ABSTRACT The all-Galaxy CO survey of Dame et al. is by far the most uniform, large-scale Galactic CO survey. Using a dendrogram-based decomposition of this survey, we present a catalog of 1064 ...massive molecular clouds throughout the Galactic plane. This catalog contains 2.5 × 108 solar masses, or 25 − 5.8 + 10.7 % of the Milky Way's estimated H2 mass. We track clouds in some spiral arms through multiple quadrants. The power index of Larson's first law, the size-linewidth relation, is consistent with 0.5 in all regions-possibly due to an observational bias-but clouds in the inner Galaxy systematically have significantly (∼30%) higher linewidths at a given size, indicating that their linewidths are set in part by the Galactic environment. The mass functions of clouds in the inner Galaxy versus the outer Galaxy are both qualitatively and quantitatively distinct. The inner Galaxy mass spectrum is best described by a truncated power law with a power index of γ = −1.6 0.1 and an upper truncation mass of M0 = (1.0 0.2) × 107 M , while the outer Galaxy mass spectrum is better described by a non-truncating power law with γ = −2.2 0.1 and an upper mass of M0 = (1.5 0.5) × 106 M , indicating that the inner Galaxy is able to form and host substantially more massive GMCs than the outer Galaxy. Additionally, we have simulated how the Milky Way would appear in CO from extragalactic perspectives, for comparison with CO maps of other galaxies.
Summary Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of ...neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies ( r2 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.
Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after ...major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol mean difference (MD) −6.34 mg; 95% credibility interval (CrI) −9.02, −3.65, NSAIDs (MD −10.18; 95% CrI −11.65, −8.72), and COX-2 inhibitors (MD −10.92; 95% CrI −12.77, −9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.
Genetics of osteoarthritis Aubourg, G.; Rice, S.J.; Bruce-Wootton, P. ...
Osteoarthritis and cartilage,
20/May , Letnik:
30, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated ...with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.
Pulse pressure and pulse wave velocity, markers of arterial stiffness, have been associated with stroke, dementia, and lowered levels of cognitive function. Here we examine longitudinal relations of ...pulse pressure and pulse wave velocity to multiple domains of cognitive function among nondemented, stroke-free persons. Up to 1749 participants from the Baltimore Longitudinal Study of Aging completed tests of verbal and nonverbal memory, attention, perceptuo-motor speed, confrontation naming, executive functions, and cognitive screening measures, as well as concurrent sphygmomanometric assessment of blood pressure (for derivation of pulse pressure) on 1 to 8 occasions over 14 years. A subset of <or=582 participants also underwent a single baseline assessment of pulse wave velocity and cognitive assessment on 1 to 6 occasions over 11 years. Results of mixed-effects regression models revealed a prospective decline on tests of verbal learning, nonverbal memory, working memory, and a cognitive screening measure among those with increasing levels of pulse pressure (P<0.05). Persons with higher baseline pulse wave velocity also exhibited prospective decline on tests of verbal learning and delayed recall, nonverbal memory, and a cognitive screening measure (P<0.05). Markers of arterial stiffness are associated prospectively with cognitive decline before dementia. Aggressive treatment of risk factors associated with greater arterial stiffness may help preserve cognitive function with individuals' increasing age.
We report a systematic review and meta-analysis of research using animal models of chemotherapy-induced peripheral neuropathy (CIPN). We systematically searched 5 online databases in September 2012 ...and updated the search in November 2015 using machine learning and text mining to reduce the screening for inclusion workload and improve accuracy. For each comparison, we calculated a standardised mean difference (SMD) effect size, and then combined effects in a random-effects meta-analysis. We assessed the impact of study design factors and reporting of measures to reduce risks of bias. We present power analyses for the most frequently reported behavioural tests; 337 publications were included. Most studies (84%) used male animals only. The most frequently reported outcome measure was evoked limb withdrawal in response to mechanical monofilaments. There was modest reporting of measures to reduce risks of bias. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. In this comprehensive summary of the use of animal models of CIPN, we have identified areas in which the value of preclinical CIPN studies might be increased. Using both sexes of animals in the modelling of CIPN, ensuring that outcome measures align with those most relevant in the clinic, and the animal's pain contextualised ethology will likely improve external validity. Measures to reduce risk of bias should be employed to increase the internal validity of studies. Different outcome measures have different statistical power, and this can refine our approaches in the modelling of CIPN.
To prospectively examine whether the association between tubal ligation, hysterectomy, unilateral oophorectomy, and ovarian cancer varied by patient, tumor, and surgical characteristics.
Two ...prospective cohort studies (Nurses' Health Study and Nurses' Health Study II).
Not applicable.
A cohort of 121,700 married US female nurses, aged 30-55 years at baseline and another cohort of 116,430 US female nurses aged 25-42 years at baseline.
We obtained data on gynecologic surgeries and ovarian cancer incidence through biennial questionnaires. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for known and suspected ovarian cancer risk factors.
Confirmed incident epithelial ovarian cancer.
Overall, tubal ligation was associated with a decreased risk of ovarian cancer (HR, 0.76; 95% CI 0.64-0.90). The inverse association was stronger for nonserous tumors (HR, 0.57; 95% CI 0.40-0.82) and among women younger than 35 years at surgery (HR, 0.67; 95% CI 0.49-0.90). Hysterectomy was associated with a decreased risk of ovarian cancer (HR, 0.80; 95% CI 0.66-0.97) and was somewhat stronger for nonserous tumors (HR, 0.70; 95% CI 0.49-1.02). Unilateral oophorectomy was associated with a 30% lower risk (HR, 0.70; 95% CI 0.53-0.91), which did not differ by histologic subtype.
Our study provides further support that tubal ligation reduces the risk of ovarian cancer, particularly for nonserous tumors and when conducted before the age of 35 years. The inverse association with hysterectomy, along with the stronger associations for nonserous tumors, supports shared biologic mechanisms for tubal ligation and hysterectomy.
This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain ...management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
Neuropathic pain remains an area of considerable unmet clinical need. Research based on preclinical animal models has failed to deliver truly novel treatment options, questioning the predictive value ...of these models. This review addresses the shortcomings of rodent in vivo models commonly used in the field and highlights approaches which could increase their predictivity, including more clinically relevant assays, outcome measures and animal characteristics. The methodological quality of animal studies also needs to be improved. Low internal validity and incomplete reporting lead to a waste of valuable research resources and animal lives, and ultimately prevent an objective assessment of the true predictivity of in vivo models.
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