Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.

A commentary on this article appears in this issue on page 1321.

Background: Catheter-based regional analgesia has been proposed as an alternative to systemic analgesia for patients with multiple rib fractures (MRF). This study sought to compare the efficacy of regional techniques for decreasing pain and improving clinical outcomes. Study design: This was a multi-institutional, retrospective cohort study of adult (≥18 years) patients admitted to four nonacademic trauma centers over two years (from 07/1/2014 to 06/30/2016). Study inclusion was MRF (≥3 fractures) with no other severe injuries. Two primary regional analgesia techniques were utilized and compared: continuous intercostal nerve blocks (CINB) and epidural (EPI) analgesia. The primary outcome, average pain scores on treatment, was examined using a repeated measures, linear regression mixed model. Secondary outcomes included hospital LOS, ICU LOS, ICU admission and hospital readmission, pulmonary complications, and incentive spirometry volumes during treatment, and were examined with univariate statistics. Results: There were 339 patients with isolated MRF; 85 (25%) required regional analgesia (CINB, n=41; EPI, n=44) and the remaining 75% received systemic analgesia only (IV, n=195; PO, n=59). There were demographic and clinical differences between regional analgesia and systemic analgesia groups; on the contrary, there were no demographic or clinical differences between the CINB and EPI groups. Adjusted pain scores were similar for the EPI and CINB groups (4.0 vs 4.4, p =0.49). Secondary outcomes were worse in the EPI group compared to the CINB group: less improvement in incentive spirometry volume ( p =0.004), longer ICU LOS ( p =0.03), longer hospital LOS ( p <0.001), and more ICU admission ( p <0.001). Conclusion: In patients requiring regional analgesia, pain management was equivalent with CINB and EPI, but CINB was associated with significantly better clinical outcomes. CINB might offer an efficient alternative for pain control in patients with MRF.

Level III, therapeutic.

No abstract