Accessing gap-junction channel structure-function relationships through molecular modeling and simulations.

BACKGROUND: Gap junction channels (GJCs) are massive protein channels connecting the cytoplasm of adjacent cells. These channels allow intercellular transfer of molecules up to ~1 kDa, including water, ions and other metabolites. Unveiling structure-function relationships coded into the molecular architecture of these channels is necessary to gain insight on their vast biological function including electrical synapse, inflammation, development and tissular homeostasis. From early works, computational methods have been critical to analyze and interpret experimental observations. Upon the availability of crystallographic structures, molecular modeling and simulations have become a valuable tool to assess structure-function relationships in GJCs. Modeling different connexin isoforms, simulating the transport process, and exploring molecular variants, have provided new hypotheses and out-of-the-box approaches to the study of these important channels. METHODS: Here, we review foundational structural studies and recent developments on GJCs using molecular modeling and simulation techniques, highlighting the methods and the cross-talk with experimental evidence. RESULTS AND DISCUSSION: By comparing results obtained by molecular modeling and simulations techniques with structural and functional information obtained from both recent literature and structural databases, we provide a critical assesment of structure-function relationships that can be obtained from the junction between theoretical and experimental evidence.

Pentafecta outcomes after robot-assisted laparoscopic radical prostatectomy: first 100 cases in Latinoamerican Hospital.

OBJECTIVE: Radical prostatectomy (RP) is the standard treatment for cancer control in the long term. The rise of minimally invasive surgery and new technologies have yielded better results and enabled us to pursue more ambitious objectives. The main works still use the trifecta as classic presentation, but this does not cover all aspects of surgery. Pentafecta is a new and more comprehensive methodology to report outcomes after RP, including complications and surgical margin status with the three major outcomes classically reported. The purpose of this study is to report our experience with robot-assisted laparoscopic radical prostatectomy (RALRP) by applying the concept of pentafecta. MATERIAL AND METHOD: Describe the experience in this institution from March 2009 to December 2012 of RALRP by pentafecta. RESULTS: We performed 101 interventions and obtained the following results: Average age 60.89 ± 7.32 years (40-77), total PSA 8.5 ± 5.57 ng/dl (0.2-29); D'Amico classification: Low 29 (28.71%), Medium 65 (64.36%), High 7 (6.93%); Operative time 253.44 ± 51.51 min (90-540), Complications 12.9% (Clavien I-II 10.89% and Clavien IIIa 1.98%); Positive surgical margins 20.83%; Biochemistry recurrence 12.5% follow-up (6-44 months); and Continence 87.5% per year and Potency 59.52%. CONCLUSIONS: RALRP is a safe and reproducible procedure with excellent results in terms of pentafecta, inclusive during the initial experience at a low volumen center for prostate cancer. A longer follow-up study and experience with higher volume of patients are required to obtain better results and data to be compared with excellence centers.

Human aquaporin 4 gating dynamics in dc and ac electric fields: a molecular dynamics study.

Water self-diffusion within human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of external ac and dc electric fields. The computed diffusive (p(d)) and osmotic (p(f)) permeabilities under zero-field conditions are (0.718 ± 0.24) × 10(-14) cm(3) s(-1) and (2.94 ± 0.47) × 10(-14) cm(3) s(-1), respectively; our p(f) agrees with the experimental value of (1.50 ± 0.6) × 10(-14) cm(3) s(-1). A gating mechanism has been proposed in which side-chain dynamics of residue H201, located in the selectivity filter, play an essential role. In addition, for nonequilibrium MD in external fields, it was found that water dipole orientation within the constriction region of the channel is affected by electric fields (e-fields) and that this governs the permeability. It was also found that the rate of side-chain flipping motion of residue H201 is increased in the presence of e-fields, which influences water conductivity further.

Molecular dynamics study of the archaeal aquaporin AqpM.

BACKGROUND: Aquaporins are a large family of transmembrane channel proteins that are present throughout all domains of life and are implicated in human disorders. These channels, allow the passive but selective movement of water and other small neutral solutes across cell membranes. Aquaporins have been classified into two sub-families: i) strict aquaporins that only allow the passage of water and ii) the less selective aquaglyceroporins that transport water and other neutral solutes, such as glycerol, CO2 or urea. Recently, the identification and characterization of a number of archaeal and bacterial aquaporins suggested the existence of a third sub-family; one that is neither a strict aquaporin nor an aquaglyceroporin. The function and phylogeny of this third family is still a matter of debate. RESULTS: Twenty nanosecond molecular dynamics (MD) simulation of a fully hydrated tetramer of AqpM embedded in a lipid bilayer permitted predictions to be made of key biophysical parameters including: single channel osmotic permeability constant (pf), single channel diffusive permeability constant (pd), channel radius, potential water occupancy of the channel and water orientation inside the pore. These properties were compared with those of well characterized representatives of the two main aquaporin sub-families. Results show that changes in the amino acid composition of the aromatic/arginine region affect the size and polarity of the selectivity filter (SF) and could help explain the difference in water permeability between aquaporins. In addition, MD simulation results suggest that AqpM combines characteristics of strict aquaporins, such as the narrow SF and channel radius, with those of aquaglyceroporins, such as a more hydrophobic and less polar SF. CONCLUSIONS: MD simulations of AqpM extend previous evidence that this archaeal aquaporin exhibits hybrid features intermediate between the two known aquaporin sub-families, supporting the idea that it may constitute a member of a novel class of aquaporins.

[Cholelithiasis in childhood. Proposals based on a multicentric study]. / Colelitiasis en la infancia. Propuestas de un estudio multicéntrico.

Fifty six cases of cholelithiasis in patients aged two months to 15 years (mean age 7.65 years) concerning to 11 hospitals are reviewed. The study protocol followed was the same in all medical records, although own criterions were considered on management performed in each center. From the cases, it follows: 1. Male/female rate is 1/1.5. 2. Symptomatology in infancy is relatively poor and pain localization is not orientative. 3. It was an incidentally finding in 41 per 100 of the cases. 4. Ultrasonography is the best examination procedure rendering diagnosis in the 51 cases it was underwent. 5. Hematologic study was abnormal in six of 46 cases. 6. Medical treatment was not performed in any hospital. 7. Existence of "lithogenic families" seems to be demonstrated. 8. The presence of four patients with Down syndrome in this series must be pointed out. 9. Among total 56 cases, 21 underwent surgical treatment, 29 were conservatively treated, two have died and four patients had spontaneous stone resolution. 10. In the face of these, we propose: A) Surgical treatment in symptomatic cases, porcelain gallbladder and nonfunctionating gallbladder. B) Expectant management and sonographic monitoring in asymptomatic cases. C) Carefully evaluation in patients with predisposing factors and patients with recurrent abdominal pain.

Pharmacokinetics of nifedipine slow release tablet in Mexican subjects: further evidence for an oxidation polymorphism.

Nifedipine kinetics after ingestion of 20 mg slow release tablets were studied in 12 young, healthy, Mexican subjects. Plasma levels were determined by a nifedipine-specific HPLC assay. Levels rose after drug administration reaching a maximum concentration of 48.7 +/- 7.3 ng/ml in 2.1 +/- 0.7 h (mean +/- SEM). Concentrations then decayed with a terminal half-life of 16.9 +/- 3.1 hours. AUC was 526 +/- 62 ng h/ml. Five individuals were fast and seven were slow nifedipine metabolizers, according to the AUC criterion proposed by Kleinbloesem and coworkers. Individual AUC/Dose values from this and from other two studies on oral nifedipine kinetics in Mexicans were cumulated and the frequency histogram and probit analyses were performed (N = 30). A bimodal distribution was clearly observed. Fast and slow metabolizers were distinguished as those subjects with AUC/Dose values either lower or higher than 22.5 ng h/ml mg. Unlike European populations, it appears that slow metabolization is more frequent in Mexicans. Data strongly support the hypothesis of the existence of a polymorphism concerning nifedipine disposition kinetics due to genetic basis.

Pharmacokinetics of oral nifedipine: relevance of the distribution phase.

Pharmacokinetics of oral Nifedipine was studied in 12 Mexican young healthy volunteers, six men and six women, who received a 10 mg capsule. Plasma levels were determined by a nifedipine specific HPLC assay. Experimental data were fitted and pharmacokinetic parameters were calculated using an open two compartment model. No statistically significant difference was detected between men and women, thus both sexes were considered as a single population. Nifedipine plasma levels rose rapidly (ka = 8.46 +/- 1.96 h-1) reaching a maximum concentration of 145 +/- 23 ng/ml in 0.61 +/- 0.07 h. Plasma levels then decayed with a distribution phase (alpha = 1.98 +/- 0.40 h-1, t1/2 alpha = 0.46 +/- 0.06 h) and a terminal elimination phase (beta = 0.17 +/- 0.03 h-1, t1/2 beta = 4.98 +/- 0.55 h). AUC was 384 +/- 41 ng h/ml. Values of AUC and t1/2 beta were higher than those reported by other authors. Differences in the AUC could be due to ethnic origin, environmental factors or nutritional habits. Ten subjects presented plasma concentration-time curves in which the distribution phase was clearly distinguishable, having a ka/alpha relationship higher than 1.5. For the other two subjects, the distribution phase was not apparent and ka/alpha was lower than 1.5. The results show that an adequate characterization of the distribution phase is required if one pretends to use pharmacokinetic data for dosage regimen design.

[Clinical and pharmacokinetic comparison of 2 oral preparations of nifedipine: 10 mg capsules and 20 mg delayed-release tablets]. / Comparación clinica y farmacocinética de dos formulaciones orales de nifedipina: cápsula de 10 mg. y comprimido de liveración prolongada de 20 mg.

The effects and pharmacokinetic parameters of two oral formulations of nifedipine, 10 mg capsule (Adaltat) and 20 mg slow release tablet (Adalat a.p.). With the 10 mg capsule nifedipine was rapidly absorbed, reaching a maximum concentration of 120 +/- 39 ng/ml in 0.52 +/- 0.07 h, and also rapidly eliminated with an apparent halflife of 5.51 +/- 0.64 h. A fall in blood pressure and a raise in heart rate, that significantly correlated with plasma levels, were observed. 83% of the subjects reported headache, that was probably due to the sudden increase in plasma levels. With the 20 mg slow release tablet nifedipine absorption was slower, reaching a maximum concentration of 39 +/- 7 ng/ml in 1.82 +/- 0.43 h, and the apparent half-life (16.89 +/- 3.14 h) was longer than with the capsule. A fall in blood pressure was observed that significantly correlated with plasma levels; however, there was no significant correlation between these and changes in heart rate. Only 17% of the subjects reported headache. Pharmacokinetic data indicate that, in most subjects, nifedipine therapeutics plasma levels (over 15 ng/ml) can be maintained with the administration of a 20 mg slow release tablet every 12 hours. This, joined to the reduction in side effects, suggest that this formulation is the adequate alternative in chronic treatments with nifedipine, such as arterial hypertension.

[Yersinia enterocolitica septicemia in a thalassemic girl]. / Septicemia por yersinia enterocolítica en una niña talasémica.

We report a four-year-old girl, previously splenectomized because of thalassemia major, who was admitted with gastroenteritis, abdominal pain and high grade fever. At laparotomy she was found to have appendicitis and mesenteric adenitis. Blood and stool cultures grew yersinia enterocolitica. Clinical course was favourable under Ampicillin-Gentamycin treatment. The importance of iron metabolism in the pathogenesis of yersinia sepsis is stressed, being this topic reviewed.

[New anti-arrhythmia drugs]. / Algunos aspectos de los nuevos medicamentos antiarrítmicos.

In this paper some of the new antiarrhythmic drugs are reviewed. The origin, electrophysiologic effects, mechanisms of action, pharmacokinetic properties, hemodynamic changes, clinical utilization with indications and contraindications as well as the collateral effects of: Verapamil Amiodarone, Aprindine, Encainide, Mexiletine and Tocainide are analyzed. A conclusion is drawn for each one of these drugs in accordance with the available information in the literature and the author's criteria and experience.

Algunos aspectos de los nuevos medicamentos antiarritmicos. / Some aspects of new antiarrhythmic drugs

En este trabajo se hace una revision de algunas nuevas drogas antiarritmicas.Se analizan el origen, los efectos electrofisiologicos, los mecanismos de accion, las propriedades farmacocineticas, los efectos hemodinamicos, el uso clinico, con sus indicaciones y contraindicaciones, asi como los efectos colaterales de: el verapamil, la amiodarona, la aprondina, la encainida, la mexiletina y la tocainida. Se establece una conclusion sobre cada uno de estos farmacos de acuerdo con los informes de la literatura y la experiencia y el criterio de los autores

[Appendiceal peritonitis in childhood, antibiotic treatment with cefoxitin]. / Peritonitis apendicular en la infancia. Tratamiento antibiótico con cefoxitina.

Twenty one cases of appendiceal peritonitis in children are reviewed. An antibiotic (sodium cefoxitine) has been used during the post-operative course to decrease the risk of suppurative complications. Cultures obtained from peritoneal exudate yielded "E. coli" and "Bacteroides" sp. as the most commonly isolated bacteria. External drainage was placed as a rutine and the percentage of suppurative complications was 14%. No patient showed evidence of adverse reactions to the antibiotic and the mortality of the serie was zero. Obtained results allow to state that cefoxitine is effective in the management of appendiceal peritonitis in children.

[Interstitial deletion of the long arms of chromosome 13]. / Un caso de delección intersticial del brazo largo del cromosoma 13.

We present a case of a child with important phenotypic abnormalities (retinoblastoma, hypoplasia of the thumbs and genital), as well as craneofacial and evident psychomotor retardation. The chromosomal study showed a interstitial delection of the long arms of a chromosome from D group. We try to correlate karyotypes and phenotype, telling about difficulties that this relation means insisting about the importance of knowing more cases of chromosome 13 delection. We also think that subbands analysis represents an important factor in this correlation.

[Congenital aplasia cutis (author's transl)]. / Aplasia congénita de cutis.

A newborn with aplasia cutis congenita is presented. The lesions involved the scalp and were symmetrical in trunk and lower extremities. Histologically there was a slightly epidermal flattening with disappearance of dermal papillae, and absence of elastic fibers and epidermal appendages. There was no evidence of either associated anomalies or familiar history of skin defects. The lesions, treated locally with antiseptics and antibiotics, healed with scarring in two-three months, and one year later were covered by a thin layer of skin devoid of hair in scalp.

[Congenital syphilis (author's transl)]. / Sífilis congénita. A propósito de 11 observaciones.

Authors present a study on eleven patients affected with congenital syphillis treated during the last six years. All of them presented bone lesions in one or more locations. Familiar antecedents, mechanism of infection, clinical symptoms and radiological findings are analized, emphasizing the importance of prophylaxis and early treatment with procaine penicillin in a dosage of 50,000 U./Kg. day for at least ten days.