The Lu(a-b-) Syndrome and an Apparent Upset of P1 Inheritance

Abstract. The inhibitor gene responsible for the dominant form of Lu(a-b-), called In(Lu) , which also inhibits Au^a, i and P₁, was the cause of an apparent upset in the rules of inheritance of the P system. The same Sardinian kindred also shows In(Lu)to be genetically independent of the P and Yt loci.     

Antigens Aua, i and P1 of Cells of the Dominant Type of Lu(a–b–)

Abstract. Red cells of the dominant type of Lu(a–b–) have long been known to be too often Au(a–); too often also are they deficient in the antigens i and P₁.
Through the kindness of colleagues we were able to test most members of the eight Lu(a–b–) kindred ourselves: for information about those members whom we did not test we thank Dr. B. P. L. Moore, Miss Charmaine Brice, Dr. J. Darnborough, Miss Betty Francis (Mrs. Hatcher) and Miss Arden Stanbury.     

Diethyldithiocarbamic Acid-Methyl Ester Distribution, Elimination, and LD50 in the Rat after Intraperitoneal Administration

Following the intraperitoneal administration of S35 diethyldithiocarbamic acid-methyl ester (S35 DDTC-Me) to male rats, maximal total radioactivity (S35) in most tissues was found 1 hr after dosing. Twelve hr after intraperitoneal S35 DDTC-Me, most of the total radioactivity was found in urine. The feces accounted for approximately 15% of the total radioactivity. No radioactivity was detected in the breath. The kidney exhibited the greatest uptake of radioactivity, while the least uptake was found in the brain and heart. Most of the radioactivity in the tissues was due to the inorganic sulfate. S35 DDTC-glucuronide was found in the gastrointestinal tract and feces. The LD50 for DDTC-Me given intraperitoneally to male rats and mice was 167 and 263 mg/kg, respectively. Symptoms of toxicity preceding death of the animals resembled those symptoms observed with disulfiram toxicity.     

Activity of IgG and IgM ABO Antibodies against Some Weak A (A3, Ax, Aend) and Weak B (B3, Bx) Red Cells

The IgG and IgM anti-A and anti-B activities from several immune and non-immune O, A and B sera were tested against a panel of weak (A (A3, AX, AND Aend) and weak B (B3 and Bx) red cells. In all cases it is the IgM which agglutinated optimally Ax (or Bx) cells, while IgG and IgM anti-A (or anti-B) reacted similarly with A3 and Aend (or B3) cells. The agglutinating activity of all these ABO antibodies was found straightly related to their association constant for the A (or the B) receptor.     

The Effect of Prostaglandin E1 on Platelet Function in Vitro and in Vivo

S ummary Low concentrations of prostaglandin E₁ (PGE₁) inhibit ADP-induced aggregation in pig and rabbit citrated platelet-rich plasma and in suspensions of washed platelets. Higher concentrations also inhibit the initial change in shape induced by ADP and the release of platelet ATP, ADP and serotonin caused by stimuli such as collagen, thrombin, antigen-antibody complexes and gamma-globulin-coated polystyrene particles. PGE₁ is not taken up by platelets and its effects can be removed by resuspending platelets in fresh medium. Immediately following an intra-arterial injection, ADP-induced platelet aggregation is suppressed, but after 5 min the response returns to normal. PGE₁ inhibits haemostasis in rabbits when given as a continuous infusion. It is concluded that the effect of PGE₁ on haemostasis involves inhibition of the release of ADP from platelets exposed to collagen and thrombin, and inhibition of ADP-induced aggregation.     

Autoimmune-prone (NZW × BXSB)F1 (W/BF1) mice escape severe thrombocytopenia after treatment with deoxyspergualin, an immunosuppressant

Summary. Male (NZW × BXSB)F₁ mice spontaneously develop a disease which closely resembles human systemic autoimmune disease, involving idiopathic thrombocytopenic purpura and glomerulonephritis. We investigated whether autoimmune thrombocytopenia in the mice responded to deoxyspergualin, as immunosuppressant. Deoxyspergualin completely prevented the development of thrombocytopenia and suppressed the increase in circulating autoantibodies against platelets. This agent also ameliorated lupus nephritis. These findings suggest that deoxyspergualin may be effective in the prevention of idiopathic thrombocytopenic purpura.     

Haemoglobin F Port Royal (α2Gγ2, 125Glu → Ala)

S ummary . A ^Gγ-chain variant, Hb F Port Royal, with an electrophoretic mobility intermediate between Hb S and Hb C, was found in a Jamaican-Negro infant, and made up 14–15% of the total Hb F. A glycinamidation procedure was employed to aid in determining the amino-acid residue substitution of γ^{125Glu → Ala}, and the presence of glycinc in position 136.     

The Role of α1 Protease Inhibitor (α1 Antitrypsin) in the Regulation of Immunologic and Inflammatory Reactions

Summary: Twenty-six different alleles have been identified for α₁ protease inhibitor (α₁ antitrypsin), each designated by a letter of the alphabet. In any individual two alleles co-dominantly determine the characteristics of α₁ protease inhibitor (Pi), including mobility on electrophoresis, serum concentration and acute phase response. Recent evidence has linked some mildly deficient phenotypes of Pi with a variety of chronic immunologic and inflammatory disorders, such as rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, asthma and fibrosing alveolitis, in addition to the well recognised association of severe deficiency with emphysema and chronic liver disease. This disease susceptibility in phenotypes associated with reduced serum levels may be due to alteration in lymphocyte responses, complement activation and leukocyte migration. Pi can also influence the autolytic effects of leukocytic enzymes on tissues and may inhibit some aspects of coagulation and fibrinolysis. Therefore patients with deficient Pi phenotypes are likely to have exaggerated immunologic and inflammatory responses.     

The Primary Rh0(D) Immune Response in Male Volunteers

After a single antigenic stimulus, not greater than 5.0 ml R₂ R₂ red cells, anti-D was detected in 79% of D-negative volunteers increasing to 88% after subsequent spaced stimuli. The use of repeated antigenic stimuli at 2- or 4-weekly intervals to induce the immune response did not appear to increase the frequency of responders. The results obtained are compared with those of other workers and evidence is presented to suggest that the immunogenicity of red cells from different donors may have a role in determining the frequency of responders with detectable anti-D and is possibly associated with the R₂ antigenic complex.     

Homozygous deletional α+ thalassaemia associated with unequal expression of the two remaining α1 genes (α1A and α1Q)

S ummary . A Cambodian family presenting several haemoglobinopathies, Hb E, Hb Q and α⁺ thalassaemia, has been investigated. DNA analysis showed that the thalassaemia syndrome corresponds to a leftward type (4.2 kb) deletional from of α⁺ thalassaemia. Genotypes found in the family are: propositus -α^A/-α^Q, β^A/β^E, mother and older sister α^Aα^A/ -α^Q, β^A/β^E; father α^Aα^A/-α^A, β^A/β^A. The propositus consistently presents an α^Q/α^A chain ratio of 60/40 although both chains are products of α₁ loci. The relatively higher expression of the α^Q chain is not observed in the mother and therefore makes it unlikely to reflect anything other than differential expression of the maternal -α^Q/ and paternal -α^A/ haplotypes. This observation raises the possibility that both haplotypes are not strictly identical and that the region of the cross-over event is important for α gene expression.     

Synergistic Effects of Inward Rectifier (IK1) and Pacemaker (If) Currents on the Induction of Bioengineered Cardiac Automaticity

Introduction: Normal heart rhythms originate in the sinoatrial node. HCN‐encoded funny current (I_f) and the Kir2‐encoded inward rectifier (I_K1) counteract each other by respectively oscillating and stabilizing the negative resting membrane potential, and controlling action potential firing. Therefore, I_K1 suppression and I_f overexpression have been independently exploited to convert cardiomyocytes (CMs) into AP‐firing bioartificial pacemakers. Although the 2 strategies have been largely assumed synergistic, their complementarity has not been investigated. Methods and Results: We explored the interrelationships of automaticity, I_f and I_K1 by transducing single left ventricular (LV) CMs isolated from guinea pig hearts with the recombinant adenoviruses Ad‐C MV‐G FP‐I RES‐HCN1‐ÄÄÄ and/or Ad‐CGI‐Kir2.1 to mediate their current densities via a whole‐cell patch clamp technique at 37°C. Results showed that Ad‐CGI‐HCN1‐ÄÄÄ but not Ad‐CGI‐Kir2.1 transduction induced automaticity (181.1 ± 13.1 bpm). Interestingly, Ad‐CGI‐HCN1‐ÄÄÄ/Ad‐CGI‐Kir2.1 cotransduction significantly promoted the induced firing frequency (320.0 ± 15.8 bpm; P < 0.05). Correlation analysis revealed that the firing frequency, phase‐4 slope and APD₉₀ of AP‐firing LV CMs were correlated with I_f (R² > 0.7) only when ?2 >I_K1 >?4 pA/pF but not with I_K1 over the entire I_f ranges examined (0.02 < R² < 0.4). Unlike I_f, I_K1 displayed correlation with neither the phase‐4 slope (R²= 0.02) nor phase‐4 length (R²= 0.04) when ?2 > I_f > ?4 pA/pF. As anticipated, however, APD₉₀ was correlated with I_K1 (R²= 0.4). Conclusion: We conclude that an optimal level of I_K1 maintains a voltage range for I_f to operate most effectively during a dynamic cardiac cycle.     

Comparative Automated Assay of Anti-P1 Antibodies in Acute Hepatic Distomiasis (Fascioliasis) and in Hydatidosis

Abstract. An automated assay of anti-P₁ allohemagglutinins has been carried out on 133 P₂ subjects: 13 with acute hepatic distomiasis (Fascioliasis), 20 with hydatidosis and 100 healthy blood donors. Anti-P₁ were detected in 100% of the distomatid sera, in 50% of the hydatid and in 29% of the healthy individuals. When compared to a reference serum test (anti-P₁ standard), their concentration was found to be weak in healthy subjects, moderate in hydatidosis and exceptionally increased in acute distomiasis (up to 5–6 times the standard anti-P₁ level). The 2-mercaptoethanol treatment showed that even the increased distomatid anti-P₁ sera were of an IgM nature. The respective origin, synthesis and strength of these allohemagglutinins are discussed and the advantages of using distomatid IgM anti-P₁ as human sera test are emphasized.     

Angiotensin II (AT1) Redeptor Antagonists, Diabetes, and Nephropathy

Do Differences Between the Renal and Systemic Circulations Explain the Outcomes Observed With ARBs and ACE Inhibitors?     

Effect of Pinealectomy on Thyroid Hormone (T4 and T3) Levels in Plasma During Annual Reproductive Cycle in the Freshwater Catfish, Clarias batrachus

Thyroxine and triiodothyronine (T3) were measured by radioimmunoassay in serum and thyroid gland of the freshwater teleost Clarias batrachus. Pinealectomy increased the glandular levels of the thyroid hormones but decreased the plasma levels of T4 concomitantly with the increase of T3 levels. Most of the effects of pinealectomy on thyroid hormones were restricted to the gonadal development periods. Pinealectomy has shown no significant impact on thyroid hormones during the other periods of the reproductive cycle. Thus, it appears that the pineal gland is inhibitory to thyroid hormones during gonadal development and maturation.     

Haemoglobin Inkster (α285 aspartic acid → valineβ2) Coexisting with β-Thalassaemia in a Caucasian Family

S ummary . Haemoglobin Inkster, a new α-chain variant, was discovered in a family which also had the gene for β-thalassaemia. The amino acid abnormality was in αTp-9 which contains 29 amino-acid residues. Structural studies were facilitated by cleavage of the abnormal α-chains with cyanogen bromide followed by tryptic digestion. The substitution was shown to be valine for aspartic acid at position 85 in the α-chain. Affected individuals had no haematological abnormalities. Individuals with both β-thalassaemia and Hb Inkster had slightly lower percentages of Hb Inkster than those found in persons heterozygous for the Hb Inkster gene alone. 'Interaction' between thalassaemia and variant haemoglobin genes involving different haemoglobin loci has been reported in another family with β-thalassaemia and an α-chain haemoglobin mutant, as well as in the converse situation of coexisting β-thalassemia and a β-chain haemoglobin mutant. This decrease in the mutant haemoglobin percentage differs from the more common 'interaction' of thalassaemia and mutant haemoglobin genes involving the same haemoglobin locus, in which the mutant haemoglobin percentage is increased. The mechanism for the 'interaction' is unknown, but the presence of an unusually low percentage of a haemoglobin variant should warrant investigation for coexisting thalassaemia involving a different haemoglobin locus.     

Chronic Ethanol Treatment Induces H2O2 Production Selectively in Pericentral Regions of the Liver Lobule

Chronic treatment with ethanol damages pericentral regions of the liver selectively, and reactive oxygen species such as H2O2 may be involved in the mechanism of hepatotoxicity. To test this idea, the effect of chronic treatment with ethanol on rates of H2O2 production was measured in tissue cylinders isolated from periportal and pericentral regions of livers from ethanol-treated rats. Rates of hydrogen peroxide production, assessed from the oxidation of methanol to formaldehyde by catalase-H2O2, were similar in tissue cylinders isolated from periportal regions in control and ethanol-treated rats. In contrast, rates of H2O2 production were over 4-fold higher in tissue isolated from pericentral regions of livers from ethanol-treated than control animals (1.7 +/- 0.5 vs. 0.4 +/- 0.3 nmol/min/mg protein, respectively). Rates of H2O2-generating acyl CoA oxidase activity were equivalent in tissue cylinders from periportal regions of livers from both groups (approximately 2 nmol/min/mg protein), but were over 2-fold higher in tissue cylinders from pericentral regions of livers from ethanol-treated rats than from controls. In contrast, catalase activity was increased nearly 2-fold in homogenates from both periportal and pericentral regions by ethanol treatment while glutathione peroxidase activity was decreased significantly in both regions. These data demonstrate that ethanol increases H2O2 generation in pericentral regions of the liver lobule in part by elevating rates of peroxisomal beta-oxidation of acyl CoA compounds and are consistent with the hypothesis that local increases in H2O2 production may be involved in the mechanism of ethanol-induced hepatotoxicity.