We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals ...closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 µL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development.
Objective
To determine the 5‐year outcome of treatment for meniscal tear in osteoarthritis.
Methods
We examined 5‐year follow‐up data from the Meniscal Tear in Osteoarthritis Research trial (METEOR) ...of physical therapy versus arthroscopic partial meniscectomy. We performed primary intent‐to‐treat (ITT) and secondary as‐treated analyses. The primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scale; total knee replacement (TKR) was a secondary outcome measure. We used piecewise linear mixed models to describe change in KOOS pain. We calculated 5‐year cumulative TKR incidence and used a Cox model to estimate hazard ratios (HRs) for TKR, with 95% confidence intervals (95% CIs).
Results
Three hundred fifty‐one participants were randomized. In the ITT analysis, the KOOS pain scores were ~46 (scale of 0 no pain to 100 most pain) at baseline in both groups. Pain scores improved substantially in both groups over the first 3 months, continued to improve through the next 24 months (to ~18 in each group), and were stable at 24–60 months. Results of the as‐treated analyses of the KOOS pain score were similar. Twenty‐five participants (7.1% 95% CI 4.4–9.8%) underwent TKR over 5 years. In the ITT model, the HR for TKR was 2.0 (95% CI 0.8–4.9) for subjects randomized to the arthroscopic partial meniscectomy group, compared to those randomized to the physical therapy group. In the as‐treated analysis, the HR for TKR was 4.9 (95% CI 1.1–20.9) for subjects ultimately treated with arthroscopic partial meniscectomy, compared to those treated nonoperatively.
Conclusion
Pain improved considerably in both groups over 60 months. While ITT analysis revealed no statistically significant differences following TKR, greater frequency of TKR in those undergoing arthroscopic partial meniscectomy merits further study.
The 21st century has seen an increasing focus on the concept of co-production in seeking to tackle the tokenistic approach often taken by services to recovery in mental health. It originated from the ...scholarly work of Elinor Ostrom in America in the 1970’s and was further developed through the works of Edgar Cahn. In a bid to create a service that is more recovery orientated, many community mental health services have adopted co-production as a foundation for all work they conduct with service users/family members and carers. It is reported that co-production can be transformative in practice if done correctly. More specifically, this can include circumstances where individuals are presenting in crisis. However, there is a paucity of research/perspectives in this specific area. The aim of this perspective paper is to highlight such literature whilst also debating the ethical considerations to co-production within the acute inpatient mental health services.
Comparisons of infectivity among the clinically important nontuberculous mycobacteria (NTM) species have not been explored in great depth. Rapid-growing mycobacteria, including
and
, can cause ...indolent but progressive lung disease. Slow-growing members of the
complex are the most common group of NTM to cause lung disease, and molecular approaches can now distinguish between several distinct species of
complex including
,
,
, and
. Differential infectivity among these NTM species may, in part, account for differences in clinical outcomes and response to treatment; thus, knowing the relative infectivity of particular isolates could increase prognostication accuracy and enhance personalized treatment. Using human macrophages, we investigated the infectivity and virulence of nine NTM species, as well as multiple isolates of the same species. We also assessed their capacity to evade killing by the antibacterial peptide cathelicidin (LL-37). We discovered that the ability of different NTM species to infect macrophages varied among the species and among isolates of the same species. Our biochemical assays implicate modified phospholipids, which may include a phosphatidylinositol or cardiolipin backbone, as candidate antagonists of LL-37 antibacterial activity. The high variation in infectivity and virulence of NTM strains suggests that more detailed microbiological and biochemical characterizations are necessary to increase our knowledge of NTM pathogenesis.
Background & Aims
:
Therapy of esophageal carcinoma is stage dependent. The role of EUS-guided fine-needle aspiration (EUS FNA) in this setting is unclear. The aims of this study were to compare the ...performance characteristics of CT, EUS, and EUS FNA for preoperative nodal staging of esophageal carcinoma and to measure the impact of each staging test on treatment decisions.
Methods
:
From December 1999 to March 2001, all patients with esophageal carcinoma seen at the Mayo Clinic Rochester were prospectively evaluated with CT, EUS, and EUS FNA. The impact of tumor stage on final therapy was assessed.
Results
:
A total of 125 patients with esophageal carcinoma were enrolled. EUS FNA was more sensitive (83% vs. 29%;
P < 0.001) than CT and more accurate than CT (87% vs. 51%;
P < 0.001) or EUS (87% vs. 74%;
P = 0.012) for nodal staging. Direct surgical resection was contraindicated in 77% of patients evaluated due to advanced locoregional/metastatic disease. Tumor location, patient age, comorbidities, and tumor stage determined by CT, EUS, and EUS FNA were associated with treatment decisions (
P < 0.05). EUS FNA resulting in a higher/worse stage than CT (41 patients) was associated with a greater rate of treatments that were not direct surgeries compared with cases in which the stage was the same or better.
Conclusions
:
EUS FNA is more accurate for nodal staging and impacts on therapy of patients with esophageal carcinoma. EUS FNA should be included in the preoperative staging algorithm of these patients.
In juvenile tree shrews that have developed minus lens-induced myopia, if lens treatment is discontinued, refractive recovery (REC) occurs. However, in age-matched juvenile animals, plus-lens wear ...(PLW) produces little refractive change, although the visual stimulus (myopia) is similar (an "IGNORE" response). Because the sclera controls axial elongation and refractive error, we examined gene expression in the sclera produced by PLW and compared it with the gene expression signature produced by REC to learn whether these similar refractive conditions produce similar, or differing, scleral responses.
Eight groups of tree shrews (n = 7 per group) were examined. Four groups wore a monocular -5 D lens for 11 days until 35 days of visual experience (DVE). Lens wear was then discontinued, and the animals recovered for 0 h (REC-0), 2 h (REC-2h), 1 day (REC-1d), or 4 days (REC-4d). Starting at 35 DVE, three groups wore a monocular +5 D lens for 2 h (PLW-2h), 1 day (PLW-1d), or 4 days (PLW-4d). A normal group (PLW-0) was examined at 38 DVE to provide baseline measures. Using quantitative real-time PCR (qPCR), we examined scleral mRNA levels in recovering, plus-lens treated, and untreated control eyes for 55 candidate genes whose protein products included signaling molecules, metallopeptidases (MPs) and their inhibitors (tissue inhibitors of metallopeptidases TIMPs), and extracellular matrix proteins.
No refractive recovery was measured in the REC-2h group. The scleral mRNA expression pattern for recovering versus untreated control eyes after 2 h of recovery was similar to that found for the group (REC-0) that had no recovery time. Many genes in both groups still had downregulated expression in the treated eyes versus the control eyes. The REC-1d group showed little refractive recovery (0.1 ± 0.1 D, mean ± standard error of the mean SEM), and the mRNA expression pattern was similar to that of the REC-2h group, but had fewer statistically significantly downregulated genes in the recovering eyes. The REC-4d group recovered refractively by 2.6 ± 0.4 D, and displayed a "STOP" gene expression signature of mostly upregulated mRNA expression in the recovering eyes compared with the untreated control eyes. The PLW-0 (normal) group and the PLW-2h group showed no statistically significant differential gene expression. The PLW-1d group showed a small hyperopic shift (0.1 ± 0.2 D). Two genes were differentially expressed:
was upregulated in the plus lens-wearing eyes, and
was downregulated. The PLW-4d group showed a similar hyperopic shift (0.3 ± 0.4 D), confirming that the plus lens-induced 5 D of myopia produced little refractive change. In the sclera, there was an IGNORE pattern of general differential upregulation of genes in the treated eyes (22 upregulated, one downregulated) that was distinct from the STOP signature found in recovery. Ten genes were upregulated in the REC-4d group and the PLW-4d group. However, ten other genes were differentially expressed in recovery, but not in plus-lens wear, while 12 genes were differentially expressed in plus-lens wear but not in recovery.
One day of recovery is not long enough for the emmetropization mechanism to produce significant gene expression changes in the sclera or refractive recovery. After 4 days, recovery and plus-lens wear produced altered scleral gene expression, but the patterns ("signatures") differed as to which genes showed altered expression, and whether the gene expression was up- or downregulated. Thus, myopia produced altered scleral mRNA expression in recovery and plus-lens wear, confirming that signals initiated by the retina reached the sclera, but the sclera in the elongated recovering eye responded differently from a normal sclera. This might have occurred because the recovering-eye sclera had remodeled during minus-lens compensation, making the sclera respond differently to the signals initiated by the retina. However, the myopia-produced retinal signals in plus lens-wearing animals also may have differed from those in the recovering eyes by the time the signals passed through the RPE and choroid to reach the sclera.
We examine the influences of a set of early life conditions (ELCs) on all-cause and cause-specific mortality among elderly individuals, with special attention to one of the most dramatic early events ...in a child's, adolescent's, or even young adult's life, the death of a parent. The foremost question is, once controlling for prevailing (and potentially confounding) conditions early in life (family history of longevity, paternal characteristics (SES, age at time of birth, sibship size, and religious affiliation)), is a parental death associated with enduring mortality risks after age 65? The years following parental death may initiate new circumstances through which the adverse effects of paternal death operate. Here we consider the offspring's marital status (whether married; whether and when widowed), adult socioeconomic status, fertility, and later life health status. Adult health status is based on the Charlson Co-Morbidity Index, a construct that summarizes nearly all serious illnesses afflicting older individuals that relies on Medicare data. The data are based on linkages between the Utah Population Database and Medicare claims that hold medical diagnoses data. We show that offspring whose parents died when they were children, but especially when they were adolescents/young adults, have modest but significant mortality risks after age 65. What are striking are the weak mediating influences of later-life comorbidities, marital status, fertility and adult socioeconomic status since controls for these do little to alter the overall association. No beneficial effects of the surviving parent's remarriage were detected. Overall, we show the persistence of the effects of early life loss on later-life mortality and indicate the difficulties in addressing challenges at young ages.
•Excess adult (age 65+) mortality was associated with early parental death.•Sons were affected more by parental deaths in early adulthood while for daughters it is parental deaths in childhood.•Adult comorbidities do not mediate the mortality effects of early parental death.•Mortality risk attributable to early parental death is greatest for heart disease.
•More information about interventions for homeless smokers is needed.•Increase in positive affect post-quit is associated with fewer CPD.•Time by affect effects on post-quit CPD support the need for ...early intervention.
Cigarette smoking disproportionately affects homeless individuals, who have a higher smoking prevalence, fewer resources, and increased stressors compared to domiciled smokers. Little is known about how to facilitate smoking cessation among this population although some findings support focusing efforts on affective variables as well as alternate outcomes in order to optimize interventions for this group.
Participants were homeless adults recruited from a Dallas, TX, shelter (N = 57, 61.4% male, Mage = 48.8 ± 9.0) to participate in tobacco cessation classes using an American Cancer Society-based therapy and support group with nicotine replacement therapy. Moment-to-moment changes in affect e.g., negative affect (NA), positive affect (PA), and stress were recorded via Ecological Momentary Assessments to assess whether they were associated with concurrent changes in cigarettes smoked per day (CPD) following a specific quit attempt. Separate generalized linear models (GLM) were evaluated for each predictor to examine the associations between affective variables and CPD in covariate-adjusted analyses.
Significant interaction effects of time and affect were found for all variables (NA: p = 0.0011, PA: p = 0.0006, stress: p = 0.0259), whereby the association of affect and CPD were significant in the early part of the week but the effects faded as time progressed. With regard to main effects, only increases in PA during the post-quit week significantly predicted fewer CPD (adjusted incidence rate ratio = 0.924, SE = 0.027, p = 0.0032).
Homeless smokers may be more likely to decrease their cigarette consumption during periods of greater PA throughout the post-quit week. Relationship between positive affect and reduction in CPD suggest focus on affective variables with homeless smokers may be an effective avenue for change in smoking behaviors, particularly in the days immediately following a quit attempt. Time effects should be further investigated to determine when these interventions might best be implemented.
A previous study found that the capacitive behavior of nanoparticles fed to the silkworm can be delivered to carbonized silk fibers, which can be used to fabricate electrodes for the construction of ...flexible supercapacitors. However, the tendency of nanoparticles to aggregate decreases the quantity of nanoparticles that enter the silk and therefore reduces the capacitance performance of the prepared carbonized silk. Here, we sprayed ammonium molybdate tetrahydrate (AMT) on the surface of mulberry leaves used for feeding silkworms and investigated the effect of feeding AMT on the growth of silkworms and the properties of spun silk. The precursor incorporated into the silk was converted into scattered MoO
2
NPs, which were embedded within the carbonized silk fiber (CSF)
via
carbothermal reduction. The specific capacitance of CSF obtained from silkworms fed with an aqueous solution of AMT-treated mulberry leaves reached up to 298 F/g at 0.2 g/A, which is much higher than that of the control group (102 F/g). Since AMT is highly water-soluble, and its concentration can be easily modulated, we believe that the proposed strategy is feasible for the large-scale fabrication of CSF with enhanced capacitive performance.
We developed a microarray hybridization-based method, 'comparative genome sequencing' (CGS), to find mutations in bacterial genomes and used it to study metronidazole resistance in H. pylori. CGS ...identified mutations in several genes, most likely affecting metronidazole activation, and produced no false positives in analysis of three megabases. We conclude that CGS identifies mutations in bacterial genomes efficiently, should enrich understanding of systems biology and genome evolution, and help track pathogens during outbreaks.
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