Linkage of PGK1 to X-linked severe combined immunodeficiency (IMD4) allows predictive testing in families with no surviving male

Summary We present a linkage map of DNA probes around the X-linked severe combined immunodeficiency (IMD4) locus at Xq11-13. DXS159 and PGK1 show no cross-overs with the disease locus (Lod 3.01 at = 0.00). The order of loci is DXS1-DXS106-(DXS159-PGK1-IMD4)-DXS72-DXYS1. Members of families whose carrier status has been established by X-inactivation patterns were included in the analysis. As the probe (pSPT/PGK), which is used for investigation of X-inactivation patterns, has been shown to be linked to the disease itself, it is possible to assign phase in mothers of sporadic cases who have been shown to be carriers, even when they have no surviving male offspring.     

Linkage analysis of seven kindreds with the X-linked lymphoproliferative syndrome (XLP) confirms that the XLP locus is near DXS42 and DXS37

Summary Analysis of seven kindreds indicates that the XLP locus exhibits 1% recombination with DXS42 (lod = 17.5) and no recombination with DXS37 (lod = 13.3).     

Antigenic specificity of antibody-dependent cell-mediated cytotoxicity directed against human immunodeficiency virus in antibody-positive sera.

Antibody-dependent cell-mediated cytotoxicity (ADCC) specific for human immunodeficiency virus (HIV) has been described for HIV-infected individuals. To determine the antigenic specificity of this immune response and to define its relationship to the disease state, an ADCC assay was developed using Epstein-Barr virus-transformed lymphoblastoid cell line targets infected with vaccinia virus vectors expressing HIV proteins. The vaccinia virus vectors induced appropriate HIV proteins (envelope glycoproteins gp160, gp120, and gp41 or gag proteins p55, p40, p24, and p17) in infected lymphoblastoid cell lines as demonstrated by radioimmunoprecipitation and syncytia formation with c8166 cells. Killer cell-mediated, HIV-specific ADCC was found in sera from HIV-seropositive but not HIV-seronegative hemophiliacs. This HIV-specific response was directed against envelope glycoprotein but was completely absent against target cells expressing the HIV gag proteins. The ADCC directed against gp160 was present at serum dilutions up to 1/316,000. There was no correlation between serum ADCC titer and the stage of HIV-related illness as determined by T-helper-cell numbers. These experiments clearly implicated gp160 as the target antigen of HIV-specific ADCC activity following natural infection. Vaccines which stimulate antibodies directed against gp160, which are capable of mediating ADCC against infected cells, could be important for protection against infection by cell-associated virus.     

Effect of sampling on variability and plateau in oxygen uptake

To evaluate the effect of the gas exchange sampling interval on variability and plateau in O2 uptake (VO2), 10 subjects underwent steady-state treadmill exercise at 50% maximal VO2 and 6 subjects underwent maximal testing using a ramp protocol. During steady-state exercise, gas exchange data were acquired by using 10 different sampling intervals. The variability in VO2 was greater as the sampling interval shortened (SD = 4.5 ml.kg-1.min-1 for breath-by-breath vs. 0.8 ml.kg-1.min-1 for 60-s samples). The breath-by-breath data suggested a Gaussian distribution, and most of the variability was attributable to tidal volume (51%). During ramp testing, the slope of the change in VO2 (for each sample) was regressed with time. Considerable variability in the slopes was observed throughout exercise, and in each subject the slopes varied about zero, demonstrating both positive and negative values throughout submaximal effort. These observations were made despite the use of large sampling intervals. Shortening the sample resulted in even greater variability. We conclude that 1) the sampling interval can have a major impact on gas exchange data during exercise and 2) considerable variability exists in the slope of the change in VO2 with a consistent change in external work regardless of the sample used, suggesting that a plateau (defined as the slope of a VO2 sample at peak exercise that does not differ significantly from a slope of zero) in VO2 is not a reliable physiological marker for maximal effort.     

Compensation of respiratory alkalosis induced after acclimation to simulated altitude

Conscious intact rats previously acclimated for 3 wk to barometric pressure of 370-380 Torr (3WHx) were made alkalotic for 3 h by a decrease in inspired O2 fraction from 0.10 to 0.075 at ambient barometric pressure (730-740 Torr). Controls were normoxic littermates (Nx) in which inspired O2 fraction was lowered from approximately 0.21 to 0.10 for 3 h. Arterial PCO2 decreased progressively and similarly in both groups (65-70% of control at 15 min). Initially, arterial pH increased less in 3WHx (0.09 +/- 0.004 vs. 0.15 +/- 0.008). As hypocapnia continued, delta[HCO3-]/delta pH (mmol.l-1.pH) became more negative in Nx, from -15.2 +/- 2.5 at 15 min to -37.0 +/- 2.9 at 3 h, indicating nonrespiratory compensation of alkalosis. In 3WHx, delta[HCO3-]/delta pH did not change during alkalosis. Cumulative renal excretion of base (mueq/100 g) during alkalosis increased by 73.2 +/- 11.1 in Nx and 25.4 +/- 7.3 in 3WHx. This difference was mainly due to a larger increase in HCO3- excretion in Nx. The data suggest that the smaller compensation of hypocapnic alkalosis in 3WHx is partly due to the smaller increase in renal base excretion. Because base availability limits renal base excretion, the smaller renal response of 3WHx may be secondary to the low plasma HCO3- concentration that accompanies altitude acclimation.     

Twin studies demonstrate a host cell genetic effect on productive human immunodeficiency virus infection of human monocytes and macrophages in vitro.

Biological and genetic variability is a prominent feature of human immunodeficiency virus (HIV) strains, especially in tropism, syncytium formation, and replicative capacity. To determine whether there were variable host cell effects on HIV replication in monocytes, three different strains of low-passage-number monocytotropic blood isolates of HIV and the laboratory-adapted strain Ba-L were inoculated into panels of adherent monocytes drawn from 44 different donors, and peak extracellular HIV p24 antigen titers were compared. The clinical HIV strains showed patterns of either moderate or low-level replication in most donor monocytes (20 to 4,000 pg/ml). However, within this range there was marked variation in peak titers in most donors. HIV type 1 Ba-L replicated in all donor monocytes to much higher levels with less variability (30 to 40 ng/ml). Furthermore, replication of 21 clinical blood-derived strains of HIV in blood monocytes and monocyte-derived macrophages (MDM) from pairs of identical twins and age-matched unrelated donors (URD) of the same sex were compared. In all of the seven pairs of identical twins, the kinetics of replication (measured by extracellular HIV p24 antigen) of panels of four clinical HIV type 1 isolates in monocytes were similar within pairs. However, marked and significant differences in kinetics of HIV production occurred within 10 of the 12 unrelated donor pairs (P = 0.0007). The remaining two URD pairs showed similar kinetic patterns, but only one pair had the same HLA-DR genotype. Similar results were observed with monocytes/MDMs obtained from a second bleed of the same donor. Hence, discordant patterns of HIV replication kinetics between URD monocyte pairs contrasted with concordant patterns in identical twin monocytes. These data strongly suggest a host cell genetic effect on productive viral replication in monocytes and MDMs. So far, no consistent genetic linkage of HIV replication pattern with HLA-DR genotype has been observed.     

Perinatal Steroid Treatments Alter Alloparental and Affiliative Behavior in Prairie Voles

This experiment was designed to examine the hypothesis that perinatal manipulation of gonadal or adrenal steroids can alter the subsequent expression of juvenile parental (alloparenting) and affiliative behavior in prairie voles (Microtus ochrogaster). Corticosterone (PRECORT), testosterone (PRE-TP), or oil injections (PRESES) were given on Prenatal Days 12–20 or on Postnatal Days 1–6 (CORT6, TP6, or SES6, respectively). Alloparenting was reduced significantly in females in the CORT6 group and in males in the TP6 group. Sibling affiliative preferences were increased significantly in PRE-TP females and stranger preferences were increased in TP6 and CORT6 females. The results suggest timing is a critical factor determining whether hormones have a facilitative or inhibitory effect on alloparental and affiliative behavior in prairie voles. In this species, corticosterone and testosterone have similar organizational effects on affiliative behavior in females. Alloparental behavior is inhibited by postnatal corticosterone administration in females and by postnatal testosterone administration in males, whereas prenatal steroid administration had no significant effect on alloparenting in either gender.     

EagI andNotI linking clones from human chromosomes 11 and Xp

EagI and NotI linking libraries were prepared in the lambda vector, EMBL5, from the mouse-human somatic cell hybrid 1W1LA4.9, which contains human chromosomes 11 and Xp as the only human component. Individual clones containing human DNA were isolated by their ability to hybridise with total human DNA and digested with SalI and EcoRI to identify the human insert size and single-copy fragments. The mean (± SD) insert sizes of the EagI and NotI clones were 18.3 ± 3.2 kb and 16.6 ± 3.6 kb, respectively. Regional localisation of 66 clones (52 EagI, 14 NotI) was achieved using a panel of 20 somatic cell hybrids that contained different overlapping deletions of chromosomes 11 or Xp. Thirty-nine clones (36 EagI, 3 NotI) were localised to chromosome 11; 17 of these were clustered in 11q13 and another nine were clustered in 11q14–q23.1. Twenty-seven clones (16 EagI, 11 NotI) were localised to Xp and 10 of these were clustered in Xp11. The 66 clones were assessed for seven different microsatellite repetitive sequences; restriction fragment length polymorphisms for five clones from 11q13 were also identified. These EagI and NotI clones, which supplement those previously mapped to chromosome 11 and Xp, should facilitate the generation of more detailed maps and the identification of genes that are associated with CpG-rich islands. Received: 27 December 1995 / Revised: 30 January 1996