Nuclear factor-kappa B (NF-κB) activation is a key early signal regulating inflammatory and cell death responses in acute pancreatitis. Our previous in vitro studies with molecular approaches on AR42J cell showed that protein kinase D (PKD/PKD1) activation was required in NF-κB activation induced by cholecystokinin 8 (CCK) or carbachol (CCh) in pancreatic acinar cells. Recently developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide potentially important pharmacological approaches to further investigate the effect of PKD in pancreatitis therapy. The aim of this study was to explore whether CID755673 and CRT0066101 block NF-κB activation with in vitro and in vivo models of experimental pancreatitis and whether the small molecule PKD inhibitors have therapeutic effects when given before or after the initiation of experimental pancreatitis. Freshly prepared pancreatic acini were incubated with CID755673 or CRT006101, followed by hyperstimulation with CCK or CCh. For in vivo experimental pancreatitis, rats were treated with intraperitoneal injection of CID755673 or CRT0066101 prior to or after administering cerulein or saline. PKD activation and NF-κB-DNA binding activity in nuclear extracts from pancreatic acini and tissue were measured. The effects of PKD inhibitors on pancreatitis responses were evaluated. Our results showed that both CID755673 or CRT0066101 selectively and specifically inhibited PKD without effects on related protein kinase Cs. Inhibition of PKD resulted in significantly attenuation of NF-κB activation in both in vitro and in vivo models of experimental pancreatitis. NF-κB inhibition by CID755673 was associated with decreased inflammatory responses and attenuated severity of the disease, which were indicated by less inflammatory cell infiltration, reduced pancreatic interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), decreased intrapancreatic trypsin activation, and alleviation in pancreatic necrosis, edema and vacuolization. Furthermore, PKD inhibitor CID755673, given after the initiation of pancreatitis in experimental rat model, significantly attenuated the severity of acute pancreatitis. Therapies for acute pancreatitis are limited. Our results indicate that small chemical PKD inhibitors have significant potential as therapeutic interventions by suppressing NF-κB activation.

Abstract Background MRSA prevalence in nursing homes often exceeds that in hospitals, but reasons for this are not well understood. We sought to measure MRSA burden in a large number of nursing homes and identify facility characteristics associated with high MRSA burden. Methods We performed nasal swabs of residents from 26 nursing homes to measure MRSA importation and point prevalence, and estimate transmission. Using nursing home administrative data, we identified facility characteristics associated with MRSA point prevalence and estimated transmission risk in multivariate models. Results We obtained 1,649 admission and 2,111 point prevalence swabs. Mean MRSA point prevalence was 24%, significantly higher than mean MRSA admission prevalence, 16%, (paired t-test, p<0.001), with a mean estimated MRSA transmission risk of 16%.In multivariate models, higher MRSA point prevalence was associated with higher admission prevalence (p=0.005) and higher proportions of residents with indwelling devices (p=0.01). Higher estimated MRSA transmission risk was associated with higher proportions of residents with diabetes (p=0.01) and lower levels of social engagement (p=0.03). Conclusions MRSA importation was a strong predictor of MRSA prevalence, but MRSA burden and transmission were also associated with nursing homes caring for more residents with chronic illnesses or indwelling devices. Frequent social interaction among residents appeared to be protective of MRSA transmission, suggesting that residents healthy enough to engage in group activities do not incur substantial risks of MRSA from social contact. Identifying characteristics of nursing homes at risk for high MRSA burden and transmission may allow facilities to tailor infection control policies and interventions to mitigate MRSA spread.

We assessed characteristics associated with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carriage among residents of 22 nursing homes. Of MRSA-positive swabs, 25% (208/824) were positive for CA-MRSA. Median facility CA-MRSA percentage was 22% (range, 0%-44%). In multivariate models, carriage was associated with age less than 65 years (odds ratio, 1.2; P<.001) and Hispanic ethnicity (odds ratio, 1.2; P=.006). Interventions are needed to target CA-MRSA.

Chlorhexidine and mupirocin are used in health care facilities to eradicate methicillin-resistant Staphylococcus aureus (MRSA) carriage. The objective of this study was to assess the frequency of chlorhexidine and mupirocin resistance in isolates from nares carriers in multiple nursing homes and to examine characteristics associated with resistance. Nasal swab samples were collected from approximately 100 new admissions and 100 current residents in 26 nursing homes in Orange County, CA, from October 2008 to May 2011. MRSA isolates were tested for susceptibility by using broth microdilution, disk diffusion, and Etest; for genetic relatedness using pulsed-field gel electrophoresis; and for qac gene carriage by PCR. Characteristics of the nursing homes and their residents were collected from the Medicare Minimum Data Set and Long-Term Care Focus. A total of 829 MRSA isolates were obtained from swabbing 3,806 residents in 26 nursing homes. All isolates had a chlorhexidine MIC of ≤4 μg/ml. Five (0.6%) isolates harbored the qacA and/or qacB gene loci. Mupirocin resistance was identified in 101 (12%) isolates, with 78 (9%) isolates exhibiting high-level mupirocin resistance (HLMR). HLMR rates per facility ranged from 0 to 31%. None of the isolates with HLMR displayed qacA or qacB, while two isolates carried qacA and exhibited low-level mupirocin resistance. Detection of HLMR was associated with having a multidrug-resistant MRSA isolate (odds ratio [OR], 2.69; P = 0.004), a history of MRSA (OR, 2.34; P < 0.001), and dependency in activities of daily living (OR, 1.25; P = 0.004). In some facilities, HLMR was found in nearly one-third of MRSA isolates. These findings may have implications for the increasingly widespread practice of MRSA decolonization using intranasal mupirocin.