Obstructive Sleep Apnea Using Watch‐PAT 200 Is Independently Associated With an Increase in Morning Blood Pressure Surge in Never‐Treated Hypertensive Patients

This study aimed to examine the association between obstructive sleep apnea (OSA) and morning blood pressure surge in never‐treated patients with essential hypertension. This prospective study included a total of 58 patients (mean age, 51.7 years; 55.2% men) with never‐treated essential hypertension. The patients were divided into non‐OSA (n=23, 49.3±12.7 years) and OSA (n=35, 53.2±9.8 years) groups. The OSA group was defined as having an apnea‐hypopnea index level >5 as measured by the Watch‐PAT 200. The authors collected 24‐hour ambulatory BP, plasma aldosterone concentration, and plasma renin activity data from all of the patients. The measured sleep‐trough morning systolic blood pressure (SBP) increases were higher in the OSA group than in the non‐OSA group (28.7±11.8 mm Hg vs 19.6±12.8 mm Hg, P=.008). The sleep‐trough morning SBP increase was inversely correlated with the lowest oxygen saturation (r=−0.272, P=.039). OSA known to be associated with increased daytime and nocturnal sympathetic activity was associated with significantly higher sleep‐trough morning SBP levels in this study.

Obstructive sleep apnea (OSA) is a common disorder characterized by episodes of upper airway obstruction during sleep. The prevalence of OSA (apnea±hypopnea index [AHI] ≥5) in adults 30 to 69 years is estimated at 17%, increasing to 23% to 35% in relatively unselected hypertensive populations.¹, ² OSA is associated with endothelial dysfunction, metabolic syndrome, atherosclerosis, and cardiovascular disorders.³, ⁴, ⁵, ⁶, ⁷ Morning blood pressure (BP) surge (MS) is a normal physiological phenomenon; however, extreme MS is a risk factor for stroke and cardiovascular mortality.⁸, ⁹, ¹⁰ Sympathetic activity is suspected to play a role as an underlying mechanism in OSA and MS.⁷, ¹¹, ¹², ¹³ Few studies have evaluated the association between OSA and MS.¹⁴, ¹⁵ Peripheral arterial tone (PAT) is based on the pulsatile plethysmographic signal that is measured on a finger, which could serve as a single noninvasive substitute for sympathetic activity.¹⁶ This study aimed to examine the association of sleep parameters with WATCH^‐PAT 200 (WP200; (Itamar Medical Ltd, Caesarea, Israel) based on measurements of PAT variations and MS in never‐treated patients with essential hypertension.¹⁶, ¹⁷, ¹⁸, ¹⁹     

Formation and dissociation of soluble fibrin in vivo

¹³¹I-fibrin solubilized in urea and ¹²⁵I-fibrinogen were prepared from purified rabbit fibrinogen and separately injected into 12 rabbits (controls). ¹³¹I-fibrin-¹²⁵I-fibrinogen complexes were made from ¹³¹I-fibrin in urea and ¹²⁵I-fibrinogen, and subsequent removal of the urea by dialysis. These complexes were injected into 12 rabbits and the elimination characteristics of both proteins traced for 6 days. The fibrin portion of the complexes behaved like ¹³¹I-fibrin solubilized in urea and the fibrinogen portion of the complexes like ¹²⁵I-fibrinogen injected as an isolated protein. Thus, fibrin-fibrinogen complexes prepared in vitro dissociate in vivo and demonstrate their own typical elimination characteristics.     

Catabolism of fibrinogen in pregnant rabbits before and after delivery

16 non-pregnant female and 19 pregnant rabbits were injected with purified rabbit 125I-fibrinogen in order to study the catabolism of fibrinogen before and after delivery. The half-life time (T 1/2) of the clottable 125I-radioactivity in pregnant rabbits during the last third of gestation was 27.3 +/- 5.3 hr in comparison to 54.4 +/- 3.7 hr in non-pregnant rabbits. After delivery, T 1/2 returned to normal values of 47.9 +/- 10.9 hr. The fractional catabolic rate (FCR) of the clotabble 125I-radioactivity was 67.1% X d-1 +/- 8.6 before and 41.6% X d-1 after delivery whereas FCR in non-pregnant rabbits amounted to 44.7% X d-1 +/- 4.8. These figures demonstrate a pronounced increase in fibrinogen catabolism during the last third of gestation in pregnant rabbits and a normalization immediately after delivery. Although in pregnant rabbits the elimination of fibrinogen from the circulating blood was pronouncedly increased, the plasma fibrinogen concentration did not change. Only after delivery did the fibrinogen concentration increase when the fibrinogen catabolism had already normalized.     

Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults

The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.     

Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma

Phenotypic modulation of airway smooth muscle (ASM) is an important feature of airway remodeling in asthma that is characterized by enhanced proliferation and secretion of pro-inflammatory chemokines. These activities are regulated by the concentration of free Ca²⁺ in the cytosol ([Ca²⁺]_i). A rise in [Ca²⁺]_i is normalized by rapid reuptake of Ca²⁺ into sarcoplasmic reticulum (SR) stores by the sarco/endoplasmic reticulum Ca²⁺ (SERCA) pump. We examined whether increased proliferative and secretory responses of ASM from asthmatics result from reduced SERCA expression. ASM cells were cultured from subjects with and without asthma. SERCA expression was evaluated by western blot, immunohistochemistry and real-time PCR. Changes in [Ca²⁺]_i, cell spreading, cellular proliferation, and eotaxin-1 release were measured. Compared with control cells from healthy subjects, SERCA2 mRNA and protein expression was reduced in ASM cells from subjects with moderately severe asthma. SERCA2 expression was similarly reduced in ASM in vivo in subjects with moderate/severe asthma. Rises in [Ca²⁺]_i following cell surface receptor-induced SR activation, or inhibition of SERCA-mediated Ca²⁺ re-uptake, were attenuated in ASM cells from asthmatics. Likewise, the return to baseline of [Ca]_i after stimulation by bradykinin was delayed by approximately 50% in ASM cells from asthmatics. siRNA-mediated knockdown of SERCA2 in ASM from healthy subjects increased cell spreading, eotaxin-1 release and proliferation. Our findings implicate a deficiency in SERCA2 in ASM in asthma that contributes to its secretory and hyperproliferative phenotype in asthma, and which may play a key role in mechanisms of airway remodeling.Asthma is a chronic inflammatory disease which is accompanied by extensive changes in normal airway tissue architecture, termed remodeling (1, 2). Airway remodeling in asthma comprises epithelial dysfunction, hypertrophy of the mucus glands, subepithelial vascularization, and changes in extracellular matrix composition (2). In addition, airway smooth muscle (ASM) from people suffering with asthma exhibits enhanced proliferative (3) and migratory responses (4, 5), as well as increased secretion of a myriad of pro-inflammatory cytokines/chemokines and growth factors (6). The mechanisms that underly the exaggerated function of ASM in asthma are unknown.Smooth muscle responses to diverse stimuli are controlled by changes in the concentration of free cytosolic Ca²⁺ ([Ca²⁺]_i). Elevation of [Ca²⁺]_i results from increased Ca²⁺ influx across the plasma membrane following activation of Ca²⁺-permeable ion channels and the Na⁺-Ca²⁺-exchanger (NCX, 3Na⁺:1Ca²⁺), and by release of stored Ca²⁺ from the sarcoplasmic reticulum (SR), in turn triggered by inositol 1,4,5-triphosphate (IP₃) or ryanodine receptor (RyR) channels (7). Termination of the cytosolic Ca²⁺ signal occurs by extracellular removal of cytosolic Ca²⁺ by the NCX and by its rapid sequestration into SR stores by the sarco/endoplasmic reticulum Ca²⁺ (SERCA) pump (7). Impaired replenishment of SR stores arising from reduced activity of the SERCA pump could impact on a wide range of Ca²⁺-dependent smooth muscle functions (8) and abnormal Ca²⁺ handling by ASM has previously been proposed to be an important determinant of the airway hyperresponsiveness that is characteristically present in asthma (9, 10).There are 3 tissue-specific members of the mammalian SERCA family, SERCA1, SERCA2 and SERCA3, each encoded by a separate gene (ATP2A1, ATP2A2, and ATP2A3) (11), with SERCA2 being the most highly expressed in smooth muscle (12, 13). The function of the different isoforms of SERCA2 is similar (14). We have investigated if the secretory and hyperproliferative phenotype of ASM in asthma is associated with impaired SERCA isoform expression.