NEO6860 is a TRPV1 antagonist when activated by capsaicin but not by heat or pH, developed to relieve pain without the adverse events reported with non-modality-selective TRPV1 antagonists.
The ...primary Objective of this study was to evaluate the analgesic efficacy and safety of NEO6860 after 1 day oral dosing in patients with Kellgren-Lawrence stage I, II or III osteoarthritis of the knee.
This randomized, double-blinded, 3-period crossover, phase II study compared 1 day (2 doses) of NEO6860 (500 mg twice a day), placebo, and naproxen in 54 patients with osteoarthritis knee pain. Primary endpoint was reduction in pain intensity (PI) on Numerical Rating Scale after exercise, using the staircase test, 8 hours after dose.
Level of PI, compared with baseline, was numerically lower during NEO6860 and naproxen periods vs placebo at 3 and 24 hours, but not at 8 hours after first dose. A statistically significant effect for naproxen and a trend for NEO6860 were observed at 3 and 24 hours. Least square means' (95% confidence interval) change in PI at 24 hours was -0.67 (-1.09 to -0.26), -0.97 (-1.39 to -0.55), -0.29 (-0.71 to 0.13) for NEO6860, naproxen, and placebo, respectively. NEO6860 exposure was ∼1.6 times higher compared with previous phase I. In this study, NEO6860 safety profile was less favorable than naproxen or placebo. Possibly NEO6860-related adverse events included: feel hot, headache, nausea, dizziness, fatigue, hypoaesthesia, and increased blood pressure.
In this exploratory study, NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception. Further studies are warranted to explore the potential of NEO6860 in other pain indications. We intent to optimize the dose and evaluate analgesic synergism with other mechanism.
Francisella tularensis, a gram-negative bacterium, is the etiologic agent of tularemia and has recently been classified as a category A bioterrorism agent. Infections with F. tularensis result in an ...inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms mediating this response have not been completely elucidated. In the present study, we determined the role of Toll-like receptors (TLRs) in mediating inflammatory responses to F. tularensis LVS, and the role of NF-kappaB in regulating these responses. Stimulation of bone marrow-derived dendritic cells from C57BL/6 wild-type (wt) and TLR4superscript -/- but not TLR2superscript -/- mice, with live F. tularensis LVS elicited a dose-dependent increase in the production of tumor necrosis factor alpha. F. tularensis LVS also induced in a dose-dependent manner an up-regulation in the expression of the costimulatory molecules CD80 and CD86 and of CD40 and the major histocompatibility complex class II molecules on dendritic cells from wt and TLR4superscript -/- but not TLR2superscript -/- mice. TLR6, not TLR1, was shown to be involved in mediating the inflammatory response to F. tularensis LVS, indicating that the functional heterodimer is TLR2/TLR6. Stimulation of dendritic cells with F. tularensis resulted in the activation of NF-kappaB, which resulted in a differential effect on the production of pro- and anti-inflammatory cytokines. Taken together, our results demonstrate the role of TLR2/TLR6 in the host's inflammatory response to F. tularensis LVS in vitro and the regulatory function of NF-kappaB in modulating the inflammatory response.
Background:
Arthroscopic partial meniscectomy (APM) is used to treat meniscal tears, although its efficacy is controversial.
Purpose:
This study used magnetic resonance imaging (MRI) to determine ...characteristics that lead to greater benefit from APM and physical therapy (PT) than from PT alone among patients with meniscal tear and knee osteoarthritis.
Study Design:
Cohort study; Level of evidence, 2.
Methods:
Using data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial, the authors first assessed whether the effect of treatment on pain scores at 6 months differed according to baseline MRI features (bone marrow lesions, cartilage and meniscal damage). Second, the authors summed MRI features associated with differential pain relief between APM and PT to create a “damage score,” which included bone marrow lesion number and cartilage damage size with possible values of 0 (least damage), 1 (moderate), and 2 (greatest). The authors used linear models to determine whether the association between damage score and pain relief at 6 months differed for APM versus PT.
Results:
The study included 220 participants: 13%, had the least damage; 52%, moderate; and 34%, greatest. Although treatment type did not significantly modify the association of damage score and change in pain (P interaction = .13), those with the least damage and moderate damage had greater improvement with APM than with PT in Knee injury and Osteoarthritis Outcome Score pain subscale—by 15 and 7 points, respectively. Those with the greatest damage had a similar improvement with APM and PT.
Conclusion:
Among patients with osteoarthritis and meniscal tear, those with less intra-articular damage on MRI may have greater improvement in pain with APM and PT than with PT alone. However, these results should be interpreted cautiously owing to the limited sample size.
REVIEW OF PARTICLE PHYSICS Olive, K.A.
Chinese physics C,
08/2014, Letnik:
38, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,283 new measurements from 899 papers, we list, evaluate, and average measured properties of ...gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as heavy neutrinos, supersymmetric and technicolor particles, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as Supersymmetry, Extra Dimensions, Particle Detectors, Probability, and Statistics. Among the 112 reviews are many that are new or heavily revised including those on： Dark Energy, Higgs Boson Physics, Electroweak Model, Neutrino Cross Section Measurements, Monte Carlo Neutrino Generators, Top Quark, Dark Matter, Dynamical Electroweak Symmetry Breaking, Accelerator Physics of Colliders, High-Energy Collider Parameters, Big Bang Nucleosynthesis, Astrophysical Constants and Cosmological Parameters. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews （and errata） are also available on the Particle Data Group website： http ：//pdg. lbl. gov.
The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET ...in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.
A rapid diagnostic test for active tuberculosis (TB) at the clinical point-of-care could expedite case detection and accelerate TB treatment initiation. We assessed the diagnostic accuracy of a rapid ...urine lipoarabinomannan (LAM) test for TB screening among HIV-infected adults in a TB-endemic setting.
We prospectively enrolled newly-diagnosed HIV-infected adults (≥18 years) at 4 outpatient clinics in Durban from Oct 2011-May 2012, excluding those on TB therapy. A physician evaluated all participants and offered CD4 cell count testing. Trained study nurses collected a sputum sample for acid-fast bacilli smear microscopy (AFB) and mycobacterial culture, and performed urine LAM testing using Determine™ TB LAM in the clinic. The presence of a band regardless of intensity on the urine LAM test was considered positive. We defined as the gold standard for active pulmonary TB a positive sputum culture for Mycobacterium tuberculosis. Diagnostic accuracy of urine LAM was assessed, alone and in combination with smear microscopy, and stratified by CD4 cell count.
Among 342 newly-diagnosed HIV-infected participants, 190 (56%) were male, mean age was 35.6 years, and median CD4 was 182/mm3. Sixty participants had culture-positive pulmonary TB, resulting in an estimated prevalence of 17.5% (95% CI 13.7-22.0%). Forty-five (13.2%) participants were urine LAM positive. Mean time from urine specimen collection to LAM test result was 40 minutes (95% CI 34-46 minutes). Urine LAM test sensitivity was 28.3% (95% CI 17.5-41.4) overall, and 37.5% (95% CI 21.1-56.3) for those with CD4 count <100/mm3, while specificity was 90.1% (95% CI 86.0-93.3) overall, and 86.9% (95% CI 75.8-94.2) for those with CD4 < 100/mm3. When combined with sputum AFB (either test positive), sensitivity increased to 38.3% (95% CI 26.0-51.8), but specificity decreased to 85.8% (95% CI 81.1-89.7).
In this prospective, clinic-based study with trained nurses, a rapid urine LAM test had low sensitivity for TB screening among newly-diagnosed HIV-infected adults, but improved sensitivity when combined with sputum smear microscopy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Protvino accelerator facility located in the Moscow region, Russia, is in a good position to offer a rich experimental research program in the field of neutrino physics. Of particular interest is ...the possibility to direct a neutrino beam from Protvino towards the KM3NeT/ORCA detector, which is currently under construction in the Mediterranean Sea 40 km offshore Toulon, France. This proposal is known as P2O. Thanks to its baseline of 2595 km, this experiment would yield an unparalleled sensitivity to matter effects in the Earth, allowing for the determination of the neutrino mass ordering with a high level of certainty after only a few years of running at a modest beam intensity of
≈
90
kW
. With a prolonged exposure (
≈
1500
kW
year
), a
2
σ
sensitivity to the leptonic CP-violating Dirac phase can be achieved. A second stage of the experiment, comprising a further intensity upgrade of the accelerator complex and a densified version of the ORCA detector (Super-ORCA), would allow for up to a
6
σ
sensitivity to CP violation and a
10
∘
-
17
∘
resolution on the CP phase after 10 years of running with a 450 kW beam, competitive with other planned experiments. The initial composition and energy spectrum of the neutrino beam would need to be monitored by a near detector, to be constructed several hundred meters downstream from the proton beam target. The same neutrino beam and near detector set-up would also allow for neutrino-nucleus cross section measurements to be performed. A short-baseline sterile neutrino search experiment would also be possible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fertilization in flowering plants initiates the development of the embryo and endosperm, which nurtures the embryo. A few genes subjected to imprinting are expressed in endosperm from their maternal ...allele, while their paternal allele remains silenced
1–3. Imprinting of the
FWA gene involves DNA methylation
4. Mechanisms controlling imprinting of the Polycomb group (Pc-G) gene
MEDEA (
MEA)
5 are not yet fully understood
6–10. Here we report that
MEA imprinting is regulated by histone methylation. This epigenetic chromatin modification is mediated by several Pc-G activities during the entire plant life cycle. We show that Pc-G complexes maintain
MEA transcription silenced throughout vegetative life and male gametogenesis. In endosperm, the maternal allele of
MEA encodes an essential component of a Pc-G complex, which maintains silencing of the paternal
MEA allele. Hence, we conclude that a feedback loop controls
MEA imprinting. This feedback loop ensures a complete maternal control of
MEA expression from both parental alleles and might have provided a template for evolution of imprinting in plants.
Objective. To better understand medical decision making in the context of “preference sensitive care,” we investigated factors associated with breast cancer patients' satisfaction with the type of ...surgery received and with the decision process.
Data Sources/Data Collection. For a population‐based sample of recently diagnosed breast cancer patients in the Detroit and Los Angeles metropolitan areas (N=1,633), demographic and clinical data were obtained from the Surveillance, Epidemiology, and End Results tumor registry, and self‐reported psychosocial and satisfaction data were obtained through a mailed survey (78.4 percent response rate).
Study Design. Cross‐sectional design in which multivariable logistic regression was used to identify sociodemographic and clinical factors associated with three satisfaction measures: low satisfaction with surgery type, low satisfaction with the decision process, and decision regret.
Principal Findings. Overall, there were high levels of satisfaction with both surgery and the decision process, and low rates of decision regret. Ethnic minority women and those with low incomes were more likely to have low satisfaction or decision regret. In addition, the match between patient preferences regarding decision involvement and their actual level of involvement was a strong indicator of satisfaction and decision regret/ambivalence. While having less involvement than preferred was a significant indicator of low satisfaction and regret, having more involvement than preferred was also a risk factor. Women who received mastectomy without reconstruction were more likely to report low satisfaction with surgery (odds ratio OR=1.54, p<.05), low satisfaction with the process (OR=1.37, p<.05), and decision regret (OR=1.55, p<.05) compared with those receiving breast conserving surgery (BCS). An additional finding was that as patients' level of involvement in the decision process increased, the rate of mastectomy also increased (p<.001).
Conclusions. A significant proportion of breast cancer patients experience a decision process that matches their preferences for participation, and report satisfaction with both the process and the outcome. However, women who report more involvement in the decision process are significantly less likely to receive a lumpectomy. Thus, increasing patient involvement in the decision process will not necessarily increase use of BCS or lead to greater satisfaction. The most salient aspect for satisfaction with the decision making process is the match between patients' preferences and experiences regarding participation.
Aliment Pharmacol Ther 2010; 32: 645–654
Summary
Background While there is evidence of ethnic variation in the prevalence of gastro‐oesophageal reflux disease (GERD) symptoms, few population‐based ...studies examine GERD symptom prevalence amongst the growing Hispanic minority in the US as well as Asians in the West.
Aim To examine the prevalence, awareness and care patterns for GERD across different ethnic groups.
Methods A population‐based, cross‐sectional survey was fielded in English, Chinese and Spanish that assessed self‐reported GERD prevalence, awareness and care patterns in four ethnic groups (Caucasian, African American, Asian, Hispanic).
Results A total of 1172 subjects were included for analysis: 34.6% experienced GERD symptoms at least monthly, 26.2% at least weekly and 8.2% at least daily. Statistically significant differences in raw prevalence rates between racial groups were found: 50% of Hispanics experienced heartburn at least monthly, compared with 37% of Caucasians, 31% of African Americans and 20% of Asians (P > 0.0001). Significant differences in knowledge and care‐seeking patterns by ethnicity were also observed.
Conclusions This study confirms the high prevalence of GERD symptoms in the US and introduces Hispanics as the ethnicity with the highest prevalence rate. Asians in the US have higher rates of symptoms than in the Far East. These data demonstrate a need for culturally appropriate education about GERD symptoms and treatment.
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