Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation.

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Experience of Insomnia Symptoms in the Elderly Living Alone in the Community / 정신간호학회지

Purpose@#The purpose of this study was to identify the experiences of insomnia symptoms in the elderly living alone in the community. @*Methods@#Eleven of the elderly with insomnia symptoms living alone in the community were interviewed. Data were collected through individual interviews July-September 2018. Colaizzi’s phenomenological methodology was used. @*Results@#Results showed that the experiences of insomnia symptoms of the elderly living alone comprised 11 themes clusters and five categories: 1) Insomnia symptoms triggered by various causes, 2) Physical symptoms exacerbated by insomnia, 3) Insomnia worsened by psychological symptoms, 4) Useless efforts to fix insomnia, 5) Living with adapted insomnia symptoms. @*Conclusion@#It is necessary to develop a sleep intervention program that includes insomnia symptoms awareness, sleep health education, and social support factors. Community nurses should focus on insomnia symptoms as well as listen and empathize with various psychological phenomena in caring for the elderly with insomnia living alone.

Case Review of Impacted Bile Duct Stone at Duodenal Papilla: Detection and Endoscopic Treatment

PURPOSE: A bile duct stone impacted at the duodenal papilla is an urgent condition that can rapidly lead to either suppurative cholangitis or acute pancreatitis due to almost complete obstruction of the bilio-pancreatic outflow. This study evaluated the clinical characteristics and results of endoscopic treatment for a bile duct stone impacted at the duodenal papilla. MATERIALS AND METHODS: Forty-six patients who had been diagnosed with an impacted papillary stone were retrospectively reviewed. RESULTS: The typical features of acute cholangitis (Charcot's triad) and pancreatitis were only observed only in 10 patients (21.7%) and 17 patients (37.0%), respectively. After the endoscopic retrograde cholangiopancreatography, 30 patients (65.2%) were found to have a solitary stone impacting the duodenal papilla and 16 patients had one or more stones in the bile duct. On the radiological studies, the former patients were associated more commonly with no visible stone or no bile duct dilatation (p < 0.05). All impacted papillary stones were successfully removed by endoscopic sphincterotomy: 23 by a needle knife and 23 by a pull type papillotome. The procedure-related complications (n = 7, 4 bleeding, 3 pancreatitis) were not serious and did not differ, based on endoscopic findings and the procedure used. CONCLUSION: A bile duct stone impacted at the duodenal papilla requires both clinical and radiographic evidence to support the diagnosis. Endoscopic sphincterotomy, either with a needle knife or a pull type papillotome, was safe and effective for removing the impacted papillary stone.

A Case of Early-stage Squamous Cell Carcinoma of the Anal Canal Diagnosed by Endoscopic Mucosal Resection / 대한소화기내시경학회지

In the past, abdominoperineal resection was routinely performed for anal canal cancer, yet it is now known that squamous cell carcinoma of the anal canal has a favorable prognosis and it rarely requires radical surgery. Furthermore, T1 anal cancer, which represents about 10% of all anal canal cancers, has an excellent prognosis. Endoscopic mucosal resection (EMR), which has been used for removal of early-stage adenocarcinoma of the rectum, has not been reported as a treatment option for squamous cell carcinoma of the anal canal because making the endoscopic diagnosis of early-stage anal canal cancer is very difficult. We have experienced a case of early-stage squamous cell carcinoma of the anal canal that was identified without symptoms during routine screening colonoscopy and it was removed by EMR. As far as we know, it is the first case of early-stage anal canal cancer that was diagnosed and treated by endoscopic mucosal resection.

Recurrent Primary Signet Ring Cell Cancer of the Colon at Anastomosis Site after Curative Resection

A primary signet ring cell cancer (SRCC) is a rare form of an adenocarcinoma of the large intestine. The prognosis of SRCC of the colon has been reported to be worse than classic adenocarcinoma of the colon; however, there is no difference in the post-operative surveillance for SRCC. We report a case of SRCC of the colon with negative resection margins that recurred at the anastomosis site 26 months after curative resection. A 55-year-old male presented to the hospital with abdominal pain. The initial colonoscopy and abdominal computed tomography revealed SRCC of the proximal ascending colon. He underwent extensive curative surgical resection and adjuvant chemotherapy for 8 months. However, 26 months post-operatively, the cancer recurred at the anastomosis site without peritoneal dissemination. Physicians should be aware that SRCC may have different recurrence patterns compared with classic adenocarcinoma, and may need more vigorous surveillance, even after curative surgery.

Recurrent Primary Signet Ring Cell Cancer of the Colon at Anastomosis Site after Curative Resection

A primary signet ring cell cancer (SRCC) is a rare form of an adenocarcinoma of the large intestine. The prognosis of SRCC of the colon has been reported to be worse than classic adenocarcinoma of the colon; however, there is no difference in the post-operative surveillance for SRCC. We report a case of SRCC of the colon with negative resection margins that recurred at the anastomosis site 26 months after curative resection. A 55-year-old male presented to the hospital with abdominal pain. The initial colonoscopy and abdominal computed tomography revealed SRCC of the proximal ascending colon. He underwent extensive curative surgical resection and adjuvant chemotherapy for 8 months. However, 26 months post-operatively, the cancer recurred at the anastomosis site without peritoneal dissemination. Physicians should be aware that SRCC may have different recurrence patterns compared with classic adenocarcinoma, and may need more vigorous surveillance, even after curative surgery.

A Case of Bleeding from a Jejunal Gastrointestinal Stromal Tumor Diagnosed by Double Balloon Enteroscopy / 대한소화기내시경학회지

Gastrointestinal bleeding from a small bowel lesion is uncommon, but it is the most common cause of obscure gastrointestinal bleeding and it can go undiagnosed using traditional upper endoscopy and colonoscopy. Recently, capsule endoscopy and double-balloon enteroscopy (DBE) were developed as new techniques for visualization of the entire small intestine and have improved access to the lesion site in patients with obscure gastrointestinal bleeding. In this report, we describe a 49-year male presenting with melena from a gastrointestinal stromal tumor (GIST) of the proximal jejunum that was diagnosed by DBE and resected by laparoscopic surgery.

Acute and Chronic Changes of Vascular Endothelial Growth Factor (VEGF)in Induced Sputum of Toluene Diisocyanate (TDI)-induced Asthma Patients

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to evaluate the role of VEGF in immediate bronchoconstriction induced by TDI inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma patients (group I), 12 chronic TDI-asthma patients with persistent asthma symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In group I, induced sputum and serum were collected before and 7 hr after placebo- and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were collected every 2 yr. VEGF levels were measured by ELISA. There were no significant differences in sputum and serum VEGF levels between patients and controls. Before and after placebo and TDI-BPT, no significant changes were noted in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05), while serum VEGF showed variable changes at 2-yr, which decreased significantly at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be involved to 2 yr after the diagnosis and the contribution may decrease after then.

Common whelk (Buccinum undatum) allergy: Sensitization rate and its relationship with other food allergens / 천식및알레르기

BACKGROUND: The common whelk (Buccinum undatum) is one of the largest and most common snails in the North Atlantic. In Korea and Japan, common whelk is a popular eatable shellfish. Although shellfish has been known as the one of the most common causes of food allergy, there has been no published report on allergenecity and clinical significance of this sea snail. In this study, we determined the sensitization rate to common whelk and its relationship with other food allergens in allergy patients. METHOD: We carried out the skin prick test (SPT) with commonly consumed foodstuffs in Korea including common whelk in 1700 patients over 1 year. The specific IgE to common whelk were detected by enzyme-linked immunosorbent assay (ELISA). ELISA inhibition test using sensitized sera was conducted. RESULTS: SPT to common whelk was positive (> or =2+) in 83 (4.9%) patients studied. Twenty-four (38.7%) of 62 SPT-positive patients had high serum specific IgE to common whelk. ELISA inhibition test showed significant inhibitions by abalone as well as by common whelk and, minimal inhibition were noted by shrimp. Significant correlation was also noted in specific IgE levels between common whelk and abalone (r=0.58, P<.05). CONCLUSION: IgE-sensitization rate to common whelk was 4.9% in allergy patients. Further studies are needed to evaluate the clinical significance of sensitized patients to common whelk, and to confirm a cross reactivity with abalone.

Two cases of hypersensitivity to isopropylantipyrine / 천식및알레르기

Isopropylantipyrine is one of the pyrazolon derivatives which are nonsteroidal anti-inflammatory drugs (NSAIDs) with potent antipyretic and pain-relieving properties. It has been known that pyrazolon-hypersensitive patients, in contrast to ASA-sensitive patients, could safely use other NSAIDs. We describe two Korean patients with isopropylantipyrine hypersensitivity without ASA/NSAID hypersensitivity.

Elevated level of serum tryptase in a patient with exercise-inuced anaphylaxis / 천식및알레르기

Exercise-induced anaphylaxis (EIA) is a medical emergency in that it derives from a physical allergy. We reported a case of food-independent EIA based on history and laboratory data. A 40-year-old male patient was presented with generalized urticaria, angioedema, and syncope after jogging. He had suffered from allergic rhinitis for 25 years. Increased level of serum tryptase was noted. Mast cell activation might be suggested in the pathophysiologic mechanism of EIA.

Leukotriene related gene polymorphisms in ASA-intolerant asthma: an association of 5-lipoxygenase haplotype / 천식및알레르기

BACKGROUND AND OBJECTIVES: A recent study has demonstrated a possible involvement of leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, while no significances were noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) for the key enzymes involved in arachidonate metabolism, and cysteinyl leukotriene receptor 1 (CYSLTR1) in a larger scale of Korean population with AIA. MATERIALS AND METHODS: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls (NC) were enrolled. Single base extension method was applied for genotyping of SNPs in 5-lipoxygenase (ALOX5, -1708G>A, 21C>T, 270G>A, 1728G>A), ALOX5 activating protein (FLAP, 218A>G), cyclooxygenase 2 (COX2, -162C>G, 10T>G, 228G>A), LTC4S (-444A>C), and CYSLTR1 (927T>C). Haplotype analyses for ALOX5 were performed as well. RESULTS: There were no significant differences in allele and genotype frequencies of the SNPs among the three groups (p>0.05). However, the frequency of ALOX5-ht1[G-C-G-A] containing genotype in the AIA group was significantly higher than those of the ATA group (p=0.01, OR =5.0, 95%CI=1.54-17.9) and the normal controls (p=0.03, OR=4.5, 95%CI=1.1-18.4) with a dominant model. CONCLUSION: These results suggest a lack of association between FLAP, COX2, LTC4S, and CYSLTR1 gene polymorphisms, and AIA phenotype in Korean population. However, a possible involvement of ALOX5-ht1[G-C-G-A] in AIA development was suggested.

Buckwheat allergy in adults: comparison of specific IgE between homemade ELISA and CAP system, and identification of IgE-binding components / 천식및알레르기

BACKGROUND AND OBJECTIVE: Ingestion and inhalation of buckwheat flour can induce IgE-mediated bronchoconstriction and anaphylaxis in sensitized individuals, especially in childhood. The aim of this study was to determine the sensitization rate of buckwheat allergen, measure the level of specific IgE to buckwheat, and identify IgE-binding components in adult patients with various allergic diseases. METHODS: 1,738 allergy patients and 40 healthy controls were enrolled. Skin prick tests were performed using homemade buckwheat extract. The specific IgE level to homemade buckwheat allergen was measured by ELISA, and results were compared to those of the CAP system. ELISA inhibition tests were done to evaluate allergenic relationships with major food allergens and IgE binding components were identified using IgE immunoblot analysis. RESULTS: Among 1,738 patients tested, 60 patients (3.5%) showed more than a 2+ response on skin prick tests to buckwheat. The prevalence of serum specific IgE to buckwheat ranged from 24% in patients with a 2+ response to buckwheat skin prick test, to 50% in patients with a 4+ response. The mean absorbance value increased with skin reactivity although it was not statistically significant. However, CAP results were significantly correlated with skin reactivity (p<0.05). A significant correlation was noted between (the) results by homemade ELISA and CAP. IgE immunoblot demonstrated 20 IgE binding components ranging from 20 to 114 kDa, and 10 components were bound to IgE in more than 50% of the patients tested. CONCLUSION: Natural buckwheat allergens should be considered as one of the causative food allergens in exposed adults. Specific IgE results by homemade ELISA were comparable with those of CAP system. Twenty IgE binding components and 10 major allergens were noted within natural buckwheat allergen. Further studies will be needed to evaluate the allergenic relationships with other food allergens.

A case of wheat-induced anaphylaxis in an adult / 천식및알레르기

Wheat is known as a causative agent of bakers' asthma, wheat-dependent exercise induced anaphylaxis and food allergies in infants and young children. However, there has been few cases of wheat-induced anaphylaxis in adult age. We report a case of wheat-induced anaphylaxis patient presented in an adult and two IgE-binding components(43 kDa and 48 kDa) were identified.

Dermatomyositis Developing in the first Trimester of Pregnancy

Dermatomyositis in pregnancy is rare. Pregnancy may be a precipitating factor at the onset or may develop during the course of dermatomyositis, which would exacerbate disease activity. In this study, we report a 22-year-old female patient who developed generalized skin rash and progressive muscle weakness in the twelfth week of pregnancy. She was diagnosed with dermatomyositis and underwent therapeutic abortion, due to the high fetal mortality rate of the disease when developed in the first trimester. Her symptoms improved with treatment of intravenous immunoglobulin and a high dose of corticosteroids.

Clinical significance of serum ECP and sero-prevalence of human toxocariasis in patients with eosinophilia / 천식및알레르기

BACKGROUND: Several studies have reported that the serum concentration of eosinophil cationic protein (ECP) reflects the intensity of eosinophilic airway inflammation in asthmatic patients, and the ratio of serum ECP concentration to peripheral blood eosinophil counts (ECP/Eo ratio) may be useful in assessing asthma severity. Human toxocariasis, of which diagnosis relies upon specific serology, is a common. worldwide helminthozoonosis and one of the causes of blood eosinophilia. OBJECTIVES: The aim of this study is to evaluate the clinical significance of serum ECP concentration, peripheral-blood eosinophil count and ECP/Eo ratio in relation to clinical severity, and the sero-prevalence of human toxocariasis in patients with eosinophilia. MATERIALS AND METHODS: Fifteen patients with eosinophilia were enrolled. Serum ECP concentrations by CAP system, peripheral-blood eosinophil counts, and ECP/Eo ratio were determined. Clinical severity of the disease was represented as the number of organs with eosinophilic infiltration, and we divided the study subjects in to two groups according to therapeutic response. The diagnosis of toxocariasis was confirmed by detecting serum specific IgE antibody to Toxocara excretory-secretory antigens (TES-Ag) by ELISA and IgG immunoblot analysis. RESULTS: A significant positive correlation was found between the number of organs with eosinophilic infiltration, serum ECP concentration, and peak peripheral-blood eosinophil count (p < 0.05, respectively). The number of organs with eosinophilic infiltration was significantly higher in the poor therapeutic response group compared to the good therapeutic response group (p < 0.01). Fourteen of 15 patients (93.3%) showed positive reactions in Toxocara serologic test. CONCLUSION: Toxocara infection should be considered as a major cause of eosinophilia in this country. Serum ECP, peak peripheral-blood eosinophil count and the number of organs with eosinophilic infiltration may be used as useful markers for assessment of therapeutic response in patients with eosinophilia.

Differences in MMP-2, MMP-9, TIMP-1, and eosinophil inflammatory markers of nasal polyp homogenates between aspirin intolerant and tolerant asthma / 천식및알레르기

BACKGROUND AND OBJECTIVE: Nasal polyps are frequently found in patients with aspirin intolerant asthma (AIA). Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are thought to play a crucial role in airway inflammation and remodeling. Eosinophil and mast cell infiltration is a consistent finding in these polyps but few studies have studied the relationship between these cells and protease-antiprotease balance in the nasal polyp tissue of aspirin intolerant asthmatics. Our purpose was to compare the differences of eosinophil cationic protein (ECP), tryptase, MMP-2, MMP-9, and TIMP-1 between aspirin intolerant and tolerant asthmatics (ATA) and also to evaluate the relationship with inflammation in nasal polyp homogenates. MATERIALS AND METHODS: Nasal polyp tissue homogenates from 10 AIA subjects (group I) and 10 ATA subjects (group II) were compared. Inflammatory cell markers such as ECP and tryptase were measured by the CAP system (Pharmacia, Sweden). MMP-2, MMP-9, and TIMP-1 levels were measured by ELISA (Biotrack, UK). RESULTS: ECP levels were significantly higher in group I (p 0.05) and no significant differences were noted between MMP-2 levels between the two groups. MMP-9/TIMP-1 ratio was lower in group I than group II although this was not significant, and there were significant correlations between ECP, and MMP-9 (r=0.65, p < 0.05), MMP-2 (r=0.61, p < 0.05), and tryptase (r=0.58, p < 0.05), but not with TIMP-1. Significant correlations were also noted between tryptase, and MMP-9 (r=0.62, p < 0.05), and MMP-2 (r=0.47, p < 0.05), but not with TIMP-1. CONCLUSION: Nasal polyps from AIA patients had more severe eosinophilic inflammation compared to ATA subjects. MMP-9 and MMP-2 may contribute to eosinophil migration and inflammation.

A case of angioedema associated with losartan / 천식및알레르기

Angioedema is a non-pitting edema that occurs in the skin and mucus membranes. It is known that major etiologies include hereditary deficiency of C1 esterase inhibitor, temperature extreme, trauma, food sensitivity, and medications such as penicillin, aspirin, NSAIDS and ACE inhibitors. ACE inhibitors are blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and increasing local levels of bradykinin, a potent vasodilator. This increased bradykinin has been theorized to cause angioedema and cough in patients on ACE inhibitors. However, there has been very few causes of angioedema induced by angiotensin II receptor blocker. This is the first report of a patient presenting angioedema induced by losartan -angiotensin II receptor blocker- in this century.

A Case of Seronegative Rheumatoid Arthritis with Idiopathic Hypereosinophilic Syndrome / 대한류마티스학회지

The idiopathic hypereosinophilic syndrome (HES) is a disorder marked by the sustained overproduction of eosinophils. The disease is characterized by damage of multiple organ including heart, nerve system, skin and lung due to eosinophilic infiltration and the diagnosis is one of exclusion. Rheumatologic manifestations of HES are infrequent. In about 10~40% of rheumatoid arthritis (RA) patients, persistent eosinophilia is observed. That can be due to the RA itself and is often associated with active disease and extra-articular features. Sometimes, it is attributed to the drug therapy, especially gold and penicillamine. We would like to report a 37-year-old female patient with HES who developed seronegative RA 2 years later.