Astrocyte-Specific Inhibition of the Primary Cilium Suppresses C3 Expression in Reactive Astrocyte.

C3-positive reactive astrocytes play a neurotoxic role in various neurodegenerative diseases. However, the mechanisms controlling C3-positive reactive astrocyte induction are largely unknown. We found that the length of the primary cilium, a cellular organelle that receives extracellular signals was increased in C3-positive reactive astrocytes, and the loss or shortening of primary cilium decreased the count of C3-positive reactive astrocytes. Pharmacological experiments suggested that Ca2+ signalling may synergistically promote C3 expression in reactive astrocytes. Conditional knockout (cKO) mice that specifically inhibit primary cilium formation in astrocytes upon drug stimulation exhibited a reduction in the proportions of C3-positive reactive astrocytes and apoptotic cells in the brain even after the injection of lipopolysaccharide (LPS). Additionally, the novel object recognition (NOR) score observed in the cKO mice was higher than that observed in the neuroinflammation model mice. These results suggest that the primary cilium in astrocytes positively regulates C3 expression. We propose that regulating astrocyte-specific primary cilium signalling may be a novel strategy for the suppression of neuroinflammation.

Telepsychiatry versus face-to-face treatment: systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The COVID-19 pandemic has transformed healthcare significantly and telepsychiatry is now the primary means of treatment in some countries. AIMS: To compare the efficacy of telepsychiatry and face-to-face treatment. METHOD: A comprehensive meta-analysis comparing telepsychiatry with face-to-face treatment for psychiatric disorders. The primary outcome was the mean change in the standard symptom scale scores used for each psychiatric disorder. Secondary outcomes included all meta-analysable outcomes, such as all-cause discontinuation and safety/tolerability. RESULTS: We identified 32 studies (n = 3592 participants) across 11 mental illnesses. Disease-specific analyses showed that telepsychiatry was superior to face-to-face treatment regarding symptom improvement for depressive disorders (k = 6 studies, n = 561; standardised mean difference s.m.d. = -0.325, 95% CI -0.640 to -0.011, P = 0.043), whereas face-to-face treatment was superior to telepsychiatry for eating disorder (k = 1, n = 128; s.m.d. = 0.368, 95% CI 0.018-0.717, P = 0.039). No significant difference was seen between telepsychiatry and face-to-face treatment when all the studies/diagnoses were combined (k = 26, n = 2290; P = 0.248). Telepsychiatry had significantly fewer all-cause discontinuations than face-to-face treatment for mild cognitive impairment (k = 1, n = 61; risk ratio RR = 0.552, 95% CI 0.312-0.975, P = 0.040), whereas the opposite was seen for substance misuse (k = 1, n = 85; RR = 37.41, 95% CI 2.356-594.1, P = 0.010). No significant difference regarding all-cause discontinuation was seen between telepsychiatry and face-to-face treatment when all the studies/diagnoses were combined (k = 27, n = 3341; P = 0.564). CONCLUSIONS: Telepsychiatry achieved a symptom improvement effect for various psychiatric disorders similar to that of face-to-face treatment. However, some superiorities/inferiorities were seen across a few specific psychiatric disorders, suggesting that its efficacy may vary according to disease type.

Late-onset non-obstructive mesenteric ischemia (NOMI) resulting from delayed absorption of overdosed antihypertensive drugs: An autopsy case report.

Non-obstructive mesenteric ischemia (NOMI) is caused by reduced blood flow to the intestines without physical occlusion in the mesenteric artery. Previous reports show that drug overdose occasionally induces late-onset NOMI; however, in most cases, the reason for the delayed onset is unclear. Here, we present an autopsy case of late-onset NOMI that was induced by a drug overdose. An 80-year-old man was admitted to the intensive care unit because of severe hypotension after an overdose of antihypertensive drugs. He received vasopressor therapy and continuous hemodiafiltration dialysis; however, gastrointestinal decontamination was not performed. He began to recover but developed acute mesenteric ischemia on the evening of day 4 and died on day 5. Autopsy showed discontinuous submucosal bleeding from the duodenum to the colon; there was no thrombus in the mesenteric artery, which led to a diagnosis of NOMI. In the stomach, there was 250 mL of reddish-brown fluid with a muddy brown substance. Histologic examination revealed ischemic necrosis in the small intestine. Quantitative analysis of serum collected during hospitalization revealed that nifedipine and cilostazol levels had peaked on day 3 of hospitalization. The formulation of nifedipine was a controlled-release tablet, and the low water solubility of cilostazol may have caused the tablets to adhere and remain in the stomach. Therefore, the drugs had been released into the blood stream several days after hospitalization, leading to delayed-onset NOMI. In cases of overdose, it is crucial to consider the formulation and properties of the involved drugs when determining medical treatment.

Parallel disease activity of Behçet's disease with renal and entero involvements: a case report.

BACKGROUND: Behçet's disease (BD) is a systemic inflammatory vasculitis with both autoimmune and autoinflammatory properties. Renal involvement in BD and its spontaneous remission have been rare. We herein describe a case of parallel disease activity of BD with entero and renal involvements, followed by a spontaneous remission without corticosteroid treatment. CASE PRESENTATION: A 54-year-old woman who had a 4-year history of BD, maintained with colchicine treatment, suffered abdominal pain, hemorrhagic stool and diarrhea. Physical examination revealed strong tenderness in the entire abdomen. Laboratory test results showed increased levels of inflammation, and a computed tomography scan revealed edematous intestinal wall thickening with ascites. Blood and stool cultures showed no specific findings. Since she was suspected to have developed panperitonitis with acute enterocolitis, she started treatment with an antibacterial agent under bowel rest. Her abdominal symptoms gradually improved, while diarrhea and high levels of inflammatory reaction persisted. Colonoscopy revealed discontinuous abnormal mucosal vascular patterns and ulcerations in the whole colon except for the rectum, and histological analyses of the intestine demonstrated transmural mucosal infiltration of inflammatory cells without epithelioid granuloma or amyloid deposition. Based on these findings, she was diagnosed with entero BD. Meanwhile, pedal edema appeared during her hospitalization. Urinalysis results were consistent with nephrotic syndrome, thus a renal biopsy was performed. Light microscopy showed no obvious glomerular and interstitial abnormalities, whereas electron microscopy revealed foot process effacement without immune complex deposition or fibrillary structure, compatible with minimal change disease (MCD). Only with conservative therapy, her proteinuria decreased, followed by a complete remission in 3 weeks from the onset of edema. The coincident episode of MCD was finally diagnosed as renal BD that paralleled disease activity to entero BD. She started adalimumab administration, resulting in the further improvement of diarrhea and inflammatory levels. CONCLUSIONS: This is the first report to demonstrate MCD as renal involvement of BD along with the disease activity of entero BD.

A Series of Mixed-Ligand Cu(I) Complexes Comprising Diphosphine-Disulfide Ligands: Effects of Diphosphine Ligands on Luminescent Properties.

Mixed-ligand Cu(I) complexes have attracted attention as alternatives to the noble- and/or rare-metal complexes, because of their remarkable photofunctions. To develop mixed-ligand Cu(I) complexes with rich photofunctions, an investigation of a suitable combination of ligands has captured more and more research interests. Herein, we report the first examples of emissive heteroleptic diphosphine-disulfide Cu(I) complexes combined with diphosphine ligands. The systematic study using a series of diphosphine ligands revealed that large π-conjugated bridging moieties between the two P atoms in the diphosphine ligands result in higher light-emission performance. When the diphosphine ligand was (R)-BINAP ((R)-BINAP = (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), the Cu(I) complex had an emission quantum yield (Φem) of 0.13 and a long emission lifetime (τem = 118 µs).

Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model.

A neuropsychiatric drug overdose impairs physiological function via central nervous system (CNS) depression. In drug-related deaths, only the drug concentration can currently provide information regarding CNS depression in victims. In this study, using a drug overdose model, we investigated the ability of neurotransmitters in the cerebrospinal fluid (CSF) to serve as biomarkers for CNS depression. Four groups of rats were orally administered diazepam (200 mg/kg) and/or phenobarbital (100 mg/kg) or vehicle. In a hot plate test performed to assess physiological impairment, drug-administered animals showed prolongation of the response latency. Serum drug concentrations were also sufficient to observe the effect of drug overdose. The levels of benzoyl-derivatized neurotransmitters were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Noradrenaline, adrenaline, serotonin, melatonin, phosphoethanolamine, and histamine levels in the CSF decreased as the response latencies in the hot plate test increased. These reduced CSF neurotransmitter levels may represent physiological dysfunction through CNS depression.

Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization.

UNLABELLED: Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent in vivo studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8(+) cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8(+) cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)(hi)/phosphorylated AMP-activated protein kinase (AMPK)(lo) subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control. IMPORTANCE: In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally boosted early CTL responses showing enhanced suppression of CTL escape mutant virus replication. Accordingly, the NAb-infused animals did not show accumulation of viral CTL escape mutations during sustained SIV control, and immunodominant CTL responses were preserved. This early functional augmentation of CTLs by NAbs provides key insights into the design of lasting and viral escape mutation-free protective immunity against HIV-1 infection.

Perceptual decisions interfere more with eye movements than with reach movements.

Perceptual judgements are formed through invisible cognitive processes. Reading out these judgements is essential for advancing our understanding of decision making and requires inferring covert cognitive states based on overt motor actions. Although intuition suggests that these actions must be related to the formation of decisions about where to move body parts, actions have been reported to be influenced by perceptual judgements even when the action is irrelevant to the perceptual judgement. However, despite performing multiple actions in our daily lives, how perceptual judgements influence multiple judgement-irrelevant actions is unknown. Here we show that perceptual judgements affect only saccadic eye movements when simultaneous judgement-irrelevant saccades and reaches are made, demonstrating that perceptual judgement-related signals continuously flow into the oculomotor system alone when multiple judgement-irrelevant actions are performed. This suggests that saccades are useful for making inferences about covert perceptual decisions, even when the actions are not tied to decision making.

Correlations between blood volatile hydrocarbon concentrations in different types of fire-related deaths.

Analysis of volatile hydrocarbons in blood from fire-related deaths provides useful information such as whether the victim inhaled smoke from the fire before death or whether an accelerant was used in the fire. In this study, we used headspace gas chromatography-mass spectrometry to quantify volatile hydrocarbons in post-mortem heart blood from 121 fire victims. The cases were classified into the following four groups according to the detected volatile hydrocarbons: construction fires without accelerants, kerosene fires, gasoline fires, and a group with no fire-related hydrocarbons detected (other fires). We investigated the relationships between blood concentrations of carboxyhemoglobin (COHb) and volatile hydrocarbons, and between various volatile hydrocarbons. The mean COHb concentrations were higher in the construction fire group than in the kerosene and gasoline fire groups. In the construction fire group, there was a high correlation coefficient between the concentrations of benzene and COHb and relatively high coefficient correlations between the concentrations of benzene and toluene, benzene and xylene, toluene and styrene, and ethylbenzene and styrene. Our results indicate that the relationships between benzene, xylene, and toluene concentrations could be used to distinguish between deaths in construction fires, kerosene fires, and gasoline fires.

Examination of the cognitive function of Japanese community-dwelling older adults in a class for preventing cognitive decline during the COVID-19 pandemic.

We examined the changes in cognitive function due to restrictions in daily life during the coronavirus disease 2019 (COVID-19) pandemic in community-dwelling older adults with mild cognitive decline. This was a retrospective, case-control study. The participants include 88 older adults with mild cognitive decline (mean age = 81.0 [standard deviation = 6.5] years) who participated in a class designed to help prevent cognitive decline. This class was suspended from early-March to end of May 2020 to prevent the spread of COVID-19, and resumed in June 2020. We collected demographic and cognitive function test data (Touch Panel-type Dementia Assessment Scale [TDAS]) before and after class suspension and questionnaire data on their lifestyle and thoughts during the suspension. Change in TDAS scores from before and after the suspension was used to divide the participants into decline (2 or more points worsening) and non-decline (all other participants) groups, with 16 (18.2%) and 72 (81.8%) participants in each group, respectively. A logistic regression model showed that the odds ratio (OR) for cognitive decline was lower in participants whose responses were "engaged in hobbies" (OR = 0.07, p = 0.015), "worked on a worksheet about cognitive training provided by the town hall" (OR = 0.19, p = 0.026), and "had conversations over the phone" (OR = 0.28, p = 0.0495). There was a significant improvement in TDAS scores after class was resumed (p < 0.01). A proactive approach to intellectual activities and social ties may be important for the prevention of cognitive decline during periods of restrictions due to COVID-19. We found that cognitive function test scores before class suspension significantly improved after resuming classes. We speculate that continued participation in this class led to positive behavioral changes in daily life during periods of restriction due to COVID-19.

High blood mirtazapine concentration in a newborn - A case of suspected postpartum infanticide.

We report a sudden death of an infant due to mirtazapine poisoning. A 15-day-old newborn boy was found dead when he was sleeping beside his mother who had suffered from panic disorder for approximately 1 year. After giving birth, she complained of palpitations and shaky hands, and was prescribed mirtazapine. The deceased newborn weighed 3,282 g and his height was 55 cm. There were no autopsy findings related to the death. The mirtazapine concentration as quantitated by liquid chromatography-tandem mass spectrometry analysis was 620 ng/mL in right heart blood, and was approximately 10 times higher than the therapeutic level in adults. Because transfer of mirtazapine into breast milk is low, mirtazapine was likely administered intentionally to the newborn. Based on the newborn's immature renal, liver, and blood-brain barrier function, the cause of death was attributed to mirtazapine poisoning. Poison-related homicide in the infant is rare. We report the first case of intentional mirtazapine poisoning case in a newborn.

Effects of arterial hemorrhage speed on the blood coagulation/fibrinolysis system and hemodynamics in rats.

: The effects of rapid hemorrhage on coagulopathy have been reported. However, the effects of different hemorrhage speeds on the blood coagulation/fibrinolysis system have not been investigated. This study aimed to compare different hemorrhage speeds for clarifying their effects on the coagulation/fibrinolysis system and circulation disorders in rats. Male Sprague-Dawley rats (301-396 g) were randomly assigned to five groups depending on hemorrhage speed and length of procedure: first, rapid (1.4 ml/min, 30-min bleeding); second, rapid-L (1.4 ml/min, 30-min bleeding and observation until 6 h); third, slow (0.1 ml/min, intermittently, 6-h bleeding); fourth, control (30-min observation); and fifth, control-L (6-h observation). Hemorrhage was induced by withdrawing blood until 40% of the estimated blood volume from the femoral artery. We measured vital signs, hematology, general chemistry, blood gas status, coagulation parameters, fibrinolytic markers [tissue-type plasminogen activator and plasminogen activator inhibitor one (PAI-1)], vascular endothelial damage (syndecan-1), and liver PAI-1 mRNA expression. Rapid hemorrhage induced elevation of lactate and syndecan-1 levels and prolonged prothrombin time and activated partial thromboplastin time in the rapid group. In contrast, slow hemorrhage did not induce these changes. Hemorrhage speed had no effect on plasma tissue-type plasminogen activator and hematology. Plasma PAI-1 levels were significantly increased in the rapid-L group, while liver PAI-1 mRNA levels were increased in the slow group. This study shows changes in the circulatory and fibrinolysis systems, depending on the hemorrhage speed. Hemorrhage might promote production of PAI-1, while tissue hypoxia due to rapid hemorrhage might promote release of PAI-1.

Photocatalytic CO2 Reduction Using Various Heteroleptic Diimine-Diphosphine Cu(I) Complexes as Photosensitizers.

The development of efficient redox-photosensitizers based on the earth-abundant metal ions as an alternative toward noble- and/or rare-metal based photosensitizers is very desirable. In recent years, heteroleptic diimine-diphosphine Cu(I) complexes have been well investigated as one of the most remarkable candidates because of their great potentials as efficient photosensitizers. Here, we investigated the effects of the structure of the diphosphine ligands on the photosensitizing abilities using a series of Cu(I) complexes bearing 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (dmpp) and various diphosphine ligands in order to explore the suitable structure for the photosensitizing reactions. The number of methylene chains between the two phosphorous atoms in the diphosphine ligands was systematically changed from two to four, and the relationship between the length of the carbon chains and the photosensitizing abilities were investigated by conducting photocatalytic CO2 reduction with the Cu(I) complexes as photosensitizers. Turnover frequencies of the CO2 reduction drastically increased with increasing the length of the carbon chains. The systematic study herein reported suggests that the large P-Cu-P angles should be one of the most important factors for enhancing the photosensitizing abilities.

Development of a fluvoxamine detection system using a Quenchbody, a novel fluorescent biosensor.

The misuse of psychotropic drugs intended for medical treatment represents a recent worldwide public health concern. Quenchbody (Q-body) is a novel fluoroimmunosensor that can detect an antigen immediately without additional reagents or washing steps. Here, we describe creating Q-bodies for the detection of the antidepressant fluvoxamine (FLV) and determining optimal conditions to achieve the highest fluorescence intensity (FI). We prepared five Q-bodies with the fluorophore labeled at either the N- or C- terminus and with different linker lengths. Fluorescence was measurable within minutes, indicating the interaction of Q-bodies with FLV. The normalized FI (FI ratio) of the N-terminus labeled Q-body increased approximately 1.5-fold upon FLV addition; Q-bodies labeled at the C-terminus did not significantly increase FI. Among the fluorescence dyes used in this study, Rhodamine 6G labeled Q-body showed the best FI ratio. EC50 values of the N-terminus labeled Q-bodies were similar (23.2-224nM) regardless of linker length or labeling dye. We examined whether the Q-body could be applicable to serum matrix instead of phosphate-buffered saline. The intact serum interfered strongly with the Q-body fluorescence. However, the FI ratios of the Q-body for FLV-spiked serum filtrate, for which proteins were removed by filtration, showed a dose-dependency for detecting FLV levels. Deproteinization, which does not interfere with Q-body fluorescence measurements, is likely necessary to detect serum FLV with high sensitivity. This study demonstrates the potential of Q-body probes as a tool towards developing creative immunoassay applications.

Genome Sequencing Verifies Relapsed Infection of Helicobacter cinaedi.

BACKGROUND: Recurrent infections of Helicobacter cinaedi are often reported, and long-term antimicrobial treatment is empirically recommended to prevent such infections. However, there have been no studies examining whether recurrent infections are relapses of former infections or reinfections with different clones. METHODS: A 69-year-old woman presented with recurrent H cinaedi bacteremia-associated cellulitis after a 51-day interval. We isolated 10 colonies from the blood cultures obtained during each of the 2 episodes and subjected them to whole-genome sequencing (WGS). High-confidence single-nucleotide polymorphisms (SNPs) were identified by an assembly based method. Heterogeneous SNP sites were identified by read mapping. The susceptibility of a representative isolate to 14 antimicrobials was also examined. RESULTS: Whole-genome sequence analysis revealed only 6 SNP sites among the 20 isolates at the whole-genome level. Based on the 6 SNPs, 5 within-host variants (referred to as genotypes) were identified. All 5 genotypes were detected in the first infection; however, only 2 genotypes were detected in the second infection. Although the H cinaedi clone showed a higher minimum inhibitory concentration to fluoroquinolones and macrolides and responsible mutations were identified, none of the 6 SNPs appeared related to additional resistance. CONCLUSIONS: The second infection analyzed here was a relapse of the first infection. A certain level of within-host genomic heterogeneity of the H cinaedi clone was already present in the first infection. Our results suggest the importance of longer treatment courses to eradicate H cinaedi for preventing the relapse of its infection.

Liquid chromatography-tandem mass spectrometry detection of benzalkonium chloride (BZK) in a forensic autopsy case with survival for 18 days post BZK ingestion.

We report a forensic autopsy case of an elderly man who ingested unknown amount of germicidal disinfectant containing 50% benzalkonium chloride (BZK). He survived for 18 days after BZK ingestion and then died because of pneumonia. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to detect three BZK compounds (C12-BZK, C14-BZK and C16-BZK) in the blood. Extraction of BZK was carried out according to a modified QuEChERS method. Chromatographic separation was achieved on an ODS column and detection was performed in selected reaction monitoring mode. The accuracy and the precision were acceptable for quantitative analysis in the concentration range of 10-200 ng/mL for the three BZK compounds. BZK was detected in heart and femoral vein blood samples even 18 days after BZK ingestion. Taking into consideration clinical information during 18 days hospitalization and the autopsy findings, the cause of death was attributed to BZK poisoning. Several toxico-kinetic factors regarding absorption and excretion of BZK in the body were also discussed to elucidate the detection of BZK such a long time after ingestion.

Simultaneous and multi-point measurement of ammonia emanating from human skin surface for the estimation of whole body dermal emission rate.

Ammonia is one of the members of odor gases and a possible source of odor in indoor environment. However, little has been known on the actual emission rate of ammonia from the human skin surface. Then, this study aimed to estimate the whole-body dermal emission rate of ammonia by simultaneous and multi-point measurement of emission fluxes of ammonia employing a passive flux sampler - ion chromatography system. Firstly, the emission fluxes of ammonia were non-invasively measured for ten volunteers at 13 sampling positions set in 13 anatomical regions classified by Kurazumi et al. The measured emission fluxes were then converted to partial emission rates using the surface body areas estimated by weights and heights of volunteers and partial rates of 13 body regions. Subsequent summation of the partial emission rates provided the whole body dermal emission rate of ammonia. The results ranged from 2.9 to 12mgh-1 with an average of 5.9±3.2mgh-1 per person for the ten healthy young volunteers. The values were much greater than those from human breath, and thus the dermal emission of ammonia was found more significant odor source than the breath exhalation in indoor environment.

Measurement of 2-nonenal and diacetyl emanating from human skin surface employing passive flux sampler-GCMS system.

It is commonly said elderly persons have a characteristic body odor, and, at present, two chemical compounds have been found to vary with age in male Japanese: 2-nonenal and diacetyl. To investigate dermal emission flux of the ageing odor related compounds, we have developed a non-invasive sampling device based on a concept of passive flux sampler (PFS). The sampler was placed on the skin surface to create a headspace, and the gases emanating from skin moved toward a disk-type adsorbent. The trapped gases were then extracted with dichloromethane and determined by GCMS. The PFS was practically applied to healthy volunteers covering a wide range of age. Since emission fluxes of both compounds remarkably varied with sampling position, the nape of the neck was fixed as regular sampling position where there are dense networks of both sebaceous and eccrine glands which are potential sources of both compounds. The emission flux of 2-nonenal increased with age for both male and female volunteers, whilst the flux of diacetyl showed highest in 30s and decreased over 40s. Although diacetyl has been known as a middle-aged male odor, this study showed the odor caused by diacetyl was not specific to male.