Toward the end of the nineteenth century a complex of problems related to ticks and tick-borne diseases of cattle created a demand for methods to control ticks and reduce losses of cattle. The discovery and use of arsenical solutions in dipping vats for treating cattle to protect them against ticks revolutionized tick and tick-borne disease control programmes. Arsenic dips for cattle were used for about 40 years before the evolution of resistance of ticks to the chemical, and the development and marketing of synthetic organic acaricides after World War II provided superior alternative products. Most of the major groups of organic pesticides are represented on the list of chemicals used to control ticks on cattle. Unfortunately, the successive evolution of resistance of ticks to acaricides in each chemical group with the concomitant reduction in the usefulness of a group of acaricides is a major reason for the diversity of acaricides. Whether a producer chooses a traditional method for treating cattle with an acaricide or uses a new method, he must recognize the benefits, limitations and potential problems with each application method and product. Simulation models and research were the basis of recommendations for tick control strategies advocating approaches that reduced reliance on acaricides. These recommendations for controlling ticks on cattle are in harmony with recommendations for reducing the rate of selection for acaricide resistance. There is a need to transfer knowledge about tick control and resistance mitigation strategies to cattle producers.
Background and Aims
We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis.
Methods
Through a systematic search through May 31, 2017, we identified eight randomized controlled trials [RCTs] of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy [PNR vs. LOR vs. intolerance]. We estimated relative risk [RR] (and 95% confidence interval [CI]) of achieving clinical remission in patients with PNR as compared with patients with LOR, and intolerance, through random effects meta-analysis.
Results
As compared with patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61–0.96]). As compared with patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56–0.97]), particularly to ustekinumab (RR,0.64 [0.52–0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85–1.58]).
Conclusion
Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.
Two patterns of pyrethroid resistance were characterized from Boophilus microplus (Canestrini) collected in Mexico. One was characteristic of a kdr mutation and the other involved esterase and cytochrome P450 enzyme systems. Very high resistance to permethrin, cypermethrin, and flumethrin, not synergized by TPP and PBO and high resistance to DDT, characterized the kdr-like pattern found in the Corrales and San Felipe strains. Esterase and cytochrome P450-dependent resistance was found in the Coatzacoalcos strain. It was characterized by resistance to permethrin, cypermethrin, and flumethrin, synergized by TPP and PBO, but no resistance to DDT. The Coatzacoalcos strain also showed 3.6-fold resistance to the organophosphate coumaphos. This factor appeared to be independent of pyrethroid resistance. Pyrethroid resistance patterns found in Mexico were similar to those found earlier in Australia. The significance of pyrethroid and coumaphos resistance to the U.S. cattle fever tick quarantine is discussed.
Rhipicephalus sanguineus (Latreille) were collected from the Corozal Army Veterinary Quarantine Center in Panama and characterized for resistance to five classes of acaricides. These ticks were highly resistant to permethrin, DDT, and coumaphos; moderately resistant to amitraz; and not resistant to fipronil when compared with susceptible strains. Resistance to both permethrin and DDT may result from a mutation of the sodium channel. However, synergist studies indicate that enzyme activity is involved. The LC50 estimate for permethrin was lowered further in the Panamanian strain then in susceptible strains with the addition of triphenylphosphate (TPP), but not with the addition ofpiperonyl butoxide (PBO). This suggests that esterases and not oxidases are responsible for at least some pyrethroid resistance. Elevated esterase activity and its inhibition by TPP were confirmed by native gel electrophoresis. The LC50 estimate obtained for coumaphos in the Panamanian strain was not lowered further than what was observed for susceptible strains by the addition of TPP or PBO. This indicates that enzyme activity might not be involved in coumaphos resistance. Resistance to amitraz was measured through a modification of the Food and Agriculture Organization Larval Packet Test. All tick strains were found to be susceptible to fipronil.
BACKGROUND & AIMS
Experimental studies in acute pancreatitis (AP) suggest strong association of acinar cell injury with cathepsin-B dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death have not been studied. In this study, we have explored, for the first time, intra-acinar events downstream of trypsin activation which lead to acinar cell death.
METHODS
Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen-7 or cathepsin-B deleted) were stimulated with supramaximal caerulein and cytosolic activity of cathepsin-B and trypsin was evaluated. Permeabilzed acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin-B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis.
RESULTS
Both in vitro and in vivo studies suggest that during AP cathepsin-B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin-B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin-B into the cytosol can lead to cell death through necrosis.
CONCLUSIONS
This is the first report which defines the role of trypsin in AP and demonstrates that cytosolic cathepsin-B but not trypsin activates cell death pathways. This is also the first report to suggest that trypsin is requisite for AP only because it causes release of cathepsin-B into the cytosol.
The levels of resistance to two organophosphate acaricides, coumaphos and diazinon, in several Mexican strains of Boophilus microplus (Canestrini) were evaluated using the FAO larval packet test. Regression analysis of LC50 data revealed a significant cross-resistance pattern between those two acaricides. Metabolic mechanisms of resistance were investigated with synergist bioassays. Piperonyl butoxide (PBO) reduced coumaphos toxicity in susceptible strains, but synergized coumaphos toxicity in resistant strains. There was a significant correlation between PBO synergism ratios and the coumaphos resistance ratios. The results suggest that an enhanced cytochrome P450 monooxygenase (cytP450)-mediated detoxification mechanism may exist in the resistant strains, in addition to the cytP450-mediated metabolic pathway that activates coumaphos. PBO failed to synergize diazinon toxicity in resistant strains, suggesting the cytP450 involved in detoxification were specific. Triphenylphosphate (TPP) synergized toxicity of both acaricides in both susceptible and resistant strains, and there was no correlation between TPP synergism ratios and the LC50 estimates for either acaricide. Esterases may not play a major role in resistance to coumaphos and diazinon in those strains. Bioassays with diethyl maleate (DEM) revealed a significant correlation between DEM synergism ratios and LC50 estimates for diazinon, suggesting a possible role for glutathione S-transferases in diazinon detoxification. Resistance to coumaphos in the Mexican strains of B. microplus was likely to be conferred by both a cytP450-mediated detoxification mechanism described here and the mechanism of insensitive acetylcholinesterases reported elsewhere. The results of this study also underscore the potential risk of coumaphos resistance in B. microplus from Mexico to the U.S. cattle fever tick eradication program.
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