Effect of metabolic control on recurrent major adverse cardiovascular events and cardiovascular mortality in patients with premature coronary artery disease: Results of the Genetics of Atherosclerotic Disease study.

BACKGROUND AND AIMS: Coronary artery disease (CAD) is the leading cause of death around the world, and its rate of presentation is increasing at young ages. Despite the evidence that secondary prevention in CAD reduces the risk of recurrent major adverse cardiovascular events (MACE), no studies have analyzed the composite control of blood pressure, lipids, and glucose control in premature CAD. METHODS AND RESULTS: This was a real-world prospective cohort study of patients with premature CAD. The composite control in blood pressure <140/80 mmHg, LDL-C <70 mg/dL, non-HDL-C <100 mg/dL, and Hemoglobin A1c <8% was considered as metabolic control. The primary endpoint was the occurrence of non-fatal and fatal MACE. The data included 1042 patients with premature CAD. The mean age of the patients was 54.1 ± 8.1 years, 18.5% were women, and had a median follow-up of 59.1 ± 11.8 months. Of them, 7% had non-fatal MACE, and 4% had a fatal MACE. Overall, 21.3% achieved metabolic control, and 3.0% did not achieve any target. Cox regression analysis showed that percutaneous coronary intervention (Hazzard ratio = 1.883 [95% CI, 1.131-3.136]), C-reactive protein (1.046 [1.020-1.073]), blood pressure >140/90 mmHg (2.686 [1.506-4.791]), fibrates (2.032 [1.160-3.562]), calcium channel blockers (2.082 [1.158-3.744]) had greater risk to present a recurrent non-fatal MACE; whereas familial history of premature CAD (2.419 [1.240-4.721]), heart failure (2.139 [1.032-4.433]), LDL-C >70 mg/dL (4.594 [1.401-15.069]), and diuretics (3.328 [1.677-6.605]) were associated with cardiovascular mortality. CONCLUSIONS: The composite goal achievement in lipids, blood pressure and glucose, reduced the risk for recurrent MACE in 80%.

Oxidative modifications of foetal LDL-c and HDL-c lipoproteins in preeclampsia.

BACKGROUND: Oxidative modifications have been observed in lipids and proteins in lipoproteins isolated from women with preeclampsia. Thus, newborns could also be susceptible to this damage directly through their mothers. In this study, we evaluated the oxidative profile of LDL-c and HDL-c lipoproteins isolated from the umbilical cord from newborns born to women with preeclampsia. METHODS: Thirty newborns born to women with preeclampsia and thirty newborns born to women with healthy pregnancies were included. Lipid-damage biomarkers, including conjugated dienes, lipohydroperoxides and malondialdehyde, were measured. The reduction of nitroblue tetrazolium, formation of dityrosines, and carbonylation of proteins were assessed as indicators of protein damage. The protective activity of paraoxonase-I on HDL-c particles was evaluated. The total antioxidant capacity and lipid profiles were quantified in plasma. Data were analysed using Student's t-tests and Pearson correlation coefficients. RESULTS: Compared with the control group, the preeclampsia group had an increase in the percentage of lipid damage in both lipoproteins. There was an increase of 23.3 and 19.9% for conjugated dienes, 82.4 and 21.1% for lipohydroperoxides, and 103.8 and 51.5% for malondialdehyde in LDL-c and HDL-c, respectively. However, these infants did not show evident damage in protein oxidation. The activity of the enzyme paraoxonase-I was decreased by 36.2%; by contrast, the total antioxidant capacity was increased by 40% (protein) and 28.8% (non-protein). CONCLUSIONS: The oxidative modifications that occur in HDL-c and LDL-c isolated from newborns from women with preeclampsia are mainly caused by lipoperoxidation processes related to evident paraoxonase-I inactivation. The absence of protein damage is likely linked to an increase in total antioxidant capacity. Therefore, antioxidant support could be helpful in reducing oxidative stress in mother/newborn dyads.

Pioglitazone improves the cardiovascular profile in patients with uncomplicated systemic lupus erythematosus: a double-blind randomized clinical trial.

OBJECTIVE: We studied the effect of pioglitazone on insulin levels, inflammation markers, high-density lipoprotein (HDL) composition and subclasses distribution, in young women with uncomplicated systemic lupus erythematosus (SLE). METHODS: This double-blind trial included 30 premenopausal women (30 ±8 years old) with SLE, who were randomized to pioglitazone (30 mg/day) or placebo treatment for 3 months. Plasma and HDL lipids were determined by colorimetric enzymatic assays, insulin by radioimmunometric assay, inflammation by immunonephelometry and HDL size and subclasses distribution by a native 4-30% polyacrylamide gradient gel electrophoresis. RESULTS: Compared with placebo, pioglitazone significantly increased HDL-cholesterol plasma levels (14.2%), reduced fasting insulin plasma levels (23.6%) and the homeostasis model assessment-insulin resistance (31.7%). C-reactive protein (70.9%) and serum amyloid A (34.9%) were also significantly reduced with the pioglitazone use, whereas the HDL particle size was increased (8.80 nm vs. 8.95 nm; p = 0.044) by changes in the distribution of HDL(2b), HDL(3b), and HDL(3c) subclasses. The change in HDL size correlated with a rise in free and cholesterol-ester content in the HDL particles. CONCLUSION: Pioglitazone significantly enhanced insulin sensitivity, reduced inflammation, and modified HDL characteristics, suggesting a potential beneficial effect of this drug in patients with SLE with a risk to develop cardiovascular disease. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov Protocol Registration System, with the number NCT01322308.

[Anemia in chronic heart failure]. / Anemia en la insuficiencia cardiaca crónica.

Anemia is one of the most common comorbidities in patients with decompensated chronic heart failure admitted to the Internal Medicine Ward. However, although there is evidence supporting its treatment to improve the functional capacity of the patients and to reduce the new admissions rate, the clinical practice guidelines do not provide any directives regarding its approach. This is an ideal clinical problem for the internist due to its multifactorial origin and the comprehensive point of view needed to approach the group of syndromes that occur in these patients (anemia, heart failure, geriatric syndromes, diabetes, etc.) The choice of treatment strategy, if such treatment is decided, should always begin after correcting the congestive signs in the outpatient with optimal treatment of heart failure.

What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.

BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

Codon usage bias covaries with expression breadth and the rate of synonymous evolution in humans, but this is not evidence for selection.

In numerous species, from bacteria to Drosophila, evidence suggests that selection acts even on synonymous codon usage: codon bias is greater in more abundantly expressed genes, the rate of synonymous evolution is lower in genes with greater codon bias, and there is consistency between genes in the same species in which codons are preferred. In contrast, in mammals, while nonequal use of alternative codons is observed, the bias is attributed to the background variance in nucleotide concentrations, reflected in the similar nucleotide composition of flanking noncoding and exonic third sites. However, a systematic examination of the covariants of codon usage controlling for background nucleotide content has yet to be performed. Here we present a new method to measure codon bias that corrects for background nucleotide content and apply this to 2396 human genes. Nearly all (99%) exhibit a higher amount of codon bias than expected by chance. The patterns associated with selectively driven codon bias are weakly recovered: Broadly expressed genes have a higher level of bias than do tissue-specific genes, the bias is higher for genes with lower rates of synonymous substitutions, and certain codons are repeatedly preferred. However, while these patterns are suggestive, the first two patterns appear to be methodological artifacts. The last pattern reflects in part biases in usage of nucleotide pairs. We conclude that we find no evidence for selection on codon usage in humans.

Molecular and functional characterization of recombinant human metabotropic glutamate receptor subtype 5.

We have isolated and characterized overlapping cDNAs that encode two isoforms of the human metabotropic glutamate receptor subtype 5 (hmGluR5). The deduced amino acid sequences of human and rat mGluR5a are 94.5% identical. However, a region in the putative cytoplasmic domain (SER926-ALA1121) displays significant sequence divergence. Genomic analysis of this region showed that the sequence divergence results from species-specific differences in the genomic sequences, not from alternative splicing. The distribution of mGluR5 mRNA in human brain was most strongly detected throughout the hippocampus, with moderate levels in the caudate-putamen, cerebral cortex, thalamus, and deep cerebellar nuclei, and at low levels in the cerebellar cortex. Activation of both hmGluR5a and hmGluR5b transiently expressed in Xenopus oocytes and HEK293 cells was coupled to inositol phosphate (InsP) formation and elevation of the intracellular free calcium ([Ca2+]i). The agonist rank order of potency for activating recombinant hmGluR5a receptors in either system was quisqualate > L-glutamate > 1S,3R-ACPD. Both the quisqualate stimulated InsP and [Ca2+]i were inhibited by (+)-MCPG. Recombinant human mGluR5a was also stably expressed in mouse fibroblast Ltk- cells, in which the efficacy and potency of quisqualate were unchanged for more than 30 cell passages.

Occult cancer in patients with venous thromboembolism: which patients, which cancers.

We have previously demonstrated that patients with idiopathic venous thromboembolism (VTE) have a higher frequency of underlying cancer. Now we present a retrospective analysis of our 5-year experience with a series of 674 consecutive otherwise healthy patients, and a more restricted battery of diagnostic tests. Occult cancer was found in 15 patients during admission. The diagnostic tools which led to suspect occult cancer were: abdominal CT-scan (4 patients); high carcinoembryonic levels (2 patients); and high prostate-specific antigen levels (9 patients). Eight further patients were diagnosed of cancer after discharge. Cancer was more commonly found in patients with idiopathic VTE: 13/105 patients (12%) versus 10/569 patients (2%); p <0.01; O.R.: 7.9 (95% CI: 3.14-20.09). During the same period of time we diagnosed VTE in 147 patients with previously known cancer. When overall considered, VTE was the first sign of malignancy in most patients with prostatic and pancreatic carcinoma. On the contrary, most patients with breast, lung, uterine and brain cancers developed VTE as a terminal event of the disease. At variance with VTE patients and previously known cancer, most patients with occult malignancy were at an early stage. Further studies are needed to confirm whether patients with idiopathic VTE could benefit from screening for occult cancer. Meanwhile, our findings may serve as guidelines for physicians in this field.

Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits.

cDNA clones encoding human neuronal nicotinic acetylcholine receptor alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha 7, beta 2, beta 3, and beta 4 subunits were isolated from brainstem, hippocampus, prefrontal cortex, substantia nigra, thalamus, and IMR32 libraries. Human alpha 2 and alpha 6 and full-length beta 3 and beta 4 clones have not been previously reported. Deduced amino acid sequences of the alpha 2, alpha 6, beta 3, and beta 4 predicted mature peptides are 503 residues (56.9 kDa), 464 residues (53.7 kDa), 440 residues (50.8 kDa), and 477 residues (54.1 kDa), respectively. These sequences show 84 (alpha 2), 87 (alpha 6), 89 (beta 3), and 84% (beta 4) identity to the corresponding rat sequences. The amino termini of the human alpha 2 and beta 3 mature peptides contain 23 and six additional residues, respectively, compared to those of rat alpha 2 and beta 3. Recombinant receptors were expressed in Xenopus laevis oocytes injected with in vitro transcripts encoding either alpha 7 alone or alpha 2, alpha 3, or alpha 4 in pairwise combination with beta 2 or beta 4. Inward currents were elicited by the application of acetylcholine (1-100 microM) and other agonists; these responses were blocked 65-97% by application of 10 microM d-tubocurare, confirming functional expression of human nicotinic receptors.

Acute alcohol alters the excitability of cerebellar Purkinje neurons and hippocampal neurons in culture.

Acute exposure to ethanol at 22 and 44 mM concentrations altered several features of the current-evoked voltage responses of cerebellar Purkinje neurons and hippocampal neurons studied in culture model systems. Whole cell current clamp techniques were used. At 22 mM, ethanol depressed current-evoked spiking in the hippocampal neurons but enhanced the current-evoked spiking in the Purkinje neurons. In both neuronal types, 44 mM ethanol depressed spiking, the amplitude of the afterhyperpolarization generated at the termination of a current pulse and the amplitude of the off-response generated at the termination of a hyperpolarizing pulse. Ethanol had little or no effect on resting membrane potential or the passive membrane properties measured near resting level in either neuronal type. Some changes in the current-voltage curves were observed at more depolarized or hyperpolarized potentials in both neuronal types. In the Purkinje neurons, where spontaneous activity was a prominent feature of some recordings, exposure to ethanol reduced the frequency of the spontaneous events. These results indicate that acute exposure to ethanol at intoxicating doses alters the membrane excitability of these two CNS neuronal types. The ethanol induced changes in neuronal excitability presumably contribute to the changes in firing properties observed in extracellular recordings from these neuronal types in vivo and the behavioral effects observed during alcohol intoxication in animal models.

Cardiopulmonary resuscitation performance of subjects over forty is better following half-hour video self-instruction compared to traditional four-hour classroom training.

Cardiopulmonary resuscitation (CPR) training is not well targeted to family members of individuals at highest risk of cardiac arrest. Participants in traditional CPR classes (TRAD) average 31 years of age, while family members of cardiac patients average 55 years. Video self-instruction (VSI) can reach older individuals and others who do not participate in TRAD classes. VSI is a combination of a 34-min videotape and an inexpensive manikin intended for use in the home, where three-quarters of all out-of-hospital cardiac arrests occur. We exposed 202 subjects 40 years of age and older (mean age 59.4 years, S.D. = 10.9) to either TRAD or VSI, and tested them individually immediately following training rising validated methods including measurement by means of a Laerdal-Skillmeter manikin. According to American Heart Association (AHA) criteria, VSI subjects performed an average of 20.8% of all compressions and 25.1% of all ventilations correctly, compared with 3.4% of compressions and 1.7% of ventilations by TRAD subjects (P < 0.0001). VSI subjects performed an average of 10.1 of the total 14 CPR assessment and sequence skills correctly, compared with an average of 4.7 for TRAD (P < 0.0001). On a measure of overall performance, 62.7% of the VSI subjects were rated 'competent' or better (i.e. capable of performing CPR that 'would probably be effective'), compared to 6.1% of TRAD subjects (P < 0.0001). Only 17.8% of VSI subjects were rated as 'not competent' (i.e. unable to obtain a combination of any chest rise and any compression of the sternum) compared with 69.1% of TRAD subjects. VSI provides an effective, convenient, and inexpensive means of training persons over 40 years of age that achieves skill performance superior to TRAD.

[Assessment of thoracic X-ray readings by emergency room physicians at a university hospital]. / Evaluación de la interpretación de la radiografía de tórax por los médicos de guardia en un hospital universitario.

BACKGROUND: We aimed to find out whether systematic reading of chest radiography (CRx) by radiologists in the emergency unit might lead to a higher diagnostic efficiency and improve health care. MATERIAL AND METHOD: Descriptive study of consecutive admissions during 3 months in an internal medicine department. We registered the CRx interpretation by the emergency unit physician first, and a radiologist the next day. In cases with different interpretations, we assessed whether these differences would have modified the treatment. RESULTS: The overall disagreement between the emergency room physician and the radiologist was 13.7%. In 19 of 29 cases with different readings, the radiologist interpretation was in agreement with the final diagnosis. In 7 of these 19 cases, the radiologist reading of CRx would have led to a positive change of treatment. However, differences between both physicians were not statistically significant. CONCLUSIONS: There seems to be a higher diagnostic efficiency when the emergency room physician interpretation of CRx is complemented by a radiologist.

[Hemolytic anemia caused by pyrimidine 5'-nucleotidase (P5N) deficiency 15 years later. Apropos of 2 new cases of hereditary deficit and another one of lead poisoning]. / Anemia hemolítica por déficit de pirimidina 5'nucleotidasa (P5N) 15 años después. A propósito de 2 nuevos casos de déficit hereditario y otro de intoxicación por plomo.

Congenital pyrimidin 5'nucleotidase deficiency manifests as hemolytic anemia with basophilic stippling. In lead poisoning, anemia, basophilic stippling and inhibition of erythrocyte pyrimidin 5' deficiency are also observed. In the present work, we report two cases of hemolytic anemia secondary to congenital deficiency of pyrimidin 5' nucleotidase and another case secondary to lead poisoning. Since 1974, when pyrimidin 5' nucleotidase deficiency was isolated, is known that hemolysis is related to the accumulation of pyrimidin nucleotides within the erythrocytes that behave as metabolic inhibitors. However, the precise metabolic process whose inhibition leads to the shortening of erythrocytes half life has not been elucidated yet.

[Frequency of selective IgA deficiency in Basque Country]. / Frecuencia del déficit selectivo de IgA en el País Vasco.

BACKGROUND: To evaluate the frequency of IgA deficiency in the Basque Country, Spain, and establish a file of IgA-deficient blood donors, using a self laboratory test and checking medical records. MATERIALS AND METHODS: A screening radial immunodiffusion system was used on 2.607 blood donors samples. A search on the patients laboratory results was realized. RESULTS: Five blood donors were detected, and 2 of 30 patients fulfilled criteria for donation. CONCLUSIONS: The frequency obtained of IgA deficiency in the Basque Country was 1/521. The used method is economical and optimum to create a file of IgA-deficient blood donors.

[Diagnostic approach to neoplasms at an internal medicine service]. / Análisis de la conducta diagnóstica de las neoplasias en un servicio de medicina interna.

BACKGROUND: The aim of this study was to investigate the diagnostic behavior of different members of a department of internal medicine towards some neoplasms, analyzing the study times, reasons for suspicion and the number of tests performed and their results. PATIENTS AND METHODS: A retrospective review of the clinical histories of the patients admitted from January 1, 1992 to June 30, 1994 whose diagnosis was a new neoplasm of the digestive tract, lung cancer, cancer of unknown origin or lymphoma was carried out. The total diagnostic study time and the different partial times were measured and confirmed. The causes leading to suspicion of the neoplasms were also analyzed by groups, and finally the efficacy of the different diagnostic tests; either non invasive, oriented at the decision of the definitive test, or invasive (biopsies and fine needle aspiration puncture). RESULTS: The median total study time was 13 days with no differences between the groups. The median time until clinical suspicion was 0 days (interquartile range 0-2), being significantly greater in the digestive neoplasms. Less than half of the total study time corresponded to the clinical work itself (5 vs. 8 days). Suspicion of neoplasms in 49% of the cases arose from radiographic alteration and in 30% from clinical alterations. With regards to diagnostic tests, the value of thorax X-ray as the first exploration, mainly in the lung neoplasms (82.5% of the radiographies showed alterations), the elevated efficacy of computerized tomography, among the non invasive tests and fine needle aspiration puncture among the invasive tests were of note. Definitive diagnosis was achieved in 62% of the cases by biopsy and in 31% by fine needle aspiration puncture. CONCLUSIONS: Not all the time spent in achieving diagnosis of neoplasms is attributable to clinical work, although this may be shortened. To do so, a faster and more adequate use of the tests of greater performance (thorax X-ray, computerized tomography and fine needle aspiration puncture) should be used and performed with greater coordination and cooperation among the clinical technicians and physicians of the different departments.

[Taxonomy of some microteids from Venezuela (Squamata), II: Nomenklature situation of Prionodactylus ampuedai and Prionodactylus phelpsorum]. / Taxonomía de algunos microtéidos de Venezuela (Squamata), II: Situación nomenclatural de Prionodactylus ampuedai y Prionodactylus phelpsorum.

New records of the poorly known microteiid lizard Prionodactylus ampuedai, morphological variation, and new data on natural history are reported. We report the loss of the holotypes of P. ampuedai and P. phelpsorum, and designate a neotype for the former. Euspondylus goeleti is resurrected from the synonymy with E. phelpsorum and this latter is transferred to the genus Prionodactylus.

[Taxonomy of some microteids (Squamata) from Venezuela, I: variation and geographic distribution of Euspondylus acutirostris and description of a new Euspondylus from northeast Venezuela]. / Taxonomía de algunos microtéidos (Squamata) de Venezuela, I: Variación y distribución geográfica de Euspondylus acutirostris y descripción de un nuevo Euspondylus del nordeste de Venezuela.

Only two species of the microteiid lizard genus Euspondylus (E. acutirostris and E. phelpsorum) had been reported from Venezuela. New records of the poorly known gymnophthalmid lizard Euspondylus acutirostris are reported extending its known range along the Coastal Range and Sierra de Aroa (north-central Venezuela) and Sierra de San Luis (northwestern Venezuela), all records occurring at the cloud forest above 1000 m. Seven body measurements were included and morphological variation is described based on at least 17 new specimens. Sexual dimorphism is determined in, at least, eight characteristics of size and squamation. Specimens were found in epiphytic bromeliads and the ground. The populations from Sierra de Aroa and Sierra de San Luis (only one specimen known from each locality), differ from those of the Coastal Range (supposedly the nominal population) in some morphological and coloration features, suggesting that the former two could represent different taxonomical entities. A new species of Euspondylus is described based on a female (taken within a bromeliad) from Cerro El Humo, Sucre, northeastern Venezuela. It differs from congeners mainly by having keeled scales on the limbs and a very acute snout.

Features and costs of patients admitted for cardiac arrhythmias in Spain.

AIM: Cardiac rhythm alterations are a frequent cause of hospital admission. However, we do not know their characteristics and economic costs. We have analyzed the epidemiology and cost of hospitalizations due to cardiac arrhythmias in the National Health System. METHODS: The characteristics and costs were reviewed in patients admitted with a principal diagnosis of cardiac arrhythmia (1997-2010;diagnosis related groups [DRG] -138 and 139 of the National Health System minimum data base set). Atrial fibrillation/flutter accounted for 65% of these DRGs. The secondary diagnoses prevalent in such DRGs were also reviewed. RESULTS: Hospitalizations due to cardiac arrhythmias were approximately 26.000 per year and close to 1.6% for mortality. In 2010 there were 26.421 hospitalizations with an estimated cost of 65 million Euros. Frequent comorbidities were recorded, such as hypertension (43%), heart failure (12%) or diabetes mellitus (20%). A total of 43% were admitted to cardiology and 36% to internal medicine. CONCLUSIONS: During the period 1997-2010, there was a significant annual number of hospitalizations for cardiac arrhythmias (mainly atrial fibrillation), with measurable costs, in Spain. More than one third were attended by internists.