Real-Time Detection of Sleep Apnea Based on Breathing Sounds and Prediction Reinforcement Using Home Noises: Algorithm Development and Validation.

BACKGROUND: Multinight monitoring can be helpful for the diagnosis and management of obstructive sleep apnea (OSA). For this purpose, it is necessary to be able to detect OSA in real time in a noisy home environment. Sound-based OSA assessment holds great potential since it can be integrated with smartphones to provide full noncontact monitoring of OSA at home. OBJECTIVE: The purpose of this study is to develop a predictive model that can detect OSA in real time, even in a home environment where various noises exist. METHODS: This study included 1018 polysomnography (PSG) audio data sets, 297 smartphone audio data sets synced with PSG, and a home noise data set containing 22,500 noises to train the model to predict breathing events, such as apneas and hypopneas, based on breathing sounds that occur during sleep. The whole breathing sound of each night was divided into 30-second epochs and labeled as "apnea," "hypopnea," or "no-event," and the home noises were used to make the model robust to a noisy home environment. The performance of the prediction model was assessed using epoch-by-epoch prediction accuracy and OSA severity classification based on the apnea-hypopnea index (AHI). RESULTS: Epoch-by-epoch OSA event detection showed an accuracy of 86% and a macro F1-score of 0.75 for the 3-class OSA event detection task. The model had an accuracy of 92% for "no-event," 84% for "apnea," and 51% for "hypopnea." Most misclassifications were made for "hypopnea," with 15% and 34% of "hypopnea" being wrongly predicted as "apnea" and "no-event," respectively. The sensitivity and specificity of the OSA severity classification (AHI≥15) were 0.85 and 0.84, respectively. CONCLUSIONS: Our study presents a real-time epoch-by-epoch OSA detector that works in a variety of noisy home environments. Based on this, additional research is needed to verify the usefulness of various multinight monitoring and real-time diagnostic technologies in the home environment.

Prediction of Sleep Stages Via Deep Learning Using Smartphone Audio Recordings in Home Environments: Model Development and Validation.

BACKGROUND: The growing public interest and awareness regarding the significance of sleep is driving the demand for sleep monitoring at home. In addition to various commercially available wearable and nearable devices, sound-based sleep staging via deep learning is emerging as a decent alternative for their convenience and potential accuracy. However, sound-based sleep staging has only been studied using in-laboratory sound data. In real-world sleep environments (homes), there is abundant background noise, in contrast to quiet, controlled environments such as laboratories. The use of sound-based sleep staging at homes has not been investigated while it is essential for practical use on a daily basis. Challenges are the lack of and the expected huge expense of acquiring a sufficient size of home data annotated with sleep stages to train a large-scale neural network. OBJECTIVE: This study aims to develop and validate a deep learning method to perform sound-based sleep staging using audio recordings achieved from various uncontrolled home environments. METHODS: To overcome the limitation of lacking home data with known sleep stages, we adopted advanced training techniques and combined home data with hospital data. The training of the model consisted of 3 components: (1) the original supervised learning using 812 pairs of hospital polysomnography (PSG) and audio recordings, and the 2 newly adopted components; (2) transfer learning from hospital to home sounds by adding 829 smartphone audio recordings at home; and (3) consistency training using augmented hospital sound data. Augmented data were created by adding 8255 home noise data to hospital audio recordings. Besides, an independent test set was built by collecting 45 pairs of overnight PSG and smartphone audio recording at homes to examine the performance of the trained model. RESULTS: The accuracy of the model was 76.2% (63.4% for wake, 64.9% for rapid-eye movement [REM], and 83.6% for non-REM) for our test set. The macro F1-score and mean per-class sensitivity were 0.714 and 0.706, respectively. The performance was robust across demographic groups such as age, gender, BMI, or sleep apnea severity (accuracy 73.4%-79.4%). In the ablation study, we evaluated the contribution of each component. While the supervised learning alone achieved accuracy of 69.2% on home sound data, adding consistency training to the supervised learning helped increase the accuracy to a larger degree (+4.3%) than adding transfer learning (+0.1%). The best performance was shown when both transfer learning and consistency training were adopted (+7.0%). CONCLUSIONS: This study shows that sound-based sleep staging is feasible for home use. By adopting 2 advanced techniques (transfer learning and consistency training) the deep learning model robustly predicts sleep stages using sounds recorded at various uncontrolled home environments, without using any special equipment but smartphones only.

Management of chronic rhinosinusitis with nasal polyps in the Asia-Pacific region and Russia: Recommendations from an expert working group.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition of the nasal and paranasal tissues, characterized by the presence of bilateral nasal polyps. An expert panel of specialists from the Asian-Pacific region and Russia was convened to develop regional guidance on the management of CRSwNP through a consensus approach. The present article presents the chief observations and recommendations from this panel to provide guidance for clinicians in these areas. Etiology and pathogenetic mechanisms in CRSwNP are heterogeneous and complex. In many patients, CRSwNP is primarily driven by type 2 inflammation, although this may be less important in Asian populations. Frequent comorbidities include asthma and other inflammatory diseases such as non-steroidal anti-inflammatory drug (NSAID)/aspirin-exacerbated respiratory disease or atopic dermatitis. Clinical management of CRSwNP is challenging, and a multidisciplinary approach to evaluation and treatment is recommended. While many patients respond to medical treatment (topical irrigation and intranasal corticosteroids, and adjunctive short-term use of systemic corticosteroids), those with more severe/uncontrolled disease usually require endoscopic sinus surgery (ESS), although outcomes can be unsatisfactory, requiring revision surgery. Biological therapies targeting underlying type 2 inflammation offer additional, effective treatment options in uncontrolled disease, either as an alternative to ESS or for those patients with persistent symptoms despite ESS.

In-Home Smartphone-Based Prediction of Obstructive Sleep Apnea in Conjunction With Level 2 Home Polysomnography.

Importance: Consumer-level sleep analysis technologies have the potential to revolutionize the screening for obstructive sleep apnea (OSA). However, assessment of OSA prediction models based on in-home recording data is usually performed concurrently with level 1 in-laboratory polysomnography (PSG). Establishing the predictability of OSA using sound data recorded from smartphones based on level 2 PSG at home is important. Objective: To validate the performance of a prediction model for OSA using breathing sound recorded from smartphones in conjunction with level 2 PSG at home. Design, Setting, and Participants: This diagnostic study followed a prospective design, involving participants who underwent unattended level 2 home PSG. Breathing sounds were recorded during sleep using 2 smartphones, one with an iOS operating system and the other with an Android operating system, simultaneously with home PSG in participants' own home environment. Participants were 19 years and older, slept alone, and had either been diagnosed with OSA or had no previous diagnosis. The study was performed between February 2022 and February 2023. Main Outcomes and Measures: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the predictive model based on the recorded breathing sounds. Results: Of the 101 participants included during the study duration, the mean (SD) age was 48.3 (14.9) years, and 51 (50.5%) were female. For the iOS smartphone, the sensitivity values at apnea-hypopnea index (AHI) levels of 5, 15, and 30 per hour were 92.6%, 90.9%, and 93.3%, respectively, with specificities of 84.3%, 94.4%, and 94.4%, respectively. Similarly, for the Android smartphone, the sensitivity values at AHI levels of 5, 15, and 30 per hour were 92.2%, 90.0%, and 92.9%, respectively, with specificities of 84.0%, 94.4%, and 94.3%, respectively. The accuracy for the iOS smartphone was 88.6%, 93.3%, and 94.3%, respectively, and for the Android smartphone was 88.1%, 93.1%, and 94.1% at AHI levels of 5, 15, and 30 per hour, respectively. Conclusions and Relevance: This diagnostic study demonstrated the feasibility of predicting OSA with a reasonable level of accuracy using breathing sounds obtained by smartphones during sleep at home.

FTY720 preserved islet ß-cell mass by inhibiting apoptosis and increasing survival of ß-cells in db/db mice.

BACKGROUND: FTY720, an analogue of sphingosine-1-phosphate, has shown potential in the treatment of several autoimmune diseases, such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus. It prevents development or cure of autoimmune diabetes in animal models. Recently, we reported that FTY720 also prevents development of diabetes in db/db mice by ß-cell regeneration in vivo. This study investigated the effect of FTY720 on apoptosis in ß-cells in db/db mice treated with FTY720 16 weeks. METHODS: Six week old female db/db mice were divided into control and FTY720 groups. FTY720 (10 mg/kg) was orally administrated daily. Body weights and fasting glucose levels were measured once a week after overnight fasting. After 16 weeks of treatment, oral glucose and insulin tolerance tests were performed, serum insulin levels and insulin contents in pancreas were determined, and then all mice were subjected to physiological and histological analyses. RESULTS: FTY720-treated mice showed normal fasting glucose levels, improved glucose tolerance with normal insulin sensitivity and restored ß-cell function to produce and secret insulin. Pancreas histology revealed that FTY720 prevented islet damage and preserved ß-cell mass by inhibiting apoptosis and increasing ß-cell survival in pancreatic islets. CONCLUSIONS: We concluded that early intervention with FTY720 in db/db mice can prevent development of diabetes through preserving ß-cell mass by inhibiting apoptosis and increasing survival of islet ß-cells.

Comparison between dexmedetomidine and remifentanil for controlled hypotension and recovery in endoscopic sinus surgery.

OBJECTIVES: We compared the efficacy of dexmedetomidine and remifentanil hydrochloride in intraoperative field conditions and recovery during endoscopic sinus surgery. METHODS: Sixty-six patients (American Society of Anesthesiologists physical status I and II) scheduled for elective endoscopic sinus surgery were enrolled in this prospective, double-blinded, randomized study. The patients were randomly assigned to two groups. Propofol, 2 to 2.5 mg/kg, was administered to both groups to induce anesthesia, which was maintained with desflurane. One group received dexmedetomidine 1 microg/kg over 10 minutes at anesthesia induction, followed by 0.4 to 0.8 microg/kg per hour infusion during maintenance, whereas the other group received remifentanil 1 microg/kg over 1 minute at anesthesia induction, followed by 0.2 to 0.4 microg/kg per minute infusion during maintenance. Surgical conditions, hemodynamic parameters, intraoperative blood loss, time to extubation, sedation, and pain in the postanesthesia care unit (PACU) were recorded. RESULTS: There were no significant differences between the two groups with respect to surgical field conditions, blood loss, or extubation time. The sedation score (Modified Observer's Assessment of Alertness/Sedation) in the PACU was significantly lower in the dexmedetomidine group than in the remifentanil group (p < 0.001). No differences were found in total blood loss, surgical field conditions, hemodynamic parameters, time to extubation, or pain in the PACU when the two groups were compared (p > 0.05). CONCLUSIONS: Although remifentanil and dexmedetomidine both enabled hypotensive anesthesia and good intraoperative fields for endoscopic sinus surgery, recovery was faster with remifentanil than with dexmedetomidine in the immediate postoperative period.

Reset-First and Multibit-Level Resistive-Switching Behavior of Lanthanum Nickel Oxide (LaNiO3-x) Thin Films.

The resistive random-access memory (RRAM) with multi-level storage capability has been considered one of the most promising emerging devices to mimic synaptic behavior and accelerate analog computations. In this study, we investigated the reset-first bipolar resistive switching (RS) and multi-level characteristics of a LaNiO3-x thin film deposited using a reactive magnetron co-sputtering method. Polycrystalline phases of LaNiO3 (LNO), without La2O3 and NiO phases, were observed at similar fractions of Ni and La at a constant partial pressure of oxygen. The relative chemical proportions of Ni3+ and Ni2+ ions in LaNiO3-x indicated that it was an oxygen-deficient LaNiO3-x thin film, exhibiting RS behavior, compared to LNO without Ni2+ ions. The TiN/LaNiO3-x/Pt devices exhibited gradual resistance changes under various DC/AC voltage sweeps and consecutive pulse modes. The nonlinearity values of the conductance, measured via constant-pulse programming, were 0.15 for potentiation and 0.35 for depression, indicating the potential of the as-fabricated devices as analog computing devices. The LaNiO3-x-based device could reach multi-level states without an electroforming step and is a promising candidate for state-of-the-art RS memory and synaptic devices for neuromorphic computing.

All polymeric conductive strain sensors with excellent skin adhesion, recovery, and long-term stability prepared from an anion-zwitterion based hydrogel.

Developing a high-performing hydrogel with long-lasting skin adhesion, high ionic conductivity, mechanical stability, and fatigue resistance is a crucial issue in the field of wearable electronic devices. Because of their weak mechanical properties, zwitterion-based hydrogels are not suitable for application in wearable strain sensors despite their excellent adhesion to the skin. In this study, a hydrogel of polymer without additive was prepared by using polymerizable monomers consisting of zwitterionic 3-(1-vinyl-3-imidazolio)propanesulfonate (VIPS), anionic 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt (AMPSs), and acrylamide (AAm); the hydrogel is abbreviated as P(AMPSs/VIPS-co-AAm). The P(AMPSs/VIPS-co-AAm) hydrogel shows exceptional adhesive strength, reaching up to 26.29 kPa (lap shear to porcine skin) and high stretchability (with a fracture strain of 1282% and stress of 40 kPa). The high polarity of the AMPSs/VIPS pair improves the interfacial adhesion to the skin, the internal cohesion and recovery tendency. Unique structural characteristics of the hydrogel impart excellent fatigue resistance, network toughening, and electrical stability after multiple deformations. Thus, the prepared hydrogel has an ionic conductivity (0.51 S m-1), strain sensitivity, and long-term skin adhesion, and it demonstrates potential to be applied for wearable strain sensors.

Accuracy of 11 Wearable, Nearable, and Airable Consumer Sleep Trackers: Prospective Multicenter Validation Study.

BACKGROUND: Consumer sleep trackers (CSTs) have gained significant popularity because they enable individuals to conveniently monitor and analyze their sleep. However, limited studies have comprehensively validated the performance of widely used CSTs. Our study therefore investigated popular CSTs based on various biosignals and algorithms by assessing the agreement with polysomnography. OBJECTIVE: This study aimed to validate the accuracy of various types of CSTs through a comparison with in-lab polysomnography. Additionally, by including widely used CSTs and conducting a multicenter study with a large sample size, this study seeks to provide comprehensive insights into the performance and applicability of these CSTs for sleep monitoring in a hospital environment. METHODS: The study analyzed 11 commercially available CSTs, including 5 wearables (Google Pixel Watch, Galaxy Watch 5, Fitbit Sense 2, Apple Watch 8, and Oura Ring 3), 3 nearables (Withings Sleep Tracking Mat, Google Nest Hub 2, and Amazon Halo Rise), and 3 airables (SleepRoutine, SleepScore, and Pillow). The 11 CSTs were divided into 2 groups, ensuring maximum inclusion while avoiding interference between the CSTs within each group. Each group (comprising 8 CSTs) was also compared via polysomnography. RESULTS: The study enrolled 75 participants from a tertiary hospital and a primary sleep-specialized clinic in Korea. Across the 2 centers, we collected a total of 3890 hours of sleep sessions based on 11 CSTs, along with 543 hours of polysomnography recordings. Each CST sleep recording covered an average of 353 hours. We analyzed a total of 349,114 epochs from the 11 CSTs compared with polysomnography, where epoch-by-epoch agreement in sleep stage classification showed substantial performance variation. More specifically, the highest macro F1 score was 0.69, while the lowest macro F1 score was 0.26. Various sleep trackers exhibited diverse performances across sleep stages, with SleepRoutine excelling in the wake and rapid eye movement stages, and wearables like Google Pixel Watch and Fitbit Sense 2 showing superiority in the deep stage. There was a distinct trend in sleep measure estimation according to the type of device. Wearables showed high proportional bias in sleep efficiency, while nearables exhibited high proportional bias in sleep latency. Subgroup analyses of sleep trackers revealed variations in macro F1 scores based on factors, such as BMI, sleep efficiency, and apnea-hypopnea index, while the differences between male and female subgroups were minimal. CONCLUSIONS: Our study showed that among the 11 CSTs examined, specific CSTs showed substantial agreement with polysomnography, indicating their potential application in sleep monitoring, while other CSTs were partially consistent with polysomnography. This study offers insights into the strengths of CSTs within the 3 different classes for individuals interested in wellness who wish to understand and proactively manage their own sleep.

Reset First Resistive Switching in Ni1-xO Thin Films as Charge Transfer Insulator Deposited by Reactive RF Magnetron Sputtering.

Reset-first resistive random access memory (RRAM) devices were demonstrated for off-stoichiometric Ni1-xO thin films deposited using reactive sputtering with a high oxygen partial pressure. The Ni1-xO based RRAM devices exhibited both unipolar and bipolar resistive switching characteristics without an electroforming step. Auger electron spectroscopy showed nickel deficiency in the Ni1-xO films, and X-ray photoemission spectroscopy showed that the Ni3+ valence state in the Ni1-xO films increased with increasing oxygen partial pressure. Conductive atomic force microscopy showed that the conductivity of the Ni1-xO films increased with increasing oxygen partial pressure during deposition, possibly contributing to the reset-first switching of the Ni1-xO films.

Advanced glycation end products downregulate glucokinase in mice.

BACKGROUND: Glucokinase, the enzyme that catalyses the conversion of glucose to G-6-P, plays a key role in glucose metabolism. AGEs are implicated in diabetic complications. A previous study reported that AGEs decreased ß-cell function through inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. This study investigated the effects of AGEs on glucokinase and islet function. METHODS: Six-month-old male C57BL6 mice were divided into bovine serum albumin (BSA) and AGE-BSA groups. BSA (200 µg/g) and AGE-BSA (60 U/g) were administered intraperitoneally twice daily. After 2 weeks, serum AGE levels were measured, oral glucose tolerance test was performed, and insulin levels during the oral glucose tolerance test were determined. Glucokinase protein expression level and activity were measured in pancreatic islets. RESULTS: We observed that the normal mice (C57/BL6) treated for 2 weeks with AGE-BSA showed impaired glucose tolerance and decrease in acute insulin release. Glucokinase activity in islets from the AGE-BSA-treated mice was significantly inhibited and accompanied by blunted response of islets to high glucose stimulation. Moreover, in vitro experiments showed that glucokinase protein expression was decreased, its activity was inhibited, and islet function was decreased. GKA partially restored glucokinase activity and islet function caused by AGEs. CONCLUSIONS: We concluded that AGEs inhibited glucokinase activity, leading to islet dysfunction in mouse pancreatic islets.

Clinical characteristics and treatment of benign paroxysmal positional vertigo after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) has been reported to be a common cause of benign paroxysmal positional vertigo (BPPV). However, only a few studies have investigated BPPV after TBI. The aim of this study was to identify the clinical characteristics of BPPV after TBI and to determine whether there are clinical differences between BPPV after TBI and idiopathic BPPV. METHODS: The authors reviewed the medical records of 192 consecutive patients with positional vertigo after head injury during the period 2003 to 2009 and investigated 112 patients with idiopathic BPPV treated over the same period. The clinical characteristics of BPPV after TBI and the clinical differences between the traumatic BPPV and idiopathic BPPV groups were investigated. RESULTS: A total of 32 patients with BPPV after TBI fulfilled the inclusion criteria. Twenty-four patients in the traumatic BPPV group had posterior semicircular canal-BPPV and 11 patients lateral semicircular canal-BPPV. A total of 58 repositioning maneuver sessions were performed in these 32 patients. Members of the traumatic BPPV group required more treatment sessions than members of the idiopathic group (p<0.05), but no tendency to recur was observed in the traumatic group (p>0.05). Recurrence rates in the traumatic and idiopathic BPPV groups were 15.6% and 18.8%, respectively (p>0.05). CONCLUSIONS: It is likely that BPPV after TBI is more difficult to treat than idiopathic BPPV, but no tendency to recur was observed in patients who developed BPPV after TBI compared with idiopathic BPPV. Further prospective clinical meta-analytic studies are needed to investigate the outcome of BPPV after TBI.

High-temperature hydrodechlorination of ozone-depleting chlorodifluoromethane (HCFC-22) on supported Pd and Ni catalysts.

The hydrodechlorination of chlorodifluoromethane (HCFC-22) was performed by a catalytic reaction and noncatalytic thermal decomposition at high temperatures of 400-800 °C. After 47 h of time-on-stream on a supported palladium (Pd) catalyst, the gas phase composition of difluoromethane (HFC-32) is 41.0%, with 4.9% of the HCFC-22 remaining, indicating the conversion of up to 95.1% of HCFC-22. The supported nickel catalyst's deactivation is significant as it exhibits the low conversion of HCFC-22 under the same reaction conditions. The deactivation of the catalyst is caused by the polymerization of adsorbed methyl radicals, which competes with the formation of HFC-32. With concentrated reactants at high reaction temperatures, there was an increase in the catalytic activity; however, unwanted tar, methane, and trifluoromethane (HFC-23) by-products are also produced. The use of catalyst suppresses the formation of these by-products. Considering the compositions of the products of the catalytic and noncatalytic reactions, we demonstrate that the use of the supported-metal catalysts and hydrogen flow suppresses tar formation and lowers the required reaction temperature.

Recent Developments in Nanoporous Graphene Membranes for Organic Solvent Nanofiltration: A Short Review.

Graphene-based membranes are promising candidates for efficient organic solvent nanofiltration (OSN) processes because of their unique structural characteristics, such as mechanical/chemical stability and precise molecular sieving. Recently, to improve organic solvent permeance and selectivity, nanopores have been fabricated on graphene planes via chemical and physical methods. The nanopores serve as an additional channel for facilitating ultrafast solvent permeation while filtering organic molecules by size exclusion. This review summarizes the recent developments in nanoporous graphene (NG)-based membranes for OSN applications. The membranes are categorized depending on the membrane structure: single-layer NG, multilayer NG, and graphene-based composite membranes hybridized with other porous materials. Techniques for nanopore generation on graphene, as well as the challenges faced and the perspectives required for the commercialization of NG membranes, are also discussed.

The small molecule kobusone can stimulate islet ß-cell replication in vivo.

OBJECTIVE: To investigate the ability of kobusone to reduce high glucose levels and promote ß-cell proliferation. METHODS: Four-week-old female db/db mice were assigned to the kobusone (25 mg/kg body weight, intraperitoneally twice a day) or control group (same volume of PBS). Glucose levels and body weight were measured twice a week. After 6 weeks, intraperitoneal glucose tolerance tests and immunohistochemical studies were performed, and insulin levels were determined. The expression of mRNAs involved in cell proliferation, such as PI3K, Akt, cyclin D3 and p57Kip2, was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: Kobusone reduced blood glucose levels after 3 weeks and more strongly increased serum insulin levels than the vehicle. Immunohistochemistry illustrated that kobusone increased 5-bromo-2'-deoxyuridine incorporation into islet ß-cells, suggesting that it can stimulate islet ß-cell replication in vivo. RT-qPCR indicated that kobusone upregulated the mRNA expression of PI3K, Akt, and cyclin D3 and downregulated that of p57Kip2. CONCLUSION: Our findings suggest that kobusone is a potent pancreatic islet ß-cell inducer that has the potential to be developed as an anti-diabetic agent.

Genetic Variants and Clinical Phenotypes in Korean Patients With Hereditary Hemorrhagic Telangiectasia.

OBJECTIVES: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. METHODS: Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. RESULTS: In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. CONCLUSION: Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

Biogenesis of non-structural protein 1 (nsp1) and nsp1-mediated type I interferon modulation in arteriviruses.

Type I interferons (IFNs-α/ß) play a key role for the antiviral state of host, and the porcine arterivirus; porcine reproductive and respiratory syndrome virus (PRRSV), has been shown to down-regulate the production of IFNs during infection. Non-structural protein (nsp) 1 of PRRSV has been identified as a viral IFN antagonist, and the nsp1α subunit of nsp1 has been shown to degrade the CREB-binding protein (CBP) and to inhibit the formation of enhanceosome thus resulting in the suppression of IFN production. The study was expanded to other member viruses in the family Arteriviridae: equine arteritis virus (EAV), murine lactate dehydrogenase-elevating virus (LDV), and simian hemorrhagic fever virus (SHFV). While PRRSV-nsp1 and LDV-nsp1 were auto-cleaved to produce the nsp1α and nsp1ß subunits, EAV-nsp1 remained uncleaved. SHFV-nsp1 was initially predicted to be cleaved to generate three subunits (nsp1α, nsp1ß, and nsp1γ), but only two subunits were generated as SHFV-nsp1αß and SHFV-nsp1γ. The papain-like cysteine protease (PLP) 1α motif in nsp1α remained inactive for SHFV, and only the PLP1ß motif of nsp1ß was functional to generate SHFV-nsp1γ subunit. All subunits of arterivirus nsp1 were localized in the both nucleus and cytoplasm, but PRRSV-nsp1ß, LDV-nsp1ß, EAV-nsp1, and SHFV-nsp1γ were predominantly found in the nucleus. All subunits of arterivirus nsp1 contained the IFN suppressive activity and inhibited both interferon regulatory factor 3 (IRF3) and NF-κB mediated IFN promoter activities. Similar to PRRSV-nsp1α, CBP degradation was evident in cells expressing LDV-nsp1α and SHFV-nsp1γ, but no such degradation was observed for EAV-nsp1. Regardless of CBP degradation, all subunits of arterivirus nsp1 suppressed the IFN-sensitive response element (ISRE)-promoter activities. Our data show that the nsp1-mediated IFN modulation is a common strategy for all arteriviruses but their mechanism of action may differ from each other.

Effect of milrinone on the inflammatory response and NF-kB activation in renal ischemia-reperfusion injury in mice.

BACKGROUND: Milrinone increases intracellular adenosine 3',5'-cyclic monophosphate concentration and enhances vascular relaxation. Nuclear factor-kappa B (NF-kB) plays a key role in inflammatory responses during ischemia-reperfusion (I/R) injury. We aimed to investigate the effect of milrinone on the inflammatory responses and NF-kB activation in renal I/R injury in mice. METHODS: Thirty C57BL/6 mice were allocated into 3 groups. In group S (n = 10), only right nephrectomy was done. In group C (n = 10), the left kidney was subjected to 30 min of ischemia after right nephrectomy. In group M (n = 10), milrinone (5 µg/kg) was administered before ischemia. After 24 hours of reperfusion, the serum creatinine was measured, kidney samples were obtained for histology, and expressions of NF-kB and proinflammatory cytokines were analyzed. RESULTS: In group C, the serum creatinine concentration was markedly elevated, compared with group S. Creatinine concentration in group M was also elevated, but it was significantly lower than that in group C. Histologic evidence of renal damage was severe in group C, but it was improved in group M. In groups C and M, expression of NF-kB, tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) mRNA increased significantly compared with group S (P < 0.05). But group M showed a lower expression of NF-kB, TNF-α, ICAM-1, MCP-1 and MIP-2 mRNA than group C (P < 0.05). CONCLUSIONS: Milrinone treatment attenuates the renal inflammatory response and activation of NF-kB, resulting in improvement of renal function and tissue injury.