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Presents a letter to the editor about the relationship between altitude and arterial fibrillation.

Abstract: Pain perception and its modulation are fundamental to human learning and adaptive behavior. This study investigated the hypothesis that pain perception is tied to pain's learning function. Thirty-one participants performed a threat conditioning task where certain cues were associated with a possibility of receiving a painful electric shock. The cues that signaled potential pain or safety were regularly changed, requiring participants to continually establish new associations. Using computational models, we quantified participants' pain expectations and prediction errors throughout the task and assessed their relationship with pain perception and electrophysiological responses. Our findings suggest that subjective pain perception increases with prediction error, that is, when pain was unexpected. Prediction errors were also related to physiological nociceptive responses, including the amplitude of nociceptive flexion reflex and electroencephalography markers of cortical nociceptive processing (N1-P2-evoked potential and gamma-band power). In addition, higher pain expectations were related to increased late event-related potential responses and alpha/beta decreases in amplitude during cue presentation. These results further strengthen the idea of a crucial link between pain and learning and suggest that understanding the influence of learning mechanisms in pain modulation could help us understand when and why pain perception is modulated in health and disease., (Copyright © 2024 International Association for the Study of Pain.)

Abstract: In response to the killing of George Floyd on May 25, 2020, and with a sense of urgency, the authors created and conducted a unique approach-a reckoning-to confronting racism in nursing. The project began with a series of five online discussions centering on the voices of nurses of color, followed by further ongoing discussions aimed at building antiracist capabilities for all participating nurses. This article describes the implementation and early outcomes of the project and provides its underlying principles, which are based on insights from activists and scholars whose work has focused on antiracist guidelines., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Cardiovascular risk factors have been implicated in the etiology of cerebral small vessel disease (CSVD); however, whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here, we use mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD., Methods: We used data from large-scale genome-wide association studies of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median MR, with validation using weighted median, MR-Egger, and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly., Results: MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits., Discussion: Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD., (© 2021 American Academy of Neurology.)

Background: The efficacy of selective Janus kinase 1/3 inhibitor R507 to prevent obliterative airway disease was analyzed in preclinical airway transplantation models., Methods: Orthotopic trachea transplantations were performed between Lewis donors and Brown Norway rat recipients. Oral everolimus (4 mg/kg once per day) or oral respective inhaled R507 (60 mg/kg twice per day, each) was used for immunosuppression. Grafts were retrieved after 6 or 60 days. Toxicity and anti-inflammatory effects of R507 were analyzed on human airway epithelial cells., Results: In 6-day animals, oral and inhaled R507 more potently diminished mononuclear graft infiltration than everolimus and preserved ciliated pseudostratified columnar respiratory epithelium. Everolimus and R507 similarly suppressed systemic cellular and humoral immune activation. In untreated rats, marked obliterative airway disease developed over 60 days. Oral and inhaled R507 was significantly more effective in reducing airway obliteration and preserved the morphology of the airway epithelium. Luciferase-positive donors revealed that a substantial amount of smooth muscle cells within the obliterative tissue was of donor origin. Only everolimus but not R507, adversely altered kidney function and lipid profiles. The R507 aerosol did not show airway toxicity in vitro but effectively suppressed activation of inflammatory signaling pathways induced by IL-1β., Conclusions: The Janus kinase 1/3 inhibitor R507 is a very well-tolerated immunosuppressant that similarly diminished obliterative airway disease with systemic or inhaled administration.

Background: Selective inhibition of lymphocyte activation through abrogation of signal 3-cytokine transduction emerges as a new strategy for immunosuppression. This is the first report on the novel Janus kinase (JAK)1/3 inhibitors R507 and R545 for prevention of acute allograft rejection., Methods: Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize the drugs. Heterotopic Brown Norway-Lewis heart transplantations were performed to study acute cardiac allograft rejection, graft survival, suppression of cellular host responsiveness, and antibody production. Therapeutic and subtherapeutic doses of R507 (60 and 15 mg/kg 2 times per day) and R545 (20 and 5 mg/kg 2 times per day) were compared with those of tacrolimus (Tac; 4 and 1 mg/kg once per day)., Results: Plasma levels of R507 and R545 were sustained high for several hours. Cell-based enzyme assays showed selective inhibition of JAK1/3-dependent pathways with 20-fold or greater selectivity over JAK2 and Tyrosine kinase 2 kinases. After heart transplantation, both JAK1/3 inhibitors reduced early mononuclear graft infiltration, even significantly more potent than Tac. Intragraft interferon-γ release was significantly reduced by R507 and R545, and for interleukin-10 suppression, they were even significantly more potent than Tac. Both JAK1/3 inhibitors and Tac were similarly effective in reducing the host Th1 and Th2, but not Th17, responsiveness and similarly prevented donor-specific immunoglobulin M antibody production. Subtherapeutic and therapeutic R507 and R545 doses prolonged the mean graft survival and were similarly effective as 1 and 4 mg/kg Tac, respectively. In combination regimens, however, only R507 showed highly beneficial synergistic drug interactions with Tac., Conclusions: Both R507 and R545 are potent novel immunosuppressants with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically interacts with Tac.

Objective: Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid-resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated., Design: In vivo and ex vivo animal study., Setting: University research laboratory., Subjects: Male adult Wistar rats., Interventions and Measurements: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction., Main Results: A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU-37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs., Conclusions: Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock.

Rationale: Vascular smooth muscle cell (VSMC) proliferation causes intimal thickening in atherosclerosis and restenosis. Previously, we demonstrated that Wnt/β-catenin signaling upregulates VSMC proliferation in vitro., Objective: We examined this pathway in vivo and investigated the involvement of specific Wnt proteins in VSMC proliferation., Methods and Results: Left carotid arteries of TOPgal (β-catenin signaling reporter) transgenic mice were ligated to induce intimal thickening. β-Catenin signaling was induced in the media and intima at 3 and 28 days after ligation, respectively, and was associated with VSMC proliferation and cyclin D1 expression. In vitro, a Wnt agonist promoted mouse VSMC proliferation, whereas Wnt inhibitory factor (WIF)-1 retarded platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation. Microarray analysis and quantitative PCR detected a significant induction of Wnt2 and Wnt4 mRNA in PDGF-BB-treated (proliferating) VSMCs compared to quiescent VSMCs. Western blotting revealed this increase was only translated into protein for Wnt4. Specific silencing RNA knockdown of Wnt4, but not Wnt2, significantly reduced VSMC proliferation. Recombinant Wnt4, but not Wnt2, significantly increased VSMC proliferation by ≈2-fold and silencing RNA knockdown revealed this is via Frizzled 1. Immunohistochemistry showed that increased Wnt4 protein correlated with VSMC proliferation and cyclin D1 expression (P<0.05 and P<0.001, respectively) during intimal thickening after rat carotid artery injury. Importantly, we also showed that intimal thickening and VSMC proliferation after carotid artery ligation was significantly retarded in Wnt4(+/-) compared to Wnt4(+/+) mice., Conclusions: This study demonstrates that Wnt/β-catenin signaling occurs in proliferating VSMCs during intimal thickening and indicates that this is a result of Wnt4 upregulation.

We describe the case of a 73-year-old woman with a history of chronic low back pain and 2 previous lumbar fusions who presented with complaints of worsening back and leg pain. Having previously undergone multiple interventions, physical therapy, and oral analgesics with limited pain relief, the patient opted for endoscopic lysis of adhesions for severe scarring of the epidural space. Subsequently, the patient developed a neurogenic bladder with urinary retention. Three years later, she experienced resolution of the neurogenic bladder symptoms that coincided with the use of the antibiotic nitrofurantoin. Upon discontinuation of the antibiotic, the patient noted that she was unable to void spontaneously. With reinstitution of nitrofurantoin, the patient was once again able to void effectively and has been maintained on nitrofurantoin for >3 years.

Background: This study aimed at investigating the role of a novel JAK3 inhibitor, R348, in the prevention of chronic airway allograft rejection., Methods: The heterotopic rat trachea transplant model was used. Recipients were treated daily with R348 (10, 20, 40, 80 mg/kg) or rapamycin (0.75 or 3 mg/kg). Blood levels of R348 and of its active metabolite R333 were measured. Grafts were harvested after 28 days to analyze epithelial morphology, mononuclear infiltration, and luminal obliteration. Plasma levels of circulating donor strain-reactive IgG antibodies were quantified., Results: R348 was well tolerated at up to 40 mg/kg, but was toxic at 80 mg/kg. Blood levels of R333 at 2 and 24 hr were consistently 10 to 15 times higher than those of R348. Airway luminal obliteration after 28 days was significantly inhibited by R348 at 40 mg/kg (20.6%+/-13.2%, P<0.05) and 80 mg/kg (15.7%+/-7.6%, P<0.05) and by rapamycin at 3 mg/kg (11.6%+/-6.7% P<0.001) versus untreated controls (100%). R348 is more than or equal to 40 mg/kg but neither dose of rapamycin preserved the physiologic epithelial coverage with its prominent goblet cells population (8.8+/-1.5 goblet cells/microm circumference in syngeneic grafts and 8.0+/-0.9 and 4.3+/-1.2 with R348 80 mg/kg and 40 mg/kg, respectively). Peritracheal graft mononuclear infiltration was most effectively suppressed by R348 is more than or equal to 40 mg/kg (P<0.05) and rapamycin 3 mg/kg (P<0.01). Donor strain-reactive IgG antibodies were significantly decreased by R348 is more than or equal to 40 mg/kg (P

Background: According to recent US census data, 52 million people reported speaking a language other than English at home, and almost 45% of this population reported limited English proficiency (LEP). Colorectal cancer (CRC) ranks among the top 3 most common cancers for several Asian ethnic groups, yet screening remains underutilized by Asian Americans., Objectives: This article describes the development of culturally and linguistically appropriate intervention materials for individuals with LEP. We discuss lessons learned from this research and implications for the translation of research into practice., Methods: The Health Behavior Framework served as the conceptual model for this study, and qualitative findings guided the development of our intervention materials (a video and pamphlet). To recommend Western preventive behaviors, the research team bridged the gap between Western and Chinese values and beliefs by devoting particular attention to: (1) the target population's sociocultural values and health beliefs; and (2) unique linguistic features of the Chinese language., Results: Key lessons learned from this study include the importance of: (1) a conceptual framework to guide intervention development; (2) incorporating sociocultural values and health beliefs into the intervention; (3) addressing and capitalizing on complex linguistics issues; (4) using qualitative methodology in cross-cultural research; and (5) contributions from a multicultural and multilingual research team. Other lessons relate to the translation of research findings into practice. We surmise that lessons learned from this study may be pertinent to the promotion of CRC screening among other patient groups with LEP and applicable to additional cancer screening tests.

Background: Janus kinase (JAK)3 is crucial for signal transduction downstream of various cytokine receptors in immune cells. This is the first report on the novel JAK3 inhibitor R348., Methods: (1) Detailed pharmacokinetic data were obtained in rats; (2) multiple in vitro enzyme inhibition assays were performed to characterize the drug; (3) prevention of acute rejection was investigated in animals treated with different doses of R348 or rapamycin for 5 days; and (4) cardiac allograft survival after a 10-day treatment period was studied for various regimens of R348, tacrolimus, or rapamycin; combination indices were calculated to evaluate drug interactions., Results: (1) Plasma levels of R348's active metabolite R333 sustained high for 8 hr or more, depending on the dose. (2) In vitro enzyme assays showed potent inhibition of JAK3- and Syk-dependent pathways. (3) R348 40 mg/kg preserved graft function, significantly reduced graft infiltration, and decreased histologic ISHLT rejection scores on postoperative day 5. Results were similar to those of rapamycin 3 mg/kg. Likewise, both drugs significantly reduced the cellular Th1 and Th2 immune responses, as determined by enzyme-linked immunosorbent assays. Intragraft inflammatory cytokine upregulation was similarly suppressed by R348 and rapamycin. R348 10 mg/kg was subtherapeutic. (4) Allograft survival was similar for R348 20 and 40 mg/kg, which was comparable with therapeutically dosed tacrolimus or rapamycin. In combination regimens, R348 demonstrated highly beneficial synergistic interactions with tacrolimus., Conclusions: R348 is a promising novel JAK3/Syk-inhibitor with favorable pharmacokinetics and biological activity. It effectively diminishes acute cardiac allograft rejection and is suitable for combination regimens with tacrolimus.

Objective: There is escalating interest in the therapeutic use of vasopressin in septic shock. However, little attention has focused on mechanisms underlying its pressor hypersensitivity, which contrasts with the vascular hyporesponsiveness to catecholamines. We investigated whether a long-term rodent model of sepsis would produce changes in endogenous levels and pressor reactivity to exogenous norepinephrine and vasopressin comparable with those seen in septic patients., Design: In vivo and ex vivo animal study., Setting: University research laboratory., Subjects: Male adult Wistar rats., Interventions and Measurements: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Biochemical and hormonal profiles were measured at time points up to 48 hrs. Pressor responses to intravenous norepinephrine, vasopressin, and F-180, a selective V1 receptor agonist, were measured at 24 hrs. Contractile responses to these drugs were assessed in mesenteric arteries taken from animals at 24 hrs using wire myography. Comparisons were made against sham operation controls., Main Results: Septic rats became unwell and hypotensive, with a mortality of 64% at 48 hrs (0% in controls). Plasma norepinephrine levels were elevated in septic animals at 24 hrs (1968 +/- 490 vs. 492 +/- 90 pg/mL in controls, p = .003), whereas vasopressin levels were similar in the two groups (4.5 +/- 0.8 vs. 3.0 +/- 0.5 pg/mL, p = not significant). In vivo, the pressor response to norepinephrine was markedly reduced in the septic animals, but responses to vasopressin and F-180 were relatively preserved. In arteries from septic animals, norepinephrine contractions were decreased (efficacy as measured by maximum contractile response, Emax: 3.0 +/- 0.3 vs. 4.7 +/- 0.2 mN, p < .001). In contrast, the potency of vasopressin (expressed as the negative log of the concentration required to produce 50% of the maximum tension, pD2: 9.1 +/- 0.04 vs. 8.7 +/- 0.05, p < .001) and F-180 (pD2 8.2 +/- 0.04 vs. 7.6 +/- 0.02, p < .001) was enhanced (n > or = 6 for all groups)., Conclusions: This long-term animal model demonstrates changes in circulating vasoactive hormones similar to prolonged human sepsis, and decreased pressor sensitivity to norepinephrine. Ex vivo sensitivity to vasopressin agonists was heightened. This model is therefore appropriate for the further investigation of mechanisms underlying vasopressin hypersensitivity, which may include receptor or calcium-handling alterations within the vasculature., ((C) 2007 Lippincott Williams & Wilkins, Inc.)

Objective: Mitochondrial dysfunction, particularly affecting complex I of the respiratory chain, could play a fundamental role in the development of multiple organ failure during sepsis. Increasing electron flow through complex II by addition of succinate may improve mitochondrial oxygen utilization and thus adenosine triphosphate production., Design: Ex vivo animal study., Setting: University research laboratory., Subjects: Male adult Wistar rats., Interventions: Fecal peritonitis was induced in conscious, fluid-resuscitated, hemodynamically-monitored rats. Sham-operation and naïve animals acted as controls. At 48 hrs, clinical severity was graded. Soleus muscle was taken for measurement of mitochondrial complex activities and oxygen consumption. The effect of glutamate plus malate (complex I substrates) and succinate (complex II substrate) on mitochondrial respiration was assessed., Measurements and Main Results: In the presence of glutamate plus malate, mitochondrial oxygen consumption was abnormally low in skeletal muscle tissue from moderately-to-severely septic animals as compared with naïve and sham-operation controls (both p < .01). On addition of succinate, mitochondrial respiration was augmented in all groups, particularly in moderately-to-severely septic animals (39% +/- 6% increase) as compared with naïve (11% +/- 5%; p < .01) and sham-operation controls (10% +/- 5%; p < .01). In the presence of succinate, mitochondrial oxygen consumption was similar between the groups., Conclusions: Succinate increases mitochondrial oxygen consumption in ex vivo skeletal muscle taken from septic animals, bypassing the predominant inhibition occurring at complex I. This warrants further exploration in vivo as a putative therapeutic modality.

Objective: The high melanin concentration in dark skin prevents the observation of a blanch response to light finger pressure. The objective of this study was to determine the ability of visible and near-infrared spectroscopy (the technique used in pulse oximetry) to monitor a blanch response from in vivo spectra in individuals with light and dark skin, based on changes in blood volume., Design: A quasi-experimental repeated measures design was employed. A stepper motor with an attached spectrophotometer probe was used to deliver controlled pressure to the participants' forearms, mimicking the finger-blanching test. Visible and near-infrared spectra were acquired throughout the blanching cycle., Setting: The In Vivo Tissue Optics Lab at the Institute for Biodiagnostics, Winnipeg, Manitoba, Canada., Participants: A convenience sample of 10 healthy light-skinned individuals and 10 healthy dark-skinned individuals., Results: Determined by analysis of the spectra, the 2 groups differed in pigmentation in both the visible (P<.01) and near-infrared (P<.01) regions of the absorbance spectrum. There was a significant difference in total hemoglobin at high and low pressure in both the visible (P<.01) and near-infrared (P<.05) regions., Conclusions: The observation of a significant difference in total hemoglobin at high and low pressure in both light- and dark-skinned groups in this study demonstrates the ability of visible and near-infrared spectroscopy to monitor blood volume changes associated with a blanch response. These findings support the potential use of this technology as the basis of a clinically useful blanch response tool that is insensitive to skin color.

Objectives: In the face of escalating medical costs for injured workers, the Washington State Department of Labor and Industries (L&I), which pays for most workers' compensation costs in the state, established guidelines for elective lumbar fusion as part of its inpatient utilization review program. The guidelines were tied to reimbursement strictures. The authors attempt to assess the effects of these guidelines, which were introduced in November 1988, upon subsequent L&I fusion procedures., Methods: Discharge data from the Comprehensive Hospital Abstract Reporting System and algorithms using International Classification of Diseases, Version 9, Clinical Modification diagnosis and procedure codes were used to identify lumbar surgical cases. Population estimates were from the 1990 US Census Bureau., Results: During the period of years 1987 through 1992, the lumbar fusion rate for the state showed a 26% decline compared with a 3% decrease for all lumbar operations. After November 1988, when the guidelines went into effect, the state fusion rate declined 33%, whereas rates for nonfusion operations essentially were unchanged. The sharpest decline corresponded in time to implementation of the guidelines. Prior to the initiation of L&I guidelines, the proportion of fusions among L&I patients was higher than among non-L&I patients. The opposite was true by the end of 1992, and the L&I proportion decreased more rapidly than the non-L&I proportion. Time series analysis revealed that both the decline in Washington state lumbar fusion rates and the decline in the proportion of lumbar fusion among L&I patients were statistically significant., Conclusions: The data suggest that the L&I lumbar fusion surgery criteria and reimbursement standards implemented in 1988 contributed to a decline in rates of performing that procedure. The utilization review aspect of the guidelines as well as the process of involving surgeons in the preparation and dissemination of guidelines also may have been contributory.

Poor mammography quality control results in the loss of important diagnostic information. Several organizations and agencies recommend or require that mammography quality assurance procedures include the periodic evaluation of equipment. The objective of this study was to assess compliance with published guidelines pertaining to the monitoring of mammography equipment. One hundred eighty-four Washington state mammography facilities were surveyed by mail during late 1989 and early 1990. The response rate was 71%. A large proportion of facilities was not complying with published guidelines concerning the frequency of evaluation of processor parameters and phantom image quality. Results suggest that many facilities were not in compliance with American College of Radiology recommendations concerning annual system evaluation by a physicist. The results of this study reinforce the importance of establishing minimum quality assurance standards and indicate a need for more mammography quality assurance technologist training.

We conducted a case-control study of the relation between smoking and placenta previa, using Washington State birth certificate data from 1984 through 1987. The study population was comprised of live, singleton births to women whose pregnancies were complicated by placenta previa (N = 598) and randomly selected controls (N = 2,422) from the same time period. We used logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI). Maternal smoking approximately doubled the risk of placenta previa after adjustment for the confounding effect of maternal age (OR = 2.1, 95% CI: 1.7-2.5).