High Levels of Cerebrospinal Fluid Kappa Free Light Chains Relate to IgM Intrathecal Synthesis and Might Have Prognostic Implications in Relapsing Multiple Sclerosis.

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1-147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2-7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

The Current Role of the Heavy/Light Chain Assay in the Diagnosis, Prognosis and Monitoring of Multiple Myeloma: An Evidence-Based Approach.

Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

Short-term transdermal estradiol enhances nitric oxide synthase III and estrogen receptor mRNA expression in arteries of women with coronary artery disease.

OBJECTIVE: To analyze the short-term effects of estradiol (E2) on the expression of nitric oxide synthase (NOS III) and estrogen receptors (ER) alpha and beta. METHODS: We studied 20 post-menopausal women with coronary artery disease (CAD) undergoing CABG surgery with left internal mammary artery (LIMA) grafting. Ten women received treatment with transdermal E2 prior to surgery (48-72 h) and 10 did not. The distal segment of the LIMA was excised and processed to determine mRNA expression of NOS III and ER alpha and beta (RT-PCR). Expression of NOS III and ER alpha and beta was measured in arbitrary densitometric units (ADUs) relative to GPdH expression, constitutively expressed in human vessels. RESULTS: NOS III and ER alpha and beta mRNA expression was enhanced in women treated with E2 as compared to the control group (NOS III: 1.69+/-0.61 versus 1.14+/-0.48 ADUs, p=0.04; ER alpha: 6.52+/-6.80 versus 1.83+/-1.22 ADUs, p=0.04; ER beta: 4.20+/-3.42 versus 1.56+/-0.59 ADUs, p=0.03). ER alpha, but not ER beta expression, correlated with NOS III expression (r=0.70, p<0.001). CONCLUSIONS: After treatment with E2, NOS III, ER alpha, and ER beta mRNA expression was enhanced in arterial vessels of postmenopausal women with CAD. NOS III mRNA expression was only correlated to ER alpha expression, suggesting that NOS III activation could be more mediated by ER alpha.

Adrenomedullin messenger RNA expression is increased in myocardial tissue of patients with idiopathic dilated cardiomyopathy.

Increased plasma levels of adrenomedullin (ADM) have been reported in patients with congestive heart failure Immunohistochemical ADM has been identified in failing human ventricle, but the gene expression pattern of ADM messenger RNA (mRNA) in myocardial tissue of patients with heart failure has not been elucidated. In this study, gene expression of ADM mRNA (analyzed by northern blot) and tissue concentration of ADM (measured by radioimmunoassay) were assessed in the explanted hearts of 17 patients with idiopathic dilated cardiomyopathy (IDC) and in 7 organ donors with no cardiopathy (controls). Myocardial tissue samples of patients with IDC showed increased ADM mRNA gene expression (p < 0.05) and decreased immunoreactive ADM protein content (p < 0.02) compared with controls.

In vitro characterization of aldosterone and cAMP effects in mouse distal convoluted tubule cells.

The distal nephron plays a capital role in the fine regulation of sodium reabsorption. Compared with the cortical collecting duct, much less information is available on the hormonal regulation of sodium transporter genes in the distal convoluted tubule (DCT), where the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is the major entry pathway for Na(+). The purpose of this study was to characterize the in vitro effects of aldosterone (Aldo; 1 microM) and cAMP (8-BrcAMP; 0.5 mM) on mouse DCT (mDCT) by using an immortalized mDCT cell line. Western blot analysis and semiquantitative RT-PCR were performed to analyze the expression of genes involved in sodium transport. The mDCTcell line expressed the 11 beta-hydroxysteroid dehydrogenase type 2 gene and both the mineralocorticoid and glucocorticoid receptor genes, suggesting Aldo responsiveness. In this sense, we found that mDCT cells expressed the amiloride-sensitive Na(+) channel (ENaC) and responded to Aldo by upregulating the alpha-subunit protein. Similarly, alpha(1) Na(+)-K(+)-ATPase protein was upregulated by Aldo and 8-BrcAMP. In addition, the Aldo intermediate gene sgk1 mRNA was increased in response to both Aldo and 8-BrcAMP, and the transcription factor HNF-3 alpha mRNA was induced by 8-BrcAMP. With respect to NCC regulation, although Aldo induced NCC protein levels in mice in vivo, neither Aldo nor 8-BrcAMP significantly induced the NCC mRNA or protein levels in mDCT cells. These results suggest that in mDCT, Aldo and cAMP modulate some downstream mediators and effectors in vitro but do not influence the expression of NCC in this cell model.

[Prognostic value of cytokines and neurohormones in severe heart failure]. / Valor pronóstico de los niveles de citocinas y neurohormonas en la insuficiencia cardíaca severa.

BACKGROUND AND OBJECTIVES: The screening of candidates for heart transplantation continues to present difficulties. High plasma levels of cytokines and neurohormones have been associated with a poor prognosis in heart failure but their usefulness for identifying candidates for heart transplantation is still not established. METHODS: In 83 patients (59 11 years old), with systolic left ventricular dysfunction and New York Heart Association functional class III-IV, we assessed levels of aldosterone, atrial natriuretic peptide, plasma renin activity, angiotensin II, norepinephrine, endothelin, interleukin-6 and tumor necrosis factor-alpha. RESULTS: Over the following year, 13 patients died and 26 received heart transplantation. Mean ejection fraction was 23 6%, end-diastolic and end-systolic diameters were 73 10 and 60 10 mm, respectively. Univariate analysis identified the following variables to be associated with poor prognosis: angiotensin II (p = 0.001), norepinephrine (p = 0.003), plasma renin activity (p = 0.02), systolic blood pressure (p = 0.006), end-diastolic diameter (p = 0.02) and end-systolic diameter (p = 0.04). Multivariate regression analysis identified the following variables to be independent predictors of death or need for heart transplantation: a low cardiac index (p = 0.007), plasma angiotensin II (p = 0.001) and pulmonary capillary wedge pressure (p = 0.04) The sensitivity and specificity of angiotensin II for predicting poor outcome was only moderate according to interpretation of the receiver operating curves. CONCLUSIONS: Although plasma angiotensin II was the best neurohormone for identifying patients with severe heart failure and the worst prognosis, its sensitivity and specificity for predicting death or the need for heart transplantation was limited. The decision to transplant should continue to be based on clinical and hemodynamic parameters.

Valor pronóstico de los niveles de citocinas y neurohormonas en la insuficiencia cardíaca severa / Prognostic value of cytokines and neurohormones in severe heart failure

Introducción y objetivos. La selección de pacientes candidatos a trasplante cardíaco sigue siendo un problema difícil. Los valores elevados de citocinas y neurohormonas se han asociado a peor pronóstico en la insuficiencia cardíaca, pero su utilidad para seleccionar pacientes candidatos a trasplante cardíaco es todavía incierta. Métodos. Se analizaron los valores plasmáticos de aldosterona, factor natriurético auricular, actividad de la renina plasmática, angiotensina II, noradrenalina, endotelina, interleucina 6 y factor de necrosis tumoral alfa, en 83 pacientes con insuficiencia cardíaca severa en clase funcional III-IV de la NYHA. Resultados. Durante el seguimiento, 13 pacientes fallecieron y 26 precisaron un trasplante cardíaco. La fracción de eyección fue del 23 ñ 6 por ciento y los diámetros telediastólico y telesistólico de 73 ñ 10 y de 60 ñ 10 mm, respectivamente. El análisis univariado identificó los valores de angiotensina II (p = 0,001), noradrenalina (p = 0,003), actividad de la renina plasmática (p = 0,02), presión arterial sistólica (p = 0,006) y los diámetros telediastólico (p = 0,02) y telesistólico (p = 0,04) como factores asociados a un peor pronóstico. El análisis de regresión multivariado identificó el índice cardíaco (p = 0,007), los títulos de angiotensina II (p = 0,001) y la presión capilar pulmonar (p = 0,04) como predictores independientes de muerte o necesidad de trasplante cardíaco. La sensibilidad y especificidad de la angiotensina II, representadas mediante las curvas ROC, para identificar a los pacientes con peor pronóstico fueron sólo moderadas. Conclusiones. La angiotensina II fue la neurohormona más eficaz para identificar a los pacientes con insuficiencia cardíaca severa y peor pronóstico. No obstante, la sensibilidad y la especificidad para detectar mayor mortalidad o necesidad de trasplante cardíaco fueron sólo moderadas. La decisión de indicar trasplante cardíaco debe seguir basándose en datos clínicos y hemodinámicos (AU)