BACKGROUND AND PURPOSE
Capsaicin, an agonist of transient receptor potential vanilloid 1 (TRPV1) channels, is pro‐nociceptive in the periphery but is anti‐nociceptive when administered into the ...ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Here, we investigated how activation of TRPV1 channels in the vlPAG leads to anti‐nociception.
EXPERIMENTAL APPROACH
We examined synaptic transmission and neuronal activity using whole‐cell recordings in vlPAG slices in vitro and hot‐plate nociceptive responses in rats after drug microinjection into the vlPAG in vivo.
KEY RESULTS
Capsaicin (1–10 µM) depressed evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in vlPAG slices presynaptically, while increasing miniature excitatory PSC frequency. Capsaicin‐induced eIPSC depression was antagonized by cannabinoid CB1 and metabotropic glutamate (mGlu5) receptor antagonists, and prevented by inhibiting diacylglycerol lipase (DAGL), which converts DAG into 2‐arachidonoylglycerol (2‐AG), an endocannabinoid. Capsaicin induced membrane depolarization in 2/3 neurons recorded but, overall, increased neuronal firings by increasing evoked postsynaptic potentials. Intra‐vlPAG capsaicin reduced hot‐plate responses in rats, effects blocked by CB1 and mGlu receptor antagonists. Effects of capsaicin were antagonized by SB 366791, a TRPV1 channel antagonist.
CONCLUSIONS AND IMPLICATIONS
Capsaicin activated TRPV1s on glutamatergic terminals to release glutamate which activated postsynaptic mGlu5 receptors, yielding 2‐AG from DAG by DAGL hydrolysis. 2‐AG induces retrograde inhibition (disinhibition) of GABA release via presynaptic CB1 receptors. This disinhibition in the vlPAG leads to anti‐nociception by activating the descending pain inhibitory pathway. This is a novel TRPV1 channel‐mediated anti‐nociceptive mechanism in the brain and a new interaction between vanilloid and endocannabinoid systems.
Inorganic bromine plays a critical role in ozone and mercury depletions events (ODEs and MDEs) in the Arctic marine boundary layer. Direct observations of bromine species other than bromine oxide ...(BrO) during ODEs are very limited. Here we report the first direct measurements of hypobromous acid (HOBr) as well as observations of BrO and molecular bromine (Br2) by chemical ionization mass spectrometry at Barrow, Alaska in spring 2009 during the Ocean‐Atmospheric‐Sea Ice‐Snowpack (OASIS) campaign. Diurnal profiles of HOBr with maximum concentrations near local noon and no significant concentrations at night were observed. The measured average daytime HOBr mixing ratio was 10 pptv with a maximum value of 26 pptv. The observed HOBr was reasonably well correlated (R2 = 0.57) with predictions from a simple steady state photochemical model constrained to observed BrO and HO2 at wind speeds <6 m s−1. However, predicted HOBr levels were considerably higher than observations at higher wind speeds. This may be due to enhanced heterogeneous loss of HOBr on blowing snow coincident with higher wind speeds. BrO levels were also found to be higher at elevated wind speeds. Br2 was observed in significant mixing ratios (maximum = 46 pptv; average = 13 pptv) at night and was strongly anti‐correlated with ozone. The diurnal speciation of observed gas phase inorganic bromine species can be predicted by a time‐dependent box model that includes efficient heterogeneous recycling of HOBr, hydrogen bromide (HBr), and bromine nitrate (BrONO2) back to more reactive forms of bromine.
Key Points
First observations of HOBr are presented
Direct evidence for high winds activating bromine
HOBr can be reproduced with model including aerosol uptake
Global warming is a challenge to animal health, because of increased heat stress, with subsequent induction of immunosuppression and increased susceptibility to disease. Toll-like receptors (TLR) are ...pattern recognition receptors that act as sentinels of pathogen invasion and tissue damage. Ligation of TLRs results in a signaling cascade and production of inflammatory cytokines, which eradicate pathogens and maintain the health of the host. We hypothesized that the TLR signaling pathway plays a role in immunosuppression in heat-stressed pigs. We explored the changes in the expression of TLR2, TLR4 and the concentration of acute inflammatory cytokines, such as IL-2, IL-8, IL-12 and IFN-γ in Bama miniature pigs subjected to 21 consecutive days of heat stress, both in vitro and in vivo models. The results showed that heat stress induced the upregulation of cortisol in the plasma of pigs (P<0.05); TLR4 mRNA was elevated, but IL-2 was reduced in peripheral blood mononuclear cells (PBMC, P<0.05). The white blood cell count and the percentage of granulocytes (eosinophilic+basophilic) decreased significantly in heat-stressed pigs (P<0.05). In the in vitro model (PBMC heat shocked for 1 h followed by a 9 h recovery period), TLR2 and TLR4 mRNA expression also increased, as did the concentration of IL-12 in supernatants. However, IFN-γ was significantly reduced in PBMC culture supernatants (P<0.05). We concluded that a consecutive heat stress period elevated the expression of TLR2 and TLR4 in PBMC and increased the plasma levels of inflammatory cytokines. These data indicate that TLR activation and dysregulation of cytokine expression in response to prolonged heat stress may be associated with immunosuppression and increased susceptibility to antigenic challenge in Bama miniature pigs.
In situ wetting–drying cycles significantly and repeatedly influence the soil water content in the active zone but not in the steady zone. To investigate effects of in situ wetting–drying cycles on ...the mechanical behaviour of intact loess, a series of pressure plate tests was carried out with an intact loess sampled from the active and steady zones. Results show that the specimens from the steady zone have higher yield stresses at given suctions and a larger inclination of normalized loading collapse (LC) curve than the specimens from the active zone. As evidenced by the scanning electron microscopy results, the clay particles accumulating around the contacts between silt particles are widely observed in the former specimens but not in the latter specimens. The distribution of clay particles in the former specimens results in a stabilized skeleton with mechanical properties sensitive to suction variations. On the other hand, the maximum collapse potential of the specimen from the steady zone is 37% larger than that of the specimen from the active zone, mainly because of the larger inclination of normalized LC curve owned by the former specimen.
For an example of brass material-Muntz alloy, the present work compared the microstructures and properties, such as, ceramic deposition efficiency, surface morphology, phase, microhardness, ...electrochemical behaviour and thermal property, of two kinds of brass-based composite coatings reinforced with SiC and Al2O3 by cold-spray additive-manufacturing. A potential application in repairing the Muntz component was implemented, and the restoration quality was assessed by the interfacial microstructure and tribological performance. In particular, cold spray was proved to be a suitable method of additive manufacturing the easily oxidized and vaporized material and repairing its component.
•Two ceramic-brass coatings produced by cold-spray additive-manufacturing show no decomposition and phase transformation.•The used ceramic materials were detected to be 6H-SiC and α-Al2O3 by Raman spectra.•Deposition efficiency, microhardness, corrosion and thermal behaviours of two ceramic-brass coatings are compared.•Machinability, interfacial microstructure and wear resistance proved an excellent restoration quality.
Summary
What is known and Objective: Teicoplanin and vancomycin show similar clinical and bacteriological efficacy in clinical trials. Teicoplanin has been reported to have a lower adverse drug ...reaction (ADR) rate than vancomycin. Cross‐reactivity between these two glycopeptides is controversial. Our aim was to study the cross‐reactivity between teicoplanin and vancomycin through an assessment of all the reported ADRs of these drugs in our University hospital.
Methods: Over a period of 2 years, 170 cases of vancomycin therapy, which were closely monitored by doctors and clinical pharmacists, were used to analyse ADRs. Teicoplanin therapy was used as an alternative in cases of vancomycin intolerance. When an ADR related to vancomycin or teicoplanin was suspected, specialists were consulted to confirm if these were true ADR and to determine whether the implicated drug should be stopped. All ADRs for the two glycopeptides were assessed for causality using the Naranjo probability scale.
Results and Discussion: Thirty‐eight of 170 patients (22·4%) treated with vancomycin developed ADRs. Twenty‐four patients were switched to teicoplanin. However, 14 of those 24 patients (58·3%) developed ADRs. The time of onset of ADRs involving vancomycin was 12·7 ± 10·9 days (range, 1–46 days). The time of onset of sequential teicoplanin‐induced ADRs was 11·7 ± 4·7 days (range, 2–20 days). Of the 14 patients with ADRs related to sequential teicoplanin therapy, six showed cross‐reactivity between vancomycin and teicoplanin. The incidence of vancomycin‐induced neutropenia was 4·7% (8/170), whereas the incidence of teicoplanin‐induced neutropenia subsequent to vancomycin intolerance was as high as 33·3% (8/24). Furthermore, 71·4% (10/14) of the teicoplanin‐induced ADRs were associated with haematological abnormalities such as neutropenia, thrombocytopenia or leucopenia.
What is new and Conclusion: Teicoplanin, used as an alternative in cases of vancomycin intolerance, was associated with a high incidence of ADRs and haematological reactions, most notably neutropenia. This high rate of ADRs suggests cross‐reactivity between the two glycopeptides.
Objective
To investigate the association of different antipsychotic treatments with hospitalization due to self‐harm among patients with schizophrenia.
Method
This retrospective cohort study was ...based on Taiwan's universal health insurance database. Patients aged 15–45 years with a newly diagnosed schizophrenic disorder in 2001–2012 were included. The study outcome was the first hospitalization due to self‐harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time‐dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD).
Results
Among 70 380 patients with a follow‐up of 500 355 person‐years, 2272 self‐harm hospitalization episodes were identified. Compared with none or former use, current use of several second‐generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self‐harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15–0.47).
Conclusion
The protective effect on self‐harm may vary across different antipsychotics. Further studies are needed to replicate the findings.
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