Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.

Although blood-heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.

Blood: tests used to assess the physiological and immunological properties of blood.

The properties of blood and the relative ease of access to which it can be retrieved make it an ideal source to gauge different aspects of homeostasis within an individual, form an accurate diagnosis, and formulate an appropriate treatment regime. Tests used to determine blood parameters such as the erythrocyte sedimentation rate, hemoglobin concentration, hematocrit, bleeding and clotting times, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean cell volume, and determination of blood groups are routinely used clinically, and deviations outside the normal range can indicate a range of conditions such as anemia, pregnancy, dehydration, overhydration, infectious disease, cancer, thyroid disease, and autoimmune conditions, to mention a few. As these tests can be performed relatively inexpensively and do not require high levels of technical expertise, they are ideally suited for use in the teaching laboratory, enabling undergraduate students to link theory to practice. The practicals described here permit students to examine their own blood and that of their peers and compare these with clinically accepted normal ranges. At the end of the practicals, students are required to answer a number of questions about their findings and to link abnormal values to possible pathological conditions by answering a series of questions based on their findings.

Impaired neutralizing activity by transplacental measles antibodies in infants born to HIV-1-infected mothers.

AIM: Growing numbers of newborns are saved from HIV infection through increased access to mother-to-child transmission prevention programmes. The maternally derived humoral immunity of these children might be impaired, both in terms of quantity and in terms of quality, with consequences for the timing of immunization against measles. METHODS: A cell-ELISA technique compared the neutralizing activity on Edmonston strain measles virus of sera from 1- to 4-month-old infants. Ten serum specimens came from noninfected infants of HIV-infected mothers and another 10 from infants of healthy mothers. The sera were matched for the level of conventional ELISA measles antibodies. RESULTS: Reflecting infection of the Vero cells by non-neutralized virus, optical density values were significantly higher for the sera from the children of the HIV-infected mothers than for those of the noninfected mothers (p < 0.001). CONCLUSION: Maternally derived protection against measles may be impaired by the mother's HIV infection, relating to the quality rather than to the quantity of transplacental antibodies. Selective, early immunization with live attenuated measles vaccine should be evaluated in noninfected children of HIV-1-infected mothers.

CspA-mediated binding of human factor H inhibits complement deposition and confers serum resistance in Borrelia burgdorferi.

Borrelia burgdorferi has developed efficient mechanisms for evading the innate immune response during mammalian infection and has been shown to be resistant to the complement-mediated bactericidal activity of human serum. It is well recognized that B. burgdorferi expresses multiple lipoproteins on its surface that bind the human complement inhibitors factor H and factor H-like protein 1 (FH/FHL-1). The binding of FH/FHL-1 on the surface of B. burgdorferi is thought to enhance its ability to evade serum-mediated killing during the acute phase of infection. One of the key B. burgdorferi FH/FHL-1 binding proteins identified thus far was designated CspA. While it is known that CspA binds FH/FHL-1, it is unclear how the interaction between CspA and FH/FHL-1 specifically enhances serum resistance. To better understand how CspA mediates serum resistance in B. burgdorferi, we inactivated cspA in a virulent strain of B. burgdorferi. An affinity ligand blot immunoassay and indirect immunofluorescence revealed that the CspA mutant does not efficiently bind human FH to its surface. Consistent with the lack of FH binding, the CspA mutant was also highly sensitive to killing by human serum. Additionally, the deposition of complement components C3, C6, and C5b-9 was enhanced on the surface of the CspA mutant compared to that of the wild-type strain. The combined data lead us to conclude that the CspA-mediated binding of human FH confers serum resistance by directly inhibiting complement deposition on the surface of B. burgdorferi.

Birds, babies and blood.

This is an autobiographical review describing the author's career in immunology research and summarizing his current understanding of the areas involved. Contributions to autoimmunity, immune deficiency, transfusion immunology, HLA-disease associations, reproductive immunology, cellular therapies, and innate immunity are included; also discussion of medical research ethics and various research-related activities.

Efeitos do tempo de prática nos parâmetros bioquímicos, hormonais e hematológicos de praticantes de jiu-jitsu brasileiro / Efectos del tiempo de práctica en los parámetros bioquímicos, hormonales y hematológicos de practicantes de jiu-jitsu brasileño / Effects of duration practice in biochemical, hormonal and hematological parameters of people who practice brazilian jiu-jitsu

Objetivo. O presente estudo objetivou quantificar parâmetros bioquímicos, hormonais e hematológicos de atletas iniciantes e experientes na prática de Brazilian jiu-jitsu (BJJ). Método. Participaram 16 homens adultos, alocados em três grupos: iniciante (INI, n = 4), experiente (EXP, n = 4) e controle (CON, n = 8), com diferença no tempo de prática entre os grupos de 5,05 ± 0,7 anos (INI = 1,95 ± 1,5 anos versus EXP = 7,0 ± 0,8 anos). Resultados. Observou-se diferença hematológica discreta, apenas associada à contagem e ao percentual do número de eosinófilos do INI em comparação aos demais (p < 0,05). A concentração de magnésio foi superior no EXP em relação ao CON (1,96 ± 0,09 mg/dL versus 1,75 ± 0,11 mg/dL; p = 0,03), ocorrendo o mesmo para creatinina (1,09 ± 0,06 mg/dL versus 0,88 ± 0,06 mg/dL; p = 0,01). Além disto, os índices de ligação do ferro apresentaram diferenças entre o EXP e CON, com INI exibindo valores intermediários. Por fim, não foram observadas diferenças significantes nos níveis de cortisol no EXP (502,60 ± 162,42 nmol/L) e INI (427,15 ± 157,16 nmol/L) e de testosterona (EXP = 5,57 ± 0,75 ng/dL contra INI = 6,43 ± 1,01 ng/dL). Conclusões. Com base nos resultados, pode-se inferir que a prática crônica do BJJ pode promover algumas alterações no quadro hematológico, bioquímico e hormonal dos praticantes

Objetivos. El presente estudio objetivó cuantificar los perfiles bioquímicos, hormonales y hematológicos de atletas principiantes y experimentados en jiu-jitsu brasileño (BJJ). Métodos. Participaron 16 hombres adultos, divididos en tres grupos: principiantes (INI, n = 4), experimentado (EXP, n = 4) y de control (CON, n = 8), con diferencia en el tiempo de práctica entre grupos de 5,05 ± 0,7 años (INI = 1,95 ± 1,5 años versus EXP = 7,0 ± 0,8 años). Resultados. Se observó diferencia hematológica discreta, apenas asociada al contaje y al porcentaje del número eosinófilo del INI en comparación a los demás (p < 0,05). La concentración de magnesio fue más elevada en el EXP que en el CON (1,96 ± 0,09 mg/dL versus 1,75 ± 0,11mg/dL; p = 0,03), ocurriendo lo mismo para creatinina (1,09 ± 0,06 mg/dL versus 0,88 ± 0,06 mg/dL; p = 0,01). Además de eso, los índices de ligación del ferro presentaron diferencias entre el EXP y CON, con INI mostrando valores intermediarios. Por fin, no se observan variación de los niveles de cortisol en el EXP (502,60 ± 162,42 nmol/L) e INI (427,15 ± 157,16 nmol/L), como también para testosterona (EXP = 5,57 ± 0,75ng/dL contra INI = 6,43 ± 1,01ng/dL). Conclusión. Con base en los resultados, se puede inferir que la práctica crónica de BJJ puede promover algunas alteraciones en el cuadro hematológico, bioquímico y hormonal de los luchadores(AU)

Objectives. This study aimed to quantify biochemical, hormonal and hematological profile of beginner and experienced athletes in brazilian jiu-jitsu (BJJ). Methods. In this study participated 16 adult men, divided into three groups: beginners (INI, n = 4), experienced (EXP, n = 4) and control (CON, n = 8), with differences in practice duration among the groups of 5,05 ± 0,7 years (INI = 1,95 ± 1,5 years versus EXP = 7,0 ± 0,8 years). Results. It has been observed discrete hematological difference, only associated to counting and to percentage of eosinophils number INI in comparison to the others (p < 0,05). Magnesium concentration was higher in the EXP than CON (1,96 ± 0,09 mg/dL versus 1,75 ± 0,11 mg/dL; p = 0,03), occurring the same for creatinine (1,09 ± 0,06 mg/dL versus 0,88 ± 0,06 mg/dL; p = 0,01). Besides that, the indexes of iron binding have presented differences between the EXP and CON, with INI showing intermediate scores. Finally, it were not observed variation of cortisol levels in the EXP (502,60 ± 162,42 nmol/L) and INI (427,15 ± 157,16 nmol/L), as well as for testosterone (EXP = 5,57 ± 0,75 ng/dL against INI = 6,43 ± 1,01 ng/dL). Conclusions. Based on the results, it can be inferred that chronic practice of BJJ could provoke alterations in the hematological, biochemical and hormonal conditions in their athletes(AU)

Valor pronóstico de las isoenzimas de LDH en pacientes con linforma no hodgkin / Prognostic value of LDH isoenzymes in patients with non-Hodgkin linforma

La enzima lactato deshidrogenasa (LDH) es un factor pronóstico en Linfoma No Hodgkin (LNH). El objetivo del trabajo consistió en evaluar prospectivamente el valor pronóstico de las isoenzimas de LDH en pacientes con LNH. Se estudiaron 67 pacientes de primera consulta con diagnóstico de LNH, sin tratamiento previo, VIH negativo y sin otras enfermedades, tiempo promedio de seguimiento 30 meses (rango 3-48 meses). Las muestras de suero se recolectaron previas al tratamiento. La LDH total (LDHT) e isoenzimas de LDH se determinaron respectivamente por método cinético y electroforesis de proteínas en gel de agarosa. Se procesaron muestras de 122 controles sanos para establecer los valores de referencia de las isoenzimas de LDH. 49(73%) LNH agresivos y 18(27%) LNH indolentes y según el Índice Pronóstico Internacional (IPI), 60 (90%) bajo riesgo y 7(10%) alto riesgo. Las isoenzimas LDH1, LDH2, LDH3, LDH4 y LDH5 presentaron niveles absolutos significativamente elevados en 25 (37%), 29 (43%), 32 (48%), 20 (39%) y 11 (16%) de los casos respectivamente (p<0,0001). La actividad porcentual de LDH4 en los pacientes con LNH agresivos fue significativamente superior respecto al grupo de LNH indolentes (p=0,01). En el análisis univariado, valores absolutos elevados de LDH1 se asociaron significativamente con una sobrevida global disminuida (p=0,0064) en el grupo total de pacientes. LDH1 conservó su valor pronóstico aún en el grupo de pacientes con valores normales de LDHT (p=0,04). En pacientes con LNH agresivos, valores elevados de LDHT e IPI alto riesgo se asociaron significativamente con una menor sobrevida global (p<0,05). En el análisis multivariado la LDHT e IPI resultaron factores pronósticos independientes de la sobrevida. Alteraciones específicas del patrón de isoenzimas de LDH sugieren la relación de LDH4 con la biología del tumor y su actividad proliferativa en LNH agresivos y el valor pronóstico de LDH1 como factor adverso de la sobrevida en el análisis univariado.

Lactate dehydrogenase (LDH) is a prognostic factor in non-Hodgkin lymphoma (NHL). Our objective was to evaluate prospectively the prognostic value of LDH isoenzymes in patients with NHL. We studied 67 newly diagnosed NHL patients, previously untreated, HIV-negative and free from other disease, median follow-up of 30 month (range 3-48 month). Before starting treatment serum samples were collected for the determination of total LDH (LDHT) and LDH isoenzymes that were respectively assayed by kinetic method and protein electrophoresis in agarose gel. In order to set reference values of LDH isoenzymes samples from122 healthy controls were processed. Results: 49(73%) of the patients were aggressive NHL and 18(27%) indolent NHL and according to the International Prognostic Index (IPI), 60(90 %) low risk and 7(10%) high risk. High absolute values of LDH1, LDH2, LDH3, LDH4 and LDH5 isoenzymes were significantly elevated in 25 (37%), 29 (43%), 32 (48%), 20 (39%) and 11 (16%) of cases respectively (p<0,0001). The percentage value of LDH4 activity in aggressive NHL patients was significantly higher compared to indolent NHL group (p=0,01). In univariate analysis increased LDH1 absolute values were significantly associated with decreased overall survival in the total group of patients (p = 0.0064). LDH1 remained a prognostic factor for survival even when considering the group of patients with normal serum LDHT values (p = 0.04). In patients with aggressive NHL increased values of LDHT and high risk IPI were significantly associated with decreased overall survival (p<0.05). In a multivariate analysis LDHT and IPI score were independent prognostic factor for survival.