Tejido adiposo epicárdico en personas que viven con VIH: ¿una ventana hacia el riesgo cardiovascular? / Epicardial adipose tissue in people living with HIV: a window towards cardiovascular risk?

Introducción: En las personas que viven con el virus de la inmunodeficiencia humana (PVVIH) se han descripto desregulaciones metabólicas que podrían vincularse a un mayor riesgo cardiovascular.Objetivo: Evaluar el espesor del tejido adiposo epicárdico (ETAE) y la relación del mismo con parámetros clínicos y bioquímicos de riesgo cardiovascular en adultos que viven con VIH, comparados con controles seronegativos.Materiales y métodos: Observacional, inclusión prospectiva. Se incluyeron PVVIH >18 años y controles seronegativos para VIH, a los cuales se les midió el espesor de TAE en dos ejes por ecocardiograma transtorácico, así como el espesor de íntima media carotídea por ecografía doppler color.Resultados: 75 pacientes, 58,7% del sexo masculino, edad de 36 años (RIQ 22). 50,7% con VIH (CD4+: 512 cél/mm3 RIQ 382; 80% indetectables). IMC de 25,2 kg/m2 (RIQ 5,3) y circunferencia de cintura de 88,5 cm (DS 12,4), sin diferencias. Las PVVIH tuvieron menor HDL, mayor proteína C reactiva, mayor dímero D y mayor glucemia en ayunas. El ETAE fue mayor en las PVVIH (4,05 vs. 3,49 mm p=0,021), y se correlacionó con la edad, glucemia en ayunas y dímero D. En las PVVIH, se correlacionó con insulinemia, índice HOMA2-IR, HDL-c y dímero D. El tratamiento con Efavirenz se asoció a un mayor ETAE.Conclusión: Las PVVIH presentaron mayor inflamación sistémica de bajo grado y un mayor espesor de TAE que los controles sanos, el cual se asoció en este grupo a insulinorresistencia

Introduction: For people living with Human Immunodeficiency Virus (PLHIV), metabolic deregulations have been described, which could be related to a higher cardiovascular risk.Objective: To assess the epicardial adipose tissue thickness (EATT), and the relationship between this value and clinical and biochemical parameters of cardiovascular risk in adults living with HIV, if compared to a healthy control group. Methods: Observational, with prospective inclusion. It included PLHIV >18 years and seronegative controls. All of them had their EAT measured in two axes by transthoracic echocardiogram, as well as the carotid intima-media thickness determined by color doppler ultrasound.Results: 75 patients, 58.7% male, age of 36 years (RIQ 22). 50.7% patients with HIV (CD4+ of 512 cells/mm3; and 80% undetectable). BMI was of 25.2 kg/m2 and waist circumference of 88.5 cm, without between-groups differences. PLHIV had lower HDL, higher C reactive protein, higher D-dimer and higher fasting blood glucose. EATT was higher in PLHIV (4.05 vs 3.49 mm, p=0.021), and this correlated with age, fasting blood glucose and D-dimer. In PLHIV, it correlated with insulinemia, HOMA2-IR index, HDL-c ; and D-dimer. Treatment with Efavirenz was associated with a higher EATT.Conclusion: PLHIV presented increased systemic inflammation of low grade and higher EATT than the seronegative control group. EATT was associated in PLHIV to insulin resistance

Tumor de Buschke Lowenstein / Buschke Lowenstein Tumor

El tumor de Buschke Lowenstein o condiloma gigante es una tumoración epitelial benigna, causada por el virus del papiloma humano, trasmisible sexualmente, en muy pocos casos se transforma en maligna. Se presentó un paciente masculino de 51 años, con tabaquismo crónico, etilismo ocasional y relaciones sexuales inestables y desprotegidas. Acudió al Servicio de Urología del Centro Oncológico Provincial de Holguín a causa de lesiones verrugosas inguinales, penoescrotales y perineales, que se trataron años antes, sin embargo, el abandono del tratamiento por parte del paciente favoreció el desarrollo de nuevas lesiones, mostró infección sobreañadida por Proteus mirabilis que respondió con ciprofloxacino. Se realizó escisión quirúrgica de las lesiones inguinoescrotales y perineales, en las lesiones penianas, se combinó con tratamiento tópico. Se administraron también inmunomoduladores. La evolución postoperatoria fue satisfactoria. Las lesiones penianas, tratadas con podofilino y 5-fluorouracilo, experimentaron ulceración y regresión total. Durante el seguimiento, realizado por un año, se observó la aparición de lesiones de pequeño tamaño que se trataron localmente. Actualmente, no existe un tratamiento completamente resolutivo para esta enfermedad.

Buschke Lowenstein tumor or Acuminate Giant Condyloma is a benign epithelial tumor, caused by Human Papillomavirus, sexually transmissible and in rare cases, it becomes to malignant one. A male patient of 51 years old, chronic smoker, occasional alcoholic was presented in this article. Unstable with sexual relations. The patient came to Urology service for inguinal, penoscrotal and perineal verrucous damages, that were treated and reduced (2009), but the patient abandoned the treatment causing the damage development. Add infection by Proteus mirabilis was solved with ciprofloxacino. Surgical reception of inguinoescrotal and perineals damages were performed. For penile damages the topic treatment was combined. Satisfactory postoperative evolution was observed. The penile damages were treated with podofilino and 5-Fluorouracilo, so ulceration and total reduction were observed. Inmunomodulators were also given. For one year the patient presented small lesions. Nowadays there is no a specific and definitive treatment.

Tumor de Buschke Lowenstein / Buschke Lowenstein Tumor

El tumor de Buschke Lowenstein o condiloma gigante es una tumoración epitelial benigna, causada por el virus del papiloma humano, trasmisible sexualmente, en muy pocos casos se transforma en maligna. Se presentó un paciente masculino de 51 años, con tabaquismo crónico, etilismo ocasional y relaciones sexuales inestables y desprotegidas. Acudió al Servicio de Urología del Centro Oncológico Provincial de Holguín a causa de lesiones verrugosas inguinales, penoescrotales y perineales, que se trataron años antes, sin embargo, el abandono del tratamiento por parte del paciente favoreció el desarrollo de nuevas lesiones, mostró infección sobreañadida por Proteus mirabilis que respondió con ciprofloxacino. Se realizó escisión quirúrgica de las lesiones inguinoescrotales y perineales, en las lesiones penianas, se combinó con tratamiento tópico. Se administraron también inmunomoduladores. La evolución postoperatoria fue satisfactoria. Las lesiones penianas, tratadas con podofilino y 5-fluorouracilo, experimentaron ulceración y regresión total. Durante el seguimiento, realizado por un año, se observó la aparición de lesiones de pequeño tamaño que se trataron localmente. Actualmente, no existe un tratamiento completamente resolutivo para esta enfermedad(AU)

Good neurocognitive performance measured by the international HIV dementia scale in early HIV-1 infection.

OBJECTIVE: To evaluate neurocognitive performance in patients with preserved immunological status using the International HIV Dementia Scale (IHDS) and compare patients on and off highly active antiretroviral therapy (HAART). DESIGN: Cross-sectional study. METHODS: Outpatients with more than 350 CD4 cells per cubic millimeter underwent evaluation by means of the IHDS, a cross-cultural scale designed to identify HIV-positive patients at risk for dementia. RESULTS: A total of 260 patients were included, 158 on HAART and viral load <1000 copies per mL and 102 treatment naïve. Mean age was 38.2 (SD 8.03) years, 86% were male. Mean score was 10.9 (SD 1.77). Only age correlated with a significantly different score; younger patients performed better. When patients on and off HAART were compared, we found no significant differences in age, sex, time from diagnosis, educational level, risk factor for HIV acquisition, and current CD4 count. CD4 nadir was lower for patients on HAART: 246.0 (200.95) vs. 492.7 (233.33), P < 0.001. There was no difference between the scores obtained by patients on and off HAART (mean 11.0, SD 2.08; mean 10.8, SD 1.17; respectively, P = 0.70). There was no difference according to efavirenz use. CONCLUSIONS: Patients with preserved immunity performed well on IHDS. It didn't seem to be any difference between patients on and off HAART regarding neurocognitive status.

Nitric oxide reactivity with globins as investigated through computer simulation.

This chapter reviews the application of classical and quantum-mechanical atomistic simulation tools used in the investigation of several relevant issues in nitric oxide reactivity with globins and presents different simulation strategies based on classical force fields: standard molecular dynamics, essential dynamics, umbrella sampling, multiple steering molecular dynamics, and a novel technique for exploring the protein energy landscape. It also presents hybrid quantum-classical schemes as a tool to obtain relevant information regarding binding energies and chemical reactivity of globins. As illustrative examples, investigations of the structural flexibility, ligand migration profiles, oxygen affinity, and reactivity toward nitric oxide of truncated hemoglobin N of Mycobacterium tuberculosis are presented.

Mechanism of product release in NO detoxification from Mycobacterium tuberculosis truncated hemoglobin N.

The capability of Mycobacterium tuberculosis to rest in latency in the infected organism appears to be related to the disposal of detoxification mechanisms, which converts the nitric oxide (NO) produced by macrophages during the initial growth infection stage into a nitrate anion. Such a reaction appears to be associated with the truncated hemoglobin N (trHbN). Even though previous experimental and theoretical studies have examined the pathways used by NO and O2 to access the heme cavity, the eggression pathway of the nitrate anion is still a challenging question. In this work we present results obtained by means of classical and quantum chemistry simulations that show that trHbN is able to release rapidly the nitrate anion using an eggression pathway other than those used for the entry of both O2 and NO and that its release is promoted by hydration of the heme cavity. These results provide a detailed understanding of the molecular basis of the NO detoxification mechanism used by trHbN to guarantee an efficient NO detoxification and thus warrant survival of the microorganism under stress conditions.

Modeling heme proteins using atomistic simulations.

Heme proteins are found in all living organisms, and perform a wide variety of tasks ranging from electron transport, to the oxidation of organic compounds, to the sensing and transport of small molecules. In this work we review the application of classical and quantum-mechanical atomistic simulation tools to the investigation of several relevant issues in heme proteins chemistry: (i) conformational analysis, ligand migration, and solvation effects studied using classical molecular dynamics simulations; (ii) electronic structure and spin state energetics of the active sites explored using quantum-mechanics (QM) methods; (iii) the interaction of heme proteins with small ligands studied through hybrid quantum mechanics-molecular mechanics (QM-MM) techniques; (iv) and finally chemical reactivity and catalysis tackled by a combination of quantum and classical tools.

Heme protein oxygen affinity regulation exerted by proximal effects.

Heme proteins are found in all living organisms and are capable of performing a wide variety of tasks, requiring in many cases the binding of diatomic ligands, namely, O(2), CO, and/or NO. Therefore, subtle regulation of these diatomic ligands' affinity is one of the key issues for determining a heme protein's function. This regulation is achieved through direct H-bond interactions between the bound ligand and the protein, and by subtle tuning of the intrinsic heme group reactivity. In this work, we present an investigation of the proximal regulation of oxygen affinity in Fe(II) histidine coordinated heme proteins by means of computer simulation. Density functional theory calculations on heme model systems are used to analyze three proximal effects: charge donation, rotational position, and distance to the heme porphyrin plane of the proximal histidine. In addition, hybrid quantum-classical (QM-MM) calculations were performed in two representative proteins: myoglobin and leghemoglobin. Our results show that all three effects are capable of tuning the Fe-O(2) bond strength in a cooperative way, consistently with the experimental data on oxygen affinity. The proximal effects described herein could operate in a large variety of O(2)-binding heme proteins-in combination with distal effects-and are essential to understand the factors determining a heme protein's O(2) affinity.

Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation.

Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways, farnesyl pyrophosphate, by the sequential head-to-tail condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP). Recently, FPPS has been shown to represent an important target for the treatment of parasitic diseases such as Chagas disease and African trypanosomiasis. Bisphosphonates, pyrophosphate analogues in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the FPPS enzyme. Moreover, nitrogen-containing bisphosphonates have been proposed as carbocation transition state analogues of FPPS. On the basis of structural and kinetic data, different catalytic mechanisms have been proposed for FPPS. By analyzing different reaction coordinates we propose that the reaction occurs in one step through a carbocationic transition state and the subsequent transfer of a hydrogen atom from IPP to the pyrophosphate moiety of DMAPP. Moreover, we have analyzed the role of the active site amino acids on the activation barrier and the reaction mechanism. The structure of the active site is well conserved in the isoprenyl diphosphate synthase family; thus, our results are relevant for the understanding of this important class of enzymes and for the design of more potent and specific inhibitors for the treatment of parasitic diseases.

The catalytic mechanism of peptidylglycine alpha-hydroxylating monooxygenase investigated by computer simulation.

The molecular basis of the hydroxylation reaction of the Calpha of a C-terminal glycine catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM) was investigated using hybrid quantum-classical (QM-MM) computational techniques. We have identified the most reactive oxygenated species and presented new insights into the hydrogen abstraction (H-abstraction) mechanism operative in PHM. Our results suggest that O(2) binds to Cu(B) to generate Cu(B)(II)-O(2)(.-) followed by electron transfer (ET) from Cu(A) to form Cu(B)(I)-O(2)(.-). The computed potential energy profiles for the H-abstraction reaction for Cu(B)(II)-O(2)(.-), Cu(B)(I)-O(2)(.-), and [Cu(B)(II)-OOH](+) species indicate that none of these species can be responsible for abstraction. However, the latter species can spontaneously form [Cu(B)O](+2) (which consists of a two-unpaired-electrons [Cu(B)O](+) moiety ferromagnetically coupled with a radical cation located over the three Cu(B) ligands, in the quartet spin ground state) by abstracting a proton from the surrounding solvent. Both this monooxygenated species and the one obtained by reduction with ascorbate, [Cu(B)O](+), were found to be capable of carrying out the H-abstraction; however, whereas the former abstracts the hydrogen atom concertedly with almost no activation energy, the later forms an intermediate that continues the reaction by a rebinding step. We propose that the active species in H-abstraction in PHM is probably [Cu(B)O](+2) because it is formed exothermically and can concertedly abstract the substrate HA atom with the lower overall activation energy. Interestingly, this species resembles the active oxidant in cytochrome P450 enzymes, Compound I, suggesting that both PHM and cytochrome P450 enzymes may carry out substrate hydroxylation by using a similar mechanism.

Two distinct heme distal site states define Cerebratulus lacteus mini-hemoglobin oxygen affinity.

The nerve tissue hemoglobin of Cerebratulus lacteus (CerHb) is the smallest naturally occurring known hemoglobin. Stabilization of the diatomic bound species (e.g., O(2)) is achieved through a network of hydrogen bonds based on three key residues TyrB10, GlnE7, and ThrE11. The first two residues are typically associated in hemoglobins with enhanced O(2) affinity, related to hydrogen bond stabilization of the heme-bound O(2) resulting in a decrease of the ligand dissociation rates. In contrast to the above observations, the affinity of CerHb for O(2) is only moderate, and the rate of O(2) dissociation is unexpectedly high. To gain insight on the diverse molecular mechanisms controlling ligand affinities, we have analyzed w.t. CerHb and its ThrE11-->Val mutant by means of joint molecular dynamics and quantum mechanics simulation techniques, complementing recent site-directed mutagenesis experiments. Our results suggest that the observed O(2) dissociation rates can only be explained through a dynamic equilibrium between high and low affinity states of the w.t. CerHb heme distal site.

Dioxygen affinity in heme proteins investigated by computer simulation.

We present an investigation of the molecular basis of the modulation of oxygen affinity in heme proteins using computer simulation. QM-MM calculations are applied to explore distal and proximal effects on O(2) binding to the heme, while classical molecular dynamics simulations are employed to investigate ligand migration across the polypeptide to the active site. Trends in binding energies and in the kinetic constants are illustrated through a number of selected examples highlighting the virtues and the limitations of the applied methodologies. These examples cover a wide range of O(2)-affinities, and include: the truncated-N and truncated-O hemoglobins from Mycobacterium tuberculosis, the mammalian muscular O(2) storage protein: myoglobin, the hemoglobin from the parasitic nematode Ascaris lumbricoides, the oxygen transporter in the root of leguminous plants: leghemoglobin, the Cerebratulus lacteus nerve tissue hemoglobin, and the Alcaligenes xyloxidans cytochrome c'.

Proximal effects in the modulation of nitric oxide synthase reactivity: a QM-MM study.

Nitric oxide synthases (NOS) are heme proteins that have a cysteine residue as axial ligand, which generates nitric oxide (NO). The proximal environment, specifically H-bonding between tryptophan (Trp) 178 and thiolate, has been proposed to play a fundamental role in the modulation of NOS activity. We analyzed the molecular basis of this modulation by performing electronic structure calculations on isolated model systems and hybrid quantum-classical computations of the active sites in the protein environment for wild-type and mutant (Trp 178 x Gly) proteins. Our results show that in the ferrous proteins NO exhibits a considerable trans effect. We also showed that in the ferrous (Fe(+2)) mutant NOS the absence of Trp, experimentally associated to a protonated cysteine, weakens the Fe-S bond and yields five coordinate complexes. In the ferric (Fe(+3)) state, the NO dissociation energy is shown to be slightly smaller in the mutant NOS, implying that the Fe(+3)-NO complex has a shorter half-life. We found computational evidence suggesting that ferrous NOS is favored in wild-type NOS when compared to the Trp mutant, consistently with the fact that Trp mutants have been shown to accumulate less Fe(+2)-NO dead end species. We also found that the heme macrocycle showed a significant distortion in the wild-type protein, due to the presence of the nearby Trp 178. This may also play a role in the subtle tuning of the electronic structure of the heme moiety.

Nitric oxide interaction with cytochrome c' and its relevance to guanylate cyclase. Why does the iron histidine bond break?

Soluble guanylate cyclase (sGC), the mammalian receptor for nitric oxide (NO), is a heme protein with a histidine as the proximal ligand. Formation of a five-coordinate heme-NO complex with the associated Fe-His bond cleavage is believed to trigger a conformational change that activates the enzyme and transduces the NO signal. Cytochrome c' (cyt c') is a protobacteria heme protein that has several similarities with sGC, including the ability to form a five-coordinate NO adduct and the fact that it does not bind oxygen. Recent crystallographic characterization of cyt c' from Alcaligenes xylosoxidans (AXCP) has yielded the discovery that exogenous ligands are able to bind to the Fe center from either side of the porphyrin plane. In this paper, we explore the molecular basis of the NO interaction with AXCP using hybrid quantum-classical simulation techniques. Our results suggest that Fe-His bond breaking depends not only on the iron-histidine bond strength but also on the existence of a local minimum conformation of the protein with the histidine away from the iron. We also show that AXCP is a useful paradigm for NO interaction with heme proteins, particularly regarding the activation/deactivation mechanism of sGC. The results presented here fully support a recently proposed model of sGC activation in which NO is not only the iron ligand but also catalyzes the activation step.

Multiple-steering QM-MM calculation of the free energy profile in chorismate mutase.

A novel technique for computing free energy profiles in enzymatic reactions using the multiple steering molecular dynamics approach in the context of an efficient QM-MM density functional scheme is presented. The conversion reaction of chorismate to prephenate catalyzed by the Bacillus subtilis enzyme chorismate mutase has been chosen as an illustrative example.

Theoretical study of the truncated hemoglobin HbN: exploring the molecular basis of the NO detoxification mechanism.

Mycobacterium tuberculosis is the causative agent of human tuberculosis. The nitric oxide reaction with oxy-truncated hemoglobin N (trHbN) has been proposed to be responsible for the resistance mechanism by which this microorganism can evade the toxic effects of NO. In this work, we explore the molecular basis of the NO detoxification mechanism using a combination of classical and hybrid quantum-classical (QM-MM) simulation techniques. We have investigated the structural flexibility of the protein, the ligand affinity properties, and the nitric oxide reaction with coordinated O2. The analysis of the classical MD trajectory allowed us to identify Phe62 as the gate of the main channel for ligand diffusion to the active site. Moreover, the opening of the channel stems from the interplay between collective backbone motions and local rearrangements in the side chains of the residues that form the bottleneck of the tunnel. Even though the protein environment is not found to make a significant contribution to the heme moiety catalyzed reaction, the binding site influences the physiological function of the enzyme at three different levels. First, by isolating the intermediates formed in the reaction, it prevents nondesired reactions from proceeding. Second, it modulates the ligand (O2, NO) affinity of the protein, which can be ascribed to both distal and proximal effects. Finally, the stabilization of the Tyr33-Gln58 pair upon O2 binding might alter the essential dynamics of the protein, leading in turn to a mechanism for ligand-induced regulation.

Linfangioma abdominal: a propósito de un caso / Lymphagiomas are benigmant: a purpose of the case

Los linfangiomas son tumoraciones benignas que se caracterizan por múltiples vasos linfáticos, y representan el equivalente linfático del Hemangioma. Pueden ser de dos tipos (congenitos y adquiridos) y se clasifican en cuatro grupos, de los cuales el linfangioma cavernoso es el más frecuente. Nosotros presentamos el caso de un paciente adolescente