Citations

Context Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. Objective To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Setting Clinical Research Unit. Design Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic) and 24-h rhythms. Results Total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. Mean 24-h cortisol concentrations were lower in premenopausal women than those in men of comparable age (176 ± 8.2 vs 217 ± 9.4 nmol/L, P = 0.02), but not in subjects older than 50 years. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than those in men (1.048 ± 0.025 vs 0.933 ± 0.023, P = 0.001), but not in subjects older than 50 years. ApEn peaked during the daytime. Conclusion Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 years, whereas age effects elevate concentrations in the late evening and early night and advance the timing of the peak diurnal rhythm.

Background: The Afirma ® Gene Expression Classifier (GEC) risk stratifies The Bethesda System for the Reporting of Thyroid Cytopathology class III/IV (indeterminate) thyroid nodules (ITNs) as suspicious for malignancy or benign. Several authors have published studies describing the diagnostic accuracy of the GEC. However, the quality of these methods has not been rigorously examined. Summary: In this study, MEDLINE and EMBASE were searched for studies published between January 1, 2010, and June 30, 2016, examining the sensitivity, specificity, negative predictive value, and positive predictive value of the GEC. The Quality of Diagnostic Accuracy Studies 2 was customized to evaluate the methods of included studies in each of four domains: nodule selection, index test execution, reference standard assignment, and flow and timing. Signaling questions were used to identify sources of potential bias in calculation of diagnostic accuracy, and issues of applicability were assessed. Three panelists applied the Quality of Diagnostic Accuracy Studies 2 tool to each study included, and divergence was resolved in conference. In 12 studies evaluated, the most common methodologic flaw was lack of reference standard diagnosis assignment to un-excised GEC-benign ITNs. Exclusion of these ITNs from the analyses resulted in unreliable estimates of specificity and negative predictive value. Other flaws identified included restriction to ITNs that had already been selected for referral for thyroidectomy or lobectomy. Conclusions: Future studies should define and assign a “true negative” label to GEC-benign nodules that do not develop malignant signs or symptoms during a pre-specified period of follow-up, and these nodules should be included in calculations of diagnostic accuracy.

ABSTRACT Carpal tunnel pressure is a key factor in the etiology of carpal tunnel syndrome. Numerous approaches have been conducted to measure carpal tunnel pressure. However, most techniques are invasive and take time and effort. We have developed an innovative approach to noninvasively assess the tunnel pressure by using the ultrasound surface wave elastography (USWE) technique. In a previous study it was shown that the shear wave speed in a tendon increased linearly with increasing tunnel pressure enclosed the tendon in a simple tendon model. This study aimed to examine the relationship between the carpal tunnel pressure and the shear wave speeds inside and outside the carpal tunnel in a human cadaveric model. The result showed that the shear wave speed inside the carpal tunnel increased linearly with created carpal tunnel pressure, while the shear wave speed outside the carpal tunnel remained constant. These findings suggest that noninvasive measurement of carpal tunnel pressure is possible by measuring the shear wave speed in the tendon. After fully establishing this technology and being applicable in clinic, it would be useful in the diagnosis of carpal tunnel syndrome. For that reason, further validation with this technique in both healthy controls and patients with carpal tunnel syndrome is required. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:477–483, 2018.

Recent research shows that butyrylcholinesterase (BChE) is not simply a liver enzyme that detoxifies bioactive esters in food and medications. In fact, in pursuing other goals, we recently found that it has an equally important role in regulating the peptide hormone ghrelin and its impact on hunger, obesity, and emotions. Here, we present and examine means of manipulating brain BChE levels by viral gene transfer, either regionally or globally, to modulate ghrelin signaling for long-term therapeutic purposes and to set the stage for exploring the neurophysiological impact of such an intervention.

Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down‐regulating dynamin 2 (Dyn2), a protein that facilitates lysosome re‐formation, contributing to hepatocellular steatosis. Primary hepatocytes were isolated from male Wistar rats fed Lieber–DeCarli control or ethanol (EtOH) liquid diets for 6‐8 weeks. Hepatocytes were incubated in complete medium (fed) or nutrient‐free medium (fasting) with or without the Dyn2 inhibitor dynasore or the Src inhibitor SU6656. Phosphorylated (active) forms of Src and Dyn2 and markers of autophagy were quantified using western blot analysis. Colocalization of LDs with autophagic machinery was determined using confocal microscopy. In hepatocytes from pair‐fed rats, LD breakdown was accelerated during fasting, as judged by smaller LDs and lower triglyceride (TG) content when compared with hepatocytes in complete media. Fasting‐induced TG loss in control hepatocytes was significantly blocked by either SU6656 or Dynasore. Compared with controls, hepatocytes from EtOH‐fed rats had 66% and 40% lower content of phosphorylated Src (pSrc) and phosphorylated Dyn2 (pDyn2), respectively, coupled with a lower rate of fasting‐induced TG loss. This slower rate of fasting‐induced TG loss was blocked in cells coincubated with Dynasore. Microscopic examination of EtOH‐fed rat hepatocytes revealed increased colocalization of the autophagosome marker LC3 on LDs with a concomitant decrease in lysosome marker LAMP1. Whole livers and LD fractions of EtOH‐fed rats exhibited simultaneous increase in LC3II and p62 over that of controls, indicating a block in lipophagy. Conclusion: Chronic ethanol administration slowed the rate of hepatocyte lipophagy, owing in part to lower levels of phosphorylated Src kinase available to activate its substrate, Dyn2, thereby causing depletion of lysosomes for LD breakdown. (Hepatology Communications 2017;1:501–512)

Abstract Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 +/− mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with ( S )-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention.

Purpose: Several studies have demonstrated that patients have a poor understanding of prognosis, survival, and effectiveness of chemotherapy, particularly in the setting of advanced cancer. This study examines oncology patients’ understanding of their illness based on accurate reporting of stage at diagnosis and knowledge of cancer status (ie, free of cancer or in remission v active disease). Materials and Methods: Two hundred eight patients with cancer previously treated at our large community-based cancer institute participated in the Consumer-Based Cancer Care Value Index field survey. Electronic medical record documentation of stage at diagnosis and cancer status was compared with patients’ self-reported responses. Concordance of responses and variables influencing discordance were evaluated. Results: In 51.0% of patients, self-reported cancer stage matched the abstracted stage, with the highest concordance in patients with advanced cancer (72%) versus patients with stage I to III disease (36.4% to 61.5%). Unexpectedly, discordance was lower among patients with advanced cancer compared with patients with stage I to III cancer ( P = .0528). Patients who were concordant for cancer stage at diagnosis were significantly more likely to be female ( P = .001), be younger than age 65 years ( P = .01), have an income > $60,000 ( P = .03), and have more education ( P = .02). In 64.4% of patients, self-reported cancer status (ie, free of cancer or in remission v active disease) matched the abstracted status. Nearly 30% of patients were not sure about their status, even when they were free of cancer or in remission. Conclusion: Our findings confirm that more than one quarter of patients with advanced cancer have poor illness understanding and highlight that an even greater number of patients with early stage I to III cancer have poor illness understanding. These observations highlight the need to improve illness understanding for patients across the entire cancer continuum.

Gallbladder cancer is a rare malignancy in most countries. The racial and sociodemographic factors associated with its incidence and survival are poorly defined. We aimed to investigate population-based gallbladder cancer incidence and survival trends on the basis of clinical characteristics and sociodemographic factors in the USA. Gallbladder cancer incidence and survival data from 2001 to 2012 were obtained from 18 registries of the Surveillance, Epidemiology, and End Results database. Incidence rates and Joinpoint trends were calculated by demographic subgroup. Survival trends were assessed using Cox proportional hazard models. A total of 7769 patients were identified. The overall gallbladder cancer incidence rates did not significantly change during the 2001–2012 period. Incidence rates were three times higher in Hispanics and 1.6 times higher in Blacks compared with Whites. Over the time period, incidence rates significantly increased among Blacks and decreased among Hispanics. Male sex [hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.03–1.17], older age (HR: 1.73, 95% CI: 1.53–1.96), and single and divorced statuses (HR: 1.19, 95% CI: 1.09–1.30 and 1.12, 95% CI: 1.01–1.24) were independently associated with shorter overall survival, whereas higher education (HR: 0.89, 95% CI: 0.82–0.97) and higher income (HR: 0.89, 95% CI: 0.82–0.96) were associated with longer survival. Furthermore, overall survival has improved in all races/ethnicities except for Hispanics and Blacks. The overall incidence rates for gallbladder cancer were stable during 2001–2012. Hispanics have the highest incidence rates, but the incidence rates in Blacks are on the rise.