Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension

Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1 ± 0.8% and 73.6 ± 2.3%, and the cumulative release at 37 °C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~ 10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39 ± 0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71 ± 0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6 ± 5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH

A case of chronic pancreatitis successfully treated by endoscopic removal of protein plugs.

A 56 years old male with chronic pancreatitis complained of intractable abdominal pain, anorexia, emaciation and peripheral edema. Medical treatment initiated only partial improvement in the general condition and hypoproteinemia. Endoscopic retrograde cholangiopancreatography revealed multiple filling defects in the dilated main pancreatic duct. Endoscopic aspiration of pure pancreatic juice yielded numerous protein plugs. The endoscopic removal of protein plugs from the pancreatic duct resulted in remarkable improvement in symptoms, laboratory findings and ERCP findings. We consider this procedure to be an important new treatment of chronic pancreatitis.</p

A case of chronic pancreatitis successfully treated by endoscopic removal of protein plugs.

A 56 years old male with chronic pancreatitis complained of intractable abdominal pain, anorexia, emaciation and peripheral edema. Medical treatment initiated only partial improvement in the general condition and hypoproteinemia. Endoscopic retrograde cholangiopancreatography revealed multiple filling defects in the dilated main pancreatic duct. Endoscopic aspiration of pure pancreatic juice yielded numerous protein plugs. The endoscopic removal of protein plugs from the pancreatic duct resulted in remarkable improvement in symptoms, laboratory findings and ERCP findings. We consider this procedure to be an important new treatment of chronic pancreatitis.</p

Thyroid storm associated with Graves' disease covered by diabetic ketoacidosis: A case report

<p>Abstract</p> <p>Background</p> <p>Thyroid storm is a condition in which multiple organ dysfunction results from failure of the compensatory mechanisms of the body owing to excessive thyroid hormone activity induced by some factors in patients with thyrotoxicosis. While diabetic ketoacidosis (DKA) is an important trigger for thyroid storm, simultaneous development of DKA and thyroid storm is rare.</p> <p>Case presentation</p> <p>A 59-year-old woman with no history of either diabetes mellitus or thyroid disease presented to our hospital because of developing nausea, vomiting and diarrhea for 2 days. Physical examination showed mild disturbance of consciousness, fever, and tachycardia. There were no other signs of thyrotoxicosis. Laboratory studies revealed elevation of random blood glucose and glycosylated hemoglobin, strongly positive of urine acetone, and metabolic acidosis. Since DKA was diagnosed, we initiated the patient on treatment with administration of insulin and adequate fluid replacement. Although the hyperglycemia and acidosis were immediately relieved, the disturbance of consciousness and tachycardia remained persistent. Levels of FT3 and FT4 were extremely high and TSH was below the detectable limit. TRAb was positive. The thyroid storm score of Burch & Wartofsky was 75/140, and the thyroid storm diagnostic criteria of the Japan Thyroid Association were satisfied. Oral administration of thiamazole, potassium iodide and propranolol resulted in immediate relief of the tachycardia.</p> <p>Discussion</p> <p>We encountered a case of thyroid storm associated with Graves' disease covered by DKA. Thyroid storm and DKA are both potentially fatal, and the prognosis varies depending on whether or not these conditions are detected and treated sufficiently early. The thyroid storm diagnostic criteria prepared in 2008 by the Japan Thyroid Association are very simple as compared to the Burch & Wartofsky scoring system for thyroid storm. The Japanese criteria may be useful in the diagnosis of this condition since they enable clinicians to identify a broad range of cases with thyroid storm. When dealing with cases of DKA or thyroid storm, it seems essential to bear in mind the possibility of the coexistence of these two diseases.</p

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Pulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 ligand in the pathogenesis of PAH.</p> <p>Results</p> <p>Spontaneous onset of PAH was stably identified in mice with immune abnormality because of overexpression of the tumor necrosis factor (TNF) family molecule OX40 ligand (OX40L). Histopathological and physical examinations revealed the onset of PAH-like disorders in the C57BL/6 (B6) strain of OX40L transgenic mice (B6.TgL). Comparative analysis performed using different strains of transgenic mice showed that this onset depends on the presence of OX40L in the B6 genetic background. Genetic analyses demonstrated a susceptibility locus of a B6 allele to this onset on chromosome 5. Immunological analyses revealed that the excessive OX40 signals in TgL mice attenuates expansion of regulatory T cells the B6 genetic background, suggesting an impact of the B6 genetic background on the differentiation of regulatory T cells.</p> <p>Conclusion</p> <p>Present findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.</p

Diagnosis of chronic pancreatitis

近年，各種膵疾患に対する検査法の発達には目を見張るものがあるが，実際の運用にあたっては各検査法の適応，限界，組合わせおよび実施する順序等に迷うことが少なくない。本研究では，最近我々が経験した慢性膵炎Ⅰ群116例の診断過程を振り返ることにより，慢性膵炎の診断における理想的な検査法の組合わせとそれぞれの役割を検討し，同時に診断名のみならず病態と病期が容易に理解できる表現方法を提案した。画像診断法，膵外分泌機能検査法（EX），膵内分泌機能検査法（EN）を比較検討し，以下の結果を得た。①画像診断法は必須である。②内視鏡的逆行性膵胆管造影（ERCP）を軸とした腹部超音波検査（US）あるいは腹部CTスキャン（CT）の組合わせは欠くことができない。③EXもまた必須の検査法である。④ENは慢性膵炎の診断に必要不可欠ではないが，治療方針を決めるうえで重要である。⑤純粋膵液（PPJ）の生化学的検査と組織化学的検査は膵炎の診断と病態生理の解明に重要である。⑥PPJ中の細胞診は慢性膵炎に合併した膵癌の検索に有用である。⑦以下に示すような診断の記載方法を提案した。"Calcified chronic pancreatitis, alcoholic, diffuse,　ERCP-3, US-2, CT-3, EX-2, EN-1, Lf(＋)"。Endoscopic retrograde cholangiopancreatography (ERCP), ultrasonography (US), computed tomography (CT), exocrine pancreatic function test (EX), endocrine pancreatic function test (EN), and analysis of pure pancreatic juice (PPJ) are currently available for the investigation of pancreatic diseases. The purpose of the present study is to evaluate the roles and preferable combinations of these tests in the diagnosis of chronic pancreatitis and then to propose a way to describe the results of the tests along with diagnosis for a better understanding of the disease process. Comparative studies of imaging, EX and EN led to the following conclusions. 1) imaging procedures (ERCP, US and CT) are mandatory, partly because they were frequently the test that showed diagnostic changes and partly because they often gave key information for operative treatment. Among the imaging procedures, ERCP combined with US and/or CT is mandatory because these combinations alone can reveal detailes of structural changes attendant on chronic pancreatitis. 2) EX is also mandatory, because it was occasionally the only test that showed diagnostic changes and partly because it often gave important information for medical treatment. 3) EN is also important, not because it was indispensable for detecting chronic pancreatitis, but because it often gave important information for medical treatment. For btter understanding of the disease process as well as diagnosis, we propose, as suggested by Seligson, that the test used for the establishment of the diagnosis and the degree as well as extent of abnormalities. An example is "Calcified chronic pancreatitis, alcoholic, diffuse, ERCP-3, US-2, CT-3, EX-2, EN-1, Lf(+)". This attitude will lead to a more rational approach to both diagnosis and treatment

SBC2007-175993 MEASUREMENT OF IN-VIVO PULMONARY VASCULAR IMPEDANCE IN TWO ANIMAL MODELS OF PULMONARY HYPERTENSION

INTRODUCTION Pulmonary vascular input impedance has been increasingly promoted as an important diagnostic for pulmonary arterial hypertension (PAH) The human studies noted above have understandably not examined detailed associations between impedance and vascular behavior and structure, since the latter data are obtainable only through focused drug studies or ex-vivo measurements. Mechanical changes to a vascular network should be reflected in its input impedance; thus, such investigation should be useful in determining how impedance varies with changes in vascular condition, such as chronic stiffening due to vascular remodeling or acute stiffening due to smooth muscle cell response and/or pressure-induced strain-stiffening. Naturally, clinical identification of such stiffness changes on a routine basis could greatly impact diagnosis. Here, we demonstrate simple-toimplement impedance measurements in two animal models as part of a larger effort to establish said links between clinically-viable diagnostics, such as impedance, and physiological changes that occur to the vasculature as part of the progression of PAH. METHODS Animal Preparation: The two animal models examined here develop PAH due to chronic exposure to a hypoxic environment. The first model consisted of 10 male Sprague-Dawley rats (300-400g), half exposed to hypoxia via hypobaric chamber for 3-4 weeks (barometric pressure ≈ 410 mmHg) and half retained at standard conditions in Denver, CO (barometric pressure ≈ 630 mmHg). The second model utilized 4 male Holstein calves (70-110lb), again with half exposed to hypoxia for two weeks (barometric pressure ≈ 460 mmHg) and the other half remaining normoxic. Both models were exposed to a 12:12-h light-dark cycle, and water and appropriate food were made available ad libitum. Animal care and use committees at both the University of Colorado Health Science Center (rat) and Colorado State University (calf) approved all protocols and procedures. Animal Data Collection and Analysis: The measurements obtained from each animal are identical; the main differences between collection methods are equipment size and type. For all measurements, rats are anesthetized with ketamine hydrochloride (40 mg/kg) and xylazine (10 mg/kg) intraperitoneally, while cows remain conscious. Right jugular access is then obtained in each animal, and a fluid filled catheter, consisting of PV1 tubing for the rat or a commercial Swan-Ganz catheter for the calf, is inserted into the main pulmonary artery (MPA) for pressure measurements. During collection of MPA pressure, blood velocity at the midline of the MPA is obtained with pulse-wave Doppler echocardiography using an FPA probe on a commercial ultrasound scanner (Vivid 5, GE Medical Systems Inc). The imaging depth dictates the probe frequency

Endoscopic diagosis of gastric malignant lymphoma

To delineate the pitfalls and counter-measures in the endoscopic diagnosis of gastric malignant lymphoma (GML), reviewed were 32 cases of primary GML and 16 cases of systemic ML with gastric involvement (secondary GML). 1) Accurate diagnosis of GML had been made in only 13 cases of primary GML ; 18 cases had been diagnosed of gastric cancer (GC); the remaining one of benign ulcer (BU). Review of the endoscopic films, however, revealed more than two of the three findings characteristic, but not pathognomomic, of GML in 84 percent. This result indicates that possibility of GML must be kept in mind in the differential diagnosis of malignant lesions despite its rarity, because endoscopists tend to be predisposed with an impression of GC. 2) Follow-up examinations made in nine cases of primary GML revealed marked changes in endoscopic findings in three cases : healing of an ulcer lesion in one case, healing of an ulcer lesion on an unchanged tumor in another and enlargement of a tumor in the remaining one. The first case had been followed up for two years with an impression of BU. This result indicates that improvement of ulcer does not necessarily rule out GML because it can show "malignant cycle" just as GC. 3) Endoscopic biopsy performed in 30 cases of primary GML had led to accurate diagnosis in only 16 cases and erroneous diagnosis of GC in five and no malignancy in nine. Review of the cases revealed the importance of having suspicion of GML at first from endoscopic findings, because it can lead to an increase of the number of biopsy specimens, careful selection of biopsy sites, careful use of biopsy instruments to obtain good specimens and closer contact with pathologists. 4) Prospective studies on systemic ML revealed gastric involvement in 17 percent. Examinations of the GI tract, especially of the stomach is one of the important steps for staging of systemic ML and deciding therapeutic modalities. 5) It is extremely difficult to diffierentate primary GML and secondary GML from endoscopic findings alone, although there are a few findings characteristic of the latter

自動運転車いすの障害物検出機能を実現するための コンピュータビジョン技術に関する研究と実装

本報告では、電動車いすの安全性を向上させることを目的に、クルマと同じような安全運転支援システムを実現するための要素技術として、最新のコンピュータビジョンについて調査を行った。その上で、その応用である物体検出機能を実装し、機械学習を行った。その結果、全体のmAP（mean Average Precision）は0.526と低い結果となった。その理由として学習に用いた画像の枚数が不足していたことが考えられるため、今後は枚数と種類を増やす必要がある。次に、単眼カメラによる距離推定機能を実装した。その結果、2m ～ 4m の距離ではほぼ正確に距離推定できたが、それ以外の距離では精度が悪かった。 今後は、安全性を確保するためにステレオカメラやRiDAR等のセンサ利用を検討する必要がある。最後に、開発した電動車いすの走行実験を行った。その結果、前方に障害物を検知すると衝突せずに安全に停止することができた一方、処理が追いつかずに衝突してしまうこともあった。journal articl