Etiology and Treatment Approach for Visual Hallucinations in PD Dementia

Visual hallucinations are a common symptom of Parkinson’s disease dementia. These can cause delusions and violent behaviors that can be significant burdens on patients and caregivers. The cause of visual hallucinations is considered to be the dysregulation of the default mode network due to the presence of Lewy bodies in the cortex and the degeneration of dopaminergic and cholinergic neurons. Dopaminergic agents, especially non-ergoline dopamine agonists, can exacerbate visual hallucinations. Reducing the dosage can ameliorate symptoms in many cases; however, this frequently worsens parkinsonism. In contrast, the administration of cholinesterase inhibitors is effective and rarely worsens motor symptoms. In advanced cases, antipsychotic drugs are required; clinical studies have shown that some drugs are beneficial while the adverse events are acceptable. An optimal treatment protocol should be selected depending on the patient’s condition

Generation of retinal pigment epithelium from human induced pluripotent stem cells showed polarized secretion of VEGF and PEDF.

Age-related macular degeneration (AMD) is one of the major diseases that cause severe visual impairment in developed countries and is related to dysfunction of the retinal pigment epithelium (RPE). Human induced pluripotent stem cells (hiPSCs) have been drawing attention as a valuable source of RPE for basic research on or treatment of AMD. Here we investigated whether RPE could be generated from hiPSCs in Kawasaki Medical School. We maintained hiPSCs retaining pluripotent markers after a series of regular culture steps involving passaging, freezing, and thawing. hiPSCs were then cultured in RPE differentiation medium, and pigmented colonies were manually isolated for further differentiation into RPE. Differentiated cells formed pigmented cells with a typical RPE cobblestone appearance, abundant apical microvilli, adherens junctions, and tight junctions. Furthermore, generated pigmented cells expressed typical RPE marker genes, exhibited a barrier function, and secreted growth factors in a polarity-dependent manner similar to native RPE. These results indicate that RPE derived from hiPSCs in our facility can be used for in vitro and in vivo research

iPS 細胞由来網膜色素上皮細胞移植のためのNaIO3誘因網膜色素上皮変性げっ歯類モデルの特性評価

網膜色素上皮（RPE）は視細胞維持に重要な役割を担い，その機能低下は加齢黄斑変性等の原因となる．近年，健常なRPE を補充するRPE 移植が注目されており，臨床応用も開始された．前臨床研究における動物実験にあたり，過去にもげっ歯類のヨウ素酸ナトリウム（NaIO3）誘因RPE 変性モデルの研究はあるが，げっ歯類は黄斑部を欠くため最適でない．黄斑を有する非ヒト霊長類における薬剤全身投与は両眼の失明を招くため動物愛護の観点から不適切であり，現在適切なモデルが存在しない．従って，我々はサルを用いた移植実験を念頭に置きNaIO3の硝子体内投与によりラット片眼にRPE 変性を誘発可能か研究した．また，NaIO3誘因RPE 変性モデルにヒト多能性幹細胞由来RPE（hiPS-RPE）を網膜下移植し視細胞の保護効果を検討した．8-10週齢のオスのWistar ラットの片眼に0.005，0.01，0.02 mg/μl のNaIO3を硝子体内投与した．経時的にHE 染色にて網膜外層厚と網膜内層厚を計測し，透過型電子顕微鏡で形態学的評価を行った．NaIO3投与後2日目にhiPS-RPE 懸濁液を網膜下に移植し，組織学的評価を行った．0.005 mg/μl 投与群では網膜内層・外層厚ともに変化はなく，0.02 mg/μl 投与群では網膜全層が障害され，0.01 mg/μl 投与群では網膜外層のみが障害された．RPE の形態学的変化はNaIO3投与後3日目から出現し，以降網膜外層厚が急速に菲薄化した．いずれの投与群も非投与眼に影響はなかった．hiPS-RPE 移植眼では，網膜外層厚が厚い傾向にあった．まとめると，NaIO3片眼硝子体内投与により，げっ歯類片眼RPE 障害モデル作製に成功した．hiPS-RPE 網膜下移植により視細胞保護効果を得られた．本方法はRPE 移植の前臨床研究の動物モデルの基礎として有用である．The retinal pigment epithelium (RPE) plays an important role in maintaining photoreceptors, and RPE dysfunction causes eye diseases such as age-related macular degeneration (AMD). RPE transplantation has garnered much attention in recent years as a way to replenish healthy RPE, and clinical applications for RPE transplantation in patients with AMD have been reported. Preclinical studies use animal models to examine treatment efficacy, however, whether conventional methods with animal models are suitable for examining RPE transplantation is controversial. Systemic administration of sodium iodate (NaIO3) has beenshown to induce RPE degeneration in rodent models, recapitulating morphological atrophy in corresponding areas. However, as rodents lack a macular region, these studies cannot precisely evaluate the effects of systemic administration. The induction of blindness in both eyes in nonhuman primates bearing a macular region is also inappropriate in terms of animal ethics. With this in mind, we investigated whether intravitreal injection of NaIO3 can selectively induce a single-eye impairment in an RPE animal model. Additionally, we investigated whether subretinal transplantation of human induced pluripotent stem cells-derived RPE (hiPS-RPE) can protect against NaIO3-induced RPE degeneration.The intravitreal injection of NaIO3 was performed in 8-10 week-old male Wistar rats with rats being grouped by dose (0.005, 0.01, and 0.02 mg/μl). We measured outer nuclear layer (ONL) thickness and inner nuclear layer (INL) thickness at 8 retinal points by hematoxylin-eosin staining and evaluated RPE morphology by transmission electron microscopy sequentially (3, 7, 14, and 28 days after injection). In addition, hiPSC-RPE cell suspension was injected into the subretinal space 2 days after NaIO3 administration and histological evaluation was performed sequentially (7, 14, and 28 days after NaIO3 injection).The results showed no significant changes in INL and ONL thicknesses in the 0.005 mg/μl group. Retinal thicknesses in the 0.02 mg/μl group had almost completely degenerated. In the 0.01 mg/μl group, ONL thickness had almost completely degenerated, but, in contrast INL thickness was preserved as well as 0.005 mg/μl injection group. RPE morphological changes and TUNEL-positive cells appeared at 3 days after NaIO3 injection, followed by rapid thinning of ONL thickness. None of the retinal thickness of contralateral eye in all groups showed any changes. Additionally, ONL thicknesses in the transplanted eyes were significantly greater than those in the nontransplanted and sham-surgery groups

A rare case of concomitant huge exophytic gastrointestinal stromal tumor of the stomach and Kasabach-Merritt phenomenon

<p>Abstract</p> <p>Background</p> <p>We report an extremely rare case of concomitant huge exophytic GIST of the stomach and Kasabach-Merritt phenomenon (KMP).</p> <p>Case presentation</p> <p>The patient was a 67-year-old man experiencing abdominal distension since September 2006. A physical examination revealed a 25 × 30 cm hard mass that was palpable in the middle and lower left abdomen minimal intrinsic mobility and massive ascites. Since the admitted patient was diagnosed with DIC, surgery could not be performed. The patient received a platelet transfusion and the DIC was treated. Due to this treatment, the platelet count recovered to 7.0 × 10⁴; tumor resection was performed at 16 days after admission. Laparotomy revealed a huge extraluminal tumor arising from the greater curvature of the stomach that measured 25 × 30 cm and had not ruptured into the peritoneal cavity or infiltrated other organs. Partial gastric resection was performed. The resected mass measured 25 × 25 × 20 cm. In cross section, the tumor appeared hard and homogenous with a small polycystic area. Histopathology of the resected specimen showed large spindle cell GIST with >5/50 HPF (high-power field) mitotic activity. The postoperative course was uneventful, and the coagulopathy improved rapidly.</p> <p>Conclusion</p> <p>Since the characteristic of tumor in this case was hypervascularity with bleeding and necrotic lesions, coagulopathy was thought to be caused by the trapping of platelets within a large vasculized tumor mass.</p