Early mortality in multiple myeloma: the time‐dependent impact of comorbidity: A population‐based study in 621 real‐life patients

Multiple myeloma is a heterogeneous disease with variable survival; this variability cannot be fully explained by the current systems of risk stratification. Early mortality remains a serious obstacle to further improve the trend toward increased survival demonstrated in recent years. However, the definition of early mortality is not standardized yet. Importantly, no study has focused on the impact of comorbidity on early mortality in multiple myeloma to date. Therefore, we analyzed the role of baseline comorbidity in a large population‐based cohort of 621 real‐life myeloma patients over a 31‐year period. To evaluate early mortality, a sequential multivariate regression model at 2, 6, and 12 months from diagnosis was performed. It was demonstrated that comorbidity had an independent impact on early mortality, which is differential and time‐dependent. Besides renal failure, respiratory disease at 2 months, liver disease at 6 months, and hepatitis virus C infection at 12 months, were, respectively, associated with early mortality, adjusting for other well‐established prognostic factors. On the other hand, the long‐term monitoring in our study points out a modest downward trend in early mortality over time. This is the first single institution population‐based study aiming to assess the impact of comorbidity on early mortality in multiple myeloma. It is suggested that early mortality should be analyzed at three key time points (2, 6, and 12 months), in order to allow comparisons between studies. Comorbidity plays a critical role in the outcome of myeloma patients in terms of early mortality. Am. J. Hematol. 91:700–704, 2016. © 2016 Wiley Periodicals, Inc.     

Structure-function relationship in viral RNA genomes: The case of hepatitis C virus

The acquisition of a storage information system beyond the nucleotide sequence has been a crucial issue for the propagation and dispersion of RNA viruses. This system is composed by highly conserved, complex structural units in the genomic RNA, termed functional RNA domains. These elements interact with other regions of the viral genome and/or proteins to direct viral translation, replication and encapsidation. The genomic RNA of the hepatitis C virus(HCV) is a good model for investigating about conserved structural units. It contains functional domains, defined by highly conserved structural RNA motifs, mostly located in the 5'-untranslatable regions(5'UTRs) and 3'UTR, but also occupying long stretches of the coding sequence. Viral translation initiation is mediated by an internal ribosome entry site located at the 5' terminus of the viral genome and regulated by distal functional RNA domains placed at the 3' end. Subsequent RNA replication strongly depends on the 3'UTR folding and is also influenced by the 5' end of the HCV RNA. Further increase in the genome copy number unleashes the formation of homodimers by direct interaction of two genomic RNA molecules, which are finally packed and released to the extracellular medium. All these processes, as well as transitions between them, are controlled by structural RNA elements that establish a complex, direct and long-distance RNARNA interaction network. This review summarizes current knowledge about functional RNA domains within the HCV RNA genome and provides an overview of the control exerted by direct, long-range RNA-RNA contacts for the execution of the viral cycle.     

Approaches for the rapid identification of drug metabolites in early clinical studies

Understanding the metabolism of a novel drug candidate in drug discovery and drug development is as important today as it was 30 years ago. What has changed in this period is the technology available for proficient metabolite characterization from complex biological sources. High-efficiency chromatography, sensitive MS and information-rich NMR spectroscopy are approaches that are now commonplace in the modern laboratory. These advancements in analytical technology have led to unequivocal metabolite identification often being performed at the earliest opportunity, following the first dose to man. For this reason an alternative approach is to shift from predicting and extrapolating possible human metabolism from in silico and nonclinical sources, to actual characterization at steady state within early clinical trials. This review provides an overview of modern approaches for characterizing drug metabolites in these early clinical studies. Since much of this progress has come from technology development over the years, the review is concluded with a forward-looking perspective on how this progression may continue into the next decade.     

Genetics of vestibular disorders: pathophysiological insights

The two most common vestibular disorders are motion sickness and vestibular migraine, affecting 30 and 1–2 % of the population respectively. Both are related to migraine and show a familial trend. Bilateral vestibular hypofunction is a rare condition, and some of patients also present cerebellar ataxia and neuropathy. We present recent advances in the genetics of vestibular disorders with familial aggregation. The clinical heterogeneity observed in different relatives of the same families suggests a variable penetrance and the interaction of several genes in each family. Some Mendelian sensorineural hearing loss also exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. However, the most relevant finding during the past years is the familial clustering observed in Meniere’s disease. By using whole exome sequencing and combining bioinformatics tools, novel variants in DTNA and FAM136A genes have been identified in familial Meniere’s disease, and this genomic strategy will facilitate the discovery of the genetic basis of familial vestibular disorders.     

Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review

Immunoglobulin-A vasculitis (IgAV) is classically a childhood small-sized blood vessel vasculitis with predominant involvement of the skin. Gastrointestinal and joint manifestations are common in patients diagnosed with this condition. Nephritis, which is more severe in adults, constitutes the most feared complication of this vasculitis. The molecular bases underlying the origin of IgAV have not been completely elucidated. Nevertheless, several pieces of evidence support the claim that genes play a crucial role in the pathogenesis of this disease. The human leukocyte antigen (HLA) region is, until now, the main genetic factor associated with IgAV pathogenesis. Besides a strong association with HLA class II alleles, specifically HLA-DRB1 alleles, HLA class I alleles also seem to influence on the predisposition of this disease. Other gene polymorphisms located outside the HLA region, including those coding cytokines, chemokines, adhesion molecules as well as those related to T-cells, aberrant glycosylation of IgA1, nitric oxide production, neoangiogenesis, renin-angiotensin system and lipid, Pyrin and homocysteine metabolism, may be implicated not only in the predisposition to IgAV but also in its severity. An update of the current knowledge of the genetic component associated with the pathogenesis of IgAV is detailed in this review.     

Effect of educational counseling alone on people with tinnitus: Meta-analysis of randomized controlled trials

ObjectiveTo review and meta-analyze the efficacy of educational counseling alone in tinnitus.MethodsWe collected randomized controlled trials (RCTs) adhered to PRISMA guidelines. Analyzed the effect of educational counseling alone versus other forms of therapy (psychological or combination) with RevMan 5.3.ResultsIn nine trials, 582 patients receiving educational counseling alone and 759 patients receiving other psychological or combination therapies. During the 3–6 months follow-up, there was no significant difference in the tinnitus recovery rate between these two groups (OR 0.62, 95% CI 0.34–1.16, P = 0.14; I² = 71%, P = 0.00, random-effects model). The tinnitus symptom severity rates were also similar during 1–12 months follow-up (mean difference, 3.59, 95% CI −0.56–7.74, P = 0.09) with heterogeneity among studies (I² = 74%, P = 0.00; random-effects model). Sensitivity analysis indicated that a single trial containing almost 40% of the patients was the cause of heterogeneity. There was no significant change in tinnitus loudness at the 3 months follow-up (OR 0.84, 95% CI 0.42–1.66, P = 0.61), with no significant heterogeneity (I² = 0%, P = 0.60).ConclusionEducational counseling alone helps to improve tinnitus and related problems, and has the same effect as other psychological or combination therapies.Practice ImplicationsThe results of the current analysis may help to develop evidence-based cost-effective treatment(s) for tinnitus, which will be minimally burdensome for the patients.     

HLA association with the susceptibility to anti-synthetase syndrome

ObjectiveTo investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD).MethodsWe conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing.ResultsA statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed.ConclusionsOur results support the association of the HLA complex with the susceptibility to ASSD.     

Alloimmune B-lymphocytes modify the myocardium contractility-inducing release of SRS-A

It has been previously demonstrated that murine alloimmune lymphoid cells were able to exert positive or negative inotropic effects on isolated mouse atria depending on the cellular type used.Here we show that BALB/c anti-C₃H B-cells induced positive inotropic action on C₃H mouse atria. Supernatants of alloimmunized B-cells co-cultivated with C₃H myocardium exerted the same biological effect as alloimmune B-cells, indicating that a soluble factor is involved.Inhibitors of lipoxygenase(s) of arachidonic acid metabolism and a SRS-A blocker inhibited the positive effect of immune cells or its supernatants. The effect was prevented when we inhibited the atria lipoxygenase activity. On the other hand, when the inhibitors were applied to effector cells the response was not modified. In addition, supernatants of B-cells cultured with alloextracts were inactive.Supernatants from alloimmune B-cells plus myocardium release higher amounts of LTC₄ than those from normal B-cells.It is proposed that SRS-A synthesis is induced in the atria by direct contact with alloimmune B-cells upon recognition of alloantigens expressed by atria cells; which in turn, triggers the positive inotropic effect.