Successful Management of Terminal Delirium With Transdermal Blonanserin Patch in a Terminally Ill Cancer Patient.

Delirium is a distressing condition in terminally ill cancer patients, often treated with antipsychotics. Administering them orally, subcutaneously, or intravenously can be challenging in severely agitated patients. Transdermal antipsychotic patches offer an alternative, but their use for terminal delirium remains underexplored. We present the case of a 73-year-old man with advanced diffuse large B cell lymphoma who developed severe mixed delirium during third-line chemotherapy. Nonpharmacological interventions and oral risperidone plus intravenous haloperidol failed to improve his condition. Subsequently, a transdermal blonanserin patch was applied, resulting in the resolution of hallucinations on day 1 and agitation on day 3, allowing improved communication. The patch was easily applied daily without notable adverse events. However, he deteriorated a week later with an estimated survival of days, ultimately requiring continuous midazolam for refractory agitation. This case underscores the potential of transdermal blonanserin patches for delirium in terminally ill cancer patients, emphasizing the need for future prospective studies.

[Easy screening of outpatients for atrial fibrillation by analyzing fingertip pulse wave variation].

AIM: Atrial fibrillation (AF), which can lead to cardioembolic stroke, is often not properly diagnosed in hospital outpatient departments or medical clinics. We therefore used a pulse analysis to screen patients for AF, and examined the benefits of using this method in screening. METHODS: We performed screening of the hospital's first-visit and ambulatory patients during the afternoon in 2014 (total number, 50,875; true number, 16,356), mainly targeting patients older than 65 years of age. Among the true number of outpatients, the device was used on 5,013 patients, 8,656 times. We independently developed a pulse analysis software application which analyzed the pulse interval variation. We assessed the accuracy of this analytical method in the detection of AF. RESULTS: AF was detected in 56 patients, who were considered for or introduced to anticoagulation treatment. In their cases, the method was considered useful for detecting undiagnosed or untreated AF. This figure amounts to 0.34% of all outpatients and 1.1% of the patients who were screened in 2014. The average age was 76.9±7.7 years, 67.9% of the patients had a CHADS2 score of more than 2, half had a history of arrhythmia in the past, and 37.5% were first-visit patients. The sensitivity of the device used was 89.7%. CONCLUSIONS: Using the method described in this study, we detected asymptomatic AF in numerous patients, and demonstrated that this method is potentially useful in screening outpatients for asymptomatic AF.

Bilateral Abducens Nerve Palsy due to Idiopathic Intracranial Hypertension as an Initial Manifestation of Systemic Lupus Erythematosus.

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure and presents as an intractable headache, vomiting, and ophthalmologic manifestations. We herein report the case of a young girl who presented with bilateral abducens nerve palsy due to IIH as the onset of systemic lupus erythematosus (SLE). The patient was successfully treated with corticosteroid therapy. Our case lacked the typical symptoms of IIH, such as headache or nausea; therefore, it is necessary to carefully determine the cause of bilateral abducens nerve palsies. The development of IIH in SLE patients is a rare occurrence, but this manifestation should not be overlooked.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Involved in Adult Mouse Hippocampal Neurogenesis After Stroke.

In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.

Involvement of 5-HT2 receptors in the expression of withdrawal diarrhea in morphine-dependent mice.

The withdrawal syndrome after the cessation of µ-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3-receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT-induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid-withdrawal diarrhea.

PACAP38 suppresses cortical damage in mice with traumatic brain injury by enhancing antioxidant activity.

The production of reactive oxygen species (ROS) and the resulting oxidative stress in mice in response to a controlled cortical impact (CCI) are typical exacerbating factors associated with traumatic brain injury (TBI). Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a multifunctional peptide that has been shown to exhibit neuroprotective effects in response to a diverse range of injuries to neuronal cells. We recently reported that PACAP38 might regulate oxidative stress in mice. The aim of the present study was to determine whether PACAP38 exerts neuroprotective effects by regulating oxidative stress in mice with TBI. Reactive oxidative metabolites (ROMs) and biological antioxidant potential (BAP) were measured in male C57Bl/6 mice before and 3, 4, and 24 h after CCI. PACAP38 was administered intravenously immediately following CCI, and immunostaining for the oxidative stress indicator nitrotyrosine (NT), and for neuronal death as an indicator of the area affected by TBI, was measured 24 h later. Western blot experiments to determine antioxidant activity [as indicated by superoxide dismutase-2 (SOD-2) and glutathione peroxidase 1 (GPx-1)] in the neocortical region were also performed 3 h post-CCI. Results showed that plasma BAP and ROM levels were dramatically increased 3 h after CCI. PACAP38 suppressed the extent of TBI and NT-positive regions 24 h after CCI, and increased SOD-2 and GPx-1 levels in both hemispheres. Taken together, these results suggest that increasing antioxidant might be involving in the neuroprotective effect of PACAP38 in mice subjected to a CCI.

A case of systemic lupus erythematosus presenting with an acute abdomen: successful treatment with steroid.

Abdominal pain continues to pose diagnostic challenges for emergency clinicians. A 56-year-old Japanese woman was referred to our hospital due to severe abdominal pain which presented as occasional epigastric pain five months before and intermittent abdominal pain. She had a past history of ileus twice, for both of which laparotomy was performed without an alimentary tract resection. The wall thickening with marked three-wall structure from terminal ileum to sigmoid colon was seen and bladder wall was irregularly thick and enhanced irregularly. Among the differential diagnosis of the acute abdomen, autoimmune diseases were suspected, especially lupus erythematosus and Henoch-Schönlein purpura. On the second day of admission, abdominal pain worsened. The results of examinations of antinuclear antibody, anti-double-stranded DNA antibody, ANCA, and the complements were not obtained at that time; however, we started 1-g steroid pulse treatment for three days with success. With the results obtained later, the patient was given a diagnosis of probable systemic lupus erythematosus (SLE). The present case shows that SLE can present with acute abdomen and should be included in the wide range of the differential diagnosis of acute abdomen.

Current status of the treatment of microscopic polyangiitis and granulomatosis with polyangiitis in Japan.

BACKGROUND: This study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan. METHODS: We used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset. RESULTS: The mean ages of the MPA and GPA patients were 69.4 ± 0.4 and 58.4 ± 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA. CONCLUSION: A dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function.

[Determination of tobacco-specific N'-nitrosamines in mainstream smoke from Japanese cigarettes].

OBJECTIVES: Mainstream smoke from cigarettes contains tobacco-specific N'-nitrosamines (TSNAs) listed as Group 1 and 3 carcinogens by the International Agency for Research on Cancer (IARC). Herein, we report on a method of measuring the concentrations of TSNAs in mainstream smoke from the ten top-selling Japanese cigarette brands using an ISO regime by International Organization for Standardization (ISO) and HCI regime of Health Canada. METHODS: Tar in mainstream smoke was collected on a Cambridge filter pad using a smoking machine. The filter pad was immersed in 40 mL of ammonium acetate (pH 6.8) and shaken for 30 min. The extract was then loaded into a C18 column. After washing with 5 mL of 10% methanol and eluting with 5 mL of 70% methanol, the eluate was concentrated to 1 mL for LC-MS/MS analysis. RESULTS: The concentrations of TSNAs in all cigarette brands were higher when determined using the HCI regime than when determined using the ISO regime. Furthermore, the concentrations of TSNAs measured using both the ISO and HCI regimes showed negligible correlation to the tar and nicotine concentrations indicated on package labels. The cigarette samples used in the study were categorized into four classes: ultralow-, low-, medium-, and high-yield brands, which corresponded to 1, 3-6, 8-10, and 14 mg tar/cigarette, respectively. The concentration of TSNAs in ultralow-yield cigarettes was 210 ng/cigarette, as measured using the HCI regime, which was nearly equal to that in high-yield cigarettes (180 ng/cigarette). CONCLUSIONS: Exposure to TSNAs from mainstream smoke from ultralow-yield cigarettes is comparable to that from high-yield cigarettes. To properly evaluate the risk of smoking, not only the concentrations of tar and nicotine but also those of other chemicals, including TSNAs, should be printed on package labels.

Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes.

Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-α, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-γ in MIN6 cells, and Gal-9 was also expressed in the pancreatic ß-cells in NOD mice, suggesting Gal-9 may be released from pancreatic ß-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 µM, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-α production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-α production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-α production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes.

Evaluation of weekly-reduction regimen of glucocorticoids in combination with cyclophosphamide for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Japanese patients.

The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups (P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection (P = 0.03) and impaired glucose tolerance (P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen.

Risk factors for infection in patients with remitted rheumatic diseases treated with glucocorticoids.

It is well known that infection is one of the major causes of morbidity and mortality in rheumatic disease patients treated with high-dose glucocorticoids, especially in the early phase after achievement of disease remission. The aim of this study was to identify the risk factors for infection, with a focus on the dose of glucocorticoids administered, following the achievement of disease remission in rheumatic diseases patients. We retrospectively analyzed the medical records of rheumatic disease patients who had been treated with glucocorticoids. The primary endpoint was the incidence rate of infection during a period from 1 to 2 months after the commencement of treatment. From April 2006 to March 2010, 19 of 92 patients suffered from infection during the observation period. Age ≧ 65 yrs, presence of interstitial pneumonia, diagnosis of systemic vasculitis and serum creatinine level ≧ 2.0 mg/dl were found to be univariate predictors for infection. However, only the presence of interstitial pneumonia was an independent risk factor for infection (HR＝4.50, 95%CI＝1.65 to 14.44) by the Cox proportional hazard model. Even after achievement of clinical remission, careful observation is needed for patients with interstitial pneumonia, more so than for those receiving high-dose glucocorticoids.

Electromagnetic field system for transsphenoidal surgery on recurrent pituitary lesions - technical note.

BACKGROUND: Post operative scar tissue makes transsphenoidal surgery for recurrent pituitary lesions very difficult. However, with the use of a new cautery system, known as the EMF system, we were able to perform the surgical procedures with relative ease. In this article, we report the advantages and clinical applications of this new instrument in transnasal reoperation. METHODS: The EMF system generates a high frequency current of 13.56 MHz that is focused on the target. This enables it to coagulate, cut, and vaporize tissue in a pinpoint fashion. The bayonet and pencil-type hand pieces of the EMF system are slim, and the tips of the probe are flexible. This enables the surgeon to easily reach deep narrow spaces. We have used the EMF system for transsphenoidal surgery on recurrent pituitary lesions in 18 patients. The system was used to cut and vaporize scar tissue and vaporize firm and fibrotic tumor tissue. RESULTS: During surgery, the system could easily cut and vaporize scarred tissues in the nasal cavity, the sphenoid sinus, and the sella, without damage to the surrounding tissue. In addition, in 3 patients who had extremely fibrotic and firm tumors, we were able to easily vaporize the tumor with safety. CONCLUSIONS: The EMF system enables the surgeon to cut and vaporize tissue with ease and with minimal injury to the surrounding structures. It was particularly valuable in the resection of firm tumors. It may also shorten the operating time because of quick vaporization of the firm tissue.

Therapeutic effects of 10 mg/day rabeprazole administration on reflux esophagitis was not influenced by the CYP2C19 polymorphism.

BACKGROUND: The acid suppressive effects of omeprazole (OPZ) and lansoprazole (LPZ) are influenced by the CYP2C19 polymorphism. On the other hand, some investigators have reported that acid suppressive effect of rabeprazole (RPZ) was not significantly affected by CYP2C19. The present study was designed to investigate whether the CYP2C19 genotype is related to the healing of reflux esophagitis (RE) in treatment with RPZ 10 mg. METHODS: One hundred and three Japanese patients with RE were treated with daily oral administration of 10 mg RPZ. At 4 and 8 weeks after the start of treatment, healing of RE was evaluated endoscopically. The CYP2C19 genotype was investigated before the treatment. RESULTS: At 4 weeks after the start of treatment, the healing rates for homo-extensive metabolizer, hetero-extensive metabolizer, and poor metabolizer patients were 83.3% (15/18), 77.3% (17/22), and 88.9% (8/9) [corrected] respectively, and at 8 weeks after the start of treatment, the healing rates were 86.1% (31/36), 92.0% (46/50), and 82.4% (14/17), respectively. There were no significant differences in the healing rate of RE among the three genotypes at either 4 or 8 weeks after the start of treatment. CONCLUSIONS: The therapeutic effects of 10 mg/day RPZ administration on RE may be uninfluenced by the CYP2C19 polymorphism.

Visualization of spinal cord motion associated with the cardiac pulse by tagged magnetic resonance imaging with particle image velocimetry software.

OBJECTIVE: The purpose of this study was to evaluate whether or not tagged magnetic resonance (MR) imaging with particle image velocimetry (PIV) software could reveal spinal cord motion clearly. METHODS: Six volunteers were enrolled in this study. Tagged MR imaging using fast spoiled gradient-recalled acquisition in the steady state with spatial modulation of the magnetization technique was performed using a 1.5-T MR system. RESULTS: Sagittal vector maps analyzed by PIV software revealed entire spinal cord motion sequentially during the cardiac cycle. The cervical spinal cord initially moved in a caudal direction and then continually oscillated from a cephalic-to-caudal direction. Each volunteer had a different cycle. In the thoracic spinal area, similar findings were observed, although they were slightly less clear than in the cervical area. CONCLUSION: Tagged MR imaging combined with PIV software, referred to as tagged MR image velocimetry, revealed spinal cord motion associated with the cardiac pulse, especially in the cervical spine.