Citations

Due to frequent abnormal breathing events and their effects on sleep architecture, patients with obstructive sleep apnea (OSA) exhibit decreased amounts of slow wave sleep (SWS). Reduced SWS has been linked to hypertension in community-based studies. We sought to investigate whether SWS percentage modifies the association between OSA and prevalent hypertension. We studied 7107 patients with OSA and 1118 primary snorers who underwent in-laboratory polysomnography. Patients were classified into quartiles of percent SWS. Hypertension was defined based either on clinic blood pressure measures or on physician diagnosis. Multivariable logistic regression model showed a significant interaction effect of OSA and SWS on prevalent hypertension ( P =0.002). Decreased SWS was associated with higher odds for hypertension in OSA but not in primary snoring, with patients with OSA exhibiting <0.1% SWS (OR, 1.44 [95% CI, 1.21–1.70]; P =0.001) and those with 0.1% to 4.8% SWS (OR, 1.20 [95% CI, 1.03–1.40]; P =0.02) being more likely to have hypertension compared with those with >11.1% SWS. In analysis stratified by OSA severity, significant associations between percent SWS and blood pressure emerged only in moderate and severe OSA. Effect modifications by sex ( P =0.040) and age ( P =0.007) were also only evident in OSA, indicating that decreased SWS was associated with hypertension only in men and in patients <60 years old. Decreased SWS is associated with a dose-dependent increase in odds of prevalent hypertension in patients with OSA. The effects of SWS are likely to be modulated by OSA severity. SWS may be implicated in the heightened risk of cardiovascular diseases exhibited by patients with OSA.

Background Past research has shown how fires, heat and hot substances are important causes of health loss globally. Detailed estimates of the morbidity and mortality from these injuries could help drive preventative measures and improved access to care. Methods We used the Global Burden of Disease 2017 framework to produce three main results. First, we produced results on incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years from 1990 to 2017 for 195 countries and territories. Second, we analysed these results to measure mortality-to-incidence ratios by location. Third, we reported the measures above in terms of the cause of fire, heat and hot substances and the types of bodily injuries that result. Results Globally, there were 8 991 468 (7 481 218 to 10 740 897) new fire, heat and hot substance injuries in 2017 with 120 632 (101 630 to 129 383) deaths. At the global level, the age-standardised mortality caused by fire, heat and hot substances significantly declined from 1990 to 2017, but regionally there was variability in age-standardised incidence with some regions experiencing an increase (eg, Southern Latin America) and others experiencing a significant decrease (eg, High-income North America). Conclusions The incidence and mortality of injuries that result from fire, heat and hot substances affect every region of the world but are most concentrated in middle and lower income areas. More resources should be invested in measuring these injuries as well as in improving infrastructure, advancing safety measures and ensuring access to care.

Sudden death syndrome (SDS) foliar symptoms consist of foliar chlorosis, foliar necrosis, leaf marginal curling, and premature defoliation, but resistance screening has been evaluated mostly based on the overall SDS foliar severity rather than on a specific foliar symptom. This study generated an F2 population derived from crossing the susceptible variety Sloan and the resistant germplasm line PI 243518, which exhibits resistance to both foliar chlorosis and necrosis. A total of 400 F2 lines were evaluated for foliar chlorosis, foliar necrosis, and overall SDS foliar symptoms, separately. Genotyping-by-sequencing was applied to obtain single nucleotide polymorphisms (SNPs) in the F2 population, and linkage mapping using 135 F2 lines with 969 high-quality SNPs identified a locus on chromosome 13 for foliar necrosis and SDS foliar symptoms. The locus partially overlaps with loci previously reported for SDS on chromosome 13, which is the third time the region from 15.98 to 21.00 Mbp has been reproduced independently and therefore qualifies this locus for a new nomenclature proposed as Rfv13-02. In summary, this study generated a new biparental population that enables not only the discovery of a locus for foliar necrosis and SDS foliar symptoms on chromosome 13 but also the potential for advanced exploration of SDS foliar resistance derived from the germplasm line PI 243518.

Conventional therapies to multiple myeloma (MM) are not aimed at specific molecular targets leading ultimately to treatment resistance. Recent reports have shown that iron is instrumental in cancer development and progression and that high intracellular iron levels are associated with poor prognosis. We have demonstrated that MM cells exhibit dysregulated iron homeostasis and that limitation of cytosolic iron inhibits MM cell growth both in vitro and in vivo. The potential therapeutic role of iron should be further investigated to better understand how targeting high-iron MM cells could prevent or delay MM development and recurrence. Our study will provide crucial insights into the iron biology of MM pathogenesis and may lead to novel MM therapy. In this study, two mouse models, young Vk*MYC and old KaLwRij mice, were injected with iron dextran (1.25 mg/kg, IP, once a week). Tumor burden was monitored by serial Serum Protein Electrophoresis (SPEP) tests, flow cytometry, and immunohistochemistry. In vitro co-culturing of ARP1 MM cells with macrophages was employed to determine iron transfer. To determine iron's roles in MM evolution, we injected iron dextran into Vk*MYC mice at 8-week age. Vk*MYC mice develop MGUS around 40-50 weeks with plasma cell (PC) bone marrow infiltration and kidney damage etc. Iron-dextran was used because it is primarily taken up by macrophages. After 14-16 weeks of iron injection, M spike was detected in the injected Vk*MYC mice. The percentage of bone marrow plasma cells (CD138+) were significantly increased to 9% in the Vk*MYC mice injected with iron compared to control mice injected with vehicle by flow cytometry and immunohistochemistry. The acceleration of disease progression via iron injection was also tested in KaLwRij mice, which also spontaneously develops MGUS in old age. M protein was detected in 12 of 15 mice (80%) injected with iron dextran for 10 weeks and 1 of 5 KaLwRij (20%) control mice at 18-months of age. CD138+ B220- plasma cells were determined by flow cytometry. A significant increase of CD138+B220- plasma cells in iron treated mice (4% versus 2%) was observed compared to vehicle control mice. Deparaffined sections of bone marrow from the above mice were stained with Prussian blue and confirmed positive staining of macrophages from iron administrated mice. These results indicate that iron accelerates MGUS development in vivo. We next evaluated whether MM cells accumulate iron from the microenvironment. ARP1 MM cells were co-cultured with primary macrophages derived from mouse bone marrow to mimic disease environment in vitro. Under these conditions, MM cells induced macrophage polarization from M0 to M1 and M2. Furthermore, increased macrophage polarization was confirmed in vivo from the KaLwRij mice injected with 5TGM1 MM cells. To confirm that MM cells uptake iron from macrophages, increased intracellular ferritin levels were observed by western blot in ARP1 MM cells following co-culture with iron-loaded macrophages. We observed that this increase in intracellular ferritin was mediated via the transferrin receptor. This iron mobilization was prevented by iron chelation. Additionally, we confirmed that ferritin levels were higher in CD138+ primary human MM cells compared to CD138- non-MM cells by western blot. Our data indicate that MM cells promote macrophage polarization resulting in the transferring of iron into MM cells. The blockade of iron trafficking between MM cells and macrophages might hold a promise for the prevention and therapy in MM. Disclosures Bergsagel: Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Zhan:BIPHARM LLC: Consultancy, Other: % Allocation of Profit.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Pharmacologic stimulation of a G protein–coupled receptor preferentially expressed on fibroblasts reverses experimental lung and liver fibrosis.

Abstract Background Ocular syphilis is an infrequent presentation of Treponema pallidum infection. It is often seen in association with neurosyphilis but can occur in isolation as well. Here we describe a case series of 10 patients with ocular syphilis seen at our institution. Methods Patients with a diagnosis of ocular syphilis at the three sites of Mayo Clinic were identified from June 2006 to February 2019. Patient’s baseline characteristics, clinical presentation, diagnostic testing, and treatment were abstracted from Electronic Medical Records. Results We identified 10 patients (17 eyes) during the study period, half being diagnosed in the last 5 years. The median age was 51 years (IQR 21–66), and the majority were males (7/10). Characteristics of the patients are outlined in Table 1. Common presenting symptoms included vision loss (8/10), photophobia (4/10), and irritation (5/10). Seven of 10 patients had bilateral involvement. Of the 17 eyes, 59% had pan-uveitis and 82% had disc edema (Table 2). Rapid Plasma Reagin (RPR) was positive in 9 patients and median serum RPR was 1:128 (IQR 1:2-1:1024). One patient was diagnosed with a positive TP-PA, and characteristic ocular findings. One patients had positive 16S Ribosomal RNA Gene PCR/Sanger Sequencing on vitreous humor specimen for Treponema species. The majority of patients had isolated ocular symptoms at presentation; two patients also had an associated skin rash. All patients underwent a lumbar puncture (LP). Half had pleocytosis (TNC > 5) and elevated protein elevated (mean 63.6 mg/dL), although not significantly high. 3/10 patients had VDRL positive in the CSF. Protein levels were much higher in those with positive VDRL. Each patient was treated with intravenous (IV) penicillin for at least 2 weeks. Nine patients received ocular steroids as well. At last available follow-up, 8 had complete and 1 had partial resolution. One had worsened eye findings with eventual scarring. Conclusion Our findings are congruent with increasing incidence of ocular syphilis nationwide. Bilateral eye involvement and pan-uveitis were the most common ocular findings. Although only 3 patients had a positive VDRL in the CSF, pleocytosis and elevated protein were found in a large number of patients. Majority of the patients had clinical resolution with appropriate treatment. Disclosures All authors: No reported disclosures.

Background: Patients with pulmonary hypertension (PH) experience distressing symptoms that can undermine quality of life (QoL) and treatment adherence. Complementary health approaches are known to help manage symptoms of chronic conditions and may have therapeutic benefits in PH. Objective: To explore the impact of Urban Zen Integrative Therapy (UZIT) on PH-related symptoms. Design: A within-subjects, pre-/post-intervention, repeated-measures design. Subjects/Setting: Community-dwelling adults with PH received weekly UZIT sessions in an outpatient setting. Measurements: Participants ( n = 14) rated symptoms before and after each session and before and after the six-week UZIT program. Mixed-effects modeling with repeated measures was used to estimate differences in mean symptom scores before and after individual sessions. Cohen's d effect sizes were used to evaluate the impact of the UZIT program on symptoms. Results: Mean scores for pain ( F (1, 105) = 19.99, p < 0.001), anxiety ( F (1, 96) = 24.64, p < 0.001), fatigue ( F (1, 120) = 15.68, p < 0.001), and dyspnea ( F (1, 68) = 16.69, p < 0.001) were significantly reduced after UZIT sessions. Effects were moderate to large for symptom severity ( d = 0.59–1.32) and moderate for symptom burden ( d = 0.56) and fatigue ( d = 0.62), and small for QoL ( d = 0.33) after the six-week UZIT program. Conclusions: Individualized UZIT sessions were associated with reductions in symptom severity for pain, anxiety, fatigue, and dyspnea. The six-week UZIT program was associated with improvements in symptom burden, activity limitation, and QoL. ClinicalTrial.gov no.: NCT03194438

Abstract Context Central and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown. Objective To investigate the effects of PYY administration on the reproductive axis in healthy young men. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2). Intervention Eight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P &gt; .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions. Conclusions Acute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.