A genetic analysis of natural resistance to nonsyngeneic cells: The role of H-2

The genetic control of natural resistance in vivo to four natural killer (NK) cell-resistant H-2 homozygous lymphoid tumor cell lines was investigated by following the survival and organ distribution of cells prelabeled with radioactive iododeoxyuridine. Backcross mice derived from DBA/2J and CBA/J parents were injected with H-2 ^dtumor cells and tumor cell elimination was lowest in H-2 ^dhomozygotes. Natural killer cell activity was also reduced in mice with the H-2 ^dhaplotype, but no direct correlation between NK cell levels against YAC-1 or SL2-5 lymphoma cells and natural resistance in vivo was demonstrable. Analysis of 23 BXD recombinant inbred strains indicated that natural resistance to H-2 ^dtumors was restricted to H-2 ^bstrains. There was no direct association of NK cell activity with H-2 type in the BXD strains and NK cell levels did not correlate with tumor survival in vivo. By comparing natural resistance to H-2 ^dand H-2 ^btumors in DBA/2, C57BL/6, B6D2F₁, and B10.D2 mice we found that H-2 nonidentity between the tumor and the host, rather than the host H-2 haplotype, determined whether natural resistance occurred. Again, NK cell activity against YAC-1 cells was not predictive of tumor survival in these strains. These results provide genetic evidence that NK cells alone cannot account for natural resistance to H-2 nonidentical cells of hemopoietic origin.     

Complete nucleotide sequence of the murine H-2Kk gene. Comparison of three H-2K locus alleles.

We have determined the DNA sequence of the H-2Kk gene of the mouse major histocompatibility complex (MHC). Comparison on the nucleotide and protein level of three H-2K alleles (Kk, Kb and Kd) reveals a high degree of homology, in particular between the Kb and Kk alleles. Differences between the two latter antigens are almost exclusively confined to the alpha 1 and alpha 2 domains. At nine positions in the extracellular part of the molecules we have found allele-specific amino acids. Interestingly, 78% of these residues are either polar or carry hydroxyl-groups. This makes it likely that they are exposed on the surface of the molecules and might then be part of antigenic determinants. We have also identified potentially allele-specific nucleotide sequences of the K genes which might be used as specific DNA probes.     

Carbohydrate composition of purified serum glycoproteins in Mucolipidosis II and Mucolipidosis III

Summary Mucolipidosis II (I-cell disease) and Mucolipidosis III (ML III) are inherited disorders in which the molecular defect may involve an abnormality in a common post-translational modification step (possibly glycosylation) shared by lysosomal hydrolases. We tested whether such an alteration might be a generalized defect in glycoprotein biosynthesis and, thus, be reflected in an abnormal carbohydrate composition of non-lysosomal glycoproteins. The apoprotein of low density lipoprotein (apo-LDL) and immunoglobulin G (IgG) were purified to apparent homogeneity. Gas liquid chromatographic (glc) analysis of the carbohydrate content of these glycoproteins from ML II, ML III and normal sera revealed no differences in the relative ratios and total amounts of mannose, galactose, N-acetylglucosamine and sialic acid. These results suggest that if the postulated post-translational defect in these disorders involves changes in carbohydrate composition, it is not a general defect in glycosylation and may be specific for lysosomal hydrolases.     

Tetrahydrofolate-dependent biosynthesis of ribothymidine in transfer ribonucleic acids of Gram-positive bacteria.

Trimethoprim, an inhibitor that prevents tetrahydrofolate-dependent transmethylation reactions inbacteria, was used in a comparative study to discriminate between two possible biosynthetic pathways, either the S-adenosylmethionine or the tetrahydrofolate-dependent formation of ribothymidine (rT) in transfer ribonucleic acids (tRNA's) of several strains of gram-positive and gram-negative microorganisms. rT-deficient tRNA's accumulate in trimethoprim-treated gram-positive Streptococcus faecium, Staphylococcus aureus, Corynebacterium bovis, Arthrobacter albidus, and all examined Bacillaceae, except Bacillus stearothermophilus. The rT-deficient rT-deficient tRNA's accept the methyl moiety from S-adenosylmethionine in vitro, with extracts from Escherichia coli (wild type) as a source of methylating enzymes; 90% of the incorporated methyl groups are present in rT. Trimethoprim does not inhibit the biosynthesis of rT in tRNA of gram-negative Enterobacteriaceae, Rhizobium lupini, and Pseudomonadaceae, suggesting that the rT-specific tRNA methyltransferases of these gram-negative strains use S-adenosylmethionine as coenzyme.     

Somatostatin and insulin release from isolated rat pancreatic islets in response to D-glucose, l-leucine, alpha-ketoisocaproic acid or D-glyceraldehyde: evidence for a regulatory role of adenosine-3' ,5'-cyclic monophosphate.

Somatostatin and insulin release from isolated rat pancreatic islets was stimulated by glucose, leucine or α-ketoisocaproic acid. D-glyceraldehyde stimulated insulin release but diminished the secretion of somatostatin. Glucagon and theophylline amplified the glucose-induced somatostatin release.A regulatory role of the D-cell's adenylate cyclase/phosphodiesterase system for the release of somatostatin is suggested. Furthermore, stimulation as well as inhibition of somatostatin release might be of significance for the secretory function of the B-cell.     

Glycogen synthase: the existence of a single demonstrable from in bovine adipose tissue.

Glycogen synthase from bovine adipose tissue has been kinetically characterized. Glucose 6-phosphate increased enzyme activity 50-fold with an activation constant (A_0.5) of 2.6 mm. Mg²⁺ reversibly decreased this A_0.5 to 0.75 mm without changing the amount of stimulation by glucose 6-phosphate. Mg²⁺ did not alter the apparent K_m for UDP-glucose (0.13 mm). The pH optimum was broad and centered at pH 7.6. The glucose 6-phosphate activation of the enzyme was reversible and competitively inhibited by ATP (K_i = 0.6 mm) and P_i(K_i = 2.0 mm). The use of exogenous sources of glycogen synthase and glycogen synthase phosphatase suggests that (i) adipose tissue glycogen synthase phosphatase activity in fed mature steers is low or undetectable, and (ii) endogenous bovine adipose tissue glycogen synthase can be activated to other glucose 6-phosphate-dependent forms by addition of adipose tissue extracts from fasted steers or fed rats.     

Kidney Stones

The prevalence of kidney stones has steadily risen during this century; passage of a calculus and a positive family history increase the probability of recurrence. Findings from recent studies on the cause of renal calculi have stressed crystallization and crystal aggregation of stone minerals from supersaturated urine, rather than excessive organic matrix. Absence of normal urine inhibitors of calcium salts is also stressed. Formation of calcium oxalate stones is the major problem. Therapy with decreased calcium and oxalate intake, thiazides, phosphate salts and allopurinol in various combinations has substantially decreased the prevalence of recurrent stones. The rationale for the use of allopurinol is that uric acid salts enhance the tendency for calcium oxalate to crystallize from supersaturated urine. The hypercalciuria seen in 30 percent to 40 percent of patients with oxalate stones is usually caused by intestinal hyperabsorption of calcium. Although patients with uric acid calculi constitute only a small fraction of those in whom stones form, they represent a group in whom good medical therapy, based on sound physiologic principles, has proved extremely successful. Renal tubular syndromes lead to nephrocalcinosis and lithiasis through hypercalciuria, alkaline urine and hypocitraturia, the latter an inhibitor of calcium salt precipitation. Recent advances in surgical techniques are discussed, including the rationale for removing staghorn calculi. The ileal ureter and coagulum pyelolithotomy deserve special emphasis.     

Clinical Value of Teichoic Acid Antibody Titers in the Diagnosis and Management of the Staphylococcemias

Differentiation of endocarditic from nonendocarditic Staphylococcus aureus (SA) septicemia is prognostically and therapeutically important. A study of 68 cases of either SA or streptococcal sepsis, including 50 cases of SA sepsis of both cardiac and noncardiac origin, was done to determine the presence and titer of serum teichoic acid antibodies (TAA''s) by double immunodiffusion. Thirty-seven uninfected controls were also examined. There was no statistical difference in either incidence or peak TAA titers in endocardial versus deepseated, extracardiac SA sepsis. However, in both of these groups, incidence and peak titers were significantly higher than in intravascular catheter-related SA sepsis, streptococcal endocarditis and controls (P<0.05). Peak TAA titers in SA sepsis develop on admission or shortly thereafter (6 to 11 days) and permit early decisions on degree of tissue infection, likelihood of metastatic seeding and necessity for higher-dose, longer-term antibiotic therapy.Cases of catheter-related SA sepsis with no clinical evidence of metastatic SA seeding and with negative or low-titered (1:1) TAA''s were classified as superficial sepsis. Treatment consisted of short-term, low-dose antistaphylococcal regimens and catheter removal. In posttherapy follow-up after 6 to 12 weeks, all of the patients were cured and no signs of endocarditis or deepseated SA infection developed.