Abstract Introduction Obesity, defined as an excess of total body fat, is a matter of concern all over the world, and its prevalence is still increasing among elderly people. Objectives To examine ...whether sedentary behaviour (hours sitting per day) is associated with higher risk of central obesity, overweight-obesity and overfat in a representative sample of non-institutionalized Spanish elderly population and if so, whether hours walking per day modified this association. Study design A cross-sectional study in a sample of 3136 people ≥65 years of age. Main outcomes measures Anthropometric measurements were obtained using standardized techniques and equipment. Active and sedentary behaviours were recorded by questionnaire. Results For both men and women, the higher prevalence of overweight-obesity, central obesity and overfat was found in those who spent sitting more than 4 h per day and walk less than 1 h, compared with those who spent sitting less than 4 h per day and walk more than 1 h (all p < 0.001, except for central obesity in women). In men, more than 4 h sitting per day was associated with 1.7-fold higher odds of having central obesity compared with those sitting less than 4 h per day ( p < 0.01). In women, this sedentary behaviour increased the risk of overweight-obesity and overfat by 1.5 and 1.4, respectively ( p < 0.01). Age or time spent walking did not significantly change these results. Conclusion Sitting time increases the risk of overweight-obesity and overfat in women and the risk of central obesity in men, independently of walking time.
A magnetic solid phase extraction method coupled to capillary electrophoresis is proposed for the determination of tetracycline, oxytetracycline, chlortetracycline and doxycycline in milk samples. ...Five different magnetic phenyl silica adsorbents covered with magnetite were synthesized by varying the molar ratio of phenyltrimethylsilane and tetramethylorthosilicate; these adsorbents were evaluated in terms of their pH and degree of hydrophobicity for tetracycline retention. The optimal, selected combination of conditions was a pH of 10.0 and a magnetic sorbent ratio of 4:1; under these conditions, the retention capacity ranged from 99.7% to 101.2% for the four tetracyclines analyzed. The elution conditions and initial sample volume of the proposed extraction method were also optimized, and the best results were obtained with 1
×
10
−3
M acetic acid in methanol as eluent and a 200
ml of sample volume. Under optimal conditions, average recoveries ranged from 94.2% to 99.8% and the limits of detection ranged from 2 to 9
μg
l
−1 for the four tetracyclines. After the proposed method was optimized and validated, 25 milk samples of different brands were analyzed, oxytetracycline residues were detected in five samples, in concentrations ranging from 98 to 213
μg
l
−1. Subsequent analysis of positive samples by SPE–CE and magnetic solid phase extraction–HPLC revealed than no significant differences were found from results obtained by the proposed methodology. Thus, the developed magnetic extraction is a robust pre-concentration technique that can be coupled to other analytical methods for the quantitative determination of tetracyclines.
Objectives
Although the benefits of albuterol delivered via metered‐dose inhalers with a spacer (MDI+S) have been increasingly recognized, the evidence regarding the cost‐effectiveness of MDI+S ...compared to nebulization (NEB) is not sufficient, especially in less‐affluent countries, where the clinical and economic burden of the disease is the greatest. The aim of the present study was to evaluate the cost‐effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations.
Methods
A decision‐analysis model was developed to estimate the cost‐effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from hospital bills and from the national manual of drug prices in Colombia. The study was carried out from the perspective of the national healthcare system in Colombia, a middle‐income country (MIC). The main outcome of the model was the avoidance of hospital admission.
Results
For the base‐case analysis, the model showed that compared to NEB, using MDI+S for the delivery of albuterol was associated with lower total costs (US$96.68 vs US$121.41 average cost per patient) and a higher probability of hospital admission avoided (0.9219 vs 0.8900), thus leading to dominance.
Conclusions
This study shows that in Colombia, an MIC, compared with NEB, the use of MDI+S for delivering albuterol for the treatment of pediatric asthma exacerbations is the preferred strategy because it is associated with a lower probability of hospital admission at lower total treatment costs.
Micro-crystal electron diffraction (MicroED) combines the efficiency of electron scattering with diffraction to allow structure determination from nano-sized crystalline samples in cryoelectron ...microscopy (cryo-EM). It has been used to solve structures of a diverse set of biomolecules and materials, in some cases to sub-atomic resolution. However, little is known about the damaging effects of the electron beam on samples during such measurements. We assess global and site-specific damage from electron radiation on nanocrystals of proteinase K and of a prion hepta-peptide and find that the dynamics of electron-induced damage follow well-established trends observed in X-ray crystallography. Metal ions are perturbed, disulfide bonds are broken, and acidic side chains are decarboxylated while the diffracted intensities decay exponentially with increasing exposure. A better understanding of radiation damage in MicroED improves our assessment and processing of all types of cryo-EM data.
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•Damage to the crystalline order is quantified in reciprocal space•Site-specific damage to sensitive moieties is assessed in real space•The effects of damage are particularly pronounced at resolutions better than 3 Å•At high resolution, damage is apparent at exposures as low as 1 e− Å−2
The scattered electrons in a cryo-EM measurement provide the information necessary to determine the atomic structure, but inevitably damage the sample. Radiation damage must be controlled to avoid compromising the result. Here, the relationship between exposure and damage is assessed in two different crystalline samples.
Abstract Background Bacillus Calmette-Guérin (BCG) maintenance therapy for 3 yr following BCG induction can reduce the progression of urothelial bladder carcinoma versus BCG induction alone, but is ...associated with high toxicity. Objective To investigate whether a modified 3-yr BCG maintenance regimen following induction therapy is more effective than standard BCG induction therapy alone and exhibits a low toxicity profile. Design, setting, and participants Patients from the outpatient clinics of the participating centres with high-risk non–muscle-invasive bladder carcinoma (NMIBC) were randomised between October 1999 and April 2007. Intervention Participants received BCG induction once-weekly for 6 wk (no maintenance arm) or BCG induction followed by one BCG instillation every 3 mo for 3 yr (maintenance arm). Outcome measurements and statistical analysis Primary endpoints were disease-free interval (DFI) and time to progression (TTP). Secondary endpoints included survival duration and toxicity. Differences between treatment arms were tested using Student's t test and χ2 and log-rank tests. Results and limitations A total of 397 patients were randomised, 195 to the no-maintenance and 202 to the maintenance arm. A median time to recurrence was not reached in either treatment arm. DFI was similar between the arms (hazard ration HR 0.83; 95% CI 0.61–1.13; p = 0.2) with disease relapse at 5 yr of 33.5% and 38.5%, respectively. TTP was also similar between the treatment arms (HR 0.79; 95% CI 0.50–1.26; p = 0.3), with a progression rate at 5 yr of 16% and 19.5%, respectively. There were no significant differences between the treatment groups for overall survival and cancer-specific survival at 5 yr. Twenty and five patients in the maintenance and no-maintenance arms, respectively, stopped treatment because of toxicity. The most common local side effects were frequency (65% of patients), dysuria (63%), and haematuria (43%); the most frequent systemic side effects were general malaise (7.2%) and fever (34%). Conclusions In NMIBC patients treated with maintenance therapy comprising a single BCG instillation every 3 mo for 3 yr following standard induction BCG, we did not observe a decrease in recurrence and progression rates versus induction therapy alone. Patient summary Patients who undergo surgery to remove bladder cancer are usually treated with bacillus Calmette-Guérin (BCG) for 6 wk if there is a high risk of disease recurrence. Extending BCG therapy by 3 yr can further minimise disease recurrence and progression, but is associated with more side effects. We report that a modified 3-yr BCG treatment regimen showed low toxicity, but seemed to be no more effective than 6-wk treatment. Trial registration CUETO 98013
Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We ...investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease.
This prospective, open-label pilot study was done at CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur in Madrid, Spain. Eligible participants had Parkinson's disease with markedly asymmetric parkinsonism. Patients with severe dyskinesia, history of stereotactic surgery or brain haemorrhage, a diagnosis of an unstable cardiac or psychiatric disease, or a skull density ratio of 0·3 or less were excluded. Enrolled patients underwent focused ultrasound unilateral subthalamotomy. The subthalamic nucleus was targeted by means of brain images acquired with a 3-Tesla MRI apparatus. Several sonications above the definitive ablation temperature of 55°C were delivered and adjusted according to clinical response. The primary outcomes were safety and a change in the motor status of the treated hemibody as assessed with part III of the Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS–UPDRS III) in both off-medication and on-medication states at 6 months. Adverse events were monitored up to 48 h after treatment and at scheduled clinic visits at 1, 3, and 6 months after treatment. The study is registered with ClinicalTrials.gov, number NCT02912871.
Between April 26 and June 14, 2016, ten patients with markedly asymmetric parkinsonism that was poorly controlled pharmacologically were enrolled for focused ultrasound unilateral subthalamotomy. By 6 months follow-up, 38 incidents of adverse events had been recorded, none of which were serious or severe. Seven adverse events were present at 6 months. Three of these adverse events were directly related to subthalamotomy: off-medication dyskinesia in the treated arm (one patient, almost resolved by 6 months); on-medication dyskinesia in the treated arm (one patient, resolved after levodopa dose reduction); and subjective speech disturbance (one patient). Four of the adverse events present at 6 months were related to medical management (anxiety and fatigue one patient each and weight gain two patients). The most frequent adverse events were transient gait ataxia (related to subthalamotomy, six patients), transient pin-site head pain (related to the head frame, six patients), and transient high blood pressure (during the procedure, five patients). Transient facial asymmetry (one patient) and moderate impulsivity (two patients) were also recorded. The mean MDS–UPDRS III score in the treated hemibody improved by 53% from baseline to 6 months in the off-medication state (16·6 SD 2·9 vs 7·5 3·9) and by 47% in the on-medication state (11·9 3·1 vs 5·8 3·5).
MRI-guided focused ultrasound unilateral subthalamotomy was well tolerated and seemed to improve motor features of Parkinson's disease in patients with noticeably asymmetric parkinsonism. Large randomised controlled trials are necessary to corroborate these preliminary findings and to assess the potential of such an approach to treat Parkinson's disease.
Fundación de investigación HM Hospitales and Insightec.
Matrix metalloproteinases (MMPs) participate in tissue repair after acute injury, but also participate in cancer by promoting a protumorigenic microenvironment. Previously, we reported on a key role ...for MMP10 in mouse liver regeneration. Herein, we investigated MMP10 expression and function in human hepatocellular carcinoma (HCC) and diethylnitrosamine (DEN)‐induced mouse hepatocarcinogenesis. MMP10 was induced in human and murine HCC tissues and cells. MMP10‐deficient mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic, C‐X‐C chemokine receptor‐4 (CXCR4), was reduced in DEN‐induced MMP10‐deficient mice livers. Human HCC cells stably expressing MMP10 had increased CXCR4 expression and migratory capacity. Pharmacological inhibition of CXCR4 significantly reduced MMP10‐stimulated HCC cell migration. Furthermore, MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand, stromal‐derived factor‐1 (SDF1), through the extracellular signal‐regulated kinase 1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. Conclusion: MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis. To our knowledge, this is the first report addressing the role of a MMP in hepatocarcinogenesis in the corresponding genetic mouse model. (Hepatology 2015;62:166‐178)
Melatonin has antitumor activity via several mechanisms including its antiproliferative and pro‐apoptotic effects as well as its potent antioxidant actions, although recent evidence has indicated ...that melatonin may perform pro‐oxidant actions in tumor cells. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was intended to evaluate the in vitro effect of melatonin on the cytotoxic and pro‐apoptotic actions of various chemotherapeutic agents in cervical cancer HeLa cells. Herein, we found that both melatonin and three of the chemotherapeutic drugs tested, namely cisplatin (CIS), 5‐fluorouracil (5‐FU), and doxorubicin, induced a decrease in HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of such chemotherapeutic agents. Consistently, costimulation of HeLa cells with any chemotherapeutic agent in the presence of melatonin further increased caspase‐3 activation, particularly in CIS‐ and 5‐FU‐challenged cells. Likewise, concomitant treatments with melatonin and CIS significantly enhanced the ratio of cells entering mitochondrial apoptosis due to reactive oxygen species (ROS) overproduction, substantially augmented the population of apoptotic cells, and markedly enlarged DNA fragmentation compared to the treatments with CIS alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in 5‐FU‐stimulated HeLa cells, as suggested by slight increments in the percentage of cells stimulated for ROS production and in the proportion of early apoptotic cells compared to the treatments with 5‐FU alone. In summary, our findings provided evidence that in vitro melatonin strongly enhances CIS‐induced cytotoxicity and apoptosis in HeLa cells and, hence, the indoleamine could be potentially applied to cervical cancer treatment as a powerful synergistic agent.
Recurrent wheezing is a common problem in young children: approximately 40% of children wheeze in their first year of life. However, only 30% of preschoolers with recurrent wheezing still have asthma ...at the age of 6 years. Nevertheless, asthma, the most prevalent chronic disease in children, is difficult to diagnose in infants and preschoolers. This article reviews the importance of determining at an early age which infants/preschoolers will have asthma later in life, analyzes the pros and cons of different predictive indices, and discusses the efficacy of the Asthma Predictive Index.
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