Pharmacological modulation of the hyperpolarization-activated current (I f) in human atrial myocytes: focus on G protein-coupled receptors

AIMS: In human atrial myocytes (HuAM) two beta-adrenergic receptors (beta-AR) and four splicing-variants of the serotonin 5-HT(4) receptor are present. Multiple coupling with G stimulatory (G(s)) and G inhibitory (G(i)) proteins has been proposed for both beta(2)-AR and 5-HT((4b)) subtypes, but no functional data exist in HuAM. Serotonin (5-HT) and catecholamines are able to trigger arrhythmias in human atrium, but the underlying cellular mechanisms are not completely understood. The pacemaker current (I(f)) is an inward Na(+)/K(+) current, constitutively present in HuAM and directly modulated by cAMP; I(f) could play a role in triggering human atrial arrhythmias. This study evaluated the different G protein coupling of beta(1)-AR, beta(2)-AR and 5-HT(4) receptors by assessing the modulation of I(f) by selective stimuli. METHODS: HuAM were isolated from right atrial appendages and utilized for patch-clamp recording. The coupling of receptor subtypes with G(i) proteins was tested by incubating HuAM in pertussis toxin (PTX). RESULTS: Beta(1)-AR stimulation (Isoprenaline [ISO] + ICI 118,551), and 5-HT caused a concentration-dependent significant shift of the half activation potential of I(f) activation curve (DeltaV(h)), P < 0.01. beta(2)-AR stimulation (ISO 1 microM + CGP 20712A) also significantly shifted V(h) (P < 0.0001), but with DeltaV(h)[beta(2)-AR] significantly smaller than the effect caused by 1 microM beta(1)-AR stimulation (P < 0.05). Pre-treatment of HuAM with PTX did not alter the effect of beta(1)-AR stimulation (both 0.1 and 1 microM) and 1 microM 5-HT on I(f), but significantly increased the effect in response to beta(2)-AR stimulation and 0.1 microM 5-HT (P < 0.05 for both), thus suggesting a G(i) protein coupling of these receptors. CONCLUSIONS: Our results provide the first functional evidence of the different G protein coupling of beta(1)-AR, beta(2)-AR and 5-HT(4) receptors in HuAM. Further they support the view that I(f) current might play an important role in triggering catecholamines and serotonin-induced atrial arrhythmias.     

Automatic Computation of Left Ventricular Volume Changes Over a Cardiac Cycle from Echocardiography Images by Nonlinear Dimensionality Reduction

Curve of left ventricular (LV) volume changes throughout the cardiac cycle is a fundamental parameter for clinical evaluation of various cardiovascular diseases. Currently, this evaluation is often performed manually which is tedious and time consuming and suffers from significant interobserver and intraobserver variability. This paper introduces a new automatic method, based on nonlinear dimensionality reduction (NLDR) for extracting the curve of the LV volume changes over a cardiac cycle from two-dimensional (2-D) echocardiography images. Isometric feature mapping (Isomap) is one of the most popular NLDR algorithms. In this study, a modified version of Isomap algorithm, where image to image distance metric is computed using nonrigid registration, is applied on 2-D echocardiography images of one cycle of heart. Using this approach, the nonlinear information of these images is embedded in a 2-D manifold and each image is characterized by a symbol on the constructed manifold. This new representation visualizes the relationship between these images based on LV volume changes and allows extracting the curve of the LV volume changes automatically. Our method in comparison to the traditional segmentation algorithms does not need any LV myocardial segmentation and tracking, particularly difficult in the echocardiography images. Moreover, a large data set under various diseases for training is not required. The results obtained by our method are quantitatively evaluated to those obtained manually by the highly experienced echocardiographer on ten healthy volunteers and six patients which depict the usefulness of the presented method.     

Rural Surgery in Niger: A Multicentric Study in 21 District Hospitals

The purpose of the study was to evaluate the qualitative aspect and global impact of surgery in a district hospital (DH) since the launching of the surgery at the district level. Surgical care was provided by general practitioners (GP) who received 12-month training in surgery, certified by a “Capacity of District Surgery” (CDS) diploma. It was a prospective study during 4 years from 2007 to 2010. Of the 34 DHs, only 21 were functional and included in this study. Most of the DHs had two or more CDS (n?=?15). The majority of the DHs had one nurse surgical aid (n?=?16) and one nurse anesthetist (n?=?17). The total number of surgical operations was 18,441 cases; emergency cases represented 51.8 % and elective surgery 48.2 %. Regarding emergency surgery, cesarean sections revealed the most common surgical procedure (37.21 %), followed by wound debridement (19.42 %). In elective surgery, hernia repair and hydrocelectomy were the most common surgical procedures (69.60 %), followed by gynecologic procedures in 12.74 % of the cases. The global complication rate was 4.34 %. The global mortality rate was 1.04 % (n?=?192), 102 deaths following cesarean section (2.87 %). No death was encountered in elective surgery. Nine hundred and fifty-five patients (5.17 %) were transferred to a higher-level facility of whom 598 patients (62.61 %) were admitted for fracture treatment. The concept of district surgery has proven to be an effective tool to counter skilled medical manpower shortage to perform emergency and elective basic surgery at the rural level and could be adopted by developing countries facing similar health challenges.     

Comparative features and outcomes of malaria at a tertiary care hospital in Karachi, Pakistan.

OBJECTIVES: A comparison of clinical and laboratory features, diagnostic methods, drug treatment, and outcomes for patients hospitalized with malaria by Plasmodium species. METHODS: Records of 521 patients hospitalized during the four and half-year study period were analyzed. RESULTS: Infections were caused by Plasmodium vivax (51.8%), Plasmodium falciparum (46.5%), P. vivax plus P. falciparum (1.3%), and Plasmodium malariae (0.4%). Vomiting (odds ratio (OR)=1.86, p=0.001) and abdominal pain (OR=1.60, p=0.024) occurred more frequently in patients infected with P. falciparum compared to P. vivax; this was also the case for hepatomegaly, splenomegaly and jaundice. Low hemoglobin levels were common but were significantly lower with P. falciparum, and creatinine levels were significantly higher with P. falciparum. Treatment regimens consisted of single drug therapy (61.5%), appropriate combination therapy (15.8%), and inappropriate combination therapy (22.7%). Antimalarials given alone included chloroquine (38.7%), quinine (19%) and doxycycline (1.5%). The overall mortality was 1.7% (n=9) and nearly 56% of patients developed disease complications, most commonly thrombocytopenia (36.4%), anemia (23.4%), and thrombocytopenia plus anemia (32.7%). CONCLUSIONS: Despite resistance, chloroquine was prescribed in patients with malaria requiring hospitalization. We found a high proportion of single antimalarial drug use as well as inappropriate combination therapy (22.7%), and inadequate use of primaquine terminal prophylaxis. Physicians need to be acquainted with malaria treatment guidelines in an endemic zone.     

Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood

Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high‐, and low‐impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome‐wide association study (GWAS)‐implicated BMD variants. We used dual‐energy X‐ray absorptiometry to estimate femoral neck, total hip, and spine areal‐BMD and total body less head (TBLH) bone mineral content (BMC) Z‐scores. The BMD genetic score was negatively associated with each bone Z‐score (eg, TBLH‐BMC: estimate = –0.03, p = 1.3 × 10^?6). Total PA was positively associated with bone Z‐scores; these associations were driven by time spent in high‐impact PA (eg, TBLH‐BMC: estimate = 0.05, p = 4.0 × 10^?10) and were observed even for children with lower than average bone Z‐scores. We found no evidence of PA‐adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA‐genetic score–Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH‐BMC in males (p interaction = 7.1 × 10^?5), where PA was associated with higher TBLH‐BMC Z‐score among the BMD‐lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10^?9). In conclusion, the beneficial effect of PA on bone, especially high‐impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS‐implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.     

Low-Dose Acetazolamide in the Treatment of Premenstrual Dysphoric Disorder: A Case Series

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.     

Effect of follicle-stimulating hormone and testosterone on colony formation of bovine spermatogonial stem cell

The complex process of spermatogenesis is regulated by various factors. In this study, the in vitro effects of follicle-stimulating hormone and testosterone on spermatogonial cell colony formation were investigated. Sertoli and spermatogonial cells were isolated from 3- to 5-month-old calves. Co-cultured Sertoli and spermatogonial cells were treated with follicle-stimulating hormone and testosterone in treatment groups before colony assay. Results indicated that follicle-stimulating hormone is the best factor for in vitro colonization of spermatogonial cells. In conclusion, using follicle-stimulating hormone provided proper bovine spermatogonial stem cell culture medium for in vitro study of these cells.