The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.

BACKGROUND/OBJECTIVES: Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN: Observational prospective cohort. SETTING: Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS: Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS: Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION: INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae. J Am Geriatr Soc 67:794-798, 2019.

Association between alendronate, serum alkaline phosphatase level, and heterotopic ossification in individuals with spinal cord injury.

CONTEXT/OBJECTIVE: Only sparse evidence exists regarding the effectiveness of oral alendronate (ALN) in the prevention of heterotopic ossification (HO) in patients with spinal cord injury (SCI). The objective of this study is to investigate the protective effect of oral ALN intake on the appearance of HO in patients with SCI. STUDY DESIGN: Retrospective database review. SETTING: A Spinal Cord Unit at a Rehabilitation Hospital. PARTICIPANTS: Two hundred and ninety-nine patients with SCI during acute inpatient rehabilitation. INTERVENTIONS: Administration of oral ALN. OUTCOME MEASURES: The incidence of HO during rehabilitation was compared between patients with SCI receiving oral ALN (n = 125) and patients with SCI not receiving oral ALN (n = 174). The association between HO and/or ALN intake with HO risk factors and biochemical markers of bone metabolism were also explored. RESULTS: HO developed in 19 male patients (6.35%), however there was no significant difference in the incidence of HO in patients receiving oral ALN or not. The mean odds ratio of not developing versus developing HO given ALN exposure was 0.8. Significant correlation was found between abnormal serum alkaline phosphatase (ALP) levels and HO appearance (P < 0.001) as well as normal serum ALP and ALN intake (P < 0.05). CONCLUSION: Even though there was no direct prevention of HO in patients with SCI by oral ALN intake, abnormal serum ALP was found more frequently in patients with HO development and without oral ALN intake. This evidence could suggest that ALN may play a role in preventing HO, especially in patients with acute SCI with increasing levels of serum ALP.

Persistence of tumor-infiltrating CD8 T cells is tumor-dependent but antigen-independent.

How tumor-infiltrating lymphocytes (TILs) that are tumor-specific but functionally tolerant persist in the antigen-expressing tumor tissue is largely unknown. We have previously developed a modified TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model where prostate cancer cells express the T-cell epitope SIYRYYGL (SIY) recognized by CD8 T cells expressing the 2C T-cell receptor (TCR) (referred to as TRP-SIY mice). In TRP-SIY mice, activated 2C T cells rapidly become tolerant following infiltration into the prostate tumor. In this study, we show that tolerant 2C T cells persist in the prostate tumor of TRP-SIY mice by proliferating slowly in a tumor-dependent, but antigen-, interleukin (IL)-7- and IL-15-independent manner. We also show that disappearance of 2C T cells from the lymphoid organs of TRP-SIY mice are due to antigen-induced T-cell contraction rather than altered trafficking or generalized T-cell depletion in the mice. Finally, we show that clonal T cells unreactive to SIY are equally capable of persisting in the prostate tumor. These findings suggest that while functional tolerance of TILs is induced by antigen, persistence of tolerant TILs in the tumor tissue is mediated by a novel mechanism: slow proliferation independent of antigen and homeostatic cytokines. These results also allow CD8 T-cell survival in the tumor environment to be compared with T-cell survival in chronic infection.

Covalent binding of 2-phenylpropionyl-S-acyl-CoA thioester to tissue proteins in vitro.

In this study, we investigated the possible involvement of acyl-CoA, reactive intermediary metabolites of 2-arylpropionic acids (profens), in protein adduct formation in rat liver homogenate and in human serum albumin (HSA) in buffer. (RS)-[1-14C]-2-Phenylpropionic acid (14C-2-PPA, 1 mM) was incubated with rat liver homogenate (1.5 mg/ml) in the presence of cofactors of acyl-CoA formation (Mg2+, ATP, and CoA). Aliquots of the incubation mixture were analyzed for covalent binding and acyl-CoA formation over a 3-h period. High-performance liquid chromatographic analysis of the products from such incubations showed the presence of 2-phenylpropionyl-S-acyl-CoA (2-PPA-CoA), which was confirmed by coelution with authentic 2-PPA-CoA, as well as by mass spectrometry. In the same incubations, 2-PPA was shown to bind covalently to hepatic proteins in a time- and ATP-dependent fashion. Inhibition of 2-PPA-CoA formation by acyl-CoA synthetase inhibitors, such as palmitic acid, lauric acid, octanoic acid, and ibuprofen, markedly decreased the extent of covalent binding of 2-PPA to hepatic proteins. Results from these in vitro studies strongly suggest that acyl-CoA thioester derivatives are chemically reactive and are able to bind covalently to tissue proteins in vitro, and, therefore, may contribute significantly to covalent adduct formation of profen drugs in vivo.