Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

Tolerance to the antinociceptive effect of mu-opioid receptor (MOPr) agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co- administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by assessment of cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross- tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low-doses of morphine and fentanyl. In conclusion, cross-tolerance does not develop between morphine and fentanyl within the vlPAG. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance following morphine and fentanyl binding to the MOPr. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to reduce opioid tolerance and other side effects. Perspective: This preclinical study shows that there is a reduction in cross tolerance between morphine and fentanyl within the periaqueductal gray which is key brain region in opioid antinociception and tolerance

JWST reveals a possible z∼11z \sim 11 galaxy merger in triply-lensed MACS0647−-JD

MACS0647$-$JD is a triply-lensed $z\sim11$ galaxy originally discovered with the Hubble Space Telescope. Here we report new JWST imaging, which clearly resolves MACS0647$-$JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. Both are very small, with stellar masses $\sim10^8\,M_\odot$ and radii $r<100\,\rm pc$. The brighter larger component "A" is intrinsically very blue ($\beta\sim-2.6$), likely due to very recent star formation and no dust, and is spatially extended with an effective radius $\sim70\,\rm pc$. The smaller component "B" appears redder ($\beta\sim-2$), likely because it is older ($100-200\,\rm Myr$) with mild dust extinction ($A_V\sim0.1\,\rm mag$), and a smaller radius $\sim20\,\rm pc$. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be out of phase. With an estimated stellar mass ratio of roughly 2:1 and physical projected separation $\sim400\,\rm pc$, we may be witnessing a galaxy merger 400 million years after the Big Bang. We also identify a candidate companion galaxy C $\sim3\,{\rm kpc}$ away, likely destined to merge with galaxies A and B. The combined light from galaxies A+B is magnified by factors of $\sim$8, 5, and 2 in three lensed images JD1, 2, and 3 with F356W fluxes $\sim322$, $203$, $86\,\rm nJy$ (AB mag 25.1, 25.6, 26.6). MACS0647$-$JD is significantly brighter than other galaxies recently discovered at similar redshifts with JWST. Without magnification, it would have AB mag 27.3 ($M_{UV}=-20.4$). With a high confidence level, we obtain a photometric redshift of $z=10.6\pm0.3$ based on photometry measured in 6 NIRCam filters spanning $1-5\rm\mu m$, out to $4300\,\r{A}$ rest-frame. JWST NIRSpec observations planned for January 2023 will deliver a spectroscopic redshift and a more detailed study of the physical properties of MACS0647$-$JD.Comment: 27 pages, 14 figures, submitted to Natur

Sensitivity of jarrah (Eucalyptus marginata) to phosphate, phosphite, and arsenate pulses as influenced by fungal symbiotic associations

Many plant species adapted to P-impoverished soils, including jarrah (Eucalyptus marginata), develop toxicity symptoms when exposed to high doses of phosphate (Pi) and its analogs such as phosphite (Phi) and arsenate (AsV). The present study was undertaken to investigate the effects of fungal symbionts Scutellospora calospora, Scleroderma sp., and Austroboletus occidentalis on the response of jarrah to highly toxic pulses (1.5 mmol kg−1 soil) of Pi, Phi, and AsV. S. calospora formed an arbuscular mycorrhizal (AM) symbiosis while both Scleroderma sp. and A. occidentalis established a non-colonizing symbiosis with jarrah plants. All these interactions significantly improved jarrah growth and Pi uptake under P-limiting conditions. The AM fungal colonization naturally declines in AM-eucalypt symbioses after 2–3 months; however, in the present study, the high Pi pulse inhibited the decline of AM fungal colonization in jarrah. Four weeks after exposure to the Pi pulse, plants inoculated with S. calospora had significantly lower toxicity symptoms compared to non-mycorrhizal (NM) plants, and all fungal treatments induced tolerance against Phi toxicity in jarrah. However, no tolerance was observed for AsV-treated plants even though all inoculated plants had significantly lower shoot As concentrations than the NM plants. The transcript profile of five jarrah high-affinity phosphate transporter (PHT1 family) genes in roots was not altered in response to any of the fungal species tested. Interestingly, plants exposed to high Pi supplies for 1 day did not have reduced transcript levels for any of the five PHT1 genes in roots, and transcript abundance of four PHT1 genes actually increased. It is therefore suggested that jarrah, and perhaps other P-sensitive perennial species, respond positively to Pi available in the soil solution through increasing rather than decreasing the expression of selected PHT1 genes. Furthermore, Scleroderma sp. can be considered as a fungus with dual functional capacity capable of forming both ectomycorrhizal and non-colonizing associations, where both pathways are always accompanied by evident growth and nutritional benefits

SAVSNET: Collating Veterinary Electronic Health Records for Research and Surveillance

Owners and pets frequently live in very close contact. As a result, surveillance of disease-related events in companion animals has the potential to deliver benefits for both animal and human health. SAVSNET"”the Small Animal Veterinary Surveillance Network"”collects and collates real-time data from veterinary diagnostic laboratories and veterinary practices across the UK to support research and disease surveillance in companion animals. The data collected by SAVSNET is made available to a wide range of interested parties including academic collaborators, PhD researchers, students and commercial companies. As such, SAVSNET is a valuable resource for One Health surveillance

SAVSNET: Collating Veterinary Electronic Health Records for Research and Surveillance

Owners and pets frequently live in very close contact. As a result, surveillance of disease-related events in companion animals has the potential to deliver benefits for both animal and human health. SAVSNET"”the Small Animal Veterinary Surveillance Network"”collects and collates real-time data from veterinary diagnostic laboratories and veterinary practices across the UK to support research and disease surveillance in companion animals. The data collected by SAVSNET is made available to a wide range of interested parties including academic collaborators, PhD researchers, students and commercial companies. As such, SAVSNET is a valuable resource for One Health surveillance

SAVSNET: Collating Veterinary Electronic Health Records for Research and Surveillance

Ha aparecido una publicación del señor C. Ljungsedt sobre el hermoso método de Jäderin con tablas de corrección para cintas de 20 metros. Este método ha sido adoptado con ventaja en varias partes, especialmente en Norte América, donde ha sido tratado entre otros por el conocido ingeniero y profesor J. B. Johnson en «The Theory and Practice of Surveying». Para facilitar el uso del método con cintas de 25 metros presento las tablas correspondientes y al mismo tiempo, para más claridad, el desarrollo del teorema gráficamente demostrado con una figura descriptiva.Facultad de Ciencias Naturales y Muse

Strain Typing and Antimicrobial Resistance of Fluoroquinolone-Resistant Neisseria gonorrhoeae Causing a California Infection Outbreak▿

Antimicrobial-resistant Neisseria gonorrhoeae is an emerging public health problem as a result of the alarming limitation in treatment options. We examined an outbreak in California of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) by evaluation of a combination of routine isolates from the Gonococcal Isolate Surveillance Project and isolates collected by expanded surveillance performed between April 2000 and June 2002. QRNG isolates were characterized by two methods: (i) determination of a combination of antibiogram, auxotype, serovar, Lip type, and patterns of amino acid alteration in the quinolone resistance-determining region of GyrA and ParC (ASLGP) and (ii) pulsed-field gel electrophoresis (PFGE). Strain typing was used to describe the QRNG outbreak strains and the associated antimicrobial resistance profiles. Among 79 isolates that were completely characterized, we identified 20 different ASLGP strain types, and 2 of the types were considered to belong to outbreak strains that comprised 65% (51/79) of the isolates. By PFGE typing, there were 24 different strain types, and 4 of these were considered outbreak types and comprised 66% (52/79) of the isolates. The overall agreement between the typing methods in distinguishing outbreak strains and non-outbreak strains was 84% (66/79). The most common QRNG ASLGP strain type had chromosomally mediated resistance to penicillin and tetracycline and an azithromycin MIC of 0.5 μg/ml. The occurrence of an outbreak caused by QRNG strains that could fail to be eradicated by most antibiotic classes reinforces the serious problem with antimicrobial resistance in Neisseria gonorrhoeae that the public health system faces. Adherence to a regimen with the recommended antibiotics at the appropriate dose is critical, and monitoring for antimicrobial susceptibility needs to be actively maintained to adapt treatment guidelines appropriately

Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population

A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 μg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34+ cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/μL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34+ cell counts than donors who did not (94 vs 79 cells/μL, P < .001). In multivariate analysis, higher post–G-CSF CD34+ cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre–G-CSF platelet count, pre–G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post–G-CSF CD34+ cell counts