Renal length in sickle cell disease: observations from a cohort study

Renal length has been measured by ultrasound in 237 subjects with homozygous sickle cell (SS) disease, 147 with sickle cell-hemoglobin C (SC) disease, and in 78 age-matched controls with a normal hemoglobin (AA) genotype. As expected, renal length increased with age in all genotypes but mean length was significantly greater in SS disease compared with SC disease (mean difference 4.3 mm after adjustment for height) and significantly greater in both genotypes than in AA controls (SS/AA difference 9.2 mm, SC/AA difference 5.0 mm after adjustment for height). Examination of relationships between renal length and some hematological indices (hemoglobin, fetal hemoglobin, reticulocyte counts, alpha thalassemia status) in SS or SC disease showed only a significant negative correlation with hemoglobin and positive correlation with reticulocyte count in SS disease. Further analysis suggested that the stronger relationship was between renal length and high reticulocyte count. The mechanism of renal enlargement is unknown although glomerular hypertrophy and increased renal blood volume are likely contributors.     

LP-BM5 virus causes changes in lactic dehydrogenase and oxygen radical production in splenocytes of C57BL/6J mice

The LP-BM5 murine leukemia virus causes acquired immunodeficiency syndrome in C57BL/6J mice (MAIDS), similar to that of AIDS in humans. The objective of this study was to determine the effect of LP-BM5 viral infection on cellular activation and membrane integrity of splenocytes. Oxidative burst in splenocytes in response to exposure to PMA (20 microg/ml) was significantly higher (p<.02) in infected than in control mice at two weeks post-infection using luminol-enhanced chemiluminescence. By 13 weeks post-infection superoxide anion production in infected mice was significantly lower when compared to controls coinciding with decreased proliferative response to mitogens. The extent of cell membrane damage as indicated by lactic dehydrogenase (LDH) activity in serum was significantly higher in infected than in control mice (p<.001). The results from this study suggests that LP-BM5 virus causes an initial stimulation of cellular activity followed by a decreased cell activation characterized by decreased proliferation of splenocytes and decreased oxygen radical production. Decreased cell membrane integrity indicated by increased LDH activity may partly be responsible for these changes.     

A PMLRARalpha transgene initiates murine acute promyelocytic leukemia

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.     

Terlipressin (glypressin) versus somatostatin in the treatment of bleeding esophageal varices--final report of a placebo-controlled, double-blind study

One hundred and six episodes of bleeding from esophageal or gastric varices in 72 patients with cirrhosis of the liver were randomized to treatment either with intravenous terlipressin 2 mg initially and 1 mg every four hours for 24 hours together with bolus injection and continuous infusion of placebo, or with somatostatin 250 micrograms as a bolus and continuous infusion of 250 micrograms/h somatostatin for 24 hours and placebo injections. Standard treatment with transfusions, fluid and electrolyte correction, and lactulose was administered in both groups. In the terlipressin group, 48 out of 53 bleeding episodes (91%) and in the somatostatin group 43 out of 53 bleeds (81%) were initially stopped by the vasoactive drugs. Four of the five bleeds not arrested by terlipressin, and nine of the ten bleeds not arrested by somatostatin, were stopped by balloon tamponade. In one patient in each group variceal bleeding could not be stopped initially, and both patients died. The failure rate of the vasoactive treatment alone, including rebleeds within the study period, was 17% in the terlipressin, and 28% in the somatostatin, group. The initial hemostasis, including balloon tamponade, were 98%, and the definitive bleeding control rates were 89% in both groups. The hospital mortality rate was 21% (11/53) in the terlipressin, and 21% (11/53) in the somatostatin, group. Blood transfusions and duration of bleeding did not differ significantly. The study indicates that a large proportion of bleeds from esophageal and fundic varices can be stopped initially (86%) and definitively controlled (77%) by vasoactive drugs alone.     

Application of HUMF13A01 (AAAG)n STR polymorphism to the genetic diagnosis of coagulation factor XIII deficiency

Deficiency of the A subunit of coagulation factor XIII causes a severe bleeding disorder requiring life long replacement therapy. The mutations causing A subunit deficiency appear to be very heterogeneous, and it is impractical to identify each mutation before genetic counselling or prenatal diagnosis can be attempted. In this study we have shown that a highly polymorphic short tandem repeat element, HUMF13A01 (AAAG)n that occurs in the 5' flanking sequence of the factor XIII A subunit gene, can be used to follow the segregation of deficiency causing mutations. We studied 6 families with factor XIII A subunit deficiency from 5 different ethnic groups. All parents were heterozygous for the repetitive element and therefore all the families were informative. The linked polymorphism was used to carry out the first prenatal diagnosis of factor XIII A subunit deficiency. The analysis of this polymorphism by the polymerase chain reaction is rapid, reliable, requires little DNA and is ideal for the genetic analysis of factor XIII A subunit deficiency.     

Heuristic lipophilicity potential for computer-aided rational drug design

In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable, results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. The HMLP is a three-dimensional and easily visualizable representation of molecular lipophilicity, suggested as a potential tool in computer-aided three-dimensional drug design.     

New actinide ternary intermetallic compounds: synthesis, characterization and physical properties

Twelve new ternary intermetallic compounds of light actinide elements from Th to Pu, namely U₄Tc₇Si₆, U₄Tc₇Ge₆, Np₄Ru₇Ge₆, U₂Tc₃Si₅, Np₂Re₃Si₅, Pu₂Re₃Si₅, Th₂Mo₃Si₄, U₂Mo₃Si₄, U₂Mo₃Ge₄, Np₂Mo₃Si₄, Np₂Mo₃Ge₄, and Pu₂Mo₃Si₄, were obtained. The structures of these compounds are discussed as well as some preliminary physical property studies. Magnetic susceptibility measurements show that An₂Mo₃(Si or Ge)₄ compounds are paramagnetic at all temperatures studied and that U₄Tc₇Si₆ orders antiferromagnetically around 25 K. Mössbauer spectroscopy on Np₄Ru₇Ge₆ does not show a magnetic splitting down to 4.2 K.     

Impact and penetration by L/D ≤ 1 projectiles

Calculations of steel target penetration by L/D ≤ 1 tungsten and tungsten alloy projectiles have been extended to L/D = 1/32 over the velocity range 1.5 to 5 km/s. The ratio of crater to projectile diameter tends to 1 as L/D decreases over this entire velocity range. For impact velocities of 1.5 and 3 km/s, penetration depth normalized by projectile length, P/L, increases with decreasing projectile L/D up to a maximum value and then decreases for still lower L/D. Experiments at impact velocities of 2 and 3 km/s confirm these results. For 5 km/s impact velocity, the calculations show P/L increasing with decreasing projectile L/D over the entire range 1/32 ≤ L/D ≤ 1. The projectile L/D for which the maximum P/L occurs appears to depend on the impact velocity. P/L generally scales with impact velocity as P/L v^f(L/D) where f(L/D) ranges from 0 for a long rod to, we believe, 2 in the limit as projectile L/D approaches zero. The calculations show for 1/8 ≤ L/D ≤ 1/2, P/L v^0.9; for L/D = 1/16, P/L v^1.5; and for L/D = 1/32, the new results give P/L v^1.9.     

Preparative isoelectric focusing in multicompartment electrolyzers: novel, hydrolytically stable and hydrophilic isoelectric membranes

Preparative isoelectric focusing in multicompartment electrolyzers is based on the production of isoelectric membranes of precise isoelectric point, able to buffer at their pI value and to titrate proteins tangent to or crossing the membranes. Up to the present, such membranes have been based on polyacrylamide chemistry; acrylamide, however, is neither stable in acidic nor basic environments. We describe here novel membranes, produced with a unique monomer, N-acryloylaminoethoxyethanol (AAEE). Poly(AAEE) membranes are extremely stable to alkaline hydrolysis (500 times more stable than polyacrylamide) and even more hydrophilic than the latter matrix. This allows production of highly reproducible membranes (these do not change their pI with time, since no acrylic acid is produced by hydrolysis upon storage) which do not adsorb proteins by hydrophobic interaction.