An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed Mycobacterium smegmatis synergistically or additively in combinations with rifampicin or ethambutol, respectively. The susceptibility to rifampicin and ethambutol was increased by knockdown of inhA, which encodes a target molecule of isoniazid. Additionally, knockdown of rpoB, which encodes a target molecule of rifampicin, increased the susceptibility to isoniazid and ethambutol, which act synergistically with rifampicin in the checkerboard assay. Moreover, CRISPRi could successfully predict the synergistic action of cyclomarin A, a novel TB drug candidate, with isoniazid or rifampicin. These results demonstrate that CRISPRi is a useful tool not only for drug target exploration but also for screening the combinatorial effects of novel combinations of anti-TB drugs. This study provides a rationale for anti-TB drug development using CRISPRi.

Prolyl-hydroxylase inhibitors reconstitute tumor blood vessels in mice.

Tumor blood vessels have leaky and low blood flow properties, which lead to hypoxia and low nutrient levels in the tumor tissue area known as the tumor microenvironment (TME). We reported that the prolyl-hydroxylase (PHD) inhibitor Roxadustat normalized tumor blood vessels, improved tumor tissue perfusion, and re-oxygenated the tumor tissue. Recently, several PHD inhibitors including Roxadustat, Daprodustat, Molidustat, and Vadadustat, were evaluated in clinical trials and approved for treating renal anemia. In this study, we showed that PHD inhibitors reconstituted tumor blood vessels and improved the TME, and some agents exhibited differential effects on tumors in a mouse model.

Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model.

Orally active hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors that stabilize HIF protein and stimulate the production of erythropoietin have been approved to treat renal anemia. Our previous report suggested that HIF-1α dependent fibrogenic mechanisms are operating at the early onset of renal fibrosis and its contribution declines with the progression in mouse unilateral ureteral obstruction (UUO) model. The aim of the study is to evaluate the renal fibrogenic potential of FG4592, a recently approved orally active HIF prolyl hydroxylase inhibitor in mouse UUO model. Male C57BL/6J mice orally given FG-4592 (12.5 mg/kg/day and 50 mg/kg/day) were subjected to UUO. Neither dose of FG-4592 affected renal fibrosis or macrophage infiltration. FG-4592 had no effects on increased mRNA of collagen I, collagen III or transforming growth factor-ß1. At 3 days after UUO, higher dose of FG-4592 potentiated the increased mRNA expression of profibrogenic molecules, plasminogen activator inhibitor 1 (Pai-1) and connective tissue growth factor (Ctgf) but such potentiation disappeared at 7 days after UUO. It is suggested that FG-4592 used in the present study had little effects on renal fibrosis even though high dose of FG-4592 used in the present study transiently potentiated gene expression of Pai-1 and Ctgf in the UUO kidney.

A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4.

Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg-1·day-1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-ß1 (TGF-ß1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-ß1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.

Efficacy and safety of idalopirdine for Alzheimer's disease: a systematic review and meta-analysis.

OBJECTIVE: The efficacy and tolerability of idalopirdine, a selective 5-hydroxytryptamine6 receptor antagonist, in patients with Alzheimer's disease (AD) is uncertain. A systematic review and meta-analysis of randomized controlled trials (RCTs) testing idalopirdine for patients with AD was performed. METHODS: We included RCTs of idalopirdine for patients with AD and used Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores as a primary measure. RESULTS: Four RCTs with 2,803 patients with AD were included. There was no significant difference in ADAS-cog between the idalopirdine and placebo groups [mean difference (MD) = -0.41, P = 0.32, I2 = 62%]. However, significant heterogeneity remained. Sensitivity analysis revealed that idalopirdine was more effective than placebo for ADAS-cog in the high dose and moderate AD subgroups (high dose subgroup: MD = -2.15, P = 0.005, moderate AD subgroup: MD = -2.15, P = 0.005). Moreover, meta-regression analysis showed that idalopirdine effect size for ADAS-cog was associated with mean dose (coefficient, -0.0289), ADAS-cog at baseline (coefficient, -0.9519), and proportion of male participants (coefficient, 0.2214). For safety outcomes, idalopirdine was associated with a higher incidence of at least one adverse event and increased γ-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, and vomiting than placebo. There were no significant differences in other secondary outcomes between both treatments. CONCLUSIONS: Idalopirdine is not effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small and may be limited.

Anti-Dementia Drugs for Psychopathology and Cognitive Impairment in Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: We conducted a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials of anti-dementia drugs plus antipsychotics for schizophrenia. METHODS: Primary outcomes of efficacy and safety included improving overall symptoms (Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores) and all-cause discontinuation, respectively. Other outcomes included psychopathology subscales (positive, negative, general, and anxiety/depressive symptoms), cognitive function (attention/vigilance, reasoning/problem solving, social cognition, speed of processing, verbal learning, visual learning, working memory, and cognitive control/executive function), Mini-Mental State Examination scores, treatment discontinuation due to adverse events and inefficacy, and individual adverse events. We evaluated the effect size using a random effects model. RESULTS: We identified 37 studies (n=1574): 14 donepezil-based (n=568), 10 galantamine-based (n=371), 4 rivastigmine-based (n=146), and 9 memantine-based (n=489) studies. Pooled anti-dementia drugs plus antipsychotics treatments were superior to placebo plus antipsychotics in improving the overall symptoms (24 studies, 1069 patients: standardized mean difference=-0.34, 95% CI=-0.61 to -0.08, P=.01), negative symptoms (24 studies, 1077 patients: standardized mean difference =-0.62, 95% CI=-0.92 to -0.32, Pcorrected=.00018), and Mini-Mental State Examination scores (7 studies, 225 patients: standardized mean difference=-0.79, 95% CI=-1.23 to -0.34, P=.0006). No significant differences were found between anti-dementia drugs plus antipsychotics and placebo plus antipsychotics regarding other outcomes. CONCLUSIONS: Although the results suggest that anti-dementia drugs plus antipsychotics treatment improves negative symptoms and Mini-Mental State Examination scores in schizophrenia patients, they possibly were influenced by a small-study effect and some bias. However, it was not superior to placebo plus antipsychotics in improving composite cognitive test score, which more systematically evaluates cognitive impairment than the Mini-Mental State Examination score. Overall, the anti-dementia drugs plus antipsychotics treatment was well tolerated.

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms-Brief Report.

OBJECTIVE: The purpose of this study was to determine the role of smooth muscle cell-derived hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of aortic aneurysms. APPROACH AND RESULTS: Control mice and smooth muscle cell-specific hypoxia-inducible factor-1α-deficient mice were infused with ß-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. Mutant mice experienced increased levels of aneurysm formation of the thoracic or abdominal aorta with more severe elastin disruption, compared with control mice. Smooth muscle cell-specific hypoxia-inducible factor-1α deficiency did not affect matrix metalloproteinase-2 activity; however, the activity of lysyl oxidase and the levels of tropoelastin mRNA in the angiotensin II- and ß-aminopropionitrile-treated aortae, associated with elastin fiber formation, were suppressed. Furthermore, we observed reduced volumes of mature cross-linked elastin in the thoracoabdominal aorta after treatment with angiotensin II and ß-aminopropionitrile. CONCLUSIONS: Deficiency of smooth muscle cell-derived hypoxia-inducible factor-1α augments aortic aneurysms, accompanied by disruption of elastin fiber formation, but not changes of elastin fiber degradation.

Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of Z-drug adjunctive therapy in antidepressant-treated major depressive disorder (MDD) patients. Randomized, placebo-, or antidepressant-alone-controlled trials of Z-drugs in MDD patients were included. The primary outcome measures for efficacy and safety were remission rate and all-cause discontinuation, respectively. The secondary outcome measures were response rate, Hamilton Depression Rating Scale (HAMD) total score improvement, discontinuation due to inefficacy and adverse events, and individual adverse effects. Risk ratio (RR), number needed to treat/harm (NNT/NNH), 95 % confidence intervals, and standardized mean difference (SMD) were calculated. We identified six studies [antidepressants were selective serotonin reuptake inhibitors and venlafaxine, mean duration of study was 10.5 weeks, mean age of patients (mean ± standard deviation) was 44.4 ± 11.8 years old, total n = 2089, eszopiclone + antidepressants = 642, placebo + antidepressants = 930, antidepressants alone = 112, and zolpidem + antidepressants = 405]. Pooled Z-drug + antidepressants was superior to placebo + antidepressants regarding the remission rate (RR = 0.85, NNT = 10). Although pooled Z-drug + antidepressants was also superior to placebo + antidepressants/antidepressants alone regarding HAMD score improvement (SMD = -0.23), there was not significant difference in response rate and discontinuation due to inefficacy between groups. There was no difference in all-cause discontinuation between groups. Although there was also no difference in discontinuation due to adverse events between groups, pooled Z-drug + antidepressants was associated with a higher incidence of at least one adverse event (RR = 1.09, NNH = 20) and dizziness (RR = 1.76, NNH = 25) compared with the placebo + antidepressants/antidepressants alone. In conclusion, Z-drugs + antidepressants improves the treatment efficacy for MDD compared with the placebo + antidepressants/antidepressants alone. However, the therapy requires close monitoring of adverse events, particularly dizziness.

Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. METHODS: Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. RESULTS: We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol. CONCLUSIONS: Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required.

Efficacy and safety of oxytocin augmentation therapy for schizophrenia: an updated systematic review and meta-analysis of randomized, placebo-controlled trials.

The aim of this study was to perform a systematic review and an updated and comprehensive meta-analysis of oxytocin augmentation therapy in patients with schizophrenia who received antipsychotic agents. Data published up to 07/11/2015 were obtained from PubMed, PsycINFO, and Cochrane Library databases. We conducted a systematic review and meta-analysis of patients' data from randomized controlled trials (RCTs) comparing oxytocin with placebo. Relative risk (RR), standardized mean difference (SMD), and 95 % confidence intervals (95 % CI) based on the random-effects model were calculated. We included seven RCTs; the total sample size was 206 patients. Oxytocin was superior to placebo for decreasing the Positive and Negative Syndrome Scale (PANSS) general subscale scores (SMD = -0.44, 95 % CI -0.82 to -0.06, p = 0.02, I (2) = 0 %, N = 4, n = 112); however, it was not different from placebo for total symptoms (SMD = -0.46, 95 % CI -1.20 to 0.28, p = 0.22, I (2) = 80 %, N = 6, n = 162), positive symptoms (SMD = -0.18, 95 % CI -0.87 to 0.51, p = 0.60, I (2) = 81 %, N = 6, n = 192), and negative symptoms (SMD = -0.34, 95 % CI -0.76 to 0.08, p = 0.12, I (2) = 55 %, N = 7, n = 214). However, a sensitivity analysis including only oxytocin administration on consecutive days studies was superior to placebo in negative symptoms (SMD = -0.44, 95 % CI -0.87 to -0.01, p = 0.04, I (2) = 51 %, N = 6 n = 192). There were no significant differences for all-cause discontinuation (RR = 1.02) and individual side effects such as headache and dizziness between oxytocin and placebo. Oxytocin may improve PANSS general subscale scores in schizophrenia and seems to be well tolerated. However, because the number of studies in the current analysis was small, further study will be required using larger sample sizes.

An autopsy case of cortical superficial siderosis with persistent abnormal behavior.

In recent years, MRI has revealed cortical superficial siderosis (cSS), which exhibits hemosiderin deposition in only the cortical surface. However, the associations between the histological findings and clinical symptoms of cSS remain unclear. We herein report an autopsy case of a 75-year-old Japanese man with cSS with persistent abnormal behavior according to cognitive impairment, hallucination and delusion. At 73 years of age, the patient presented with unusual behavior that indicated auditory hallucination and delusion. One year later, he was admitted to the hospital for malignant lymphoma. On admission, cognitive impairment was detected by a screening test. Soon after hospitalization, he presented with active delirium including visual hallucination and delusion. The patient's excited behavior was improved by the administration of a major tranquilizer. However, the abnormal behavior and cognitive impairment persisted. At 75 years of age, he died of heart failure. A neuropathological investigation revealed hemosiderin depositions in the superficial layer of the cortex in the medial and lateral frontal lobe, the lateral temporal lobe, the parietal lobe, and the medial and lateral occipital lobe. Neuritic plaques and diffuse plaques were extensively observed, which corresponded to Braak stage C and CERAD B, although NFTs were observed that corresponded to Braak stage II. Cortical amyloid angiopathy was not observed in any regions. Ischemic change of brain was also mild. Our report suggests that localized deposition of hemosiderin in the cortex might affect the manifestation of cognitive impairments and hallucination. Further clinicopathological studies are needed to clarify the clinical manifestations of patients with cSS.

DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response.

The ataxia telangiectasia mutated and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis is the major signaling pathway activated in response to replication stress and is essential for the intra-S checkpoint. ATR phosphorylates and activates a number of molecules to coordinate cell cycle progression. Chk1 is the major effector downstream from ATR and plays a critical role in intra-S checkpoint on replication stress. Activation of Chk1 kinase also requires its association with Claspin, an adaptor protein essential for Chk1 protein stability, recruitment and ATR-dependent Chk1 phosphorylation. We have previously reported that, on replication stress, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is rapidly phosphorylated by ATR at the stalled replication forks and is required for cellular resistance to replication stresses although the impact of DNA-PKcs onto the ATR signaling pathway remains elusive. Here we report that ATR-dependent Chk1 phosphorylation and Chk1 signaling are compromised in the absence of DNA-PKcs. Our investigation reveals that DNA-PKcs is required to maintain Chk1-Claspin complex stability and transcriptional regulation of Claspin expression. The impaired Chk1 activity results in a defective intra-S checkpoint response in DNA-PKcs-deficient cells. Taken together, these results suggest that DNA-PKcs, in addition to its direct role in DNA damage repair, facilitates ATR-Chk1 signaling pathway in response to replication stress.

Hypochondriasis as an early manifestation of dementia with Lewy bodies: an autopsied case report.

Discrepancies between clinical and pathological diagnoses of dementia with Lewy bodies (DLB) may occur because the full disease progression remains unclear, especially during the early stage. Herein, we report the case of a 78-year-old Japanese man with hypochondriasis who had autopsy-confirmed limbic-type DLB pathology. He exhibited no core clinical features of DLB. We attempted to identify the clinicopathological correlations in the early stages of DLB. At the age of 77, he became hypochondriacal and exhibited progressive cognitive decline after the death of his wife. He was concerned about his poor physical condition, but hospital examinations did not identify any overtly abnormal findings. At 78 years of age, he consulted a neurologist with complaints of facial numbness and irritability. Neurological examination revealed no overt abnormality, and he scored 21 points on the Mini-Mental State Examination. Magnetic resonance imaging of the brain showed mild bilateral ventricular enlargement. The patient was clinically diagnosed as having possible Alzheimer's disease. Approximately 1 month after his consult, he died of acute pneumonia in a psychiatric hospital to which he had been admitted for severe aggressive behaviour. He exhibited no core clinical features pointing towards a clinical diagnosis of DLB. Neuropathological investigation revealed limbic-type Lewy body disease with concurrent minimum Alzheimer-type pathology, which corresponds to high-likelihood DLB pathology based on the Third Consortium DLB pathological criteria. The patient had minimum nigral degeneration, which is consistent with the absence of parkinsonism. This autopsied case suggests that some DLB patients exhibit hypochondriasis in the early stage of the disease, even if they lack the core clinical features of DLB.

Protection against Brain Atrophy by Anti-dementia Medication in Mild Cognitive Impairment and Alzheimer's Disease: Meta-Analysis of Longitudinal Randomized Placebo-Controlled Trials.

BACKGROUND: There has not been conclusive evidence for prevention of brain atrophy by anti-dementia drugs in mild cognitive impairment and Alzheimer's Disease. METHODS: Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to 16 May, 2015. Only double-blind, randomized, placebo-controlled clinical trials of anti-dementia drugs in patients with mild cognitive impairment or Alzheimer's Disease were included. Primary outcomes were annualized percent change of total brain volume (%TBV/y), annualized percent change of hippocampal volume (%HV/y), and annualized percent change of ventricular volume (%VV/y) measured by magnetic resonance imaging. Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated for relevant outcomes. RESULTS: Seven randomized, placebo-controlled clinical trials (n=1708) were found to meet the inclusion criteria, including 4 mild cognitive impairment studies (n=1327) and 3 Alzheimer's Disease studies (n=381) [3 donepezil studies (2 mild cognitive impairment studies and 1 Alzheimer's Disease study), 1 galantaime study for mild cognitive impairment, 2 mementine studies for Alzheimer's Disease, and 1 rivastigmine study for mild cognitive impairment]. Pooled anti-dementia drugs showed superior protective outcomes compared with placebo regarding %TBV/y (SMD=-0.21, 95%CI=-0.37 to -0.04, P=.01, N=4, n=624) and %VV/y (SMD=-0.79, 95%CI=-1.40 to -0.19, P=.01, N=3, n=851). However, %HV/y failed to show difference between both groups. Among anti-dementia drugs, donepezil showed significantly greater protective effects than placebo regarding %TBV/y (SMD=-0.43, 95%CI=-0.74 to -0.12, P=.007, N=1, n=164) and %VV/y (SMD=-0.51, 95%CI=-0.73 to -0.29, P<.00001, N=2, n=338). Rivastigmine was also superior to placebo regarding %VV/y (SMD=-1.33, 95%CI=-1.52 to -1.14, P<.00001). CONCLUSIONS: The results favored the hypothesis that anti-dementia drugs may prevent brain atrophy in patients with mild cognitive impairment and Alzheimer's Disease.

Cholinesterase Inhibitors for Lewy Body Disorders: A Meta-Analysis.

BACKGROUND: We performed a meta-analysis of cholinesterase inhibitors for patients with Lewy body disorders, such as Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies. METHODS: The meta-analysis included only randomized controlled trials of cholinesterase inhibitors for Lewy body disorders. RESULTS: Seventeen studies (n = 1798) were assessed. Cholinesterase inhibitors significantly improved cognitive function (standardized mean difference [SMD] = -0.53], behavioral disturbances (SMD = -0.28), activities of daily living (SMD = -0.28), and global function (SMD = -0.52) compared with control treatments. Changes in motor function were not significantly different from control treatments. Furthermore, the cholinesterase inhibitor group had a higher all-cause discontinuation (risk ratio [RR] = 1.48, number needed to harm [NNH] = 14), discontinuation due to adverse events (RR = 1.59, NNH = 20), at least one adverse event (RR = 1.13, NNH = 11), nausea (RR = 2.50, NNH = 13), and tremor (RR = 2.30, NNH = 20). CONCLUSIONS: Cholinesterase inhibitors appear beneficial for the treatment of Lewy body disorders without detrimental effects on motor function. However, a careful monitoring of treatment compliance and side effects is required.

Memantine for Lewy body disorders: systematic review and meta-analysis.

OBJECTIVE: To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders. METHODS: The meta-analysis included randomized controlled trials of memantine for Lewy body disorders in all patients with Lewy body disorders. Motor function, activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Exam, discontinuation rate, and individual side effects were evaluated. RESULTS: No significant effects of memantine on motor function scores, Mini-Mental State Exam scores, Neuropsychiatric Inventory scores, and activity of daily living scores were found. However, memantine was superior to placebo in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference: -0.26; 95% confidence interval: -0.51 to -0.02; z = 2.08; p = 0.04; two studies; N = 258). Dropout due to all causes, inefficacy, or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo, and confusion were found between the groups. CONCLUSION: Our results suggest that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorders. Further, memantine is well tolerated.

A cross-sectional survey to investigate the prevalence of pain in Japanese patients with major depressive disorder and schizophrenia.

We conducted a cross-sectional survey to assess the prevalence of physical pain in Japanese major depressive disorder (MDD) and schizophrenia (SZ) patients as well as in healthy controls (HCs). We also examined the association between their psychopathology and characteristics of pain according to a face-to-face survey by an experienced psychiatrist and psychologist. We analyzed 233 HCs, 94 MDD patients, and 75 SZ patients using the McGill Pain Questionnaire (MPQ) and SF-8 (all participants), the Hamilton Depression Rating Scale 21 items (MDD patients), and the Positive and Negative Symptom Scale (SZ patients). Although MDD patients experienced more pain than HCs, there was no difference in the prevalence of pain between SZ patients and HCs. Moreover, HCs with pain did not have higher SF-8 total scores than those without pain, whereas both MDD and SZ patients with pain had higher SF-8 total scores than those without pain. The severity of psychopathology in MDD and SZ patients was also positively associated with both the prevalence of pain and MPQ scores. MPQ scores were also associated with positive symptoms in SZ patients. Considering these results, physicians need to query MDD patients about physical pain during examination if they are to ensure a favorable and quick response to treatment. The severity of positive symptoms (i.e., clinical status) in SZ patients might also be associated with pain sensitivity, and warrants further investigation.

Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation.

Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD.

Combination therapy with cholinesterase inhibitors and memantine for Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer's disease. METHODS: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. RESULTS: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=-0.13), activity of daily living scores (standardized mean difference=-0.10), and global assessment scores (standardized mean difference=-0.15). In addition, cognitive function scores (standardized mean difference=-0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer's disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. CONCLUSIONS: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer's disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated.

[The effect of PHD inhibitor on tumor microenvironment and tumor immune response].

Since the approval of HIF-PH inhibitors, HIF-PH inhibitors have been used clinically, and many studies and clinical case reports have been reported in Japan. A lot of information has been accumulated on clinical usage. However, HIF-PH inhibitors require careful administration for cancer patients due to their action mechanism through upregulating hypoxia-inducible factors (HIFs) level. In cancer cells, HIFs affect tumor progression and contribute to chemo- and radio-resistance. On the other hand, upregulation of HIFs in immune cells is associated with inflammation and suppress tumor progression. However, these controversial effects are not clear in in vivo model. It is needed to reveal whether upregulating HIFs level is beneficial for cancer therapy or not. We have previously reported that HIF-PH inhibitor treatment in tumor bearing mice model led to reconstitute tumor blood vessel and inhibit tumor growth. In addition, these phenomena were caused by tumor infiltrated macrophages and they altered these phenotypes. In this review, we will describe our findings on the mechanism of tumor growth suppression by HIF-PH inhibitors. We also want to mention the risks and benefits of future HIF-PH inhibitors.