Ventricular septal defect with bidirectional shunting: Mathematical considerations

Previously proposed formulae for the quantitative estimation of bidirectional shunts across ventricular septal defects require determination of the oxygen contents of mixed venous, pulmonary artery, pulmonary venous, and aortic blood. Because these formulae do not take into account the mixing of oxygenated with unoxygenated blood within the ventricles, their use must result in underestimation of shunt flows in each direction. A mathematical model for a ventricular defect is examined, in which it is assumed that mixing of blood occurs in each of six sites in the venae cavae or right atrium, right ventricle, pulmonary artery, left atrium, left ventricle, and aorta. A total of fourteen streams of blood can flow from one to another of these mixing sites. As long as complete mixing occurs in the six specified mixing sites, any degree of mixing or non-mixing of the various streams is permitted. From the equations characterizing the model, formulae are derived in which the shunt flow in each direction is expressed in terms of the oxygen contents in the six mixing sites and the fractions of blood which enter the shunt from either side without prior mixing in a ventricular mixing site. The previously reported formulae, which apply when no ventricular mixing is allowed to occur, lead to theoretical minimum values for the shunt flows in each direction. At the opposite extreme where all the shunting blood is required to mix in a ventricle before entering the shunt, formulae for maximum possible shunt flows are also obtained. The absolute values for the left-to-right and right-to-left shunt flows, which must lie somewhere between the theoretical maximum and minimum values, cannot be computed from blood gas data alone. This work was supported in part by grant HE-07563 from the National Heart Institute of the National Institutes of Health and grants-in-aid from the American and North Carolina Heart Associations and the Life Insurance Medical Research Fund. Work completed during tenure as U.S.P.H.S. post-doctoral fellow.     

The Plasma Phenolsulfonphthalein Index (PSPI) of Renal Function: I. Theoretical Considerations and Investigative Studies

A simple method is described for the assessment of renal function, without collection of urine. Phenolsulfonphthalein (PSP) is injected intravenously in a dosage of 1 mg./kg. body weight, and blood samples are taken at timed intervals. Only one venepuncture is required. The index is based on the rate of decrease in concentration of PSP in the plasma 15 to 35 minutes after injection, during which time this rate is exponential. The methodology and normal range, and the influence of dose, urine flow rate, age and body surface are defined. The extrarenal component of the PSP index and the distribution of PSP in body fluids are discussed.     

Induction of murine lymphokine-activated killer cells by recombinant IL-7

The data demonstrate that IL-7, a cytokine that was originally identified, purified, and cloned based upon its ability to support the growth of pre-B cells in vitro, also induces proliferation and promotes the generation of lymphokine-activated killer (LAK) cell activity in populations of resting peripheral lymphoid cells. Although the kinetics of LAK induction by IL-7 (which peaked at days 6 to 8 of culture) was slower than that detected in cultures containing IL-2 (which peaked at day 4), IL-7 was significantly more effective at maintaining cytotoxic activity over longer periods of time, and greater viable cell recoveries, than was IL-2. A wide range of murine tumor target cells were found to be lysed in an MHC-unrestricted fashion by IL-7 induced LAK, but syngeneic Con A-induced lymphoblasts were not; nor were target cells from the human tumors K562 or Daudi lysed by IL-7 LAK. IL-7 LAK were induced in populations of lymphoid cells obtained from secondary lymphoid tissues (peripheral lymph nodes and spleen), but not from primary lymphoid tissues (thymus and bone marrow). LAK induced by IL-7 from unfractionated populations of lymphoid cells were completely eliminated by treatment with anti-CD8 or anti-Thy-1+C, and unaffected by treatment with anti-CD4, anti-asialo GM1 or anti-NK1.1+C. Interestingly, although no detectable CD4+ effector cells could be detected in populations of LAK generated from unfractionated populations of lymphoid cells stimulated by IL-7, they were found to be generated from populations of lymphoid cells from which CD8+ cells had been eliminated before being cultured in medium containing IL-7. These data suggest that CD4+ T cells do not normally give rise to IL-7-induced LAK unless they are first separated from CD8+ T cells. LAK induced by IL-7 appear to be distinct from LAK activity induced by IL-2 in that there is no detectable involvement of NK-like effector cells at either the precursor or effector cell stages.     

Temporal expression of different pathways of 1-arginine metabolism in healing wounds

Arginine can be metabolized by inflammatory cells through at least two pathways. One is an oxidative l-arginine deiminase (OAD) that results in the formation of citrulline and reactive nitrogen intermediates. The other is arginase, which determines the production of ornithine and urea. The temporal expression of these pathways in an experimental wound model (s.c. implanted polyvinyl alcohol sponges in the rat) was investigated by examining the concentrations of amino acids and of nitrite in fluids obtained from the sponges 6 h to 15 day after implantation. These analyses revealed two distinct periods during which the arginine concentration in the fluids was markedly below plasma levels. During the early period (less than 3 days after sponge implantation) wound fluid contained more citrulline and nitrite than at any other time, suggesting OAD activity. In contrast, ornithine accumulated in the fluids during the late decrease in arginine concentration that extended beyond day 3, during which time the wound fluid also contained a high arginase activity. This time-dependent expression of different pathways of arginine metabolism in wounds was confirmed in sponge cultures containing [guanido-14C]-l-arginine. Cells contained in sponges harvested less than 48 h after implantation metabolized labeled arginine mainly to labeled citrulline, whereas labeled urea was produced during culture of sponges harvested after this time. The low arginine content of wound fluid did not appear to be rate limiting for the expression of OAD in late sponges because no OAD activity was evidenced when 4 mM arginine was added to the cultures. These results indicate that the OAD pathway is expressed in this model predominantly during the early, polymorphonuclear leukocyte-predominant, phase of repair. At this time, the reactive nitrogen intermediates resulting from the metabolism of arginine may mediate some of the events characteristic of early inflammation, including microbiostasis, vasodilation, and inhibition/reversal of platelet aggregation. In turn, the late suppression of this pathway and the catabolism of arginine through arginase may promote macrophage function within wounds.     

Ectonucleotidase Activities Associated with the Olfactory Organ of the Spiny Lobster

The olfactory system of the Florida spiny lobster, Panulirus argus, has olfactory receptors that are excited by the purine nucleotides AMP, ADP, and ATP. These receptors reside on chemosensory neurons that are contained within aesthetasc sensilla on the lateral filaments of the antennules. Also associated with the lobster's olfactory system are ectonucleotidase activities that dephosphorylate excitatory nucleotides, resulting in the production of the nonstimulatory nucleoside adenosine. Our studies of the 5'-ectonucleotidase, ecto-ADPase, and ecto-ATPase activities of this olfactory system showed that each activity was characterized by Michaelis-Menten kinetics; Michaelis constants ranged from 6.9 to 33.5 microM, and maximum velocities ranged from 2.5 to 28.8 fmol/sensillum/s. Evidence that AMP dephosphorylation may serve as an inactivation process was shown by the close correlation between the kinetics of 5'-ectonucleotidase activity and the periodicity of olfactory sampling. Decreased magnesium ion concentration or increased calcium ion concentration resulted in increased ecto-ATPase activity; this activity was insensitive to vanadate ion. Ectonucleotidase activities may have multiple effects on the detection of exogenous nucleotides by a chemosensory system. These effects can be either direct, such as the conversion of an odorant to an inactive compound, or indirect, such as the conversion of an odorant to another compound that can activate or inhibit either receptors or enzymes associated with the system.     

Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus.

Adenomatous polyps are an intermediate in the pathway to colon carcinoma. An inherited disorder, familial adenomatous polyposis coli (APC), is characterized by hundreds to thousands of adenomatous polyps. A previously reported family had colon cancer associated with a low average but highly heterogenous number of colonic polyps, this phenotype mapped to the APC locus on 5q. Four new families have been ascertained in which the phenotypic pattern was different from classical polyposis but similar to that of the "prototype" kindred reported earlier. By multilocus linkage analysis, the gene responsible for the disease phenotype was mapped, with a high level of confidence, to the APC locus in two of the four families with the attenuated or variant form of polyposis (AAPC); the results for the two remaining kindreds were inconclusive. A combined maximum LOD score of approximately 7.6 at a recombination fraction of 0 was obtained when the results were summed over the four pedigrees with markers closest to the APC locus. The establishment of genetic linkage in such families may point to the APC locus as having a more significant role in inherited predispositions to colorectal cancer than was previously thought.