Paracetamol is arguably the most commonly used analgesic and antipyretic drug worldwide, however its mechanism of action is still not fully established. It has been shown to exert effects through ...multiple pathways, some actions suggested to be mediated via N-arachidonoylphenolamine (AM404). AM404, formed through conjugation of paracetamol-derived p-aminophenol with arachidonic acid in the brain, is an activator of the capsaicin receptor, TRPV1, and inhibits the reuptake of the endocannabinoid, anandamide, into postsynaptic neurons, as well as inhibiting synthesis of PGE
by COX-2. However, the presence of AM404 in the central nervous system following administration of paracetamol has not yet been demonstrated in humans. Cerebrospinal fluid (CSF) and blood were collected from 26 adult male patients between 10 and 211 minutes following intravenous administration of 1 g of paracetamol. Paracetamol was measured by high-performance liquid chromatography with UV detection. AM404 was measured by liquid chromatography-tandem mass spectrometry. AM404 was detected in 17 of the 26 evaluable CSF samples at 5-40 nmol⋅L
. Paracetamol was measurable in CSF within 10 minutes, with a maximum measured concentration of 60 μmol⋅L
at 206 minutes. This study is the first to report on the presence of AM404 in human CSF following paracetamol administration. This may represent an important finding in our understanding of paracetamol's mechanism of action, although measured concentrations were far below the previously documented IC50 for this metabolite.
Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the ...pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.
Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or ...substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential.
The commercialization of dicamba-resistant soybean will lead to increased use of dicamba herbicide and importance of proper stewardship in performing these applications. Off-target injury to ...broadleaf plants from dicamba may occur through physical spray particle drift during the application, volatility of dicamba from the soil or leaf surfaces following the dicamba application, or spray equipment contamination with dicamba in subsequent applications to sensitive crops. In order to help combat the concern for off-target movement by vapor drift in dicamba tolerant soybean, product formulations of dicamba that reduce the potential for volatility have been developed. Other spray application factors that can influence the volatility of dicamba include adjuvant, carrier volume, droplet size, and plant sensitivity to dicamba. A field experiment was conducted to determine dicamba vapor movement as influenced by target surface of the sprayed area and the addition of adjuvant. Volatility was reduced when applied to bare soil compared to vegetation based on soybean plants as the bio-indicator. At 21 days after treatment, an oil emulsifier adjuvant reduced soybean injury from dicamba volatility compared to no adjuvant. As has been previously published, this research, confirms that volatility from a soil surface was less than that from a vegetative surface. In a field experiment, efficacy of dicamba was not different across adjuvants on any broadleaf weed except common lambsquarters, where all adjuvants classified as activators increased weed control compared to no adjuvant used with dicamba. In order to quantify dicamba volatility under controlled environmental conditions, a series of experiments were conducted in a growth chamber with conditions set to an average day in June (i.e. 35 C, 40% R.H., 14-h day). The addition of adjuvant, increasing carrier volume, and ultra coarse droplets decreased volatility of dicamba from soybean vegetation. New formulations of dicamba that were developed specifically for use in dicamba-resistant soybean and have not previously been tested by a third party showed reduced dicamba volatility compared to an older formulation of dicamba. There was no difference in volatility of dicamba following applications to soybean plants tolerant to dicamba and plants that were sensitive to dicamba during the onset of leaf death. In order to optimize dicamba applications for improving weed management and reduce off-site injury, applicators must understand variable under their control than can contribute to dicamba volatility.
Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the ...pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, ... mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD. (ProQuest: ... denotes formulae/symbols omitted.)
We report the time‐resolved supramolecular assembly of a series of nanoscale polyoxometalate clusters (from the same one‐pot reaction) of the form: H(10+m)Ag18Cl(Te3W38O134)2n, where n=1 and m=0 for ...compound 1 (after 4 days), n=2 and m=3 for compound 2 (after 10 days), and n=∞ and m=5 for compound 3 (after 14 days). The reaction is based upon the self‐organization of two {Te3W38} units around a single chloride template and the formation of a {Ag12} cluster, giving a {Ag12}‐in‐{W76} cluster‐in‐cluster in compound 1, which further aggregates to cluster compounds 2 and 3 by supramolecular Ag‐POM interactions. The proposed mechanism for the formation of the clusters has been studied by ESI‐MS. Further, control experiments demonstrate the crucial role that TeO32−, Cl−, and Ag+ play in the self‐assembly of compounds 1–3.
Cluster‐in‐cluster: Polyoxometalate clusters H(10+m)Ag18Cl(Te3W38O134)2n with n=1 and m=0, n=2 and m=3, and n=∞ and m=5 were isolated after 4, 10, and 14 days from the same reaction mixture. The proposed mechanism for the formation of the clusters was confirmed by ESI‐MS studies and control experiments, which demonstrate the crucial role that TeO32−, Cl−, and Ag+ play in the self‐assembly of these compounds.
Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its ...actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 “superkine” with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retained high affinity for IL-2Rβ, inhibiting binding of endogenous IL-2, but their interaction with γc was weakened, attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.
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•Partial IL-2 agonists with altered signaling amplitudes have been created•A cell’s activation state influences its response to particular partial agonists•One IL-2 mutant, H9-RETR, blocked actions of IL-2 and IL-15, with therapeutic utility•Our approach should be broadly applicable to many other cytokines
There is resurging interest in controlling the actions of interleukin-2. Leonard, Garcia, and colleagues generated partial agonists of IL-2 with enhanced binding to IL-2Rβ but attenuated γc interaction. These reagents yielded a spectrum of signaling amplitudes and biological effects, including the mutein H9-RETR that blocked IL-2- and IL-15-mediated proliferation and cytotoxicity, with therapeutic utility.
Abstract
Participation is a major outcome area for physical therapists serving young children with disabilities. Contemporary models of disability such as the International Classification of ...Function, developmental theories such as the system perspective, and evidence-based early childhood practices recognize the interdependence of developmental domains, and suggest that change in 1 area of development influences change in another. Physical therapy provided in naturally occurring activities and routines, considered the preferred service delivery method, promotes participation of young children with disabilities. Research indicates that: (1) children develop skills, become independent, and form relationships through participation; and (2) with developing skills, children can increasingly participate. The purpose of this Perspective article is to synthesize the literature examining the relationship between motor skill development and the social interaction dimension of participation in young children. Current research examining the influence of motor skill development on social interactions in children with autism spectrum disorder will be discussed, exemplifying the interdependence of developmental domains. Implications for physical therapist practice and recommendations for future research are provided.
As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on ...women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions.
To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB.
For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017.
Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected.
Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded.
The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB.
A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% 95% CI, 6%-9% to 12% 95% CI, 9%-15%; P < .001 for heterogeneity) and geographic region (range, 5% 95% CI, 3%-11% in North America to 13% 95% CI, 9%-19% in Western Europe; P = .09 for heterogeneity).
Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making.
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![Elevated hepatic 11[Beta]-h...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0027-8424/small "Elevated hepatic 11[Beta]-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia")
