Endothelial cells lining blood vessels regulate vascular barrier function, which controls the passage of plasma proteins and circulating cells across the endothelium. In most normal adult tissues, endothelial cells preserve basal vascular permeability at a low level, while they increase permeability in response to inflammation. Therefore, vascular permeability is tightly controlled by a number of extracellular stimuli and mediators to maintain tissue homeostasis. Accordingly, impaired regulation of endothelial permeability causes various diseases, including chronic inflammation, asthma, edema, sepsis, acute respiratory distress syndrome, anaphylaxis, tumor angiogenesis, and diabetic retinopathy. Vascular endothelial (VE)-cadherin, a member of the classical cadherin superfamily, is a component of cell-to-cell adherens junctions in endothelial cells and plays an important role in regulating vascular permeability. VE-cadherin mediates intercellular adhesion through trans-interactions formed by its extracellular domain, while its cytoplasmic domain is anchored to the actin cytoskeleton via α- and β-catenins, leading to stabilization of VE-cadherin at cell-cell junctions. VE-cadherin-mediated cell adhesions are dynamically, but tightly, controlled by mechanisms that involve protein phosphorylation and reorganization of the actomyosin cytoskeleton. Phosphorylation of VE-cadherin, and its associated-catenins, results in dissociation of the VE-cadherin/catenin complex and internalization of VE-cadherin, leading to increased vascular permeability. Furthermore, reorganization of the actomyosin cytoskeleton by Rap1, a small GTPase that belongs to the Ras subfamily, and Rho family small GTPases, regulates VE-cadherin-mediated cell adhesions to control vascular permeability. In this review, we describe recent progress in understanding the signaling mechanisms that enable dynamic regulation of VE-cadherin adhesions and vascular permeability. In addition, we discuss the possibility of novel therapeutic approaches targeting the signaling pathways controlling VE-cadherin-mediated cell adhesion in diseases associated with vascular hyper-permeability.

Molecular imaging implies the method capable of pictorially displaying distribution of target molecules and their relative concentration in space. In clinical medicine, where non-invasiveness is mandatory, diagnostic molecular imaging has been considered virtually identical to positron emission tomography (PET). However, there is another powerful, apparently underutilized molecular imaging, namely, proton magnetic resonance spectroscopic imaging (¹H-MRSI). The technique can detect target molecules endogenous in brain in virtue of their own specific resonance frequencies (chemical shift) and can create quantitative images of each molecule. ¹H-MRSI is conventionally utilized for imaging relatively easily detectable molecules such as N-acetyl-aspartate or lactate. More recently, however, the method is extended into imaging of more challenging molecules such as glutamate or γ-aminobutyric acid (GABA). In this small review, we summarize basic concept of ¹H-MRSI and introduce an advanced technique, i.e. chemical exchange saturation transfer magnetic resonance imaging (CEST MRI), which made realistic glutamate imaging in vivo possible.

Propofol is primarily a hypnotic, and is widely used for induction and maintenance of anesthesia, as well as for sedation in various medical procedures. The exact mechanisms of its action are not well understood, although its neural mechanisms have been explored in in vivo and in vitro experiments. Accumulating evidence indicates that one of the major targets of propofol is the cerebral cortex. The principal effect of propofol is considered to be the potentiation of GABA_A receptor-mediated inhibitory synaptic currents, but propofol has additional roles in modulating ion channels, including voltage-gated Na⁺ channels and several K⁺ channels. We focus on the pharmacological actions of propofol on cerebrocortical neurons, particularly at the cellular and synaptic levels.

Recently, neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) has been recommended for selected patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV disease and bulky tumors. The aim of this study was to evaluate associations between post-NACT serum CA 125 levels, surgical outcomes, and clinical outcomes in patients with advanced epithelial ovarian cancer. We retrospectively analyzed 107 patients with FIGO stage III or IV ovarian cancer who were treated with NACT-IDS at the Gynecology Department of Kanagawa Cancer Center between January 2001 and December 2012. Serum CA 125 levels after NACT were significantly lower in the complete/optimal IDS group compared to the suboptimal IDS group (mean±standard deviation: 48.1±27.6 vs. 346.5±295.2 U/mL, p<0.01). Patients with low preoperative CA 125 levels (<35 U/mL) had a higher probability of optimal IDS (78.1±41.9% vs. 33.3±19.2%, p<0.01) and longer progression-free survival (mean±standard deviation: 30.4±14.3 months vs. 21.3±7.3 months, p<0.05) than patients with high CA 125 levels (>100 U/mL). Patients with low CA 125 levels (<35 U/mL) had a higher probability of complete/optimal IDS and longer progression-free survival compared to patients with high CA 125 levels (>100 U/mL).

Bacterial infections often cause fatal systemic infections in patients with primary immunodeficiency. To prevent unfortunate results, the selection, dose, and dosage of antibiotics are extremely important. Here, we report a case of Wiskott-Aldrich syndrome in a patient undergoing peritoneal dialysis because of chronic renal failure in whom methicillin-resistant Staphylococcus aureus sepsis developed. Because of the primary disease and complications, teicoplanin was the only chosen anti-S. aureus drug to prevent side effects. We used parameter estimation and dosage adjustment from a therapeutic drug monitoring simulation software program to overcome the challenges with teicoplanin treatment.

Deafferentation pain induced by subarachnoid block (SAB) is rare, but it can appear in the form of recurrent phantom lower limb pain, new acute-onset stump pain in amputees, lower limb pain in patients with tabes dorsalis, and neuropathic pain. We have previously reported that thiopental is an effective treatment for deafferentation pain induced by therapeutic SAB applied to treat neuropathic pain of central origin. Here, we report the case of an amputee who developed new stump pain in his lower limb immediately after subarachnoid tetracaine was administered prior to appendectomy. A 51-year-old man who had previously undergone right below-knee amputation for acute arterial thrombosis, and who had not previously experienced chronic phantom limb or stump pain, was scheduled for emergency open appendectomy. For anesthesia, we induced SAB with a hyperbaric tetracaine solution. No paresthesia occurred during administration. However, the patient immediately complained of severe, lightning-bolt pain in the right lower limb stump after the SAB was established. He was given intravenous pentazocine, which promptly resolved the pain. Appendectomy was then performed under sedation using intravenous midazolam. The patient did not experience further deafferentation pain during his hospital stay and has reported no stump pain since discharge from the hospital. This case report suggests that SAB induces deafferentation pain in some patients and that this unusual pain can be treated with pentazocine.

Intracranial aneurysms (IAs) that undergo rupture causing subarachnoid hemorrhage (SAH), are common in young patients with coarctation of the aorta (CoA), but rarer in middle-aged and elderly patients. The pathogenesis of IAs associated with CoA remains unclear. We report the case of a 50-year-old woman who presented with SAH. On evaluation, six IAs were distributed among the anterior communicating artery (ACoA) (ruptured), distal segments of both anterior cerebral arteries (ACA), the left internal carotid artery (ICA), the bifurcation of the left middle cerebral artery (MCA)/MCA early branch, and the inferior trunk of the left MCA. CoA was also diagnosed. The ruptured ACoA IA, and two other unruptured IAs, were successfully clipped during emergency surgery. Postoperative intensive care was instituted to avoid cerebral vasospasm and renal or spinal cord ischemia. During the same hospitalization, the remaining three IAs were clipped at a second surgery. She was discharged with slight cognitive impairment eighty days after admission. Subsequently, she underwent elective treatment for the CoA. According to the literature, IAs associated with CoA have a higher tendency to involve the ACoA than IAs without CoA. Moreover, adult CoA patients tend to have multiple IAs, considered to be due to hypertension associated with CoA, as well as genetic predisposition. In CoA patients, ruptured IAs should be treated as early as possible before correction of the CoA. Close postoperative observation with management of cerebral vasospasm, renal or spinal cord ischemia, and respiratory compromise in the perioperative period is vital.

Heyde syndrome describes the triad of aortic stenosis, acquired coagulopathy, and anemia due to bleeding from intestinal angiodysplasia. An 87-year-old man with iron deficiency anemia due to melena was admitted to our hospital. On examination, a systolic murmur was heard and echocardiography confirmed the presence of aortic stenosis. Esophagogastroduodenoscopy and colonoscopy were unremarkable. Capsule endoscopy and double balloon endoscopy revealed angiodysplasia throughout the small intestine. Laboratory investigations were significant for reduced plasma levels of high molecular weight von Willebrand factor multimers. On the basis of these findings, the patient was diagnosed with Heyde syndrome. The patient required frequent blood transfusions because of the intestinal bleeding, and underwent bioprosthetic aortic valve replacement. Twenty months after the operation, the gastrointestinal bleeding resolved and the patient no longer required blood transfusions. This is the first case report to describe an improvement in bleeding from angiodysplasia, one year after aortic valve replacement. It demonstrates the effective treatment of Heyde syndrome with aortic valve replacement, and highlights the importance of considering this differential diagnosis when evaluating patients presenting with repeated episodes of gastrointestinal bleeding and a concurrent systolic murmur.

An external dental fistula is a skin manifestation caused by an underlying dental problem. We report a rare case of external dental fistula associated with a fixed cantilever denture. A 77-year-old Japanese woman presented with an enlarging reddish granulomatous lesion on her right cheek that was diagnosed as an external dental fistula. A fixed cantilever denture had initially been attached to her upper jaw with her seven bona fide teeth. However, six teeth were completely lost and the denture was attached to only one tooth, which showed apical periodontitis. Subsequently, the external dental fistula developed. We should keep in mind that a patient with a fixed cantilever denture can suffer from apical periodontitis and a subsequent external dental fistula due to a failure to maintain appropriate oral hygiene.