Cardiotrophin-1 (CT-1) is a cytokine with antiobesity properties and with a role in lipid metabolism regulation and adipose tissue function. The aim of this study was to analyze the molecular mechanisms involved in the lipolytic actions of CT-1 in adipocytes. Recombinant CT-1 (rCT-1) effects on the main proteins and signaling pathways involved in the regulation of lipolysis were evaluated in 3T3-L1 adipocytes and in mice. rCT-1 treatment stimulated basal glycerol release in a concentration and time-dependent manner in 3T3-L1 adipocytes. rCT-1 (20 ng/ml for 24 h) raised cAMP levels and in parallel increased PKA-mediated phosphorylation of perilipin and HSL at Ser660. siRNA knock down of HSL or PKA as well as pretreatment with the PKA inhibitor H89 blunted the CT-1-induced lipolysis, suggesting that the lipolytic action of CT-1 in adipocytes is mainly mediated by activation of HSL through PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased ATGL content in adipose tissue. These results showed that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects.
Purpose:To deepen our knowledge on the basis of intrafamilial genetic heterogeneity of inherited retinal dystrophies (RD) to further discern the contribution of individual alleles to the pathology. Methods:Families with intrafamilial locus and/or allelic heterogeneity were selected from a cohort of 873 characterized out of 2468 unrelated RD families. Clinical examination included visual field assessments, electrophysiology, fundus examination and audiogram. Molecular characterization was performed using a combination of different methods: genotyping microarray, SSCP, dHPLC, HRM, MLPA, Sanger sequencing, whole-genome homozygosity mapping and next-generation sequencing (NGS). Results:Overall, intrafamilial genetic heterogeneity was encountered in a total of 8 pedigrees. There were 5 out of 873 families (~0.6%) with causative mutations in more than one gene (locus heterogeneity), involving the genes: (1) USH2A, RDH12 and TULP1; (2) PDE6B and a new candidate gene; (3) CERKL and CRB1, (4) BBS1 and C2orf71; (5) ABCA4 and CRB1. Typically, in these cases, each mutated gene was associated to different phenotypes. In the 3 other families (~0.35%), different mutations in the same gene (allelic heterogeneity) were found, including the frequent RD genes ABCA4 and CRB1. Conclusions:This systematic research estimates that the frequency of overall mutation load promoting RD intrafamilial heterogeneity in our cohort of Spanish families is almost 1%. The identification of the genetic mechanisms underlying RD locus and allelic heterogeneity is essential to discriminate the real contribution of the monoallelic mutations to the disease, especially in the NGS era. Moreover, it is decisive to provide an accurate genetic counselling and in disease treatment.
Abstract Objective: To evaluate the effects of holmium laser enucleation of the prostate (HoLEP) on sexual function. Methods: A retrospective analysis of 202 sexually active patients who underwent HoLEP was performed. Patients were assessed at baseline and 3 and 12 months post-HoLEP. Evaluations included uroflowmetry and symptom questionnaires (five-item version of the International Index of Erectile Function [IIEF-5], ICIQ-male sexual matters associated with LUTS [ICIQ-MLUTSsex], American Urological Association symptom score [AUA-SS], and single-question quality of life [QoL] score). Nonparametric, Fisher's exact, and chi-squared tests were used to assess changes from baseline and to identify risk factors, if any, associated with deterioration of sexual function after surgery. Results: No significant differences were found between the preoperative and postoperative scores on the questionnaires that evaluated erection quality. However, 6.9% and 12.4% of the patients reported an increase or a reduction, respectively, of greater than five points in total IIEF-5 score. The reduction in IIEF-5 score was statistically significant only in the subgroup of patients without preoperative erectile dysfunction (ED). No preoperative characteristics and no parameters related to the surgery or postoperative outcome were significantly associated with the impairment of erection quality after surgery. In fact, neither capsular perforation nor the total laser energy used during the procedure affected erections. Loss of antegrade ejaculation was found in 70.3% of patients, while 21% reported a reduction in semen quantity. However, concern regarding ED or ejaculatory dysfunctions decreased with surgery. Conclusions: Although erectile function was not altered in the vast majority of patients after HoLEP, patients without preoperative ED displayed a relatively small, but still significant, negative effect on erections. The overwhelming majority of patients suffered from retrograde ejaculation after surgery.
Background and study aims: A novel large-diameter, lumen-apposing, self-expanding metal stent with bilateral flanges was recently developed for endoscopic ultrasound (EUS)-guided transmural drainage of symptomatic pancreatic fluid collections (PFCs). The aim of this study was to evaluate the efficacy and safety of this stent in a large cohort. Patients and methods: Patients with a PFC undergoing EUS-guided drainage with this novel stent were prospectively enrolled in this multicenter cohort study. Results: There were 61 patients: 46 patients (75?%) with walled-off necrosis (WON) and 15 (25?%) with a pancreatic pseudocyst. Stent placement was technically successful in 60 patients (98?%, 95?%CI 95?%?-?100?%). Clinical success, defined as resolution of clinical symptoms in combination with a decrease in the PFC size to ??2?cm on imaging, was achieved in 93?% of patients with a pancreatic pseudocyst (95?%CI 77?%?-?100?%) and in 81?% of patients with WON (95?%CI 69?%?-?94?%). Treatment failure occurred in nine patients (16?%, 95?%CI 6?%?-?26?%), including four patients who required surgical intervention. Stent removal was performed in 82?% of patients after a median of 32 days (range 2?-?178) and was rated as easy in all but one patient. In 10 patients, endoscopic stent removal was not performed because of stent migration (n?=?3), stent dislodgement during necrosectomy (n?=?3), stent removal during surgery (n?=?2), or refusal by the patient (n?=?2). In total, five major complications were reported (9?%, 95?%CI 2?%?-?16?%), including PFC infection (n?=?4) and perforation (n?=?1). Conclusion: EUS-guided drainage using this novel stent is feasible and the clinical results obtained are promising with a low major complication rate.
We studied the validity and responsiveness of an item response theory (IRT) scoring method for assessing major depressive episode (MDE) and generalized anxiety disorder (GAD) severity based on direct assessment of DSM-IV-TR symptoms.
The aim of this study was to assess the intersession and interobserver reliability of central corneal thickness (CCT) measurements using a posterior-segment spectral domain optical coherence tomography (SD-OCT).
The advances achieved in technology, medicine, and communications in the past decades have created an excellent scenario for the improvement and expansion of eHeath and mHealth in particular. Mobile phones, smartphones, and tablets are exceptional means for the application of mobile health, especially for those diseases and health conditions that are the deadliest worldwide.
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.
Decitabine (5-aza-2'-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) recognizes 5-azadC-induced lesions in DNA and mediates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci after 5-azadC treatment, suggesting a novel and specific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defective cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relocation to DNA damage sites, disrupts XRCC1-DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5-azadC to improve treatment of MDS and AML.
The main multidimensional carbon allotropes could be classified into carbon nanotubes as 1D material, graphene as 2D material, as well as graphite and diamond as 3D carbon materials. Along with this review, a discussion using these four structures as electrochemical detectors in CE and ME will permit us to explore the recent advances in this field.
Reported is an enantiodivergent approach for the synthesis of both enantiomers of sulforaphane (SFN) homologues with different chain lengths between the sulfinyl sulfur and the isothiocyanate groups and different substituents on the sulfinyl sulfur. The homologues were designed in order to unravel the effect of all the diversity elements included in sulforaphane's structure. The key step of the approach is the diastereoselective synthesis of both sulfinate ester epimers at sulfur, using as single chiral auxiliary the sugar derived diacetone-d-glucose. The approach allows the first synthesis of both enantiomers of 5-methylsulfinylpentyl isothiocyanate, and the biologically important 6-methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish, wasabi (Wasabia japonica). The ability of the synthesized compounds as inductors of phase II detoxifying enzymes has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2. The cytotoxic activity of all the synthesized compounds against human lung adenocarcinoma (A549) and foetal lung fibroblasts (MRC-5) is also reported.
Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats.
Brown adipose tissue (BAT) is a specialized organ responsible for thermogenesis, a process required for maintaining body temperature. BAT is regulated by the sympathetic nervous system (SNS), which activates lipolysis and mitochondrial uncoupling in brown adipocytes. For many years, BAT was considered to be important only in small mammals and newborn humans, but recent data have shown that BAT is also functional in adult humans. On the basis of this evidence, extensive research has been focused on BAT function, where new molecules, such as irisin and bone morphogenetic proteins, particularly BMP7 and BMP8B, as well as novel central factors and new regulatory mechanisms, such as orexins and the canonical ventomedial nucleus of the hypothalamus (VMH) AMP- activated protein kinase (AMPK)-SNS-BAT axis, have been discovered and emerged as potential drug targets to combat obesity. In this review we provide an overview of the complex central regulation of BAT and how different neuronal cell populations co-ordinately work to maintain energy homeostasis.
GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.
Increasing evidence indicates that the Trypanosoma brucei flagellum (synonymous with cilium) plays important roles in host-parasite interactions. Several studies have identified virulence factors and signaling proteins in the flagellar membrane of bloodstream-stage T. brucei, but less is known about flagellar membrane proteins in procyclic, insect-stage parasites. Here we report on the identification of several receptor-type flagellar adenylate cyclases (ACs) that are specifically upregulated in procyclic T. brucei parasites. Identification of insect stage-specific ACs is novel, as previously studied ACs were constitutively expressed or confined to bloodstream-stage parasites. We show that procyclic stage-specific ACs are glycosylated, surface-exposed proteins that dimerize and possess catalytic activity. We used gene-specific tags to examine the distribution of individual AC isoforms. All ACs examined localized to the flagellum. Notably, however, while some ACs were distributed along the length of the flagellum, others specifically localized to the flagellum tip. These are the first transmembrane domain proteins to be localized specifically at the flagellum tip in T. brucei, emphasizing that the flagellum membrane is organized into specific subdomains. Deletion analysis reveals that C-terminal sequences are critical for targeting ACs to the flagellum, and sequence comparisons suggest that differential subflagellar localization might be specified by isoform-specific C termini. Our combined results suggest insect stage-specific roles for a subset of flagellar adenylate cyclases and support a microdomain model for flagellar cyclic AMP (cAMP) signaling in T. brucei. In this model, cAMP production is compartmentalized through differential localization of individual ACs, thereby allowing diverse cellular responses to be controlled by a common signaling molecule.
Obesity is a major health problem around the globe. The statistics of overweight and obesity at early ages have reached alarming levels and placed our country in the first place in regard to childhood obesity. In the development of obesity two major factors take part, one genetic and the other one environmental. From the perspective of environmental changes both overweight and obesity result from the imbalance in the energy balance: people ingest more energy than they expend. Despite people live in the same obesogenic environment not all of them develop obesity; it requires genetic factors for this to happen. This review focuses on the description of the main methodologies to find genetic markers, as well as the main loci in candidate genes, whose single nucleotide polymorphisms (SNPs) are associated with obesity and its comorbidities in children, highlighting the association of these genes in the Mexican population. Knowledge of the genetic markers associated with obesity will help to understand the molecular and physiological mechanisms, the genetic background and changes in body mass index in the Mexican population. This information is useful for the planning of new hypotheses in the search for new biomarkers that can be used in a predictive and preventive way, as well as for the development of new therapeutic strategies.
A novel approach based on the use of nanometallic-decorated hollow fibers to assist electromembrane extraction is proposed. Microporous polypropylene hollow fibers, on which nanometallic silver was deposited, have been used for the first time as liquid membrane support in electromembrane extraction (EME). Different methods for the generation/deposition of silver nanoparticles (AgNPs) were studied. The best results were obtained with chemical reduction of silver nitrate using NaBH4 in aqueous solution followed by direct deposition on the hollow fibers. The extraction performance of the new supports was compared with a previously developed EME procedure used for the extraction of selected non-steroidal anti-inflammatory drugs (NSAIDs), resulting in an increase in the extraction ratio by a factor of 1.2-2 with a 30% reduction in the extraction time. The new nanometallic-decorated supports open new possibilities for EME due to the singular properties of nanometallic particles, including chemical fiber functionalization.
Asthma is a common pulmonary disease with chronic inflammation of the airways, and obesity is a chronic state of low-grade inflammation. Toll-like receptors (TLRs) are involved in the innate immune response. This study was designed to analyze whether obesity has an effect on the immune response of patients with asthma. We included obese asthmatic, obese, asthmatic, and healthy children. Biochemical and anthropometric analyses were performed. Interleukin (IL)-2, interferon (IFN) gamma, IL-4, IL-10, IL-1beta, and tumor necrosis factor alpha were measured. Peripheral blood mononuclear cells were analyzed by immunostaining with anti-TLR2 and anti-TLR9 antibodies. The data were expressed as means ± SEM or medians and percentiles. Kruskal-Wallis test and Dunn's multiple comparison test were applied. Asthmatic patients, both obese and nonobese, exhibited a mild asthma phenotype; none had infectious process, exacerbation, or acute symptoms during the 30 days before the inclusion in the study. The IL-2 and IFN-gamma levels in the obese asthmatic group were lower than in the other three groups. IL-4 levels in the obese asthmatic group were almost equal to those of the asthmatic group and more than in the other two groups, without significant difference. There were higher levels of TLR2 and TLR9 in obese asthmatic patients than in the other three groups. There is a decrease in Th1 cytokines in obese asthmatic patients, and we only found a trend to an increased Th2 profile. Patients studied do not appear to fit into any of the endotypes described until now. This is the first study showing the high expression of TLR2 and TLR9 in obese asthmatic patients. It is necessary to study other cytokines in obese asthmatic patients to see if it is possible to fit them into any of the already described endotypes or if it is a distinct endotype.
Over the past few decades, obesity and its related metabolic disorders have increased at an epidemic rate in the developed and developing world. New signals and factors involved in the modulation of energy balance and metabolism are continuously being discovered, providing potential novel drug targets for the treatment of metabolic disease. A parallel strategy is to better understand how hormonal signals, with an already established role in energy metabolism, work, and how manipulation of the pathways involved may lead to amelioration of metabolic dysfunction. The thyroid hormones belong to the latter category, with dysregulation of the thyroid axis leading to marked alterations in energy balance. The potential of thyroid hormones in the treatment of obesity has been known for decades, but their therapeutic use has been hampered because of side-effects. Data gleaned over the past few years, however, have uncovered new features at the mechanisms of action involved in thyroid hormones. Sophisticated neurobiological approaches have allowed the identification of specific energy sensors, such as AMP-activated protein kinase and mechanistic target of rapamycin, acting in specific groups of hypothalamic neurons, mediating many of the effects of thyroid hormones on food intake, energy expenditure, glucose, lipid metabolism, and cardiovascular function. More extensive knowledge about these molecular mechanisms will be of great relevance for the treatment of obesity and metabolic syndrome.
The Latin American Dialysis and Renal Transplant Registry (RLADTR) was founded in 1991; it collects data from 20 countries which are members of Sociedad Latinoamericana de Nefrología e Hipertension. This paper presents the results corresponding to the year 2010. This study is an annual survey requesting data on incident and prevalent patients undergoing renal replacement treatment (RRT) in all modalities: hemodialysis (HD), peritoneal dialysis (PD) and living with a functioning graft (LFG), etc. Prevalence and incidence were compared with previous years. The type of renal replacement therapy was analyzed, with special emphasis on PD and transplant (Tx). These variables were correlated with the gross national income (GNI) and the life expectancy at birth. Twenty countries participed in the surveys, covering 99% of the Latin American. The prevalence of end stage renal disease (ESRD) under RRT in Latin America (LA) increased from 119 patients per million population (pmp) in 1991 to 660 pmp in 2010 (HD 413 pmp, PD 135 pmp and LFG 111 pmp). HD proportionally increased more than PD, and Tx HD continues to be the treatment of choice in the region (75%). The kidney Tx rate increased from 3.7 pmp in 1987 to 6.9 pmp in 1991 and to 19.1 in 2010. The total number of Tx's in 2010 was 10 397, with 58% deceased donors. The total RRT prevalence correlated positively with GNI (r (2) 0.86; P < 0.05) and life expectancy at birth (r (2) 0.58; P < 0.05). The HD prevalence and the kidney Tx rate correlated significantly with the same indexes, whereas the PD rate showed no correlation with these variables. A tendency to rate stabilization/little growth was reported in the most regional countries. As in previous reports, the global incidence rate correlated significantly only with GNI (r (2) 0.63; P < 0.05). Diabetes remained the leading cause of ESRD. The most frequent causes of death were cardiovascular (45%) and infections (22%). Neoplasms accounted for 10% of the causes of death. The prevalence of RRT continues to increase, particularly in countries with 100% public health or insurance coverage for RRT, where it approaches rates comparable to those displayed by developed countries with a better GNI. The incidence also continues to increase in both countries that have not yet extended its coverage to 100% of the population as well as in those that have an adequate program for timely detection and treatment of chronic kidney disease (CKD) and its associated risk factors. PD is still an underutilized strategy for RRT in the region. Even though renal Tx is feasible, its growth rate is still not as fast as it should be in order to compensate for the increased prevalence of patients on waiting lists. Diagnostic and prevention programs for hypertension and diabetes, appropriate policies promoting the expansion of PD and organ procurement as well as transplantation as cost-effective forms of RRT are needed in the region. Regional cooperation among Latin American countries, allowing the more developed to guide and train others in starting registries and CKD programs, may be one of the key initiatives to address this deficit.
This article aims to characterize the different types of Facebook and Twitter groups for different mental diseases, their purposes, and their functions. We focused the search on depressive disorders, dementia, and Alzheimer's and Parkinson's diseases and examined the Facebook (www.facebook.com) and Twitter (www.twitter.com) groups. We used four assessment criteria: (1) purpose, (2) type of creator, (3) telehealth content, and (4) free-text responses in surveys and interviews. We observed a total of 357 Parkinson groups, 325 dementia groups, 853 Alzheimer groups, and 1127 depression groups on Facebook and Twitter. Moreover, we analyze the responses provided by different users. The survey and interview responses showed that many people were interested in using social networks to support and help in the fight against these diseases. The results indicate that social networks are acceptable by users in terms of simplicity and utility. People use them for finding support, information, self-help, advocacy and awareness, and for collecting funds.
A flow-injection analysis chemiluminescence method based on the enhancement effect of the flumequine-Tb(III) complex on the weak native emission of the Ce(IV)-Na2SO3 system has been developed for the determination of flumequine. The method includes a cleanup and preconcentration stage (750-fold) of the sample by hollow-fiber liquid-phase microextraction using an Accurel(®) Q 3/2 polypropylene hollow fiber impregnated with 1-octanol as the supported liquid membrane. The obtained 50 ?L acceptor phase was injected in a 1 mM Tb(III) + 4 mM Ce(IV) in 5% v/v H2 SO4 stream and mixed with a 2 mM Na2 SO3 stream before its introduction into the flow cell. The chemiluminescence signal was linear in the 0.3-15 ng/mL range, with detection and quantitation limits of 0.1 and 0.3 ng/mL, respectively. The method allows the selective extraction and determination of flumequine in wastewater samples, using simpler and lower-cost instrumentation and with shorter extraction and analysis times than traditional high-performance liquid chromatography analysis.
Currently, cardiovascular diseases are the deadliest diseases with a total of 17 million deaths worldwide. Hence, they are the focus of many mobile applications for smartphones and tablets. This paper will assess the ex-ante economic impact as well as will determine the cost-effectiveness analysis that the use of one of this app, CardioManager, by patients with heart failure will have in a Spanish community, Castile and Leon. For this, a cost-effectiveness analysis using the hidden Markov model were performed in a hypothetical cohort of patients diagnosed with heart failure, based on the information of epidemiological parameters and the costs derived from the management and care of heart failure patients by the Public Health Care System of Castile and Leon. The costs of patient care were estimated from the perspective of the Ministry of Health of Spain using a discount rate of 3 %. Finally, an estimation of the ex-ante impact that would suppose the introduction of CardioManager in the Health Care System is performed. It is concluded that the introduction of CardioManager may generate a 33 % reduction in the cost of management and treatment of the disease. This means that CardioManager may be able to save more than 9,000 € per patient to the local Health Care System of Castile and Leon, which can be translated in a saving of 0.31 % of the total health expenditure of the region.
Tumor cells often have defects in DNA repair pathways that make them vulnerable to specific DNA-damaging anticancer agents. The identification of DNA repair defects in tumor cells and the evaluation of their influence on the cytotoxicity of anticancer drugs are active areas of scientific investigation that may help rationalize and improve cancer chemotherapy. This article reviews the available data on the influence of defects in proteins involved in the major DNA repair pathways (i.e., homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, Fanconi anemia repair, translesion synthesis and direct reversal repair) on the cytotoxicity of the FDA-approved anticancer drugs. It is shown that specific deficiencies in these DNA repair pathways alter the cytotoxicity of 60 anticancer drugs, including classical DNA-targeting drugs (e.g., alkylating agents, cytotoxic antibiotics, DNA topoisomerase inhibitors and antimetabolites) and other drugs whose primary pharmacological target is not the DNA (e.g., antimitotic agents, hormonal and targeted therapies). This information may help predict response to anticancer drugs in patients with tumors having specific DNA repair defects.
During competition, high-performance swimmers are subject to repeated physical demands that affect their final performance. Measurement of lactate concentration in blood seeks to indirectly gauge physiologic responses to the increase in physical exercise. Swimmers face multiple maximal-exertion events during competition. Strenuous physical exercise leads to fatigue and, thus, a decrease in sports performance.
Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na(+)/K(+)-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.
Mobile health (m-health) apps can bring health prevention and promotion to the general population. The main purpose of this article is to analyze different m-health apps for a broad spectrum of consumers by means of three different experiences. This goal was defined following the strategic documents generated by the main prospective observatories of Information and Communications Technology for health. After a general exploration of the app markets, we analyze the entries of three specific themes focused in this article: type 2 diabetes, obesity, and breast-feeding. The user experiences reported in this study mostly cover the segments of (1) chronically monitored consumers through a Web mobile app for predicting type 2 diabetes (Diab_Alert app), (2) information seekers through a mobile app for maternity (Lactation app) and partially (3) the motivated healthy consumers through a mobile app for a dietetic monitoring and assessment (SapoFit app). These apps were developed by the authors of this work.
Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ER?) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
Assisted reproductive technology (ART) with washed semen can achieve pregnancy with minimal risk of horizontal and vertical transmission of chronic viral diseases (CVD) such as human immunodeficiency virus (HIV), hepati- tis C virus (HCV) and hepatitis B virus (HBV) among serodiscordant couples. How- ever, few studies have been made of the use made by these couples of ARTs or of the obstetric results achieved.
Hypothalamic endoplasmic reticulum (ER) stress is a key mechanism leading to obesity. Here, we demonstrate that ceramides induce lipotoxicity and hypothalamic ER stress, leading to sympathetic inhibition, reduced brown adipose tissue (BAT) thermogenesis, and weight gain. Genetic overexpression of the chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) in the ventromedial nucleus of the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress and increasing BAT thermogenesis, which leads to weight loss and improved glucose homeostasis. The pathophysiological relevance of this mechanism is demonstrated in obese Zucker rats, which show increased hypothalamic ceramide levels and ER stress. Overexpression of GRP78 in the VMH of these animals reduced body weight by increasing BAT thermogenesis as well as decreasing leptin and insulin resistance and hepatic steatosis. Overall, these data identify a triangulated signaling network involving central ceramides, hypothalamic lipotoxicity/ER stress, and BAT thermogenesis as a pathophysiological mechanism of obesity.
Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.
Polyamines (PAs) are low molecular weight aliphatic compounds that have been shown to be an important part of plant responses to salt stress. For that reason in this work we have investigated the involvement of PAs in the response to salt stress in root nodules of Phaseolus vulgaris in symbiosis with Rhizobium tropici. The level and variety of PAs was higher in nodules, compared to leaves and roots, and in addition to the common PAs (putrescine, spermidine and spermine) we found homospermidine (Homspd) as the most abundant polyamine in nodules. UPLC-mass spectrometry analysis revealed the presence of 4-aminobutylcadaverine (4-ABcad), only described in nodules of Vigna angularis before. Indeed, the analysis of different nodular fractions revealed higher level of 4-ABcad, as well as Homspd, in bacteroids which indicate the production of these PAs by the bacteria in symbiosis. The genes involved in PAs biosynthesis in nodules displayed an induction under salt stress conditions which was not consistent with the decline of free PAs levels, probably due to the nitrogen limitations provoked by the nitrogenase activity depletion and/or the conversion of free PAs to theirs soluble conjugated forms, that seems to be one of the mechanisms involved in the regulation of PAs levels. On the contrary, cadaverine (Cad) and 4-ABcad concentrations augmented by the salinity, which might be due to their involvement in the response of bacteroids to hyper-osmotic conditions. In conclusion, the results shown in this work suggest the alteration of the bacteroidal metabolism towards the production of uncommon PAs such as 4-ABcad in the response to salt stress in legume root nodules.
The role of ghrelin in regulating metabolism and energy balance has been a subject of intense focus ever since its discovery. Ghrelin regulates energy balance in the short term by induction of appetite and in the longer term by increasing body weight and adiposity. It is the only known peripheral orexigenic hormone and one of the most potent endogenous orexigenic factors discovered to date. However, whilst extensively studied, the mechanism of ghrelin secretion is not well understood. A better understanding of the pathways controlling ghrelin secretion could be useful in the development of new therapeutic approaches to appetite-related disorders. Here, we discuss current knowledge of the processes that control ghrelin secretion, focusing on neural, chemical and hormonal stimuli. In addition, we share our view on the potential of targeting ghrelin for the treatment of eating disorders such as obesity, anorexia nervosa and cachexia.
The aim of this study was to assess the random error of the thinnest point and midperipheral pachymetry with a combined Placido-scanning-slit system (Orbscan II) in the intermediate-term follow-up of excimer laser keratorefractive surgery for treating myopia.
The toxicological effects of diverse pollutants typically found on wastewaters of diverse origin (industrial, urban, etc.) have led to regulation of their emission by national and trans-national organizations, and an increasing interest in the development of fast and reliable methods for their analysis. This paper is an up-to-date comprehensive review on the analytical applications of chemiluminescence technique (characterized by high sensitivity, wide dynamic ranges and simple instrumentation) to the analysis of wastewaters, emphasizing the different kinds of pollutants that have been studied with these methods and discussing the different approaches followed by the authors as CL reactions, devices and coupled methods.
?-Lipoic acid (?-LA) is a natural occurring antioxidant with beneficial effects on obesity. The aim of this study was to investigate the putative effects of ?-LA on triglyceride accumulation and lipogenesis in subcutaneous adipocytes from overweight/obese subjects and to determine the potential mechanisms involved.
Although the Pgp efflux transport protein is overexpressed in resected tissue of patients with epilepsy, the presence of polymorphisms in MDR1/ABCB1 and MRP2/ABCC2 in patients with antiepileptic-drugs resistant epilepsy (ADR) is controversial. The aim of this study was to perform an exploratory study to identify nucleotide changes and search new and reported mutations in patients with ADR and patients with good response (CTR) to antiepileptic drugs (AEDs) in a rigorously selected population. We analyzed 22 samples In Material and Methods, from drug-resistant patients with epilepsy and 7 samples from patients with good response to AEDs. Genomic DNA was obtained from leukocytes. Eleven exons in both genes were genotyped. The concentration of drugs in saliva and plasma was determined. The concentration of valproic acid in saliva was lower in ADR than in CRT. In ABCB1, five reported SNPs and five unreported nucleotide changes were identified; rs2229109 (GA) and rs2032582 (AT and AG) were found only in the ADR. Of six SNPs associated with the ABCC2 that were found in the study population, rs3740066 (TT) and 66744T?>?A (TG) were found only in the ADR. The strongest risk factor in the ABCB1 gene was identified as the TA genotype of rs2032582, whereas for the ABCC2 gene the strongest risk factor was the T allele of rs3740066. The screening of SNPs in ACBC1 and ABCC2 indicates that the Mexican patients with epilepsy in this study display frequently reported ABCC1 polymorphisms; however, in the study subjects with a higher risk factor for drug resistance, new nucleotide changes were found in the ABCC2 gene. Thus, the population of Mexican patients with AED-resistant epilepsy (ADR) used in this study exhibits genetic variability with respect to those reported in other study populations; however, it is necessary to explore this polymorphism in a larger population of patients with ADR.
Gluten content from barley, rye, wheat and in certain oat varieties, must be avoid in individuals with celiac disease. In most of the Western countries, the level of gluten content in food to be considered as gluten-free products is below 20 parts per million measured by ELISA based on specific anti-gluten peptide antibody. However, in beverages or food suffering complex hydrolytic processes as beers, the relative proportion of reactive peptides for celiac patients and the analytical techniques may differ, because of the diversity of the resulting peptide populations after fermentations. A beer below 20 parts per million of gluten but yet detectable levels of gluten peptides by anti-gliadin 33-mer antibodies (G12 and A1) was analyzed. We identified and characterized the relevant peptides for either antibody recognition or immunoactivity in celiac patients. The beer was fractionated by HPLC. The relative reactivity of the different HPLC fractions to the G12/A1 antibodies correlated to the reactivity of peripheral blood mononuclear cells isolated from 14 celiac individuals. Peptides from representative fractions classified according to the relative reactivity to G12/A1 antibodies were identified by mass spectrometry. The beer peptides containing sequences with similarity to those of previously described G12 and A1 epitopes were synthesized and confirmed significant reactivity for the antibodies. The most reactive peptides for G12/A1 also confirmed the highest immunogenicity by peripheral blood mononuclear cell activation and interferon ? production from celiac patients. We concluded that preparative HPLC combined with anti-gliadin 33-mer G12/A1 antibodies were very sensitive and specific methods to analyze the relevant immunogenic peptides in hydrolyzed gluten.
Chronic kidney disease (CKD) is a progressive deterioration of the kidney function, which may eventually lead to renal failure and the need for dialysis or kidney transplant. Whether initiated in the glomeruli or the tubuli, CKD is characterized by progressive nephron loss, for which the process of tubular deletion is of key importance. Tubular deletion results from tubular epithelial cell death and defective repair, leading to scarring of the renal parenchyma. Several cytokines and signaling pathways, including transforming growth factor-? (TGF-?) and the Fas pathway, have been shown to participate in vivo in tubular cell death. However, there is some controversy about their mode of action, since a direct effect on normal tubular cells has not been demonstrated. We hypothesized that epithelial cells would require specific priming to become sensitive to TGF-? or Fas stimulation and that this priming would be brought about by specific mediators found in the pathological scenario.
During our search for cytotoxic compounds from Andalusian vascular plants, the ethyl acetate extract from the leaves of Corema album (L.) D. Don (Ericaceae) was selected for its cytotoxic activity against the HT-29 human colon adenocarcinoma cell line. Two dihydrochalcones, 2,4-dihydroxydihydrochalcone (1) and 2-methoxy-4-hydroxydihydrochalcone (2), have been isolated from the leaves of C. album. Their structural identification was based on 1H NMR and 13C NMR data, including 2D NMR, and mass spectrometry. These compounds were subjected to the sulfhorhodamine B (SRB) cytotoxic assay against human colon adenocarcinoma cells (HT-29). Compounds 1 and 2 showed higher cytotoxicity than the positive control 5-fluorouracil (5-FU); the IC50 values (microM +/- SEM) were 1.8 +/- 0.4 for compound 1, 8.5 +/- 2.1 microM for compound 2, and 8.7 +/- 4.0 for 5-FU. The cytotoxic activity of 1 and 2 was reduced in the presence of the antioxidants N-acetylcysteine (NAC) and Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), therefore suggesting that reactive oxygen species generation participates in the cytotoxic activity of these dihydrochalcones.
The aim of this study is to analyze mitochondrial DNA and Y-chromosome lineages in a range of Atlantic and Mediterranean populations of the Iberian Peninsula in search of genetic differences between both façades and to uncover the most probable geographic origin and coalescence ages of lineages.
Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies.
The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
Fifteen years ago orexins were identified as central regulators of energy homeostasis. Since then, that concept has evolved considerably and orexins are currently considered, besides orexigenic neuropeptides, key modulators of sleep-wake cycle and neuroendocrine function. Little is known, however, about the effect of the neuroendocrine milieu on orexins effects on energy balance. We therefore investigated whether hypothalamic-pituitary axes have a role in the central orexigenic action of orexin A (OX-A) by centrally injecting hypophysectomized, adrenalectomized, gonadectomized (male and female), hypothyroid, and GH-deficient dwarf rats with OX-A. Our data showed that the orexigenic effect of OX-A is fully maintained in adrenalectomized and gonadectomized (females and males) rats, slightly reduced in hypothyroid rats, and totally abolished in hypophysectomized and dwarf rats when compared with their respective vehicle-treated controls. Of note, loss of the OX-A effect on feeding was associated with a blunted OX-A-induced increase in the expression of either neuropeptide Y or its putative regulator, the transcription factor cAMP response-element binding protein, as well as its phosphorylated form, in the arcuate nucleus of the hypothalamus of hypophysectomized and dwarf rats. Overall, this evidence suggests that the orexigenic action of OX-A depends on an intact GH axis and that this neuroendocrine feedback loop may be of interest in the understanding of orexins action on energy balance and GH deficiency.
Ghrelin, a stomach-derived peptide, stimulates feeding behavior and adiposity. For its orexigenic action, ghrelin triggers a central SIRT1/p53/AMPK pathway. The tumor suppressor p53 also plays an important role in white adipose tissue (WAT), where it is up-regulated in the adipocytes of obese mice. It is not known, however, whether p53 has any role in mediating the peripheral action of ghrelin. In the present study, chronic peripheral ghrelin treatment resulted in increased body weight and fat-mass gain in wild-type mice. Correspondingly, mRNA levels of several adipogenic and fat-storage-promoting enzymes were up-regulated in WAT, whereas hepatic triglyceride content and lipogenic enzymes were also increased in wild-type mice following ghrelin treatment. In contrast, mice lacking p53 failed to respond to ghrelin treatment, with their body weight, fat mass, and adipocyte and hepatic metabolism remaining unchanged. Thus, our results show that p53 is necessary for the actions of ghrelin on WAT and liver, leading to changes in expression levels of lipogenic and adipogenic genes, and modifying body weight.
Recent evidence suggests that cardiac glycosides might be used for the treatment of cancer. The ornamental shrub Nerium oleander has been used in traditional medicine for treating several disorders including cancer, and extracts from the leaves of this plant have already entered phase I clinical trials. In this communication, we have prepared a hydroalcoholic extract from the leaves of Nerium oleander (containing 4.75 ± 0.32 % of cardenolides) and have assessed its cytotoxic activity in A549 lung cancer cells vs. MRC5 nonmalignant lung fibroblasts. The results showed that the cytotoxicity of the Nerium oleander extract against the cancer cell line was significantly higher than that against the nonmalignant cell line, with a potency and selectivity similar to those of the anticancer drug cisplatin. Pretreatment of A549 cells with the antioxidants N-acetylcysteine and catalase slightly prevented the cytotoxicity of the extract, therefore suggesting that the formation of reactive oxygen species participates in its cytotoxic activity but does not play a major role. Nerium oleander extract-induced cytotoxicity and DNA damage (gamma-H2AX focus formation) were slightly higher in cells lacking BRCA2 (deficient in homologous recombination repair) than in parental cells; this indicates that the induction of DNA damage may also play a role in the cytotoxicity of the extract. Nerium oleander extract induced a marked inhibition of glycolysis (glucose consumption and lactate production) in A549 cells, comparable to that of the glycolysis inhibitor dichloroacetate (currently in clinical development for cancer therapy). Because platinum compounds are widely used in the treatment of lung cancer, we tested the cytotoxicity of several combinations of cisplatin with the extract and found a moderate synergism when Nerium oleander extract was administered after cisplatin but a moderate antagonism when it was added before cisplatin. Our results suggest that extracts from Nerium oleander might induce anticancer effects in patients with lung cancer and support their possible advancement into phase II clinical trials for the treatment of this type of cancer.
In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisins action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.
The rapid spread of smartphones and tablets in the last years has created a new software industry whose fast growth has propitiated numerous low-quality applications to be revised and improved. The main aim of this paper is to develop a tool to assess the Quality of Experience (QoE) of mobile Health (mHealth) applications in order to improve the quality of the existing apps and the ones to be released. Firstly, a review of the applications of mHealth has been done in order to obtain a general classification. Secondly, the tool for measuring the QoE is developed in the form of a survey with the help of psychologists. Finally, this tool is evaluated using a sample of applications selected with the aid of the classification obtained. A survey with 21 questions using the Likert scale and destined to users has been successfully created, and its evaluation has been positive, resulting in a good method for measuring the QoE of the different features that the applications in the field of health care usually have. The tool created can be very useful for developers in order to assess the quality of their health care apps, indicating their positive aspects and the ones which must be revised and improved, avoiding the releasing of low-quality apps.
The G protein-coupled receptor GPR55 has been proposed as a new cannabinoid receptor associated with obesity in humans. We have investigated the regulation of GPR55 in rat white adipose tissue (WAT) in different physiological and pathophysiological settings involved in energy balance. We compared GPR55 expression with Cannabinoid Receptor type 1 (CB1), which mediates the metabolic actions of endocannabinoids, by real time PCR and western blotting. Circulating levels of lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, were measured by liquid chromatography-mass spectrometry. Both WAT CB1 and GPR55 levels were increased after fasting and recovered after leptin treatment. Their expression was decreased during gestation and increased throughout lifespan. Orchidectomy diminished WAT CB1 and GPR55 expression whereas ovariectomized rats showed increased GPR55 but decreased CB1 levels. Alterations in pituitary functions also modified WAT CB1 and GPR55 levels. Serum LPI levels were inversely regulated by fasting and gonadectomy in comparison to WAT GPR55. Our findings indicate that GPR55 and LPI are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in energy status.
The Cloud Computing paradigm offers eHealth systems the opportunity to enhance the features and functionality that they offer. However, moving patients medical information to the Cloud implies several risks in terms of the security and privacy of sensitive health records. In this paper, the risks of hosting Electronic Health Records (EHRs) on the servers of third-party Cloud service providers are reviewed. To protect the confidentiality of patient information and facilitate the process, some suggestions for health care providers are made. Moreover, security issues that Cloud service providers should address in their platforms are considered.
Patients with severe mental illness have higher prevalences of cardiovascular risk factors (CRF). The objective is to determine whether interventions to modify lifestyles in these patients reduce anthropometric and analytical parameters related to CRF in comparison to routine clinical practice. Systematic review of controlled clinical trials with lifestyle intervention in Medline, Cochrane Library, Embase, PsycINFO and CINALH. Change in body mass index, waist circumference, cholesterol, triglycerides and blood sugar. Meta-analyses were performed using random effects models to estimate the weighted mean difference. Heterogeneity was determined using i(2) statistical and subgroups analyses. 26 studies were selected. Lifestyle interventions decrease anthropometric and analytical parameters at 3 months follow up. At 6 and 12 months, the differences between the intervention and control groups were maintained, although with less precision. More studies with larger samples and long-term follow-up are needed.
Recent data suggest that hydroxytyrosol, a phenolic compound of virgin olive oils, has anticancer activity. This communication reports the synthesis of decyl and hexadecyl hydroxytyrosyl ethers, as well as the cytotoxic activity of hydroxytyrosol and a series of seven hydroxytyrosol alkyl ether derivatives against A549 lung cancer cells and MRC5 non-malignant lung fibroblasts. Hydroxytyrosyl dodecyl ether (HTDE) showed the highest selective cytotoxicity, and possible mechanisms of action were investigated; results suggest that HTDE can moderately inhibit glycolysis, induce oxidative stress, and cause DNA damage in A549 cells. The combination of HTDE with the anticancer drug 5-fluorouracil induced a synergistic cytotoxicity in A549 cancer cells but not in non-malignant MRC5 cells. HTDE also displayed selective cytotoxicity against MCF7 breast cancer cells versus MCF10 normal breast epithelial cells in the 1-30 ?M range. These results suggest that the cytotoxicity of HTDE is more potent and selective than that of parent compound hydroxytyrosol.
Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-?-MHC mouse line (referred to as ?-MHCMet-KO). Although ?-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as ?-MHC and ANF, was also observed. By the age of 9months, ?-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in ?-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-? production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in ?-MHCMet-KO mice. Consistently, we show that HGF acts through p38? to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.
5-Aza-2-deoxycytidine (5-azadC) is a DNA methyltransferase (DNMT) inhibitor increasingly used in treatments of hematological diseases and works by being incorporated into DNA and trapping DNMT. It is unclear what DNA lesions are caused by 5-azadC and if such are substrates for DNA repair. Here, we identify that 5-azadC induces DNA damage as measured by ?-H2AX and 53BP1 foci. Furthermore, 5-azadC induces radial chromosomes and chromatid breaks that depend on active replication, which altogether suggest that trapped DNMT collapses oncoming replication forks into double-strand breaks. We demonstrate that RAD51-mediated homologous recombination (HR) is activated to repair 5-azadC collapsed replication forks. Fanconi anemia (FA) is a rare autosomal recessive disorder, and deaths are often associated with leukemia. Here, we show that FANCG-deficient cells fail to trigger HR-mediated repair of 5-azadC-induced lesions, leading to accumulation of chromatid breaks and inter-chromosomal radial fusions as well as hypersensitivity to the cytotoxic effects of 5-azadC. These data demonstrate that the FA pathway is important to protect from 5-azadC-induced toxicity. Altogether, our data demonstrate that cytotoxicity of the epigenetic drug 5-azadC can, at least in part, be explained by collapsed replication forks requiring FA-mediated HR for repair.
A series of new aziridines ?-D-galactopyranoside derivatives were synthesized from alkenyl ?-D-galactopyranosides employing Sharpless conditions. The structures of the compounds were established by (1)H NMR, (13)C NMR, MS, HRMS and elemental analysis. The stereoselectivity of the reaction and the structural requirements of the alkenyl precursor for improving diastereoisomeric excesses of the direct aziridination reaction were also studied. The new compounds were subjected to a preliminary screening for cytotoxic activity against human lung cancer cells vs. human non-malignant lung cells. Terminal aziridine derivatives showed activity and, most notably, selectivity. One of the most active and selective compounds was also evaluated against breast cancer cells, melanoma cells, and non-malignant cells from the same origin. Its cytotoxic activity was similar to that of the positive controls, displaying a highly selective cytotoxic activity against both types of cancer cells.
The alpha, beta-unsaturated lactones 2-furanone and 2-pyrone are part of the chemical structure of a variety of naturally occurring compounds (e.g., cardenolides, bufadienolides, acetogenins, coumarins, and food-flavoring furanones), some of which have shown anticancer activity and/or DNA damaging effects. Here we report that 2-furanone and 2-pyrone induce cellular DNA damage (assessed by the comet assay and the gamma-H2AX focus assay) and the formation of topoisomerase I- and topoisomerase II-DNA complexes in cells (visualized and quantified in situ by the TARDIS assay). Cells mutated in BRCA2 (deficient in homologous recombination repair) were significantly hypersensitive to the cytotoxic activity of 2-pyrone, therefore suggesting that BRCA2 plays an important role in the repair of DNA damage induced by this lactone. Both lactones were cytotoxic in A549 lung cancer cells at lower concentrations than in MRC5 non-malignant lung fibroblasts. The possible involvement of 2-furanone and 2-pyrone in the anticancer and DNA-damaging activities of compounds containing these lactones is discussed.
Recent evidence suggests that ghrelin, a peptidic hormone stimulating food intake, interacts with the dopamine signaling. This interaction has been demonstrated to modulate several effects of ghrelin, such as locomotor activity, memory, and food intake. Ghrelin increases dopamine levels in the shell of the nucleus accumbens stimulating food intake, while ablation of the ghrelin receptor attenuates the hypophagia caused by the activation of dopamine receptor 2. However, it is not known whether the orexigenic action of ghrelin is due to changes in central dopamine receptors.
Recent data suggest that ghrelin exerts its orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element-binding protein and forkhead box O1. Finally, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance for the understanding and treatment of obesity.
New possibilities for mHealth have arisen by means of the latest advances in mobile communications and technologies. With more than 1 billion smartphones and 100 million tablets around the world, these devices can be a valuable tool in health care management. Every aid for health care is welcome and necessary as shown by the more than 50 million estimated deaths caused by illnesses or health conditions in 2008. Some of these conditions have additional importance depending on their prevalence.
Classically, medical textbooks taught that most effects of thyroid hormones (THs) on energy homeostasis are directly exerted in peripheral tissues. However, current evidence is changing (and challenging) our perspective about the role of THs from a peripheral to a central vision, implying that they affect food intake, energy expenditure, and metabolism by acting, to a large extent, at the central level. Interestingly, effects of THs are interrelated with global energy sensors in the central nervous system (CNS), such as uncoupling protein 2 (UCP2), AMP-activated protein kinase (AMPK; the AMPK-BAT axis), and mechanistic target of rapamycin (mTOR). Here, we review what is currently known about THs and their regulation of energy balance and metabolism in both peripheral and central tissues.
The opioid system is well recognized as an important regulator of appetite and energy balance. We now hypothesized that the hypothalamic opioid system might modulate the orexigenic effect of ghrelin. Using pharmacological and gene silencing approaches, we demonstrate that ghrelin utilizes a hypothalamic ?-opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin-induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. Our novel data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin.
To assess the repeatability, intersession and interobserver reproducibility, and agreement of central corneal thickness (CCT) measurements obtained by scanning-slit topography (SST) and noncontact specular microscopy (NCSM) after advanced surface ablation (ASA).
To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardts disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP), and to assess genotype-phenotype correlation and disease progression in 10 years by considering the type of variants and age at onset.
The functional mechanisms involved in angiogenesis and the potential role of endoglin (ENG), recently described as a new marker for this process, have not been explored in Myelodysplastic Syndromes (MDS). In order to gain insight in MDS angiogenesis a combined analysis in bone marrow (BM) of gene expression levels, angiogenesis-related soluble factors and functional angiogenesis-related studies was carried out. Ninety-seven MDS patients and forty-two normal BM samples were studied. The morphology of the capillary-like structures originated by two endothelial cells lines in the BM environment of patients with refractory cytopenia with multilineage dysplasia (RCMD) was different from those of the remaining MDS. In addition, the BM mononuclear cells from RCMD patients displayed over-expression of VEGF, HIF and FN1 while they showed reduced expression of ENG in contrast to the normal ENG expression of the remaining low-risk MDS and the high expression of ENG in high-risk MDS subtype. Moreover, higher soluble ENG and soluble FLT-1 levels in BM microenvironment were observed in RCMD cases, which distinguished them from other individuals. Therefore, the present study suggests that the patterns of angiogenesis are different between the MDS subtypes. The differences in angiogenesis observed in RCMD patients could be related to ENG abnormalities.
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