Usefulness of 24-hour ambulatory blood pressure monitoring in a population with high cardiovascular risk.

BACKGROUND: High blood pressure is considered a disease and at the same time a cardiovascular risk factor, mainly involved in ischemic heart disease, cerebrovascular disease and kidney failure, causing high mortality worldwide. OBJECTIVE: The objective was to follow up with 24-hour ambulatory blood pressure monitoring in patients with high blood pressure belonging to a population with high cardiovascular risk. METHOD: Descriptive, observational, retrospective study, which analyzes 24-hour outpatient pressure controls of 1858 patients, in Cartagena, Colombia. RESULTS: 1173 exams were validated and included in the study. The median age was 66 years. 66.8% (783) were women and 33.2% (390) were men. The main changes occurred during the night, when 79.1% of the patients had high systolic pressure loads, 65.6% recorded diastolic pressure averages and 83.7% had abnormal circadian patterns. Only 11% of the studies were normal in all parameters. CONCLUSIONS: 24-hour ambulatory blood pressure monitoring proved to be a useful tool to identify uncontrolled hypertensive patients, detect nocturnal hypertension and abnormal circadian patterns, which are risk markers for cardiovascular morbidity and mortality.

ANTECEDENTES: La hipertensión arterial es considerada una enfermedad y al mismo tiempo un factor de riesgo cardiovascular, involucrada principalmente en la cardiopatía isquémica, la enfermedad cerebrovascular y la insuficiencia renal, causando una elevada mortalidad. OBJETIVO: Realizar seguimiento con monitoreo ambulatorio de la presión arterial de 24 horas en pacientes con hipertensión arterial pertenecientes a una población con alto riesgo cardiovascular. MÉTODO: Estudio descriptivo, observacional, retrospectivo, en el que se analizaron los monitoreos ambulatorios de presión de 24 horas de 1858 pacientes, en Cartagena, Colombia. RESULTADOS: Se incluyeron 1173 registros. La mediana de edad fue de 66 años. El 66.8% (783) fueron mujeres y el 33.2% (390) fueron hombres. Las principales alteraciones ocurrieron durante la noche, cuando el 79.1% de los pacientes tuvieron cargas elevadas de presión sistólica, el 65.6% registraron promedios elevados de presión diastólica y el 83.7% tuvieron patrones circadianos anormales. Solo el 11% de los estudios fueron normales en todos los parámetros. CONCLUSIONES: El monitoreo ambulatorio de la presión arterial de 24 horas demostró ser una herramienta útil para identificar a los pacientes hipertensos no controlados, detectando hipertensión nocturna y patrones circadianos anormales, los cuales son marcadores de riesgo para morbilidad y mortalidad cardiovascular.

VLPs Derived from the CCMV Plant Virus Can Directly Transfect and Deliver Heterologous Genes for Translation into Mammalian Cells.

Virus-like particles (VLPs) are being used for therapeutic developments such as vaccines and drug nanocarriers. Among these, plant virus capsids are gaining interest for the formation of VLPs because they can be safely handled and are noncytotoxic. A paradigm in virology, however, is that plant viruses cannot transfect and deliver directly their genetic material or other cargos into mammalian cells. In this work, we prepared VLPs with the CCMV capsid and the mRNA-EGFP as a cargo and reporter gene. We show, for the first time, that these plant virus-based VLPs are capable of directly transfecting different eukaryotic cell lines, without the aid of any transfecting adjuvant, and delivering their nucleic acid for translation as observed by the presence of fluorescent protein. Our results show that the CCMV capsid is a good noncytotoxic container for genome delivery into mammalian cells.

Muerte súbita debida a cardiotoxicidad aguda inducida por antraciclinas / Sudden death due to anthracycline-induced acute cardiotoxicity

Resumen Antraciclinas como la doxorrubicina, así como anticuerpos monoclonales, como el trastuzumab, y agentes alquilantes, como la ciclofosfamida, son compuestos muy útiles como quimioterapia citotóxica al reducir en forma significativa la mortalidad relacionada con el cáncer. Sin embargo, su potencial cardiotoxicidad es un efecto adverso mayor que puede presentarse en cualquier momento de su administración o posterior a la misma, en especial cuando se usan combinados. La toxicidad cardiovascular por doxorrubicina suele ser dependiente de dosis e irreversible, mientras la ocasionada por trastuzumab no lo es. Se han encontrado cambios electrocardiográficos habituales durante la administración de quimioterapia, independiente de la dosis acumulada; a estos cambios agudos se les ha dado poca importancia, aunque pueden suceder hasta en el 40% de los pacientes. A pesar de la aparición documentada de arritmias tanto en humanos como en modelos animales, la muerte súbita cardiaca durante o inmediatamente después de la infusión de quimioterapia no está bien descrita. Se presenta el caso de un adulto joven sin antecedentes cardiovasculares, con linfoma no-Hodgkin y corazón con imagen ecocardiográfica muy sugestiva de infiltración linfomatosa del ventrículo izquierdo, quien desarrolla alteraciones del ritmo cardiaco que condicionan muerte súbita tras la infusión endovenosa lenta de doxorrubicina y trastuzumab.

Abstract Anthracyclines, such as doxorubicin, and monoclonal antibodies, such as trastuzumab, are compounds of wide clinical use as cytotoxic chemotherapy as they significantly reduce cancer-related mortality. However, the toxicity is a major adverse effect of these agents, which may occur at any time in their administration or afterwards, especially when used in combination. Cardiovascular toxicity by doxorubicin is dose-dependent and irreversible, while that caused by trastuzumab is not. Common electrocardiographic changes have been found during the administration of chemotherapy, independent of the cumulative dose, but these acute changes have been given little importance, although they may occur up to 40% of patients. Despite documented evidence of arrhythmias in both human and animal models, sudden cardiac death during or immediately after the infusion of chemotherapy is not well described. This paper describes a young adult with no history of cardiovascular disease, with non-Hodgkin´s lymphoma and a heart image very suggestive of left ventricle lymphomatous infiltration. The patient developed heart rhythm disturbances that lead to sudden death after slow intravenous infusion of doxorubicin.

Gating the glutamate gate of CLC-2 chloride channel by pore occupancy.

CLC-2 channels are dimeric double-barreled chloride channels that open in response to hyperpolarization. Hyperpolarization activates protopore gates that independently regulate the permeability of the pore in each subunit and the common gate that affects the permeability through both pores. CLC-2 channels lack classic transmembrane voltage-sensing domains; instead, their protopore gates (residing within the pore and each formed by the side chain of a glutamate residue) open under repulsion by permeant intracellular anions or protonation by extracellular H(+). Here, we show that voltage-dependent gating of CLC-2: (a) is facilitated when permeant anions (Cl(-), Br(-), SCN(-), and I(-)) are present in the cytosolic side; (b) happens with poorly permeant anions fluoride, glutamate, gluconate, and methanesulfonate present in the cytosolic side; (c) depends on pore occupancy by permeant and poorly permeant anions; (d) is strongly facilitated by multi-ion occupancy; (e) is absent under likely protonation conditions (pHe = 5.5 or 6.5) in cells dialyzed with acetate (an impermeant anion); and (f) was the same at intracellular pH 7.3 and 4.2; and (g) is observed in both whole-cell and inside-out patches exposed to increasing [Cl(-)]i under unlikely protonation conditions (pHe = 10). Thus, based on our results we propose that hyperpolarization activates CLC-2 mainly by driving intracellular anions into the channel pores, and that protonation by extracellular H(+) plays a minor role in dislodging the glutamate gate.

The EPA2 adhesin encoding gene is responsive to oxidative stress in the opportunistic fungal pathogen Candida glabrata.

Candida glabrata has emerged as an important opportunistic pathogen in both mucosal and bloodstream infections. C. glabrata contains 67 adhesin-like glycosylphosphatidylinositol-cell-wall proteins (GPI-CWPs), which are classified into seven groups and the largest is the Epa family. Epa proteins are very diverse and their expression is differentially regulated. Like many of the EPA genes, EPA2 is localized in a subtelomeric region where it is subject to chromatin-based transcriptional silencing and its role remains largely unexplored. In this study, we show that EPA2 gene is induced specifically in vitro in the presence of oxidative stress generated by H2O2. This induction is dependent on both Yap1 and Skn7, whereas Msn4 represses EPA2 expression. Interestingly, EPA2 is not induced during phagocytosis, but its expression can be identified in the liver in a murine model of systemic infection. Epa2 has no effect on the virulence of C. glabrata. The work presented herein provides a foundation for future studies to dissect the molecular mechanism(s) by which EPA2 of C. glabrata can be induced in the presence of oxidative stress in a region subject to subtelomeric silencing.

Patient preferences and treatment safety for uncomplicated vulvovaginal candidiasis in primary health care.

BACKGROUND: Vaginitis is a common complaint in primary care. In uncomplicated candidal vaginitis, there are no differences in effectiveness between oral or vaginal treatment. Some studies describe that the preferred treatment is the oral one, but a Cochrane's review points out inconsistencies associated with the report of the preferred way that limit the use of such data. Risk factors associated with recurrent vulvovaginal candidiasis still remain controversial. METHODS/DESIGN: This work describes a protocol of a multicentric prospective observational study with one year follow up, to describe the women's reasons and preferences to choose the way of administration (oral vs topical) in the treatment of not complicated candidal vaginitis. The number of women required is 765, they are chosen by consecutive sampling. All of whom are aged 16 and over with vaginal discharge and/or vaginal pruritus, diagnosed with not complicated vulvovaginitis in Primary Care in Madrid.The main outcome variable is the preferences of the patients in treatment choice; secondary outcome variables are time to symptoms relief and adverse reactions and the frequency of recurrent vulvovaginitis and the risk factors. In the statistical analysis, for the main objective will be descriptive for each of the variables, bivariant analysis and multivariate analysis (logistic regression).. The dependent variable being the type of treatment chosen (oral or topical) and the independent, the variables that after bivariant analysis, have been associated to the treatment preference. DISCUSSION: Clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient.

Control of volume-sensitive chloride channel inactivation by the coupled action of intracellular chloride and extracellular protons.

The volume-sensitive chloride current (I(ClVol)) exhibit a time-dependent decay presumably due to channel inactivation. In this work, we studied the effects of chloride ions (Cl(-)) and H(+) ions on I(ClVol) decay recorded in HEK-293 and HL-60 cells using the whole-cell patch clamp technique. Under control conditions ([Cl(-)](e) = [Cl(-)](i) = 140 mM and pH(i) = pH(e) = 7.3), I(ClVol) in HEK cells shows a large decay at positive voltages but in HL-60 cells I(ClVol) remained constant independently of time. In HEK-293 cells, simultaneously raising the [Cl(-)](e) and [Cl(-)](i) from 25 to 140 mM (with pH(e) = pH(i) = 7.3) increased the fraction of inactivated channels (FIC). This effect was reproduced by elevating [Cl(-)](i) while keeping the [Cl(-)](e) constant. Furthermore, a decrease in pH(e) from 7.3 to 5.5 accelerated current decay and increased FIC when [Cl(-)] was 140 mM but not 25 mM. In HL-60 cells, a slight I(ClVol) decay was seen when the pH(e) was reduced from 7.3 to 5.5. Our data show that inactivation of I(ClVol) can be controlled by changing either the Cl(-) or H(+) concentration or both. Based on our results and previously published data, we have built a model that explains VRAC inactivation. In the model the H(+) binding site is located outside the electrical field near the extracellular entry whilst the Cl(-) binding site is intracellular. The model depicts inactivation as a pore constriction that happens by simultaneous binding of H(+) and Cl(-) ions to the channel followed by a voltage-dependent conformational change that ultimately causes inactivation.

Lack of coupling between membrane stretching and pannexin-1 hemichannels.

We investigated whether pannexin-1, a carbenoxolone-sensitive hemichannel activated in erythrocytes by swelling, could be activated by swelling stress and contribute to swelling-activated chloride currents (I(Cl,swell)) in HEK-293 cells. We used ethidium bromide uptake as an index of pannexin-1 activation and I(C,swell) activation as an index of plasma membrane stretching. I(Cl,swell) activated by a hypotonic solution was reversible inhibited by carbenoxolone (IC(50) 98+/-5 microM). However, the hypotonic solution that activated I(Cl,swell) did not induce ethidium bromide uptake indicating that pannexin-1 was not activated by cell swelling. The mimetic peptide (10)panx1, a pannexin-1 antagonist, did not affect I(Cl,swell) activation but completely inhibited the ATP-induced ethidium bromide uptake coupled to P2X(7) receptors activation. We conclude that carbenoxolone directly inhibited I(Cl,swell) independent of pannexin-1 and that pannexin-1 hemichannels are not activated by swelling in HEK-293 cells.

Na+ modulates anion permeation and block of P2X7 receptors from mouse parotid glands.

We previously reported that mouse parotid acinar cells display anion conductance (I(ATPCl)) when stimulated by external ATP in Na+-free extracellular solutions. It has been suggested that the P2X7 receptor channel (P2X7R) might underlie I(ATPCl). In this work we show that I (ATPCl) can be activated by ATP, ADP, AMP-PNP, ATPgammaS and CTP. This is consistent with the nucleotide sensitivity of P2X7R. Accordingly, acinar cells isolated from P2X7R( -/- ) mice lacked I(ATPCl). Experiments with P2X7R heterologously expressed resulted in ATP-activated currents (I(ATP-P2X7)) partially carried by anions. In Na(+)-free solutions, I (ATP-P2X7) had an apparent anion permeability sequence of SCN(-) > I(-) congruent with NO3(-) > Br(-) > Cl(-) > acetate, comparable to that reported for I(ATPCl) under the same conditions. However, in the presence of physiologically relevant concentrations of external Na+, the Cl(-) permeability of I(ATP-P2X7) was negligible, although permeation of Br(-) or SCN(-) was clearly resolved. Relative anion permeabilities were not modified by addition of 1 mM: carbenoxolone, a blocker of Pannexin-1. Moreover, cibacron blue 3GA, which blocks the Na(+) current activated by ATP in acinar cells but not I(ATPCl), blocked I(ATP-P2X7) in a dose-dependent manner when Na+ was present but failed to do so in tetraethylammonium containing solutions. Thus, our data indicate that P2X7R is fundamental for I(ATPCl) generation in acinar cells and that external Na+ modulates ion permeability and conductivity, as well as drug affinity, in P2X7R.

Novel outwardly rectifying anion conductance in Xenopus oocytes.

We describe a novel, strongly outwardly rectifying anion current in Xenopus laevis oocytes, that we have named I(Cl,Or)- The properties of I(Cl,Or) are different from those of any other anion conductance previously described in these cells. Typically, I(Cl,Or) amplitude was small when extracellular Cl- (Cle) was the permeant anion. However, when Cle was replaced by lyotropic anions I(Cl,Or) became evident as a time-independent current. (ICl,Or) was voltage dependent and showed a remarkable outwards rectification with little or no inwards tail current. The relative selectivity sequence determined from current amplitudes was: SCN- > or = ClO4- > I- > Br- > or = NO3- > Cl- x I(Cl,Or) was insensitive to Gd3+ but was blocked by micromolar concentrations of niflumic acid, DIDS or Zn2+. Furthermore, I(Cl,Or) was not affected by buffering intracellular Ca2+ with BAPTA. Low extracellular pH inhibited I(Cl,Or) with a pK of 5.8. We propose that I(Cl,Or) might result from activation of endogenous ClC-5-like Cl- channels present in Xenopus oocytes.

Evaluación clínica del buflomedil en pacientes adultos con síndrome demencial / Clinical evaluation of buflomedil in adult patients with demential syndrome

Se realizó un estudio simple ciego paralelo con duración de seis meses, para evaluar la eficacia de buflomedil y vincamina en pacientes con síndrome demencial. De sesenta y dos pacientes que reunieron los criterios de inclusión (7 ó más puntos de la escala isquémica de Haschinski), hubo 14 deserciones; los 48 pacientes restantes se dividieron en dos grupos: 25 recibieron buflomedil (450 mg/día) y 23 vincamina (60mg/día) durante 180 días sin interrupción. Se les practicó: a) examen neurológico, b) psicométrico, c) registro de signos vitales, d) datos de tolerancia al medicamento y electroencefalograma los días 0,90 y 180. Los estudios a, c y d, también se hicieron los días 30, 60, 120 y 150. Los dos medicamentos modificaron estadísticamente los parámetros psicométricos y no hubo cambios neurológicos, modificación electroencefalográfica, ni en los signos vitales, ni hubo datos de intolerancia al medicamento. El buflomedil modificó favorablemente los parámetros de inteligencia en la prueba de Wais tanto para el cociente verbal como de ejecución. Así mismo, los pacientes menores de 75 años mejoraron el cociente mnésio. Cambios similiares también se observaron en otros parámetros (cociente mnésico global) en la prueba de Weschler y Bender en los tratados con vincamina. Ambos medicamentos pueden ser útiles como un recurso más en la terapéutica del paciente con síndrome demencial