Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients

BACKGROUND AND PURPOSE Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides≥150 mg/dL). METHODS We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19,100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10,498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. RESULTS A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14-1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03-1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93-1.65 in SPARCL). Time-varying analysis confirmed these findings. CONCLUSIONS The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.

Minimal residual disease in cancer therapy - Small things make all the difference

Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer cells appear to be an important target in the attempt to eradicate residual cancer cells, and eventually cure patients who repeatedly respond to anticancer therapy but lack complete tumor eradication.

Gallbladder and Pancreas in Henoch-Schönlein Purpura: Review of the Literature

OBJECTIVE Involvement of the pancreato-biliary system has been occasionally noted in Henoch-Schönlein purpura. Furthermore, cases of this vasculitis syndrome sometimes develop in the context of a viral hepatitis or after hepatitis vaccination. METHODS We completed a review of the literature. RESULTS Fifty reports published between 1977 and 2015 were retained for the analysis. A pancreato-biliary involvement was recognized in 34 individually well-described patients (♂:♀ = 19:15) with severe abdominal pain: pancreatitis (N = 20), acalculous cholecystitis (N = 11), both pancreatitis and cholecystitis (N = 3). In all of the pancreatitis patients, full recovery occurred (within ≤3 weeks in three-fourths of the patients). Cholecystectomy was performed in 8 cholecystitis patients. Seventeen Henoch-Schönlein patients (♂:♀ = 9:8) were associated with a viral liver disease and 4 (♂:♀ = 1:3) with a hepatitis vaccination. The vasculitis syndrome rapidly remitted in the 7 patients accompanying hepatitis A or E, in 2 patients of hepatitis B, and in the 4 patients preceded by a vaccination. Henoch-Schönlein purpura seemed to be serious in 5 patients with chronic hepatitis B and in 3 with chronic hepatitis C. CONCLUSIONS This analysis indicates that pancreato-biliary involvement is unusual in Henoch-Schönlein purpura. This complication deserves consideration in patients with especially severe abdominal pain. Finally, viral hepatitides and hepatitis vaccinations seem to be rare triggers of Henoch-Schönlein purpura.

Genetic epidemiology of gallbladder disease in Mexican Americans and cholesterol 7$\alpha$-hydroxylase gene sequence variation

Among Mexican Americans, the second largest minority group in the United States, the prevalence of gallbladder disease is markedly elevated. Previous data from both genetic admixture and family studies indicate that there is a genetic component to the occurrence of gallbladder disease in Mexican Americans. However, prior to this thesis no formal genetic analysis of gallbladder disease had been carried out nor had any contributing genes been identified.^ The results of complex segregation analysis in a sample of 232 Mexican American pedigrees documented the existence of a major gene having two alleles with age- and gender-specific effects influencing the occurrence of gallbladder disease. The estimated frequency of the allele increasing susceptibility was 0.39. The lifetime probabilities that an individual will be affected by gallbladder disease were 1.0, 0.54, and 0.00 for females of genotypes "AA", "Aa", and "aa", respectively, and 0.68, 0.30, and 0.00 for males, respectively. This analysis provided the first conclusive evidence for the existence of a common single gene having a large effect on the occurrence of gallbladder disease.^ Human cholesterol 7$\alpha$-hydroxylase is the rate-limiting enzyme in bile acid synthesis. The results of an association study in both a random sample and a matched case/control sample showed that there is a significant association between cholesterol 7$\alpha$-hydroxylase gene variation and the occurrence of gallbladder disease in Mexican Americans males but not in females. These data have implicated a specific gene, 7$\alpha$-hydroxylase, in the etiology of gallbladder disease in this population.^ Finally, I asked whether the inferred major gene from complex segregation analysis is genetically linked to the cholesterol 7$\alpha$-hydroxylase gene. Three pedigrees predicted to be informative for linkage analysis by virtue of supporting the major gene hypothesis and having parents with informative genotypes and multiple offspring were selected for this linkage analysis. In each of these pedigrees, the recombination fractions maximized at 0 with a positive, albeit low, LOD score. The results of this linkage analysis provide preliminary and suggestive evidence that the cholesterol 7$\alpha$-hydroxylase gene and the inferred gallbladder disease susceptibility gene are genetically linked. ^

La biomasa residual lignocelulósica como recurso energético renovable en el Oasis Norte de la provincia de Mendoza, Argentina

El objetivo de esta tesina es evaluar la disponibilidad de biomasa residual lignocelulósica, proveniente de la viticultura, olivicultura y fruticultura, en el Oasis Norte de la provincia de Mendoza, como recurso energético renovable. Se utilizan datos del Registro Único de la Tierra para conocer, por distrito, la superficie cultivada de cada especie vegetal. A través de consultas a profesionales locales, recopilación de información y datos de trabajos del ámbito local, nacional e internacional, se identifican coeficientes de disponibilidad de biomasa y las particularidades que condicionan su aprovechamiento. Los datos se procesan con planillas de cálculo y se aplican en la elaboración de mapas y resultados. Por último se comparan los resultados obtenidos con otros provenientes de estudios regionales en la materia. Los resultados arrojan cifras esperadas y comparables con estudios previos. Se dispone entre 86.286 y 440.669 t*año-1 de biomasa lignocelulósica y entre 1.114.160 GJ*año-1 y 5.856.385 GJ*año-1 de energía según los distintos escenarios evaluados. A nivel del Oasis Norte se puede instalar una planta de generación de energía por incineración de esta biomasa de una potencia entre 8,5 MWe a 76,6 MWe según escenarios. La gran variabilidad de los resultados de cada escenario se debe a la diferencia de factores de Relación de Generación de Residuos y Escobajos, poniendo de manifiesto la importancia de fomentar la investigación en este campo.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.