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.

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.

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.

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.

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.

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.

Two cases of complete remission of aspirin-sensitive asthma / 천식및알레르기

Appreciable numbers of aspirin-sensitive asthmatic patients have chronic severe asthmatic symptoms. We report two cases of aspirin-sensitive asthmatics with mild asthmatic symptoms, whose methacholine PC20 levels were 9.07 and 7.06 mg/ml at first visit. The aspirin sensitivity was confirmed by lysine-aspirin bronchoprovocation at initial diagnosis. After anti-asthmatic medications and avoidance of salicylate-containing agents, respiratory symptoms, airway hyperrespon-siveness, and aspirin sensitivity disappeared after 33 and 45 months. These results suggest that early detection and careful avoidance of salicylate-containing agents may have beneficial effects resulting in resolution of airway hyperresponsiveness and aspirin sensitivity in aspirin-sensitive asthmatic patients.

Are there any links between mugwort pollen and food allergens such as celery and carrot based upon allergy skin prick tests? / 천식및알레르기

Background and objectives: Mugwort pollen is one of the major causative allergens in this country. There have been a few reports suggesting a significant association between mugwort pollen and food allergens. The aim of this study was to evaluate the allergenic relationship between mugwort pollen and food allergens based upon skin prick tests. Material and method: Of 2,909 allergy patients who had been skin tested to identify causative allergens at the Allergy Clinic of Ajou University Hospital, 471 patients sensitized to mugwort, ragweed, or Hop Japanese pollens on skin prick test (2+ of A/H ratio) were enrolled for this study. Positive rates to common inhalant or food allergens and their allergenic relationships with other pollens or food allergens were analyzed based upon skin prick test results. RESULTS: The positive rates (2+ of A/H) to nettle, rye grass, Bermuda grass, birch, and alder pollens were significantly higher in those sensitized to mugwort pollen than in those of negative responders (p<0.05, respectively). In regard to food allergens, positive rates to celery (15.3%) and carrot (14.5%) were significantly higher in patients sensitized to mugwort pollen (p<0.05, respectively). Significant association was noted between mugwort pollen and celery allergen (p< 0.05). CONCLUSION: Positive response to mugwort pollen can be associated with celery and carrot sensitivity on skin prick tests.

A case of cobalt-induced occupational asthma / 천식및알레르기

Cobalt is known as a hard metal used in cement and various household products. Occupational exposure occurs during the production of cobalt powder, the processing of hard metals, the polishing of diamonds, and the processing of cobalt alloys. There have been cases of cobalt induced interstitial pneumonitis, occupational asthma, and allergic dermatitis. We report a 21-year-old patient with rhinitis and asthma induced by cobalt in a factory manufacturing diamond-cutter made from hard metal. The patient complained of rhinorrhea, sneezing, and dyspnea 5 months after working in the diamond-cutting industry. Skin prick test and patch test with cobalt(CoCl2) showed negative responses. Bronchoprovocation with CoCl2 showed a early asthamtic response. In conclusion, we report a case of cobalt-induced occupational rhinitis and asthma who worked in a factory manufacturing diamond-cutter. Further studies will be needed to investigate the pathogenesis of bronchoconstriction induced by cobalt.

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.

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.

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.

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.

Specific IgE determination to shrimp (Metapenaeus joyneri) and identification of its allergen / 대한내과학회지

BACKGROUND: Shrimp is one of the major causative crustacean food allergen. An investigation has been reported that tropomyosin belonged to muscle protein is a major allergen within shrimp. But there have been a few investigations on shrimp allergen in Korea. The aim of this study is to evaluate skin reactivity and specific IgE sensitization to Metapenaeus joyneri which is one of the major shrimp in this country, and to identitify IgE binding components and evaluate allergenic relationship with other species. METHODS: We performed skin prick test with M. joyneri extract in 1,738 patients. ELISA was performed for detection of serum specific IgE antibody. To evaluate the cross allergenecity between M. joyneri and other crustaceans (crab, lobster, crayfish), Dermatophagoides pteronyssinus (Dpt), triton shell, abalone and buckwheat. ELISA inhibition tests were performed with each four patient's sera showing high specific IgE antibody. To identify IgE binding components, SDS-PAGE followed by IgE-Immunoblot were applied. RESULTS: 211 patients (12.2%) showed positive responses (A/H >or=2+) on skin prick test. Serum specific IgE antibodies were detected in 61 patients (37.2%) of 164 sensitzed patients. ELISA inhibition test using four patient's sera showed significant inhibitions by M. joyneri. and other crustaceans including lobster, crab and crayfish, partial inhibitions were noted by Dpt, triton shell, buckwheat and abalone. SDS-PAGE and IgE-imunoblot with patients' individual sera sensitized to M. joyneri showed 12 IgE binding components (31, 32, 38-44, 57, 70, 81 kDa) and two (31, 32 kDa) were bound to IgE in more than 50% of sera tested. Five (43, 44, 57, 70 and 81 kDa) were bound to IgE in more than 25% of sera tested. CONCLUSION: Specific IgE was detected in 37.2% of allergy patients sensitized to M. joyneri. Twelve IgE binding components and two (31, 32 kDa) major allergens were indentified. Cross allergenecity was noted with other crustaceans.

Two cases of anaphylaxis due to bee venom acupuncture / 천식및알레르기

Bee venom acupuncture has been widely used as a method to treat chronic pain, multiple sclerosis, myalgia, arthritis, and neuralgia. However, bee stings can induce anaphylaxis in both children and adults. We experienced two cases of anaphylaxis after bee venom acupuncture. A 42-year-old woman who had received venom acupuncture on the head, neck and back, experienced facial edema, generalized urticaria, and dyspnea 10 min. after the treatment. High levels of serum specific IgE to honeybee venom measured by CAP method was noted. The other patient was a 39-year-old woman who also received venom acupuncture on the back and experienced facial edema, generalized urticaria, dyspnea, and lower abdominal pain 10 min. after the treatment. High levels of serum specific IgE to honeybee venom by CAP method was also noted. Therefore, due to its wide use, bee venom acupuncture could induce IgE-sensitization and anaphylaxis in this country.

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.

A case of bronchial asthma due to cefadroxil in a housewife / 천식및알레르기

Cephalosporins are the most important -lactams that induce IgE-mediated reactions. Also, cephalosporins have been known as a causative agent for occupational asthma in pharmaceutical workers. To our knowledge, this is the first report of cephalosporin-induced bronchial asthma in a housewife with no history of occupational exposure. We experienced a 30-year old female who had developed shortness of breath, coughing and itching sensation of the skin since 3 years ago whenever she handled drug powder for upper respiratory infections (URI) prescribed for her two sons with bronchial asthma. She had handled drug powder for 7 years because her sons had experienced frequent URI. Skin prick test with cefadroxil (10mg/ml) and cefaclor (10mg/ml) showed positive reactions. Bronchial challenge test with cefadroxil showed immediate asthmatic reaction, and bronchial challenge with cefaclor showed immediate urticaria and angioedema without significant fall in FEV1. We confirmed cefadroxil-induced bronchial asthma sensitized by intermittent inhalation in a non-occupational setting.

A case of episodic angioedema with eosinophilia / 천식및알레르기

Episodic angioedema with eosinophilia is characterized by recurrent angioedema, urticaria, fever, weight gain and hypereosinophilia. Although this syndrome shows similarities to idiopathic hypereosinophilic syndrome, it differs in that it has good prognosis and has no organ involvement. The pathogenesis is unclear, but IL-5 is thought to be major cytokine of pathogenesis. It has benign course with spontaneous remission or low-dose prednisolone treatment. Here, we describe a patient whose clinical and laboratory features are similar to those observed in episodic angioedema with eosinophilia.