The impact of insite, North America's first supervised injection facitity, and possible implementation in Massachusetts

The impact of the opioid crisis has been worsening in recent years. Opioid-related overdose deaths in the United States have reached 9.0 per 100,000 people and in Massachusetts the number is even worse at 17.3 per 100,000. People who inject drugs (PWID) are at high risk of overdose death, of superficial and deep tissue bacterial infections, and of chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), which can be transmitted through shared injection equipment. Although abstinence from substances is the best way to avoid these outcomes, the complicated nature of substance use disorder (SUD) means that not everyone will be able to stop substance use at any given time. The concept of harm reduction is based on engaging PWID who are not ready or able to stop substance use, to reduce the frequency of adverse outcomes. One intervention supported by harm reductionists is medically supervised infection facilities (SIFs), which are locations where PWID may inject substances under medical supervision. People are provided with clean equipment and are monitored post-injection so that medical intervention can be provided in case of an overdose. Furthermore, people are able to access a variety of health services, including wound care, condom access, and referrals to SUD treatment. In 2003, Insite in Vancouver, Canada became North America’s first legally sanctioned SIF. Research conducted since its opening has shown many positive benefits. Insite has been credited with the prevention of overdose deaths and the encouragement of safer injection practices both inside and outside of the facility. In addition, the facility has been shown to be an effective bridge to addiction treatment, particularly among higher risk PWID. The presence of Insite has also been associated with a reduction in public injections. Furthermore, Insite does not appear to increase the number of people who are actively injecting, nor does it serve as a location for people who are injecting drugs for the first time. Because of these benefits, there has been growing interest in establishing an SIF within the United States. Advocacy groups, including the Massachusetts Medical Society, have begun to press for one within Massachusetts. Moreover, the PWID community in Boston has expressed interest in taking advantage of the harm reduction benefits that an SIF can offer. Efforts to establish an SIF, however, face several barriers including state and federal drug laws and political opposition to such a facility. The stigma associated with SUD and the very idea of an SIF is an issue that must be addressed in order to bring this life saving tool to Massachusetts

Harmonic allocation using IEC/TR 61000-3-6 at the distribution/transmission interface

IEC Technical Report 61000-3-6 gives principles to be applied to ensure acceptable harmonic levels in power systems. Detailed analysis methods have been developed to apply these principles to both distribution and transmission systems. At the transmission/distribution interface, it is found that transmission harmonic allocations can be as little as one third of the allocation which would be given to an equivalent distribution load. Possible adverse consequences are discussed and several modifications to avoid this mismatch are given. The recommended modification is a hybrid approach combining aspects of both the distribution and transmission allocation methods

Sequential alterations in catabolic and anabolic gene expression parallel pathological changes during progression of monoiodoacetate-induced arthritis

Chronic inflammation is one of the major causes of cartilage destruction in osteoarthritis. Here, we systematically analyzed the changes in gene expression associated with the progression of cartilage destruction in monoiodoacetate-induced arthritis (MIA) of the rat knee. Sprague Dawley female rats were given intra-articular injection of monoiodoacetate in the knee. The progression of MIA was monitored macroscopically, microscopically and by micro-computed tomography. Grade 1 damage was observed by day 5 post-monoiodoacetate injection, progressively increasing to Grade 2 by day 9, and to Grade 3-3.5 by day 21. Affymetrix GeneChip was utilized to analyze the transcriptome-wide changes in gene expression, and the expression of salient genes was confirmed by real-time-PCR. Functional networks generated by Ingenuity Pathways Analysis (IPA) from the microarray data correlated the macroscopic/histologic findings with molecular interactions of genes/gene products. Temporal changes in gene expression during the progression of MIA were categorized into five major gene clusters. IPA revealed that Grade 1 damage was associated with upregulation of acute/innate inflammatory responsive genes (Cluster I) and suppression of genes associated with musculoskeletal development and function (Cluster IV). Grade 2 damage was associated with upregulation of chronic inflammatory and immune trafficking genes (Cluster II) and downregulation of genes associated with musculoskeletal disorders (Cluster IV). The Grade 3 to 3.5 cartilage damage was associated with chronic inflammatory and immune adaptation genes (Cluster III). These findings suggest that temporal regulation of discrete gene clusters involving inflammatory mediators, receptors, and proteases may control the progression of cartilage destruction. In this process, IL-1β, TNF-α, IL-15, IL-12, chemokines, and NF-κB act as central nodes of the inflammatory networks, regulating catabolic processes. Simultaneously, upregulation of asporin, and downregulation of TGF-β complex, SOX-9, IGF and CTGF may be central to suppress matrix synthesis and chondrocytic anabolic activities, collectively contributing to the progression of cartilage destruction in MIA

Tyrosine Phosphorylation of Tau by the Src Family Kinases Lck and Fyn

<p>Abstract</p> <p>Background</p> <p>Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated. The Src-family kinase Fyn has been linked circumstantially to the pathology of Alzheimer's disease, and shown to phosphorylate Tyr18. Recently another Src-family kinase, Lck, has been identified as a genetic risk factor for this disease.</p> <p>Results</p> <p>In this study we show that Lck is a tau kinase. <it>In vitro</it>, comparison of Lck and Fyn showed that while both kinases phosphorylated Tyr18 preferentially, Lck phosphorylated other tyrosines somewhat better than Fyn. In co-transfected COS-7 cells, mutating any one of the five tyrosines in tau to phenylalanine reduced the apparent level of tau tyrosine phosphorylation to 25-40% of that given by wild-type tau. Consistent with this, tau mutants with only one remaining tyrosine gave poor phosphorylation; however, Tyr18 was phosphorylated better than the others.</p> <p>Conclusions</p> <p>Fyn and Lck have subtle differences in their properties as tau kinases, and the phosphorylation of tau is one mechanism by which the genetic risk associated with Lck might be expressed pathogenically.</p

OMO-1 reduces progression and enhances cisplatin efficacy in a 4T1-based non-c-MET addicted intraductal mouse model for triple-negative breast cancer

c-MET is considered a driver of cancer progression, impacting tumor growth and tumor-supporting stroma. Here, we investigated the therapeutic efficacy of OMO-1, a potent and selective c-MET inhibitor, in an immunocompetent intraductal mouse model for triple-negative breast cancer (TNBC). OMO-1 reduced non-c-MET addicted 4T1 tumor progression dose dependently as monotherapeutic and provided additional disease reduction in combination with cisplatin. At the stromal level, OMO-1 significantly reduced neutrophil infiltration in 4T1 tumors, promoted immune activation, and enhanced cisplatin-mediated reduction of tumor-associated macrophages. OMO-1 treatment also reduced 4T1 tumor hypoxia and increased expression of pericyte markers, indicative for vascular maturation. Corroborating this finding, cisplatin delivery to the 4T1 primary tumor was enhanced upon OMO-1 treatment, increasing cisplatin DNA-adduct levels and tumor cell death. Although verification in additional cell lines is warranted, our findings provide initial evidence that TNBC patients may benefit from OMO-1 treatment, even in cases of non-c-MET addicted tumors

Appearance of microvascular obstruction on high resolution first-pass perfusion, early and late gadolinium enhancement CMR in patients with acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>The presence and extent of microvascular obstruction (MO) after acute myocardial infarction can be measured by first-pass gadolinium-enhanced perfusion cardiovascular magnetic resonance (CMR) or after gadolinium injection with early or late enhancement (EGE/LGE) imaging. The volume of MO measured by these three methods may differ because contrast agent diffusion into the MO reduces its apparent extent over time. Theoretically, first-pass perfusion CMR should be the most accurate method to measure MO, but this technique has been limited by lower spatial resolution than EGE and LGE as well as incomplete cardiac coverage. These limitations of perfusion CMR can be overcome using spatio-temporal undersampling methods. The purpose of this study was to compare the extent of MO by high resolution first-pass <it>k-t </it>SENSE accelerated perfusion, EGE and LGE.</p> <p>Methods</p> <p>34 patients with acute ST elevation myocardial infarction, treated successfully with primary percutaneous coronary intervention (PPCI), underwent CMR within 72 hours of admission. <it>k-t </it>SENSE accelerated first-pass perfusion MR (7 fold acceleration, spatial resolution 1.5 mm × 1.5 mm × 10 mm, 8 slices acquired over 2 RR intervals, 0.1 mmol/kg Gd-DTPA), EGE (14 minutes after injection with a fixed TI of 440 ms) and LGE images (1012 minutes after injection, TI determined by a Look-Locker scout) were acquired. MO volume was determined for each technique by manual planimetry and summation of discs methodology.</p> <p>Results</p> <p><it>k-t </it>SENSE first-pass perfusion detected more cases of MO than EGE and LGE (22 vs. 20 vs. 14, respectively). The extent of MO imaged by first-pass perfusion (median mass 4.7 g, IQR 6.7) was greater than by EGE (median mass 2.3 g, IQR 7.1, p = 0.002) and LGE (median mass 0.2 g, IQR 2.4, p = 0.0003). The correlation coefficient between MO mass measured by first-pass perfusion and EGE was 0.91 (p < 0.001).</p> <p>Conclusion</p> <p>The extent of MO following acute myocardial infarction appears larger on high-resolution first-pass perfusion CMR than on EGE and LGE. Given the inevitable time delay between gadolinium administration and acquisition of either EGE or LGE images, high resolution first-pass perfusion imaging may be the most accurate method to quantify MO.</p

Photocatalytic Activity Of Core/shell Semiconductor Nanocrystals Featuring Spatial Separation Of Charges

The present study investigates the photocatalytic activity of ZnSe/CdS core/shell semiconductor nanocrystals. These nanoparticles exhibit a spatial separation of photoinduced charges between the core and the shell domains, which makes them potentially viable for photocatalytic applications. Unfortunately, one of the excited charges remains inside the core semiconductor and thus cannot efficiently react with the external environment. Here, we explore this issue by investigating the mechanisms of hole extraction from the ZnSe core to the surface of the CdS shell. In particular, the effect of shell thickness in ZnSe/CdS core/shell nanocrystals on the ability of core-localized charges to perform oxidative reactions was determined. By using a combination of time-resolved spectroscopy and electrochemical techniques, we demonstrate that the use of hole-scavenging surfactants facilitates an efficient transfer of core-localized holes to the surface even in the case of shells exceeding 7 nm in thickness. These measurements further demonstrate that photoinduced holes can be extracted from the core faster than they recombine with shell-localized electrons, indicating that most of the absorbed energy in ZnSe/CdS nanocrystals can be used to drive catalytic reactions