Publications

Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.

PURPOSE

Previous studies analyzing the relationship between Body Mass Index (BMI) and complications after partial nephrectomy have been underpowered. We use a national surgical database to explore the association of BMI with postoperative outcomes for Open Partial Nephrectomy (OPN) and Minimally Invasive Partial Nephrectomy (MIPN).

PATIENTS AND METHODS

Years 2005-2012 of the National Surgical Quality Improvement Program (NSQIP) were queried for OPN and MIPN. Postoperative complications were organized according to Clavien Grades and compared across normal weight (BMI kg/m(2)=18.5-<25.0), overweight (BMI=25.0-<30.0), and obese (BMI≥30.0) patients using standard descriptive statistics and multivariate regression modeling.

RESULTS

Of 1667 OPNs and 2018 MIPNs, 46.2% of patients were obese. Operative time was 16.91 minutes longer on average for obese patients (p<0.001). The overall complication rate after OPN was 17.9%, 17.2%, and 17.9% (p=0.945) for normal weight, overweight, and obese patients, respectively; while the overall complication rate after MIPN was 6.9%, 6.3%, and 8.7% (p=0.147). Multivariate regression analysis demonstrated that overweight and obese patients were not at increased risk for any complication grade after OPN and MIPN compared to normal weight patients. When comparing procedures, MIPN had a lower complication rate compared to OPN for obese (8.7% vs 17.9%, p<0.001) and morbidly obese patients (9.2% vs 22.2%, p=0.001).

CONCLUSIONS

Although surgery in obese patients is longer compared to normal weight patients, it does not appear to increase the likelihood of 30-day postoperative complications for OPN or MIPN. However, obese patients undergoing MIPN had lower complication rates than those undergoing OPN.

BACKGROUND

Several cohort studies have indicated associations between S. pneumoniae and other microbes in the nasopharynx. To study causal relationships between the nasopharyngeal microbiome and pneumococcal carriage, we employed an experimental human pneumococcal carriage model. Healthy adult volunteers were assessed for pneumococcal carriage by culture of nasal wash samples (NWS). Those without natural pneumococcal carriage received an intranasal pneumococcal inoculation with serotype 6B or 23F. The composition of the nasopharyngeal microbiome was longitudinally studied by 16S rDNA pyrosequencing on NWS collected before and after challenge.

RESULTS

Among 40 selected volunteers, 10 were natural carriers and 30 were experimentally challenged. At baseline, five distinct nasopharyngeal microbiome profiles were identified. The phylogenetic distance between microbiomes of natural pneumococcal carriers was particularly large compared to non-carriers. A more diverse microbiome prior to inoculation was associated with the establishment of pneumococcal carriage. Perturbation of microbiome diversity upon pneumococcal challenge was strain specific. Shifts in microbiome profile occurred after pneumococcal exposure, and those volunteers who acquired carriage more often diverted from their original profile. S. pneumoniae was little prominent in the microbiome of pneumococcal carriers.

CONCLUSION

Pneumococcal acquisition in healthy adults is more likely to occur in a diverse microbiome and appears to promote microbial heterogeneity.

Fetal lymphoid tissue inducer (LTi) cells are required for lymph node and Peyer's patch (PP) organogenesis, but where these specialized group 3 innate lymphoid cells (ILC3s) develop remains unclear. Here, we identify extrahepatic arginase-1(+) Id2(+) fetal ILC precursors that express a transitional developmental phenotype (ftILCPs) and differentiate into ILC1s, ILC2s and ILC3s in vitro. These cells populate the intestine by embryonic day (E) 13.5 and, before PP organogenesis (E14.5-15), are broadly dispersed in the proximal gut, correlating with regions where PPs first develop. At E16.5, after PP development begins, ftILCPs accumulate at PP anlagen in a lymphotoxin-α-dependent manner. Thus, ftILCPs reside in the intestine during PP development, where they aggregate at PP anlagen after stromal cell activation and become a localized source of ILC populations.