Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

BackgroundThe 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published.MethodsWe performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1,000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke.ResultsThe cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84–0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73–0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79–0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes.ConclusionsIn a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.     

Evidence for Expression of the Joa Blood Group Antigen on the Gya/Hy-Active Glycoprotein

The phenotypic association between the non-assigned high-incidence antigen Jo^a and the Gy^a collection antigens Gy^a and Hy was investigated by haemagglutination studies, flow cytometric analysis, immune precipitation and immunoblotting experiments. In haemagglutination tests anti-Jo^a gave the same pattern of reactivity with erythrocytes pre-treated with pronase, trypsin, α-chymotrypsin and thiol reducing agents as did anti-Gy^a and anti-Hy. In addition, similar to that found for anti-Gy^a and anti-Hy, anti Jo^a also showed reduced binding, as determined by haemagglutination and flow cytometric analysis, to erythrocytes from patients with paroxysmal nocturnal haemoglobinuria. Immune precipitates prepared from radio-iodinated antigen-positive red cells with anti-Jo^a, anti-Gy^a and anti-Hy gave similar results – a major component of M_r 49,000–60,000 (the Gy^a/Hy-active glycoprotein) and a second component of M_r 85,000–92,000 (this may be a dimer of the Gy_a/Hy-active glycoprotein, or a coprecipitated protein). These immune precipitates, when probed with both anti-Gy^a and anti-Hy under non-reducing conditions, gave a positive immunoblotting reaction to both the M_r 49,000–60,000 and the M_r 85,000–92,000 components. These results strongly suggest that the Jo^a antigen is expressed on the same glycoprotein that carries the Gy^a and Hy antigens.     

Immunochemical characterization of the new platelet alloantigen system Bra/Brb

We report the immunochemical characterization of the new platelet-specific alloantigens Bra and Brb. Bra antibodies were from mothers of children with neonatal alloimmune thrombocytopenia (NAIT), and anti-Brb was found in the serum of a polytransfused patient. By radioimmunoprecipitation, anti-Bra and anti-Brb precipitated two proteins with apparent relative molecular masses in sodium dodecyl sulphate-polyacrylamide gel electrophoresis of 155,000 and 130,000 under non-reduced conditions, and of 165,000 and 148,000 under reduced conditions. In two-dimensional polyacrylamide gel electrophoresis, the two bands moved with isoelectric points ranging from 5.2 to 5.4 and from 4.5 to 4.7, respectively. These features fulfil previously defined criteria for platelet membrane glycoproteins (GP) Ia and IIa. The results were supported by data obtained by an assay employing monoclonal antibody (mab)-specific immobilization of platelet antigens (MAIPA). By this technique, Bra and Brb antigens could be immobilized by mabs specific for the GP Ia/IIa complex (mab Gi 14) or a mab specific for the very late antigen-2 (mab 12 F1), but not by a mab specific for GP IIb/IIIa complex (mab Gi3). Furthermore, platelets from a thrombasthenic patient with complete absence of GP IIb/IIIa expressed the Brb antigen normally as shown in MAIPA; this antigen could be immunoprecipitated with anti-Brb and was identical to that of normal platelets. This confirms that the antigens of the Br system are not associated with the GP IIb/IIIa complex. By direct binding studies using mabs Gi3 and Gi14, we calculated that 51,500 +/- 3900 molecules of anti-GP IIb/IIIa and 6,470 +/- 500 molecules of anti-GP Ia/IIa were bound per platelet at saturation. Our results provide evidence for the first platelet-specific alloantigen system residing on the GP Ia. The difficulty in detecting anti-Bra and anti-Brb by direct binding assays may be related to the small number of GP Ia/IIa complexes on platelets.     

New Variants in the ABOH Blood Group System due to Interaction of Recessive Genes Controlling the Formation of H Antigen in Erythrocytes: the ''Bombay''-Like Phenotypes OHm, OBHm and OABHm

Abstract. New variants of the ABOH blood group system are described which are similar to the 'Bombay' phenotype, but differ from it by Le(a-b+) erythrocytes and secretion of ABH and Le^a and Le^b antigens. The erythrocytes of the proposita and members of her family are group O, negative with anti-H; agglutinins if the 'Bombay' type, active also at 37°C, but weakened owing to interference by the secreted antigens, were found in the sera. The genetic background of the observed phenotypes is discussed. It appears likely that the atypical blood groups are due to a pair of recessive genes at a locus designated as Z/z and responsible for biosynthesis of H antigen in erythrocytes. The Z/z locus very probably belongs to the operator/regulator gene complex for the structural gene H , and has a position similar that of the Y/y pair in relation to A gene. The homozygous combination zz causes suppression (modification) of the H phenotype in erythrocytes. As a result, the expression of the blood groups, as determined by the structural gene A or B , is also suppressed. It is suggested that these variants (phenotypes) be given the symbols O_Hm, O^A_Hm, O^B_Hm and O^AB_Hm if the genetic information O, A, B or AB can be demonstrated only indirectly, and symbols A_Hm and B_Hm if the phenotype can be demonstrated by specific agglutination reactions.     

A Study of the Serological Behaviour and Nature of the Anti-B/P/Pk Activity of Salmonidae Roe Protectins

Abstract. Salmonidae protectins cross-react with human red cells having B, P, P₁ and P^k antigens, probably combining with an α-galactosyl-like determinant common to all these antigens. They have an apparent molecular weight of the order of 2 × 10⁵ (S₂₀w = 8 · 9), which may explain the enhanced haemagglutinating activity in albumen displacement or enzyme tests.
The saline anti-B activity for A₁B cells rapidly deteriorated in storage. Cells previously suspended with albumin were no longer agglutinated by the protectins. It was only possible to obtain serologically active partially purified protectins from Sephadex G-200 gel filtration when normal human serum was added to the crude protectin reagent before applying to the gel. This may reflect lability of the tertiary structure of these proteins.     

2011年ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS颅外颈动脉和椎动脉疾病患者处理指南

导言医疗专业人员在对与疾病检测、处理或预防中使用的药物、装置和操作相关的证据的严格评价中扮演的核心角色是十分必要的。对涉及这些疗法和操作的绝对和相对益处和风险的现有资料进行适当和严格的专业分析,可通过将资源集中于最有效的治疗策略,从而改善治疗效果、优化患者转归和合理控制成本。这些资料的一种重要应用是制定临床实践指南,后者进而能为其他各种应用,如绩效评价、合理应用标准、临床决策支持工具和质量改进工具提供依据。     

Haemolytic Disease of the Newborn due to Anti-Dia and Incidence of the Dia Antigen in Poland

A strong complement-fixing incomplete anti-Dia was found in the serum of a Polish mother who gave birth to a newborn suffering from a severe haemolytic anaemia. The whole family was of Polish origin. 9,661 donor blood samples from different regions of Poland were tested against antiserum derived from that mother. Dia antigen was present on red cells of 45 (0.46%) individuals. All of them were of Polish origin. In some cases, family studies were undertaken.     

Anti-Dia and the Dia Blood Group

Abstract. In an Austrian family the Di^a antigen was discovered by causing hemolytic disease of the newborn. No mongoloid admixture has so far been detected. No linkage to other blood groups, serum groups or red cell enzymes could be found.     

Serological Characteristics of the Third Anti-Aua

The third example of anti-Au^a is reported. The antibody, probably immune in origin, was detected 37 years after a single pregnancy. The serological and immunological features of anti-Au^a are discussed.     

Influence of imipramine on the hypothalamic/pituitary/thyroid axis of the rat

The effects of the tricyclic antidepressant drug imipramine at different levels of the hypothalamic/pituitary/thyroid axis were investigated in the rat. Intraperitoneal (IP) treatment for 14 days with imipramine at 10 mg/kg, but not 2 mg/kg, reduced serum total thyroxine (T₄) and triiodothyronine (T₃). A similar decrease in serum total T₄ was observed in thyroidectomized T₄-treated rats, suggesting that imipramine treatment enhances T₄ clearance instead of reducing T₄ secretion. There were no parallel decreases in serum free T₄ and T₃ concentrations, due to the simultaneous increase in the free fractions of both T₄ and T₃ following imipramine treatment. In vitro experiments using equilibrium dialysis indicated that neither imipramine nor its metabolite desipramine directly influenced the binding of T₄ or T₃ to their transport proteins following addition to normal serum, suggesting an indirect effect of imipramine or desipramine on free hormone concentrations in vivo. Concentrations of T₄ and T₃ in the brain, liver, and heart were unaffected by imipramine treatment, suggesting that the drug did not affect cellular uptake and metabolism of T₄ and T₃. Serum concentrations of thyrotropin (TSH) were unaffected by imipramine pretreatment at either dose level, compatible with the fact that serum free T₄ and T₃ concentrations were not reduced. Moreover, there was no difference in thyrotrope responsiveness to stimulation by TSH-releasing hormone (TRH) and to inhibition by T₄ and T₃ in rat anterior pituitary cells cultured ex vivo for 18 hours from control and imipramine-treated rats. Furthermore, in vitro exposure of cultured rat anterior pituitary cells to imipramine and desipramine indicated that both agents decreased TSH secretion only at concentrations greater than 10⁻⁶ mol/L. These concentrations of imipramine and desipramine in the culture medium would exceed the free concentrations of these drugs see in vivo therapeutically. In addition, no direct effects of 10⁻⁶ mol/L imipramine or desipramine on the TSH response to TRH or to T₃ were observed in vitro in cultured pituitary cells. A potential indirect effect of imipramine or desipramine on TSH secretion via altered hypothalamic control of thyrotropes does not seem likely, due to the lack of effect of imipramine treatment on serum TSH concentrations in imipramine-treated rats. In conclusion, imipramine treatment reduces serum total T₄ and T₃ in the rat, with enhanced clearance being the most likely explanation for the effect on T₄. There was no evidence for altered tissue T₄ or T₃ concentrations or for altered thyrotrope function. The enhanced T₄ clearance may explain the reduction in total T₄ reported for imipramine-treated depressed patients. However, the effects of imipramine treatment on the transport of thyroid hormones in plasma need to be examined in more detail in patients, since interspecies differences in the nature of the transport proteins preclude extrapolation of the present results from the rat.     

Identification of the First Example of Anti-Cob

S ummary A new blood group antibody has been detected in the serum of a male patient who has been transfused on several occasions. In addition to anti-E + C^w, the patient's serum contains anti-Co^b.     

Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells

The chimaeric bcr/abl oncogene is detected in virtually all cases of chronic myelogenous leukaemia (CML). It encodes a constitutively active tyrosine kinase of 210kDalton, p210^bcr/abl, which stimulates a variety of cytosolic signalling intermediates. The effects of bcr/abl on the activity of growth factor receptors are less well known. In order to investigate interaction of p210^bcr/abl with the receptor tyrosine kinase p145^c-kit, we used two myeloid, factor-dependent cell lines, MO7 and 32D, to generate bcr/abl positive sublines, MO7p210 and 32Dp210, by transfection with the bcr/abl gene. Since 32D and 32Dp210 cells did not express p145^c-kit, a c-kit retrovirus was used to generate c-kit positive cell lines (32Dkit, 32Dp210kit). In contrast to MO7 and 32Dkit cells, MO7p210 and 32Dp210kit cells were factor independent and did not respond to the growth-promoting effects of recombinant human Steel factor (rhSF). Preincubation with a monoclonal antibody (MAb) neutralizing the binding of SF to p145^c-kit did not affect the growth of MO7p210 cells, thus eliminating the possibility of an autocrine SF secretion. 32Dkit cells transfected with bcr/abl containing an inactivating point mutation (Lys→Arg271) in the Abl kinase domain (32Dp210(Arg271)kit) retained their responsiveness to the effects of rhSF. Immune complex kinase assays showed that the kinase activity of p145^c-kit was several-fold higher in MO7p210 and 32Dp210kit cells than in MO7, 32Dkit and 32Dp210(Arg271)kit cells, suggesting that Abl kinase activity was necessary to activate p145^c-kit. Co-immunoprecipitation experiments with anti-Kit and anti-Abl MAbs demonstrated that p145^c-kit and p210^bcr/abl were associated in an intracellular complex in human bcr/abl positive, c-kit positive cell lines (MO7p210; GM/SO). Finally, colony assays with bone marrow from bcr/abl positive CML patients showed that the haemopoietic progenitors of three of four patients did not respond to rhSF. Taken together, the results suggest that p145^c-kit can be activated by p210^bcr/abl via an Abl-kinase dependent mechanism involving the complex formation of both proteins. These findings could explain some clinical features (basophilia, increase of immature myeloid cells) of chronic-phase CML.