heat transfer was related to the BSA/wt ratio and environmental conditions. Marked circulatory instability was a primary factor in the lower tolerance of the prepubertal girls to work in the heat probably due to a shift in blood volume from the central to the peripheral circulation.


Effect of aging alone on mechanical properties of the normal adult human lung.

For plethysmographic studies of respiratory mechanics, we selected, from a general population, 51 subjects, aged 25-75 yr, who had never smoked, had no present or past cardiorespiratory symptoms or disease, were alpha1-antitrypsin MM phenotypes, and were normal by physical examination, vectorcardiography, and chest roentgenography. Approximately equal numbers of men and women were represented in each of three age groups; 25-35, 36-64, and 65-75. Both sexes demonstrated loss of lung elastic recoil with age, most significant at high lung volumes, but the rate of loss was less than previously reported. Males had higher lung recoil than females of comparable age, but if lung size was taken into account, there were no sex differences in bulk elastic properties. Maximum expiratory flow diminished with age only at low volumes, suggesting that equal pressure points are more centrally located at low lung volumes in the elderly.


Mechanism of respiratory responses to intravenous NaHCO3, HCl, and KCN.

We studied the mechanism by which respiratory responses are produced by rapid injection of NaHCO3, HCl, or KCN into the superior vena cava of lightly anesthetized dogs. To estimate independently circulatory transit time to receptor sites, the solutions were injected at 0 degrees C and their arrival time at the ascending aorta and carotid sinus was detected by thermocouples. All of the ventilatory responses were observed to begin after the substances had reached the ascending aorta and 94% began after the carotid sinus had been reached. The injections were repeated following bilateral vagotomy and/or carotid body resection. Vagotomy produced no significant changes in ventilatory responses, but carotid body resection considerably reduced them. Following both procedures, few ventilatory responses were observed, and the time lag to the onset of the response increased greatly. We conclude that all of the observed ventilatory responses can be accounted for by the known arterial and central chemoreceptors, and that no evidence for pulmonary chemoreceptors was obtained.


Fetal cerebral oxygen consumption at different levels of oxygenation.

Cerebral oxygen consumption (VCO2) was measured in 10 unanesthetized, chronically catheterized fetal sheep at 130-140 days of gestation. The VCO2 was calculated using cerebral blood flow (QC) measured with radioactive microspheres and the cerebral arteriovenous difference of O2 content (C(a-V)O2) calculated from preductal arterial and sagittal sinus venous blood. The ewe was exposed to varying concentrations of oxygen, resulting in fetal arterial oxygen contents (CaO2) of 0.89-5.58 mM, arterial oxygen tension (PaO2) values of 14-36 Torr, and cerebral venous oxygen tension (PVO2) values of 9-25 Torr. Although there was a clear relationship between the fetal CaO2 and C(a-V)O2, this was shown to be the result of changes in Qc rather than changes in VCO2. There was not a statistically significant correlation between either CaO2 or PVO2 and VCO2 over this range of oxygenation. On the other hand, C(a-V)O2 was highly correlated with Qc. There is no evidence that VCO2 is a function of oxygen tension (PO2) in the unanesthetized fetal sheep as long as the sagittal sinus PO2 is greater than or equal to 9 Torr.


Effects of lung inflation on longitudinal distribution of pulmonary vascular resistance.

A low-viscosity bolus technique was employed to determine the influence of lung inflation on the distribution of pulmonary vascular resistance in isolated cat lungs. When the lungs were collapsed, the longitudinal distribution of resistance was concentrated near the proximal (arterial) part of the vascular bed. As the lungs were inflated, the resistance became more evenly distributed with the maximum located close to the midpoint of the total blood volume. The fraction of total pressure drop across the lung which occurred proximal to the midpoint of the total lung blood volume decreased from 0.69 in the collapsed lung to 0.43 at a transpulmonary pressure of 16 cmH2O.


Longitudinal distribution of vascular resistance in the lung.

We have modified the low-viscosity bolus technique for determining the longitudinal distribution of pulmonary vascular resistance. A bolus of saline was introduced into the pulmonary artery of an isolated cat lung. As this low-viscosity bolus passed through the lung, a fall in inflow pressure was recorded which had a characteristic shape depending on the changing shape and position of the low-viscosity bolus and the longitudinal distribution of resistance. The shape and position of the bolus within the lung at a given time were calculated using the change in viscosity of the blood measured as the bolus entered the pulmonary artery and as it emerged from the left atrium. Assuming that the hemodynamic resistance of a small segment of the vasculature is proportional to the product of the viscosity and its geometric factor, we employed a sequential-pattern search technique to calculate the "best" longitudinal distribution of the geometric factor, compatible with the position and dispersion of the bolus at any time and the arterial pressure curve.


Measurement of body temperature in neonatal mice.

A simple method is described for obtaining repeated measurements of body temperature in young mice with minimal error introduced through stress. Temperatures are measured by an external thermocouple attached to the thorax in the region of the heart. A sling around the animal's thorax provides insulation for the thermocouple from surrounding air and mild restraint of the animal during measurement. Comparison with temperatures obtained in other locations indicates that external thoracic temperature as described gives a reliable estimate of true body temperature in mice up to 21 days old. Typical results with normal mice aged 1 day to 6 wk postpartum are included, together with a brief discussion of the technique's applicability.


Determinants of transmembrane bicarbonate flux during acid-base changes.

Experiments were designed to determine the contribution of increased extracellular HCO3- concentration, [HCO-3e], to the net extracellular-to-intracellular HCO3- flux observed in hearts during hypercapnia. Isolated rabbit hearts were perfused by recirculating for 15-min periods a small volume of Ringer solution in which [HCO-3e] and carbon dioxide tension (PCO2) could be independently altered. A net HCO-3 flux was evidenced by a decrease in [HCO-3e] during recirculation. [HCO-3e] was randomly increased from 19 mM over a range of 19-42 mM at a constant PCO2 of 38.7 Torr. The resulting flux increased linearly with the [HCO-3e] existing at the start of recirculation. The same relationship was observed at 95.8 Torr PCO2. The disappearance of HCO-3 from the perfusate could not be explained by dilution in the interstitium or by lactate accumulation. When PCO2 was increased from 40 Torr over a range of 40-160 Torr at a constant [HCO-3e] of 20 or 30 mM, a small flux was observed only at the highest PCO2 levels. Essentially the same results were obtained when recirculation time was prolonged to 30 min. These results suggest that the major determinant of the HCO-3 flux is a change in extracellular HCO-3 concentration.


Pulmonary mechanics in normal rats.

A versatile, whole-body pressure, or volume plethysmographic system for the study of pulmonary mechanics in anesthetized, tracheotomized rats has been described. Lung volumes and lung compliance values were in good agreement with those previously reported. Pulmonary resistance and chest wall compliance values were lower than those previously reported. Total dynamic compliance remained independent of respiratory frequency between 40 and 320 breaths/min. Flow-limiting behavior was demonstrated from a series of imposed forced expiratory maneuvers of graded effort. With a deflation pressure of 30 cmH2O, the effort-independent range of maximum flow extended to 40-50% of vital capacity. Maximal flow-static recoil pressure relationships were essentially linear over the effort independent portion of the flow-volume curve. Substitution of a low-density gas mixture (80% He-20% O2) for air resulted in increased forced expiratory flow rates but the magnitude of the response was considerably less than that which has been reported in man.


Diminished hormonal responses to exercise in trained rats.

Male rats (120 g) either were subjected to a 12-wk physical training program (T rats) or were sedentary controls (C rats). Subsequently the rats were killed at rest or after a 45- or 90-min forced swim. At rest, T rats had higher liver and muscle glycogen concentrations but lower plasma insulin. During exercise, blood glucose increased 60% in T rats but decreased 20% in C rats. Plasma glucagon and insulin concentrations did not change in T rats but plasma glucagon increased and insulin decreased markedly in C rats. Plasma epinephrine (90 min: range, 0.78-2.96 ng-ml-1, (T) vs. 4.42-15.67 (C)) and norepinephrine (90 min: 0.70-2.22 (T) vs. 2.50-6.10 (C)) were lower in T than in C rats. Hepatic glycogen decreased substantially and, as with muscle glycogen, the decrease was parallel in T and C rats. The plasma concentrations of free fatty acids were higher but lactate and alanine lower in T than in C rats. In trained rats the hormonal response to exercise is blunted partly due to higher glucose concentrations. In these rats adipose tissue sensitivity to catecholamines is increased, and changes in glucagon and insulin concentrations are not necessary for increased lipolysis and hepatic glycogen depletion during exercise.


Ventilatory responses to hypercapnia and hypoxia during continuous aspirin ingestion.

Hypercapnic and hypoxic ventilatory responses were serially measured in nine normal subjects given 3.9 g aspirin (ASA) per day for 9 days. Minute ventilation (VE), end-tidal carbon dioxide tension (PETCO2), venous bicarbonate concentration [HCO3-], oxygen consumption (VO2), hypercapnic ventilatory response (deltaVE/deltaPCO2), and isocapnic hypoxic ventilatory response (A) were determined before, 2 h after the first dose, and at 72-h intervals during the next 14 days. Serum salicylate levels averaged 18.6 +/- 2.0 mg/dl. VE increased (P less than 0.05, PETCO2 decreased (P less than 0.05), and [HCO3-] did not change significantly during drug ingestion. deltaVE/deltaPCO2 increased gradually to a value 37% greater than control by day 3 and remained constant (P less 0.01). A increased by 251% and VO2 by 18% within 2 h and remained constant for the remainder of the ASA period (P less than 0.01). All values returned to base line within 24 h following cessation of ASA. We conclude that during continuous ASA ingestion there is a gradual increase of hypercapnic ventilatory response. This may reflect slow entrance of ASA into the central nervous system. In contrast, there is a rapid rise in hypoxic ventilatory response which may be mechanically linked to changes in metabolic rate.


The radionuclide ejection fraction: a comparison of three radionuclide techniques with contrast angiography.

Left-ventricular ejection fraction (EF) can be measured by several radionuclide methods. The EFs determined by three such methods (first-transit time-activity, equilibrium blood-pool time-activity, and equilibrium blood-pool area-length) were compared in 30 patients with EFs measured by area-length analysis of x-ray contrast angiograms. Both time-activity methods (first-transit and blood-pool) yielded EFs that correlated well with x-ray contrast EFs (r=0.86 and 0.84, respectively). Area-length analysis of blood-pool images yielded EFs that agreed less well with x-ray contrast EFs (r=0.73 in the RAO view, 0.70 in the LAO view). We conclude that first-transit and blood-pool techniques are equally accurate methods for determining EF when the time-activity method of analysis is employed.


Thallium-201: non-invasive determination of the regional distribution of cardiac output.

Sapirstein (1) employed cationic radiopotassium to determine the fractional distribution of cardiac output to several organs. Thallium-201 can substitute for radiopotassium in myocardial imaging, and was evaluated in the present studies to determine the distribution of cardiac output in the anesthetized dog in comparison with tracer microspheres, both under control circumstances and following the infusion of norepinephrine in a dose sufficient to raise the blood pressure 20 mm Hg above control levels. The concentrations of thallium-201 and microspheres were similar in the heart, kidney, thyroid, and skeletal muscle in both control and norepinephrine-treated animals (r=0.93). Thallium concentration in the liver and lung exceeded that of microspheres, however, and probably is not related solely to the regional distribution of arterial perfusion. These data suggest that in the heart, kidney, thyroid, and skeletal muscle, thallium-201 distribution reflects the fractional distribution of cardiac output.


Accumulation of technetium-99m stannous pyrophosphate in contused myocardium.

The uptake of technetium-99m stannous pyrophosphate in contused myocardium was measured as a function of time from the insult. The free wall of the dog's left ventricle was surgically exposed and struck with a spring-loaded paddle. Pyrophosphate was injected intravenously from 1 1/2 to 47 1/2 hr after the injury. After 1/2 hr of incubation the hearts were removed and the Tc-99m content of contused and noncontused myocardium was measured. Pyrophosphate was concentrated in contused myocardium at all of the time periods tested. Contused-to-normal ratios for pyrophosphate uptake ranged from 8.1 (8 hr) to 41.9 (48 hr).


ECG-gated scintillation probe measurement of left ventricular function.

A nonimaging, ECG-gated scintillation-probe system is described that permits real-time quantification, at high temporal resolution, of the time variation of left ventricular (LV) volume over a complete, average cardiac cycle. Linearity between counting rate and volume, probe positioning, and background correction were investigated for both cylindrically collimated (CC) and parallel-hole-collimated (PC) detectors. In 53 patient studies, results obtained with these probes were compared with results obtained from an ECG-gated gamma camera system (CS) with high temporal resolution. Time-activity curves obtained by all three devices were essentially identical in shape (for CC against CS, r=0.93; for PC against CS, r=0.98) and in intracycle timing. Left-ventricular ejection fractions obtained with the probes showed workable agreement with the camera; for CC against CS, r=0.85 (N=31; for PC against CS, r=0.90 (N=21). When LV background is removed as a source of error, the correlation between (PC) probe and camera is improved (r=0.95, N=21). This suggests that the portable probe system be used in circumstances where exact knowledge of LV background is minimally important--e.g., continuous bedside monitoring of changes in LV function.


Facial bone scanning by emission tomography.

A single-photon emission tomographic system was used to study the normal anatomy of the facial bones and the usefulness of emission computed tomography in evaluating diseases of the bones of the face. The examination was performed following routine bone scintigraphy and took an additional 20-30 min. The anatomy of the facial bones was well defined, with clear separation of deep and superficial structures. Early experience with tumor, infection, bone grafts, and postirradiation osteonecrosis indicates that useful added diagnositc information can be obtained by this method.


Evaluation of Tc-99m pyridoxal-phenylalanine as a hepatobiliary imaging agent. Part 1. Experimental studies.

In this experimental study, the usefulness of a new radiotracer, Tc-99m pyridoxal-phenylalanine ("Tc-PPh"), is evaluated as a hepatobiliary imaging agent, and results are compared with those of conventional cholangiography. In the presence of a normal biliary tree or in cholelithiasis, information derived from conventional cholangiography is of better quality. The radiotracer technique, however, is very useful for the demonstration of cholopeptic bypass procedures, even in the presence of jaundice, and also in cases of intraperitoneal bile leakage.


Evaluation of Tc-99m pyridoxal-phenylalanine as a hepatobiliary agent. Part 2. Clinical tests.

Twenty-four patients with normal or diseased hepatobiliary systems were subjected to a clinical trial in order to evaluate Tc-99m pyridoxal-phenylalanine as a biliary imaging agent. The investigation was combined with i.v. cholecysto-cholangiography in most cases, and the results were compared. It is concluded that qualitative information derived from conventional i.v. cholangiography is better in demonstrating the normal biliary tree or gallstones. The radiotracer techniques, however, are valuable in dynamic studies of Oddi's sphincter, in showing patency of biliary by-pass procedures, and in differentiating hepatocellular from obstructive jaundice.


Marked thyroid uptake of thallium-201 in patients with goiter: case report.

Marked thyroid uptake of thallium-201 was observed in four patients with goiter, namely one case each of hyperthyroidism, primary hypothyroidism due to chronic thyroiditis, chronic thyroiditis in the mild hypothyroid state, and nontoxic nodular goiter.


Radioactivity in gastric juice-a simple adjunct to the Yb-169 DTPA cisternographic diagnosis of CSF rhinorrhea: concise communication.

A new method is offered as an adjunct to radionuclide cisternography and the measuring of radioactivity in nasal pledgets. The activity in gastric juice following the intrathecal injection of Yb-169-DTPA is measured and the ratio of gastric juice to blood is calculated. In patients suffering from CSF rhinorrhea the ratios significantly exceed the normal range. This method can be used to detect CSF leakage at the back of the nasopharynx, and in patients with head injuries too severe to permit the use of nasal pledgets.


Bone scan findings in hypervitaminosis D: case report.

Bone scans in three patients showed generalized symmetrical increased uptake of radiopharmaceutical by the skeleton and absent or faint kidney images. It is thought that these appearances may be attributable to excess vitamin D, but other possible contributing factors, including the presence of renal osteodystrophy, are discussed.


Torsion of the spleen with incomplete infarction: case report.

Torsion and infarction of a "wandering spleen" is a rare disease which is often confused with other acute abdominal crises. A correct preoperative diagnosis, when made, has usually been determined by arteriographic studies. A child is described in whom changes in the TcSC scan made a correct diagnosis possible by non-invasive methods.


Tumor location with 1-aminocyclopentane [11C] carboxylic acid: preliminary clinical trials with single-photon detection.

High specific activity [11C] Carboxyl-labeled 1-aminocyclopentane-carboxylic acid ([11C] ACPC) was tested as a tumor-scanning agent in thirty-eight patients. This artificial amino acid clears the blood to a level of less than 12% within 45 min; thus, imaging is possible within the useful life of C-11. [11C] ACPC can be produced in amounts adequate for clinical scanning. Doses between 12 and 45 mCi were given by i.v. injection, and scans obtained only in the single-photon mode gave clinical information on the sites of tumors. There was no evidence of any toxic effects from [11C] ACPC, and the radiation doses as extrapolated from animal data are approximately 0.01 rad per mCi for the whole body and less than 0.06 rad per mCi for the pancreas. In all but five of the 38 patients [11C] ACPC scans were compared with those obtained with Ga-67 citrate. There were 19 positive [11C] ACPC scans and 24 positive Ga-67 scans. The results indicate that [11C] ACPC is likely to be of diagnostic value for cancer patients if used in conjunction with positron tomography instrumentation.


Preparation of various Tc-99m dimercaptosuccinate complexes and their evaluation as radiotracers.

The organ distributions of four different Tc-99m dimercaptosuccinate complexes ("Tc-DMS", Complexes 1 to 4) were determined using mice and were evaluated as renal imaging agents. The highest kidney uptake was observed with Complex 2:21.7% of dose, 3 hr after injection. The biologic distributions and gel chromatographic analyses using carrier Tc-99 and Sn-113 indicate that there is little possibility of mixed metal complexes of the type Tc-Sn-DMS: rather they contain only Tc + DMS. The labeling procedure for Tc-99m DMS as a renal agent proceeds in two steps: a rapid formation of Complex 1, and a slower, rate-determining step from Complex 1 to Complex 2. A reproducible lyophilized kit has been prepared. The yield of complex 2 greatly depends on the reconstitution volume of 99mTcO4-; yield averages 89% using 2 ml of 99mTcO4-eluate.


Rapid miniaturized chromatographic quality-control procedures for Tc-99m radiopharmaceuticals.

Our laboratory has adopted a complete miniaturized charomatography system for Tc-99m radiopharmaceuticals in order to improve upon the commercial systems currently available. Three distinct, separate, chromatographic procedures are used to determine the labeling efficiencies of Tc-99m-labeled sulfur colloid, MAA, stannous chloride, phytate, DMSA, DTPA, pyrophosphate, diphosphonate, methylene diphosphonate, polyphosphate, and glucoheptonate. The chromatographic systems include Whatman 31 ET paper and acetone, Gelman ITLC-SG and 0.9% sodium chloride, and Gelman ITLC-SA and acetone. The chromatographic strips are miniaturized (1 X 6 cm), colored-coded, marked, and numbered. All the chromatographic quality-control procedures are simple, rapid, and can easily be incorporated into the routine quality-control program of any nuclear medicine facility.


Influenza in New Jersey in 1976: isolations of influenza A/New Jersey/76 virus at Fort Dix.

An outbreak of febrile respiratory disease at Fort Dix, New Jersey, beginning in January 1976, yielded five isolates of influenza A/New Jersey/76 virus and 42 isolates of strains resembling influenza A/Victoria/75 virus. Despite extraordinary efforts and the study of 305 verified cases of infection with type A influenza virus throughout the region, no additional instances of infections with influenza A/New Jersey virus were detected in humans.


Swine influenza A at Fort Dix, New Jersey (January-February 1976). I. Case finding and clinical study of cases.

After the isolation of A/New Jersey/76 (Hsw1N1) influenza virus from five soldiers at Fort Dix, New Jersey, case finding was initiated by obtaining specimens for viral isolation from 95 patients with acute respiratory disease and determining antibody to influenza A/Mayo Clinic/103/74 (Hsw1N1) antigen in paired sera from 74 soldiers who had been hospitalized with acute respiratory disease. Influenza A/New Jersey virus was not isolated, but serologic studies identified eight additional soldiers as A/New Jersey influenza patients. Development of heterotypic antibody to A/Mayo Clinic antigen following infection and/or immunization with influenza A (H3N2) strains was studied and was found to occur infrequently. One of the 13 identified patients had died, and postmortem findings were consistent with viral pneumonia. Four of the 12 surviving patients had radiologic evidence of pneumonia, but clinical syndromes in all 12 were similar to those described for other influenza A infections.


Swine influenza A at Fort Dix, New Jersey (January-February 1976). II. Transmission and morbidity in units with cases.

Epidemiologic study of 13 influenza A/New Jersey/76 (Hsw1N1) patients indicated that person-to-person transmission had occurred in several distinct military units. Soldiers in eight of these units (companies) were studied to determine whether they had experienced influenza A/New Jersey infections and associated acute respiratory disease. Titers of hemagglutination-inhibiting antibody to influenza A/Mayo Clinic/103/74 (Hsw1n1) antigen were determined. In seven of these eight companies, individuals with titers of greater than or equal to 1:20 were found. In these seven companies, members of platoons with cases (contact platoons) had antibody prevalences of 7%-56%, and members of platoons without cases had prevalences of 0-40%. Hospital admissions for acute respiratory disease were proportionately greater in trainees with A/Mayo Clinic antibody titers of greater than or equal to 1:20 than in trainees without antibody in five of six contact platoons studied.


Swine influenza A at Fort Dix, New Jersey (January-February 1976). III. Extent of spread and duration of the outbreak.

The extent and duration of transmission of influenza A/New Jersey/76 virus at Fort Dix, New Jersey, was examined with use of titers of hemagglutination-inhibiting antibody to influenza A/Mayo Clinic/74 (HswN1) antigen as an index of infection. Five hundred ninety-three soldiers (a 9.3% sample) in basic combat training (BCT) were grouped in weekly cohorts by the date on which BCT was started. Cohorts with 11 of the 12 BCT cases of A/swine influenza began training on January 12, 19, and 26, 1976, respectively; 9%-19% of the trainees in these cohorts had titers of antibody to A/Mayo Clinic antigen of greater than or equal to 1:20. In five other cohorts without cases, which began training before January 12 or after January 26, 0-5% of trainees had titers of greater than or equal to 1:20. Titers observed in persons from military units not in BCT and in the civilian population of the post were not consistent with widespread transmission of the virus. Transmission of influenza A/New Jersey virus at Fort Dix probably occurred between mid-January and mid-February with little involvement of people outside of BCT units.


Identification and preliminary antigenic analysis of swine influenza-like viruses isolated during an influenza outbreak at Fort Dix, New Jersey.

The sequence of events and the laboratory procedures that resulted in the identification of swine influenza-like viruses isolated during an influenza outbreak at Fort Dix, New Jersey in January and February of 1976 are described. Preliminary antigenic analysis suggested that the isolates from Fort Dix are closely related to a 1975 isolate of swine influenza virus and distinguishable from earlier swine influenza strains.


Correlation of laboratory studies with clinical responses to A/New Jersey influenza vaccines.

The large, uniformly performed clinical investigations with influenza A/New Jersey vaccines provided an opportunity to correlate results of laboratory tests of vaccine with human reactivity and antibody responses. These vaccines were given to large numbers of subjects under code, and significant differences in immunogenicity and reactivity were observed in unprimed individuals. A single, relatively large dose of intact virus was more immunogenic and reactive than split-virus vaccines in unprimed subjects. Differences in immunogenicity and reactivity in unprimed subjects correlated with the amount of intact virus in the vaccines (measured by column chromatography or electron microscopy) and with the amount of viral hemagglutinin in the vaccine (measured by immunodiffusion), but not with the number of chick cell-agglutinating units.


Evaluation and control of vaccines for the National Influenza Immunization Program.

The National Influenza Immunization Program of 1976 offered an ideal opportunity to test the capability of the system in the United States for production and distribution of maximal amounts of inactivated influenza virus vaccine of carefully regulated quality. The four licensed manufacturers were able to produce and distribute greater than 10 million doses of vaccine per week over a 14-week period. Assays showed that the quality of these vaccines was comparable to or exceeded that of vaccines produced in recent years under less stressful circumstances. Because of the extensive clinical trials conducted as part of the program, it was possible to make an unprecedented evaluation of the significance of various laboratory tests of vaccines in relation to their pertinence in prediction of immunogenicity and reactivity for humans. This experience demonstrated the superiority of immunodiffusion methods as compared with the standard chick cell-agglutination method for assay of vaccine potency. Qualitative differences in immunogenicity between whole-virus and disrupted-virus vaccines were recognized that are not measured by in vitro potency tests. The results also indicated that influenza viral components are responsible for most febrile reactions to the vaccine.


Neuraminidase content of influenza vaccines and neuraminidase antibody responses after vaccination of immunologically primed and unprimed populations.

Vaccines prepared with influenza A/swine/1976/37-like virus contained neuraminidase activity comparable to that of H3N2 vaccines, whereas little neuraminidase activity could be detected in influenza A/New Jersey/76 vaccines. In single-dose vaccine studies, A/swine/1976/37-like split-virus vaccine induced antibody to neuraminidase (NAAb) in about 20% of children younger than 18 years and this NAAb response was better than or equal to the antibody response to the vaccine's hemagglutinin (HAAb). In immunologically primed adults, the NAAb response to a single dose of Hsw1N1 or H3N2 vaccine was 38%-54%, but this value was about 1.7-fold lower than that for HAAb response. Children six to 17 years old given two doses of A/swine/1976/37-like vaccine had an overall 70% NAAb response, whereas children of similar age had an overall 30%-48% NAAb response to two doses of A/Victoria/3/75 (H3N2) virus. The findings support a hypothesis that the NAAb response to influenza vaccines can be suppressed if subjects receiving the vaccine are immunologically primed to its hemagglutinin component. NAAb responses in the absence of HAAb responses occur in only about 5% of vaccinated persons who are immunologically primed to both the hemagllutinin and neuraminidase of the vaccine.


Antibody response of young adults to experimental influenza A/New Jersey/76 virus vaccines.

In military personnel aged 17-25 years, only one of four experimental influenza A/New Jersey/76 virus vaccines produced a satisfactory hemagglutination-inhibiting (HAI) antibody response when a dose of 200 chick cell-agglutinating (CCA) units was used. A second injection of 400 CCA units of vaccine caused seroconversion in all persons. Although an early comparison of experimental split-product and whole-virus vaccines suggested that the former were relatively ineffective, a later comparison with different lots of the vaccines showed no difference between vaccines of these two types. The influenza A/NJ/76 virus vaccine evoked a high HAI antibody response to influenza A/PR/8/34 (H0N1) virus but not to H1N1 or H3N2 strains.


The immunizing effect of influenza A/New Jersey/76 (Hsw1N1) virus vaccine administered intradermally and intramuscularly to adults.

2The immunogenicity and reactogenicity of inactivated influenza A/New Jersey/76 (Hsw1N1) whole-virus vaccine administered intradermally (40 chick cell-agglutinating units/0.1-ml dose) and intramuscularly (im; 200 chick cell-agglutinating units/0.5-ml dose) to human adults were evaluated. Among 18-24-year-old persons initially free of detectable antibody, intradermal vaccination induced lower titers of hemagglutination-inhibiting antibodies than did im vaccination, and a sequence of intradermal and im vaccinations did not offer any serologic advantage over one im dose. In contrast, persons over the age of 24 who initially lacked detectable antibody had as good a serologic response to intradermal vaccination as to im vaccination. Among individuals who had antibody before vaccination, immunization by either route induced greater increases in titers of hemagglutination-inhibiting antibody than occurred in initially antibody-negative persons, even when the latter were given two doses of vaccine. Somewhat fewer systemic reactions occurred after intradermal than after im vaccination, but the intradermal route was associated with local reactions in almost all vaccinees and with some residual pigmentary changes. These results suggest that intradermal vaccination should be used only in very selected circumstances.


Comparison of the hemagglutination-inhibiting and neutralizing antibody responses of volunteers given 400 chick cell-agglutinating units of influenza A/New Jersey/76 split-virus vaccine.

Thirty-two volunteers 25 years of age or older who were employees of the Laboratory of Infectious Diseases (National Institute of Allergy and Infectious Diseases, Bethesda, Md.) were given 400 chick cell-agglutinating units of influenza A/New Jersey/76 virus vaccine (Wyeth Laboratories, Philadelphia, Pa.) intramuscularly. Sera were assayed for hemagglutination-inhibiting (HAI) and neutralizing antibody before and after inoculation. All 32 subjects had a fourfold rise in titer of HAI antibody, and 25 of 32 had a similar rise in titer of neutralizing antibody. The average log2 rise was 4.5 for HAI antibody and 4.1 for neutralizing antibody. Therefore, this vaccine is believed to be capable of stimulating HAI and neutralizing antibodies to an equal extent.


Acceptibility and antigenicity of influenza A/Victoria/75 virus vaccines in adults of different ages.

Influenza A/Victoria/75 virus vaccines were tested for acceptability and antigenicity in adults of different ages. Whole-virus vaccines prepared by Merck Sharp and Dohme (West Point, Pa.) and Merrell-National Laboratories (Cincinnati, Ohio) and subunit vaccines prepared by Parke, Davis and Company (Detroit, Mich.) and Wyeth Laboratories (Philadelphia, Pa.) were given intramuscularly in concentrations of 800, 400, or 200 chick cell-agglutinating units per dose. Systemic and local side effects of all vaccine preparations were negligible. In volunteers with low or absent (less than or equal to 10) titers of hemagglutination-inhibiting antibody before vaccination, titers of greater than or equal to 40 were attained after vaccination in 43%-67%, 40%-58%, and 20%-38% of volunteers receiving the 800, 400, and 200 chick cell-agglutinating unit preparations, respectively.


Serologic responses after two sequential doses of influenza A/New Jersey/76 virus vaccine in normal young adults.

The serologic responses after two sequential nonreactive doses of either chemically disrupted or whole-virus influenza A/New Jersey/76 virus vaccine were evaluated in 112 normal young adults. In general, levels of hemagglutination-inhibiting (HAI) antibody were low after the first dose of vaccine and increased significantly (P less than 0.05) in response to a second dose. Whereas one dose of the preparation from Merck Sharp and Dohme (West Point, Pa.) effectively vaccinated this population, two doses of the vaccines prepared by Parke, Davis and Company (Detroit, Mich.) and Merrell-National Laboratories (Cincinnati, Ohio) were required to produce a similar serologic response. The preparation from Wyeth Laboratories (Philadelphia, Pa.) produced low levels of HAI antibodies even after two doses. These different serologic responses correlated with the viral hemagglutinin content of each vaccine.


Sequential immunization of laboratory personnel with influenza A/New Jersey/76 split- and whole-virus vaccines.

One hundred thirty-three healthy, at-risk Fort Detrick laboratory workers were inoculated with 400 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 split-virus vaccine (Wyeth Laboratories, Philadelphia, Pa.). Systemic and local reactions were infrequent, mild, and comparable to those of a sham-vaccinated group of volunteers. Only 28% of subjects 19-24 years old developed titers of hemagglutination-inhibiting (HAI) antibody of greater than or equal to 1:20, whereas titers of 91%-100% of subjects 25-62 years old reached this level. Thirty-one vaccinated subjects with no or low titers of antibody were given a booster dose (400 CCA units) of Wyeth vaccine six weeks after the first inoculation. Only 58%-67% of these vaccinees achieved HAI titers of greater than or equal to 1:20 after the booster. Fourteen persons required a second booster dose for protection; after vaccination with 400 CCA units of whole-virus vaccine from Merck Sharp and Dohme (West Point, Pa.), 89%-100% of the 14 vaccinees finally achieved HAI titers of greater than or equal to 1:20. The split-virus vaccine was safe, but it was poorly antigenic as a primary vaccine in persons 19-24 years old and as a booster in persons of all ages who have poor antibody responses in general.


Ether-treated, subunit Hsw1N1 influenza vaccines: response of immunologically primed subjects to two antigenic variants.

Two bivalent, ether-treated, subunit influenza vaccines were compared in adults greater than or equal to 45 years old. Both vaccines contained 200 chick cell-agglutinating (CCA) units of A/Victoria/3/75 antigen/dose. The Hsw1N1 components, also at a level of 200 CCA units/dose and designated A/Shope and A/X-53, were antigenically representative of the A/swine/1976/31 and A/New Jersey/8/76 viruses, respectively. A/Shope virus possessed about 100 times more neuraminidase activity than A/X-53 virus. The two vaccine groups had equivalent geometric mean titers (GMTs) of antibody to A/NJ virus, with about 95% of each group having titers of greater than or equal to 1:40 after vaccination. Group GMTs of antibody to A/Vic virus were also equivalent. Failure of the A/X-53 vaccinees to respond according to the dogma of original antigenic sin and a highly significant between-group difference in response to A/PR/8/34 antigen are interpreted as due to a difference in vaccine neuraminidase levels. It is suggested that, although A/Shope was as serologically effective against A/NJ virus as A/X-53 in this age group, under similar conditions a recombinant with the A/NJ hemagglutinin and the stable A/swine neuraminidase antigens might be more effective against A/NJ than either of the present vaccines.


Single-dose trials of monovalent A/New Jersey/76 (Hsw1N1) influenza virus vaccine in children in Durham, North Carolina.

Ninety-two children received single doses of one of 13 monovalent vaccines derived from influenza virus strain A/New Jersey/8/76 (A/NJ), and 18 children received placebo. Five influenza virus vaccines were whole-virus vaccines, and eight were split-product vaccines. Samples of sera were taken once three weeks after vaccination. All of the 29 children receiving whole-virus vaccines developed a titer of antibody to A/NJ virus of greater than or equal to 1:20, and the geometric mean titers were 1:14-1:45. One of the 60 children who received split-product vaccines developed a titer of antibody to A/NJ of greater than or equal to 1:20, and geometric mean titers were all less than 1:10. There was a trend toward correlation between titers of hemagglutination-inhibiting (HAI) antibody to A/NJ and titers of HAI antibody to A/Victoria/3/75 viruses, with a correlation coefficient of 0.40 for children who received whole-virus vaccines. Three of 60 recipients of split-product vaccines and two of 20 recipients of whole virus developed a fever of greater than or equal to 38 C. One of the two febrile children who had received whole-virus vaccine had otitis media. Therefore, reactogenicity of whole-virus vaccines and split-product vaccines appeared to be similar in these children.