Despite historical in vitro susceptibility data of S. intermedius, antimicrobial therapy may be ineffective, and more extreme measures may be needed to achieve a successful outcome. Early, appropriate antimicrobial therapy needs to remain the mainstay of the treatment of CAP in an attempt to prevent fatal complications such as this from occurring.

No abstract

Hydrocephalus is a developmental disorder that affects children worldwide with an incidence of approximately 1:1000 births. Multiple causes have been implicated, including a dysfunction of the homeostatic mechanisms of cerebrospinal fluid (CSF) secretion from the choroid plexus, a decreased reabsorption from the subarachnoid granules, or a blockage of CSF circulation, leading to excessive accumulation of CSF within the brain ventricles. One animal model of developmental hydrocephalus involves rats carrying a point mutation on the TMEM67 gene. The homozygous form of this mutation causes a ciliopathy that was originally found in rats with polycystic kidney disease (PKD). Rats homozygous for the TMEM67 mutation show severe hydrocephalus and PKD and do not survive beyond postnatal day (P) 18. Recently we identified a TRPV4 antagonist that appears to protect against the ventriculomegaly in preweaning homozygous rats. We propose that this drug has effects directly on the choroid plexus, and since it is administered intraperitoneally, must gain access to the choroid epithelial cells. Animals heterozygous for the TMEM67 mutation develop a milder degree of hydrocephalus, no renal disease, and live past 1 year. The current study tested the hypothesis that treatment of heterozygous adult animals with the TRPV4 antagonist, RN1734, can limit the extent of hydrocephalus thereby protecting against the associated adverse effects on neurobehavioral function. In the current experiments, the behavioral studies assessed exploration of a complex novel environment called the multivariate concentric square field (MCSF), a 100 x 100 cm arena containing multiple defined zones with a large center area, three dimly‐illuminated perimeter corridors, one brightly illuminated slope and bridge, an enclosed dark corner room (DCR), and a corner hurdle. Video recordings of the single 20‐minute session of each rat are scored by two observers blind to group membership, and quantitative measures of behavioral categories (locomotor activity, exploratory activity, shelter seeking, risk assessment, risk taking) are derived from scores of the type, number and duration of activities in the various zones. MRI's were performed on P300 and P331, and the rats were assigned to either RN1734 or vehicle treatment on P301‐P330, and testing on the MCSF occurred on P315. Several interesting and unexpected results emerged from these studies. Regardless of genotype, the proportion of males that developed hydrocephalus was significantly higher than that of females. Regardless of genotype and drug treatment, the females were more active and engaged in less shelter seeking than males. Because of these sex differences the current studies were underpowered to determine effects of genotype and drug treatment on the behavioral activities.Support or Funding InformationHydrocephalus Association and Department of Defense Office of the Congressionally Directed Medical Research Programs (CDMRP)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

As human lifespan increases, comorbid conditions that impact quality of life have become a serious problem. FAT10 has been identified as a gene that when knocked out, improves age associated metabolic dysfunctions and increased longevity in mice (1). There is increased Fat10 expression in the liver in obesity (2,5). Providing evidence that fat10 expression may be important for triggering the transition to metabolic dysfunction in aging. Adult LEW.1WR1(1WR1) rats have increased body mass without excess abdominal fat mass compared to control rats (3). Yet, it was unclear where the excess mass was stored. We hypothesized that the 1WR1 rat would develop increased liver fat mass as a product of increased insulin resistance in response to increased liver fat10 expression over time. To test this hypothesis, we did insulin tolerance tests(7 weeks & 15 weeks), triglyceride assays, and histological analysis of the liver(23 weeks), in 1WR1 rats(n=7) and Wistar Furth (WF) rats(n=7) on control diets. We analyzed images using histological scoring for nonalcoholic fatty liver disease from the literature (4). We also assessed the slides for Mallory Denk bodies (MBs). The body mass of 1WR1 rats were increased compared to WF rat groups starting from the age of 7 weeks (391.4∓8.572g vs. 271.8∓11.62g; p <0.0006). 1WR1 rats became more insulin resistant with age, the 1WR1 rat group has increased AUC of 7 and 15 week Insulin Tolerance Tests (401.5∓23.54 vs. 245.3∓10.20 7w ITT1; p= 0.0728, 15w ITT2 328.2∓14.86 vs. 217.8∓9.; p <0.0003) compared to WF rats. 1WR1 rats have increased liver mass (11.85g∓0.7699g vs. 7.235g∓0.3864g; p=0.0006) liver triglyceride levels compared to WF rats (192.8∓21.8 mg/mL vs. 130.1∓13.075 mg/mL; p=0.0728). 1WR1 rats have increased steatosis scores(1.857∓0.2608 vs. 1.143∓0.1429;p= 0.0862) yet significantly reduced inflammatory foci level (2∓0.8165 vs. 3∓0;p= 0.007), most 1WR1 hepatocytes are enlarged (ballooned) and contained MBs compared to WF rats suggesting 1WR1 rats have already passed the early inflammation stage. Adult 1WR1 rats developed reduced insulin sensitivity and lipid accumulation in the liver. These data support our hypothesis that 1WR1 rats would develop increased liver fat and impaired insulin resistance in response to aging and show that this process may be inflammation driven. (1) Canaan et al.,PNAS. April 2014; 111 (14): 5313-5318.(2)Vidal et al., FASEB.2020, 34: 1-1,(3) Collins et al., J Endocr Soc. 2019;3(1),(4).Kleiner et al., Hepatology, 2005; 41 (6): 1313–1321,(5).Dali-Youcef et al., Hepatol Commun. 2019;3(9):1205-1220.

Non alcoholic Fatty Liver Disease(NAFLD) is a disease usually found alongside diabetes in patients and is known as a manifestation of the metabolic disorder. The disease describes a progression of increasingly malignant conditions affecting the liver starting from benign steatosis. Steatosis can progress to steatohepatitis, damaging cells and encouraging scar tissue formation. The LEW.1WR1(1WR1) rat overexpresses fat10, a gene which plays a role in age‐related inflammation, insulin resistance, adiposity, and hepatocellular carcinoma. This gene has been shown to be essential in maintaining liver cell protein quality control and Mallory Denk body(MDB) formation(Jia, Ji, & French, 2020). 1WR1 rats have been shown to become more glucose intolerant as they age, developing insulin resistance increasing risk of Diabetes and NAFLD. They have also been shown to develop increased body mass while not having significantly different epididymal fat pad deposits and increased fat10 concentration in the liver compared to control animals (Collins, Clopp, Mercado, Gibson, & Love‐Rutledge, 2019). Increasing understanding of fat10’s functions is important for future research in reducing disease susceptibility in NAFLD. For this project we hypothesized that because weight was not being added to the fat pads in the previous study it would be added to the organs; therefore these animals would develop increased liver mass or fatty liver as they age increasing risk of NAFLD. This project studied glucose intolerance, triglyceride levels, liver weight, MDBs, and NAFLD Activity score(NAS) of 1WR1 and WF/NHsd(WF) rat livers. These rats were subjected to a 7% sucrose or normal diet type by Research Diets from 5‐7 weeks of age. At 21 weeks old a 120 minute human like glucose tolerance test was done after a fasting period of 8 hours. Triglyceride concentrations in the blood, liver, and muscles were measured. Sacrifice occurred at 18 weeks of study and the livers were weighed and formalin fixed. They were then sent to Histowiz for slide processing and digitalization. Scoring for MDBs and NAS were done on the resulting slides. The results of the glucose tolerance test confirmed these rats became more glucose intolerant during the study as their glucose levels were unable to return to baseline after 120 minutes. The Triglyceride assay showed significantly higher concentrations of liver and muscle triglyceride levels to the control. The liver mass measurements showed the 1WR1 rats had significantly heavier livers to the control. The MDB scoring showed their presence primarily in the 1WR1 rats. Finally, the results of our NAS scoring indicated that the 1WR1 rats developed steatosis at a higher rate than the control. The steatosis development at a higher rate correlates to a higher risk of steatohepatitis and further malignant forms of NAFLD. Fat10’s roles in age related glucose intolerance and liver function increases risk of development of later malignant NAFLD forms.