Diagnostic role of an immunoassay-detected polymorphism of factor IX for potential carriers of hemophilia B

In hemophilia B, assays based on a monoclonal antifactor IX specific for the Thr-148 variant of an exonic polymorphism have diagnosed carriers in selected families by either establishing linkage or by indicating the presence or absence of a given normal factor IX. The sensitivity of the immunoassays for detecting heterozygous women was explored by comparing results from immunoassays with solid-phase polyclonal v the monoclonal antifactor IXs. Factor IX with the normal Ala-148 variant gave a flat dilution curve, qualitatively distinct from factor IX with the Thr-148 variant in the monoclonal assay. The two were indistinguishable in the polyclonal assay. Mixtures of equal amounts of the two types gave an intermediate result, about half as reactive in the monoclonal as compared with the polyclonal assay system. Whereas mixtures with 10% Ala-148 and 90% Thr-148 factor IXs could not readily be distinguished from Thr-148 factor IX plasma, as little as 1% of the Thr-148 protein was detected in Ala-148 factor IX plasma. The frequency of the Ala-148 variant varied in individuals with different ethnic backgrounds; it was found in 29% of white, 12% of black, and none of Asian blood donors' factor IX genes in Seattle. Only 4% of samples from South African black men were nonreactive (ie, Ala- 148). The Thr/Ala-148 dimorphism is in strong linkage disequilibrium with Taql restriction fragment length polymorphisms (RFLPs). Three recombinations were noted in normal white genes and one in a normal black factor IX gene (less than 2% of those examined). In 34 white families with at least one woman being a possible carrier, genetically, the immunoassay results were informative in 18. RFLP analyses were informative in eight of the 15 families tested. In five families each, assignment of carrier status was made to a woman by only DNA or only immunoassay results, whereas the other approach was noninformative. The immunoassays provide a rapid, inexpensive screening test and complement DNA analysis in white women who are potential carriers of hemophilia B.     

The man who feels two hearts: the different pathways of interoception

Recent advances in neuroscience have provided new insights into the understanding of heart–brain interaction and communication. Cardiac information to the brain relies on two pathways, terminating in the insular cortex (IC) and anterior cingulate cortex (ACC), along with the somatosensory cortex (S1-S2). Interoception relying on these neuroanatomical pathways has been shown to modulate social cognition. We report the case study of C.S., a patient with an ‘external heart’ (an extracorporeal left-univentricular cardiac assist device, LVAD). The patient was assessed with neural/behavioral measures of cardiac interoception complemented by neuropsychological and social cognition measures. The patient’s performance on the interoception task (heartbeat detection) seemed to be guided by signals from the artificial LVAD, which provides a somatosensory beat rather than by his endogenous heart. Cortical activity (HEP, heartbeat-evoked potential) was found decreased in comparison with normal volunteers, particularly during interoceptive states. The patient accurately performed several cognitive tasks, except for interoception-related social cognition domains (empathy, theory of mind and decision making). This evidence suggests an imbalance in the patient’s cardiac interoceptive pathways that enhances sensation driven by the artificial pump over that from the cardiac vagal-IC/ACC pathway. A patient with two hearts, one endogenous and one artificial, presents a unique opportunity to explore models of interoception and heart–brain interaction.     

Are the Effects of High-Intensity Exercise Training Different in Patients with COPD Versus COPD+Asthma Overlap?

Purpose

This study aimed to investigate whether patients with chronic obstructive pulmonary disease (COPD) presenting asthma overlap (ACO) benefit similarly in comparison to patients with only COPD after a 12-week high-intensity exercise training (ET) program.

Methods

Subjects with a diagnosis of COPD alone or ACO were evaluated and compared before and after a high-intensity ET program composed of walking and cycling plus strengthening exercises of the upper and lower limbs (3 days/week, 3 months, 36 sessions). Assessments included spirometry, bioelectrical impedance, 6-min walk test (6MWT), London Chest Activity of Daily Living Scale (LCADL), Hospital anxiety and depression Scale, modified Medical Research Council Scale (mMRC), Saint George Respiratory Questionnaire (SGRQ), and respiratory and peripheral muscle strength [manovacuometry and 1-repetition maximum test (quadriceps femoris, biceps and triceps brachialis), respectively]. ACO was defined according to Sin et al. (Eur Respir J 48(3):664-673, 2016).

Results

The sample was composed of 74 subjects (57% male, age 67 ± 8 years, BMI 26 (21–32) kg/m², FEV₁ 47 ± 17%predicted), and 12 (16%) of them were classified as presenting ACO. Both groups improved pulmonary function, 6MWT, peripheral and inspiratory muscle strength, LCADL, and SGRQ after ET (p < 0.005 for all). There were no significant interactions between ACO and COPD on ET effects (p > 0.05 for all). Likewise, there was no difference in the proportion of patients achieving the minimum clinical important difference for 6MWT and mMRC.

Conclusion

High-intensity exercise training generates similar benefits in patients with COPD regardless of whether presenting asthma overlap or not.

     

Discoid lupus erythematosus

Discoid lupus erythematosus is a manifestation of chronic cutaneous lupus erythematosus with a small risk of systemic involvement. In this review article, the role of predisposing factors such as haplotype, hormones, antibodies and sunlight are discussed. The clinical features, including variants and associations, and management options are presented.     

Evidence for direct action of human biosynthetic (recombinant) GM-CSF on erythroid progenitors in serum-free culture

The biologic activity of human biosynthetic granulocyte-monocyte colony stimulating factor (GM-CSF) was investigated in serum-free culture of erythroid progenitors derived from adult peripheral blood. The morphology of erythroid bursts and the cloning efficiency of BFU-E under serum-free conditions were similar to those observed in dishes with fetal bovine serum (FBS). For these experiments, progenitor cells were partially purified by Ficoll-Paque density centrifugation, adherence to a plastic surface, and complement-mediated cytotoxicity of Leu-1+ elements. For some studies, blastlike cells were harvested directly from 6-day-old semisolid cultures. In serum-free culture of the light-density cell fraction, biosynthetic erythropoietin (Ep) was sufficient for formation of pure and mixed erythroid colonies whereas GM-CSF was required for granulocyte-monocytic colonies. When adherent and Leu-1+ cells were removed, or when in vitro differentiated blast cells were used as a source of progenitors, neither Ep or GM-CSF alone induced colony formation. In dishes supplemented with both growth factors, erythroid bursts were detected. Although the presence of GM- CSF alone did not induce formation of any colony or clusters, BFU-E were recorded when Ep was added 8 days later, suggesting that BFU-E could be maintained. Terminal maturation of the resulting erythroid bursts was delayed by 8 days. These results provide evidence that GM- CSF acts directly on early erythroid progenitors. Furthermore, they suggest that both Ep and GM-CSF are necessary to start the differentiation process.