Inhibition of agonist-induced down-regulation of the delta-opioid receptor with a proteasome inhibitor attenuates opioid tolerance in human embryonic kidney 293 cells

This study was designed to test the hypothesis that inhibition of agonist-induced delta-receptor down-regulation would block the development of opioid tolerance in a cell-based model. A human embryonic kidney 293 cell line was established that expressed an epitope-tagged delta-opioid receptor (DOR). Treatment of DOR cells with Tyr-d-Ala-Gly-Phe-d-Leu-enkephalin (DADL) resulted in a time-dependent decrease in the B(max) of delta-opioid receptor binding sites and immunoreactive receptor protein. When cells were coincubated with the proteasome inhibitor N-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal (ZLLL) and DADL, the magnitude of the agonist-induced decrease in B(max) and immunoreactive receptor protein was reduced compared with DADL treatment alone. Acute treatment of DOR cells with DADL caused a 3-fold increase in the level of phosphorylated mitogen-activated protein (MAP) kinase. Prior exposure of DOR cells to DADL completely abrogated the agonist-induced activation of MAP kinase. When DOR cells were coincubated with DADL and ZLLL, the proteasome inhibitor prevented the loss of agonist activation of MAP kinase. Acute treatment of DOR cell membranes with DADL stimulated [(35)S]guanosine 5'-3-O-(thio-)triphosphate (GTPgammaS) binding. When DOR cells were preincubated with DADL, the agonist-induced increase in [(35)S]GTPgammaS binding was attenuated. Coincubation of ZLLL and agonist partially prevented the decreased responsiveness to agonist stimulation. The results of this study demonstrated that inhibition of agonist-induced down regulation with a proteasome inhibitor attenuated opioid tolerance in a cellular model, and suggest that coadministration of a proteasome inhibitor with chronic opioid agonist treatment may be useful for limiting opioid tolerance in vivo.     

Navigating the impact of COVID‐19 on palliative care for head and neck cancer

Health care services are being confronted by a daily dilemma of who can receive critical care and who cannot. In a palliative care clinic, this apprehension gets exemplified, as these patients have limited life expectancy. The head and neck region further makes things critical, as it comprises of all the sites through which the SARS‐CoV‐2 can be transmitted. This document strives to define the ways in which the head and neck cancer services can contribute to better patient care in a triage context. Practical steps suggested are protective equipment use, ensuring access to critical drugs (such as opioids), greater use of telemedicine consultations, discussing advance care plans, and embracing the role of a wider community support.     

Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium

Increased steady shear stress stimulates nitric oxide synthase (eNOS) in part by Akt-dependent phosphorylation. Arteries in vivo are exposed to pulse perfusion (PP) combining phasic shear with stretch. In compliant vessels, enhancing PP lowers vascular tone by stimulating eNOS; whereas in aged, stiff arteries, flow-mediated dilation declines and PP is a prominent risk factor. Here, we tested the hypothesis that reduced wall distensibility alters PP-induced eNOS/Akt mechano-signaling. Bovine aortic endothelial cells cultured within distensible tubes were exposed to physiological nonreversing steady or PP (7 dynes/cm(2) mean shear, pulse pressure 0 or 90 mm Hgx2 hours) in a custom servo-system. In compliant tubes, PP doubled Akt phosphorylation above nonpulsatile flow levels, whereas P-Akt declined to static levels from PP in stiffer tubes. eNOS phosphorylation (S-1179) similarly increased with PP in compliant tubes but was nearly undetectable with increased PP in stiffer tubes. After PP, brief exposure of cells to ultraviolet irradiation (oxidant stress) and subsequent culture revealed cytoprotection in compliant tubes but diffuse cytotoxicity and cell detachment in stiffer tubes. NOS inhibition by L-NAME converted compliant-tube post-UV behavior to that of stiffer tubes. These data provide novel evidence that wall compliance can directionally mediate endothelial Akt/eNOS phosphorylation and mechano-signaling. This may help explain increased vascular risks resulting from artery stiffening.     

Evaluation of serum ferritin in screening for iron deficiency in tuberculosis

Serum ferritin (SF) values 10 µg/l are diagnostic of absent Bone Marrow Iron (BMI) stores and therefore of iron deficiency (ID). However, SF, which may be elevated as a part of acute phase reaction, is an unreliable indicator of BMI stores in the setting of chronic disorders, making it difficult to diagnose ID in these patients. Thus, in chronic disorders (CD) such as tuberculosis, bone marrow examination is the only reliable way to establish ID. This study was done in order to identify levels of SF that would be indicative of absent BMI stores and also to study a combination of hematological and biochemical parameters that would be helpful in raising the predictive power of SF in patients of tuberculosis. Fifty-five tuberculosis patients were studied and classified into Iron Deplete (ID) and Iron Replete (IR) based on BMI. Raising the cut-off values of SF from 10 µg/l to 30 µg/l diagnosed 88% of ID cases correctly, as compared with 61% when cut-off levels of 10 µg/l were used. At cut-off values higher than 30 µg/l, the sensitivity was markedly reduced. Therefore, raising cut-off levels of SF to 30 µg/l was most effective in predicting absent BMI, especially in a population where ID is highly prevalent. Combination of SF 30 µg/l with mean corpuscular volume (MCV), erythrocyte sedimentation rate (ESR) and total iron binding capacity (TIBC) did not improve the predictive power of SF further. Also, 89.5% cases could be correctly classified by logistic regression equations using SF with ESR and C- reactive protein (CRP).Abbreviations SF Serum ferritin - BMI Bone marrow iron - ID Iron deplete - IR Iron replete - CD Chronic disorders - MCV Mean corpuscular volume - TIBC Total iron binding capacity - ESR Erythrocyte sedimentation rate - ACD Anemia of chronic disorders - IDA Iron deficiency anemia - Hb Hemoglobin concentration - TLC Total leukocyte count - RBC Red blood cell - RDW Red cell distribution width - % TS Percent transferrin saturation - SI Serum iron     

Birth weight, childhood growth and abdominal obesity in adult life.

OBJECTIVE: To examine the relationship of adult abdominal obesity to birth weight, childhood growth and lifetime socioeconomic circumstances. METHODS: A cohort of 3200 men and women with measured waist and hip circumference, height and weight at age 43 who have been followed since their birth in March 1946 in England, Scotland and Wales. Regression models were used to examine mean waist-hip ratio and waist circumference in relation to prospective measures of birth weight, weight relative to height in childhood at ages 4, 7, 11 and 15 and adult body mass index, and to test the independent and interactive nature of the associations and adjust for childhood and adult social class. RESULTS: There was a small inverse effect of birth weight on waist-hip ratio (P=0.037) but not waist circumference in women, after adjustment for current body size. Relative weight at age 7 was inversely related to waist-hip ratio and waist circumference in men (P<0.001 for both) and waist circumference in women (P=0.007) after adjustment for current body size. These relationships were attenuated in men of large body mass index (P<0.01 for interactions between relative weight at 7 y and body mass index in both cases) but were not modified by birth weight. Relative weights at other ages showed similar patterns to those observed at age 7, the effect being weakest at age 4. These findings were independent of lifetime socioeconomic circumstances. CONCLUSION: This study found a small prenatal inverse effect of fetal growth on adult waist-hip ratio due to a reduced hip size. There was also an inverse postnatal effect of childhood growth such that for any given adult body size those who had been lighter in childhood were more at risk of abdominal obesity. These relationships were independent of childhood socioeconomic circumstances and support the idea that insulin resistance may be linked to low weight in childhood.     

Therapeutic nipple-sparing mastectomy: trends based on a national cancer database

Background

Current reports on nipple-sparing mastectomy (NSM) are limited to single-institution series. We use the National Cancer Institute's Surveillance, Epidemiology, and End Results database to report on the national experience with NSM.

Methods

Population-level deidentified data were extracted from the Surveillance, Epidemiology, and End Results database. All female breast cancer patients treated with NSM from 2005 to 2009 were included. Case analysis was performed with respect to demographic and oncologic characteristics.

Results

Four hundred forty-nine patients underwent therapeutic NSM; this number increased from 66 patients in 2005 to 133 in 2009. Patients were distributed across 16 regions, although nearly 50% were from a region of California. Tumor diameter was <2 cm in 224 patients (50%). Lymph nodes were positive in 59 patients (13%), while radiation was delivered to 74 patients (16%).

Conclusions

NSM use has been increasing over the past several years. A majority of patients have tumor size <2 cm, although the number of patients with tumor size ≥2 cm has increased over time. Further population-based studies of NSM may benefit from collection of oncologic data such as tumor-to-nipple distance and tumor location.     

Cross-sectional area of the abdomen predicts complication incidence in patients undergoing sternal reconstruction

Background

Sternal reconstruction with vascularized flaps is central to the management of sternal wound infections and mediastinitis but carries a high risk of complications. There is a need to identify reliable predictors of complication risk to help inform patients and clinicians in preparation for surgery. Unfortunately, body mass index and serum albumin may not be reliable predictors of complication rates. Analytic morphomics provides a robust quantitative method to measure patients' obesity as it pertains to their risk of complications in undergoing sternal reconstruction.

Methods

We identified 34 patients with preoperative computed tomography scans of the abdomen from a cohort of sternal reconstructions performed between 1997 and 2010. Using semiautomated analytic morphomics, we identified the patients' skin and fascia layers between the ninth and 12th thoracic spine levels; from these landmarks, we calculated morphomic measurements of the patients' abdomens, including their total body cross sectional area and the cross sectional area of their subcutaneous fat. We obtained the incidence of complications from chart review and correlated the incidence of complications (including seroma, hematoma, recurrent wounds, mediastinitis, tracheostomy, and death) with patients' morphomic measurements.

Results

Sixty-two percent of patients (n = 21) suffered complications after their operation. Those who suffered from complications, relative to those who did not have complications, had increased visceral fat area (12,547.2 mm²versus 6569.9 mm², P = 0.0080), subcutaneous fat area (16,520.2 mm²versus 8020.1 mm², P = 0.0036), total body area (91,028.6 mm²versus 67,506.5 mm², P = 0.0022), fascia area (69,238.4 mm²versus 56,730.9 mm², P = 0.0118), total body circumference (1101.8 mm versus 950.2 mm, P = 0.0017), and fascia circumference (967.5 mm versus 868.1 mm, P = 0.0077). We also demonstrated a significant positive correlation between the previously mentioned morphomic measurements and the incidence of complications in multivariate logistic regression models, with odds ratios ranging from 1.19–3.10 (P values ranging from 0.010–0.022).

Conclusions

Increases in abdominal morphomic measurements correlate strongly with the incidence of complications in patients undergoing sternal reconstruction. This finding may influence preoperative risk stratification and surgical decision making in this patient population.