Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels.

TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30-50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.

Cognitive impairment and postoperative outcomes in patients undergoing primary total hip arthroplasty: A systematic review.

STUDY OBJECTIVE: Total hip arthroplasty (THA) is a common surgical procedure in the elderly. Varying degrees of cognitive impairment (CI) are frequently seen in this patient population. To date, there has been no systematic review of the literature specifically examining the impact of CI on outcomes after elective THA. The aim of this systematic review was to identify studies that compare the postoperative outcomes of patients with and without CI after undergoing elective primary THA. DESIGN: We conducted a systematic review of prospective and retrospective studies. A systematic literature review was conducted by searching MEDLINE, PubMed, and Embase from between January 1, 1997 and January 1, 2018. A total of 234 articles were reviewed and 22 studies were selected. SETTING: Operating room and short-term and long-term postoperative recovery up to 2 years. PATIENTS: Patients with CI who underwent an elective primary THA that required general anesthesia with a comparator group of patients who did not have dementia. INTERVENTIONS: Patients who underwent elective primary total hip arthroplasty. MEASUREMENTS: Outcomes included post-operative delirium (POD), mortality and other complications, discharge disposition, length of stay (LOS), mortality, short-term (30 days) and long-term (1 month-2 years) complications. MAIN RESULTS: 22 studies with 5,705,302 participants were included in the systematic review. Sample sizes varied greatly, ranging from 14 to 2,924,995 participants. There was an association between patients with CI and an increase in POD, in-hospital mortality, complications during hospitalization, non-routine disposition, LOS, mortality between 1 month to 2 years, and worse postoperative functional status. CONCLUSIONS: We demonstrate that there are strong associations between patients with pre-existing CI undergoing THA and increased POD, hospital mortality, hospital complications, and hospital LOS. We report good quality evidence linking complications after THA to preexisting CI. Screening for CI can improve care and better predict the risk of developing postoperative complications such as delirium. Further investigations can address perioperative factors that can help reduce complications and show the utility of more widespread assessment of preoperative cognitive impairment.