Citations

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml−1·min−1; Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men ( P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP ( r = −0.83 and r = −0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.

New Findings What is the central question of this study? Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor‐mediated responses in humans. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia). What is the main finding and its importance? We show that hypoglycaemia‐mediated changes in heart rate variability and baroreflex sensitivity cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range during hypoglycaemia. These results provide a potential mechanism for impaired glycaemic control and increased risk of cardiac arrhythmias in patients with carotid chemoreceptor overactivity (i.e. sleep apnoea). Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor‐mediated responses. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia) by testing the following hypotheses: (i) activation of the carotid body chemoreceptors with hypoglycaemia would reduce spontaneous cardiac baroreflex sensitivity (sCBRS) in healthy humans; and (ii) desensitization of the carotid chemoreceptors with hyperoxia would restore sCBRS to baseline levels during hypoglycaemia. Ten young healthy adults completed two 180 min hyperinsulinaemic [2 mU (kg fat‐free mass)−1 min−1], hypoglycaemic (∼3.2 μmol ml−1) clamps, separated by at least 1 week and randomized to normoxia (arterial partial pressure of O2, 122 ± 10 mmHg) or hyperoxia (arterial partial pressure of O2, 424 ± 123 mmHg; to blunt activation of the carotid body glomus cells). Changes in heart rate, blood pressure, plasma catecholamines, heart rate variability (HRV) and sCBRS were assessed. During hypoglycaemia, HRV and sCBRS were reduced (P < 0.05) and the baroreflex working range was shifted to higher heart rates. When hyperoxia was superimposed on hypoglycaemia, there was a greater reduction in blood pressure and a blunted rise in heart rate when compared with normoxic conditions (P < 0.05); however, there was no detectable effect of hyperoxia on sCBRS or HRV during hypoglycaemia (P > 0.05). In summary, hypoglycaemia‐mediated changes in HRV and sCBRS cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors appear to play a role in resetting the baroreflex working range during hypoglycaemia.

Key Points Leukocyte cell-derived chemotaxin-2–associated amyloidosis (ALect2) is a common cause of systemic amyloidosis involving the liver. Recognition and accurate diagnosis of hepatic ALect2 amyloidosis is essential for accurate management of patients with hepatic amyloidosis.

Abstract Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P &lt; 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm vs. 263 cells/mm; P &lt; 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. Cancer Immunol Res; 2(4); 361–70. ©2014 AACR.

Objective: We evaluate the prevalence, etiology, and outcomes of hypoglycemia requiring emergency medical services (EMS) in patients without diabetes mellitus (non-DM). Methods: We reviewed medical records of all ambulance calls for non-DM with blood glucose <70 mg/dl in Olmsted County, Minnesota, between January 1, 2003, and December 31, 2009. Results: A total of 131 patients (age 51 ± 19 years; 54 % females) made 142 EMS calls, while 10 patients made repeated calls. Causes of hypoglycemia were critical illness (42; 32%), alcohol and polysubstance use (36; 27.5 %), insulinoma/ bariatric surgery (10; 8%), restricted oral intake (7; 5%), and multiple factors (3; 27.5 %). Patients with alcohol and polysubstance abuse were younger ( p = .002). A total of 54 patients had additional hypoglycemia predisposing comorbidities/factors [adrenal insufficiency (2), end-stage renal disease (11) and chronic liver disease (7), beta blockers use (34), and pentamidine use (1)]. Repeated calls and emergency room transportation were similar, but hospitalization varied across the etiologies, with the lowest proportion in the multiple-factor-related hypoglycemia group ( p = .01). Duration of follow-up was 1.28 (interquartile range 0.13–2.70) years. A total of 38 patients died, and age-adjusted mortality varied across different etiologies ( p < .001), with highest among critically ill. Cancer caused the highest number of deaths (7/38; 18%), while 1 death was due to hypoglycemia. Conclusions: There were multiple etiologies for hypoglycemic episodes in community-dwelling non-DM that required EMS. Critical illness, multifactorial causes, and alcohol/polysubstance abuse were common causes. Hospitalization and mortality were higher with critical illnesses.

Background: An institutional policy was previously established for patients with diabetes on insulin pump therapy undergoing elective surgical procedures. Method: Electronic medical records were reviewed to assess documentation of insulin pump status and glucose monitoring during preoperative, intraoperative, and postanesthesia care unit (PACU) phases of care. Results: Twenty patients with insulin pumps underwent 23 procedures from March 1 to December 31, 2011. Mean (standard deviation) age was 58 (13) years, mean diabetes duration was 28 (17) years, and mean duration of insulin pump therapy was 7 (6) years. Nearly all cases (86%) during the preoperative phase had the presence of the device documented—an improvement over the 64% noted in data collected before the policy. Intraoperatively, 13 cases (61%) had the presence of the pump documented, which was higher than the 28% before implementation of the policy. However, documentation of pump status was found in only 38% in the PACU and was actually less than the 60% documented previously. Over 90% of cases had glucose checked in the preoperative area and the PACU, and only 60% had it checked intraoperatively, which was nearly identical to the percentages seen before policy implementation. No adverse events occurred when insulin pump therapy was continued. Conclusions: Although some processes still require improvement, preliminary data suggest that the policy for perioperative management of insulin pumps has provided useful structure for care of these cases. The data thus far indicate that insulin pump therapy can be continued safely during the perioperative period.