Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF.

PURPOSE: Patients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF. METHODS: A patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq). RESULTS: CITE-seq analysis revealed that before treatment, the patient's PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs-e.g., STAT1, IRF1, MX1, and OAS1-were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient's autoimmune features were aggravated, which is in line with sustained epigenetic abnormality. CONCLUSIONS: In a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs.

Exploring the link between pediatric headaches and environmental noise exposure.

BACKGROUND: Headaches are the most common neurologic symptoms in the pediatric population. Most primary headache in children and adolescents focuses on associated factors, including noise. Auditory discomfort is related to recognizing the pain. We aimed to analyze the headache profile of pediatric populations and the connection between noise exposure and head pain in children and adolescents. METHODS: We reviewed retrospectively medical records of the pediatric population with headaches in Gyeongsang National University Changwon Hospital from January 2022 to April 2023. Personal headache profiling from self-questionnaires and environmental noise data from the National Noise Information System (NNIS) were used to analyze each variable, and chi-square tests and linear regression models by SAS were used to analyze the statistical correlation. RESULTS: Of the 224 participants, 125 were clinically diagnosed with headaches. Of the 104 pubertal subjects, 56.7% were diagnosed with headaches, compared to 60% in the prepubertal group. Both daytime and nighttime noise was significantly higher in the diagnosed headache group than in the non-diagnosed group. Headache duration increased by daytime and nighttime noise with statistical significance in age-adjusted models. CONCLUSION: We found that noise exposure is correlated to headaches in children and adolescents. Daytime and nighttime environmental noise exposure was significantly associated with the duration of headaches through our data. Therefore, we assume that noise exposure is vitally relevant to prolonged headaches in the pediatric population. Further research is needed to improve our data.

The Impact of an Antimicrobial Stewardship Program on Days of Therapy in the Pediatric Center: An Interrupted Time-Series Analysis of a 19-Year Study.

BACKGROUND: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients. METHODS: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ². RESULTS: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period (P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period (P = 0.881). CONCLUSION: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia.

TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain.

OBJECTIVE: TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-ß1 (TGF-ß1), has been developed as a novel cell-based gene therapy and a candidate for disease modifying osteoarthritis drug (DMOAD). We aim to investigate analgesic mechanism of TG-C in a pre-clinical animal model with monoiodoacetate (MIA)-induced pain. DESIGN: We used a rat MIA model of osteoarthritis (OA) pain. We examined that TG-C can regulate pain by inhibiting the upregulation of various pain mediators in both knee joint tissue and dorsal root ganglia (DRG) (n = 112) and alleviating pain behavior (n = 41) and neuronal hyperexcitability in DRG (n = 60), afferent nerve fiber (n = 24), and spinal cord (n = 35). RESULTS: TG-C significantly alleviated pain-related behavior by restoring altered dynamic weight bearing and reduced mechanical threshold of the affected hindlimb. TG-C significantly suppressed the expression of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) in inflamed joint tissue. TG-C significantly suppressed the upregulation of tropomyosin receptor kinase A (TrkA) and nerve injury/regeneration protein (GAP43) and activation of Iba1-positive microglial cells in DRG. TG-C significantly recovered neuronal hyperexcitability by restoring RMP and firing threshold and frequency of DRG neurons, attenuating firing rates of mechanosensitive C- or Aδ-nerve fiber innervating knee joint, and lowering increased miniature and evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) in the spinal cord. CONCLUSION: Our results demonstrated that TG-C exerted potent analgesic effects in a rat MIA model of OA pain by inhibiting the upregulation of pain mediators and modulating neuronal sensitization.

Complications of the Central Nervous System in Pediatric Patients With Common Cold Coronavirus Infection During 2014-2019.

BACKGROUND: In pediatric patients, the common cold coronavirus (ccCoV) usually causes mild respiratory illness. There are reports of coronavirus causing central nervous system (CNS) infection in experimental animal models. Some immunocompromised patients have also been reported to have fatal CNS infections with ccCoV. The aim of this study was to investigate the clinical characteristics of CNS complications related to ccCoV infection. METHODS: From January 2014 to December 2019, a retrospective analysis was performed of medical records from hospitalized patients under 19 years of age whose ccCoV was detected through polymerase chain reaction in respiratory specimens. The CNS complications were defined as clinically diagnosed seizure, meningitis, encephalopathy, and encephalitis. RESULTS: A total of 436 samples from 420 patients were detected as ccCoV. Among the 420 patients, 269 patients were immunocompetent and 151 patients were immunocompromised. The most common type of ccCoV was OC43 (52% in immunocompetent, 37% in immunocompromised). CNS complications were observed in 9.4% (41/436). The most common type of CNS complication was the fever-provoked seizure under pre-existing neurologic disease (42% in immunocompetent and 60% in immunocompromised patients). Among patients with CNS complications, two immunocompetent patients required intensive care unit admission due to encephalitis. Three patients without underlying neurological disease started anti-seizure medications for the first time at this admission. There was no death related to ccCoV infection. CONCLUSION: ccCoV infection may cause severe clinical manifestations such as CNS complications or neurologic sequelae, even in previously healthy children.

The Changes in Respiratory and Enteric Adenovirus Epidemiology in Korea From 2017 to June 2022.

Since October 2021, severe acute hepatitis of unknown etiology in pediatric patients has been observed in many countries around the world. Adenovirus (mainly enteric adenovirus) was detected in more than 50% of the cases. Nationwide surveillance on acute hepatitis of unknown etiology in pediatric patients was started in May 2022 in Korea. Taking into account the severity of the illness and the urgency of the epidemiological situation worldwide, we report a summary of changes in adenovirus epidemiology during the past five years and six months in Korea.

Susceptibility to Fosfomycin and Nitrofurantoin of ESBL-Positive Escherichia coli and Klebsiella pneumoniae Isolated From Urine of Pediatric Patients.

BACKGROUND: Pediatric urinary tract infection (UTI) caused by extended-spectrum ß-lactamase (ESBL)-positive gram-negative bacilli (GNB) has limited options for oral antibiotic treatment. The purpose of this study was to investigate the susceptibility of ESBL-positive Escherichia coli and Klebsiella pneumoniae isolates from pediatric urine samples to two oral antibiotics (fosfomycin and nitrofurantoin). METHODS: From November 2020 to April 2022, ESBL-positive E. coli and K. pneumoniae isolates from urine samples were collected at Samsung Medical Center, Seoul, Korea. Patients over 18 years of age or with malignancy were excluded. For repeated isolates from the same patient, only the first isolate was tested. Minimum inhibitory concentrations (MICs) were measured using agar (fosfomycin) or broth (nitrofurantoin) dilution methods. MIC50 and MIC90 were measured for fosfomycin and nitrofurantoin in both E. coli and K. pneumoniae. RESULTS: There were 117 isolates from 117 patients, with a median age of 7 months (range, 0.0-18.5 years). Among 117 isolates, 92.3% (108/117) were E. coli and 7.7% (9/117) were K. pneumoniae. Isolates from the pediatric intensive care unit (PICU) and general ward (GW) was 11.1% (13/117) and 88.9% (104/117), respectively. Among 108 E. coli isolates, MIC50 and MIC90 for fosfomycin were 0.5 µg/mL and 2 µg/mL, respectively. Fosfomycin susceptibility rate was 97.2% (105/108) with a breakpoint of 128 µg/mL. Fosfomycin susceptibility rate was significantly lower in PICU isolates than in GW isolates (81.8% vs. 99.0%, P = 0.027). For nitrofurantoin, both the MIC50 and MIC90 were 16 µg/mL. Nitrofurantoin susceptibility rate was 96.3% (104/108) with a breakpoint of 64 µg/mL based on Clinical and Laboratory Standards Institute guidelines. Among the nine K. pneumoniae isolates, the MIC50 and MIC90 for fosfomycin was 2 µg/mL and 32 µg/mL, respectively. MIC50 and MIC90 for nitrofurantoin were 64 µg/mL and 128 µg/mL, respectively. CONCLUSION: For uncomplicated UTI caused by ESBL-positive GNB in Korean children, treatment with fosfomycin and nitrofurantoin for E. coli infections can be considered as an effective oral therapy option.

Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation.

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (Rin) of most LF-GCs is lower than 200 MΩ, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and Rin, but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.SIGNIFICANCE STATEMENT The sparse activity of dentate granule cells (GCs), which is essential for pattern separation, is supported by high inhibitory inputs and low intrinsic excitability of GCs. Low excitability of GCs is thought to be attributable to a high K+ conductance at resting membrane potentials, but this study identifies Kv4.1, a depolarization-activated K+ channel, as a key ion channel that regulates firing of GCs without affecting resting membrane potentials. Kv4.1 expression is developmentally regulated and Kv4.1 currents are detected only in mature GCs that show low-frequency firing, but not in less mature high-frequency firing GCs. Furthermore, mice depleted of Kv4.1 transcripts in the dentate gyrus show impaired pattern separation, suggesting that Kv4.1 is crucial for sparse coding and pattern separation.

Childcare Exposure to Severe Acute Respiratory Syndrome Coronavirus 2 for 4-Year-Old Presymptomatic Child, South Korea.

Data on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from preschool-age children to children and adults are limited. We investigated SARS-CoV-2 exposure at a childcare center in South Korea. A 4-year-old child, probably infected by his grandmother, attended the center during the presymptomatic period (February 19-21, 2020). Fever developed on February 22, and he was given a diagnosis SARS-CoV-2 infection on February 27. At the center, 190 persons (154 children and 36 adults) were identified as contacts; 44 (23.2%) were defined as close contacts (37 children and 7 adults). All 190 persons were negative for SARS-CoV-2 on days 8-9 after the last exposure. Two close contacts (1 child and 1 adult) showed development of symptoms on the last day of quarantine. However, subsequent test results were negative. This investigation adds indirect evidence of low potential infectivity in a childcare setting with exposure to a presymptomatic child.

Epidemiology and Clinical Features of Myocarditis/Pericarditis before the Introduction of mRNA COVID-19 Vaccine in Korean Children: a Multicenter Study.

BACKGROUND: Korean health authority plans to vaccinate adolescents against coronavirus disease 2019 (COVID-19) starting high school seniors during the summer vacation of 2021. However, the myocarditis/pericarditis following COVID-19 vaccine has been reported recently in adolescents and young adults. This study was performed to answer the urgent questions about the basic epidemiology and clinical course of myocarditis/pericarditis in hospitalized patients prior to the introduction of COVID-19 vaccines in pediatric population. METHODS: A retrospective medical record analysis including frequency, clinical characteristics, etiology and outcome of myocarditis/pericarditis was conducted in 17 years and younger patients who were hospitalized in two referral hospitals in Korea between 2010 and 2019. RESULTS: Total 142 patients with myocarditis (n = 119) and/or pericarditis (n = 23) were identified. Median age was 5.4 years (interquartile range, 0.6-12.9 years; range, 11 days-17.8 years), and male was 61%. In adolescents aged 12-17 years, the male to female ratio was 3.2. Myocarditis/pericarditis occurred 0.70 per 1,000 in-patients during the study period: 0.96 (< 1 year), 0.50 (1-5 years), 0.67 (6-11 years) and 1.22 (12-17 years) per 1,000 in-patients, respectively. There was an increasing tendency for the annual frequency from 0.34 in 2010 to 1.25 per 1,000 in-patients in 2019 (P = 0.021). Among the 56 (40%) proven pathogens at admission, Mycoplasma pneumoniae (n = 11, 8%) and enterovirus (n = 10, 7%) were most common. Of the 142 patients, 99 (70%) required pediatric intensive care unit care and 10 (7%) received heart transplantation. In addition, 61 patients (61/131, 47%) without heart medication at admission needed heart medication when they were discharged. Eleven (7.7%) patients died, of which five patients were previously healthy. The median age of deceased patients was lower than the survival group (0.8 vs. 6.3 years, P = 0.014). CONCLUSION: The frequency of myocarditis/pericarditis was highest among male adolescent in-patients; however, the outcome was favorable in this group without any mortality.

Stepwise School Opening and an Impact on the Epidemiology of COVID-19 in the Children.

BACKGROUND: Data on severe acute respiratory syndrome coronavirus-2 transmission from a pediatric index patient to others at the school setting are limited. Epidemiological data on pediatric coronavirus disease 2019 (COVID-19) cases after school opening are warranted. METHODS: We analyzed data of the pediatric patients with COVID-19 collected from the press release of the Korea Centers for Disease Control and Prevention. Information on the school opening delay and re-opening policies were achieved from the press release of the Korean Ministry of Education. RESULTS: The school openings were delayed three times in March 2020. Online classes started from April 9, and off-line (in-person) classes started from May 20 to June 8 at four steps in different grades of students. There was no sudden increase in pediatric cases after the school opening, and the proportion of pediatric cases among total confirmed cases in the nation around 7.0%. As of July 31, 44 children from 38 schools and kindergartens were diagnosed with COVID-19 after off-line classes started. More than 13,000 students and staffs were tested; only one additional student was found to be infected in the same classroom. The proportions of pediatric patients without information on infection sources were higher in older age groups than in younger age groups (17.4% vs. 52.4%, P = 0.014). In the younger age group, 78.3% of children were infected by family members, while only 23.8% of adolescents in the older age group were infected by family members (P < 0.001). CONCLUSION: Korea had a successful transition from school closure to online and off-line school opening, which did not cause significant school-related outbreak among the pediatric population.

Prevalence and prognostic implications of psychological distress in patients with gastric cancer.

BACKGROUND: The aim of this study was to investigate the prevalence and prognostic significance of psychological distress in gastric cancer patients. METHODS: The study population included 229 gastric cancer patients visiting Yonsei Cancer Center between November 2009 and March 2011. The distress was measured by available tools including the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies-Depression Scale (CES-D). Patients with psychological distress were defined as those who scored above the cut-off values in both the MDT and either one of the HADS or CES-D. RESULTS: The median age of patients was 56 (range, 20 to 86) and 97 (42.4%) patients were with stage IV disease status at enrollment. The overall prevalence of psychological distress was 33.6% (95% CI: 27.5-39.8%) in 229 gastric cancer patients. In multiple logistic regression analysis, lower education level (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.11-5.17, P = 0.026) and higher disease stage (OR 2.72; 95% CI 1.47-5.03, P = 0.001) were associated with psychological distress. In stage I-III disease, patients with psychological distress had worse disease-free survival (DFS) (5-year DFS rate: 60% vs 76%, P = 0.49) compared with those without psychological distress. In stage IV disease (n = 97), patients with psychological distress showed poorer overall survival than those without psychological distress (median OS (Overall Survival): 12.2 vs. 13.8 months, P = 0.019). CONCLUSION: Psychological distress is common in patients with all stages of gastric cancer and is associated with worse outcomes.

Altered intrinsic brain activity after chemotherapy in patients with gastric cancer: A preliminary study.

OBJECTIVES: To characterize the pattern of altered intrinsic brain activity in gastric cancer patients after chemotherapy (CTx). METHODS: Patients before and after CTx (n = 14) and control subjects (n = 11) underwent resting-state functional MRI (rsfMRI) at baseline and 3 months after CTx. Regional homogeneity (ReHo), amplitude of low-frequency fluctuation (ALFF), and fractional ALFF (fALFF) were calculated and compared between the groups using the two-sample t test. Correlation analysis was also performed between rsfMRI values (i.e., ReHo, ALFF, and fALFF) and neuropsychological test results. RESULTS: Patients showed poor performance in verbal memory and executive function and decreased rsfMRI values in the frontal areas even before CTx and showed decreased attention/working memory and executive function after CTx compared to the control subjects. In direct comparison of values before and after CTx, there were no significant differences in neuropsychological test scores, but decreased rsfMRI values were observed at the frontal lobes and right cerebellar region. Among rsfMRI values, lower ALFF in the left inferior frontal gyrus was significantly associated with poor performance of the executive function test. CONCLUSIONS: We observed decreased attention/working memory and executive function that corresponded to the decline of frontal region activation in gastric cancer patients who underwent CTx. KEY POINTS: • Intrinsic brain activity of gastric cancer patients after chemotherapy was described. • Brain activity and neuropsychological test results were correlated. • Working memory and executive function decreased after chemotherapy. • Decreased cognitive function corresponded to decreased activation of the frontal region.

Neurocognitive impairments in individuals at ultra-high risk for psychosis: Who will really convert?

OBJECTIVE: Impairments in neurocognitive function are considered as core features of schizophrenia. Individuals at ultra-high risk (UHR) for psychosis, the 'putative' prodrome of schizophrenia, generally show levels of impairments intermediate between schizophrenia patients and healthy controls. We investigated the neurocognitive performance of individuals at UHR for psychosis, comparing them with patients with first-episode schizophrenia (FES) and healthy controls (HC), and explored the predictivity of baseline neurocognitive function in the UHR group for transition to overt psychosis. METHOD: Individuals at UHR for psychosis (n = 60), patients with FES (n = 39), and HC subjects (n = 94) participated in the present study. All participants performed a comprehensive neurocognitive battery, consisting of tests for five separate neurocognitive domains (executive function, attention/working memory, processing speed, verbal memory, and spatial memory). UHR subjects were assessed for transition every month during 24 months of follow-up. RESULTS: Neurocognitive performance in the UHR group was largely at intermediate levels. Attention/working memory and verbal memory were significantly different from both the FES and HC groups. In the UHR group, processing speed was decreased to the level of the FES group, while executive function and spatial memory were relatively preserved. In the Cox regression model, spatial memory significantly predicted the transition to overt psychosis in the UHR group. CONCLUSIONS: The present study showed that neurocognitive impairments were evident in UHR individuals prior to the onset of overt psychosis. Our findings generally support the neurodevelopmental model of schizophrenia and suggest that there could be different developmental trajectories between converters and non-converters.

Antimicrobial resistance genes harbored in invasive Acinetobacter calcoaceticus-baumannii complex isolated from Korean children during the pre-COVID-19 pandemic periods, 2015-2020.

Background: Acinetobacter baumannii (AB) has emerged as one of the most challenging pathogens worldwide, causing invasive infections in the critically ill patients due to their ability to rapidly acquire resistance to antibiotics. This study aimed to analyze antibiotic resistance genes harbored in AB and non-baumannii Acinetobacter calcoaceticus-baumannii (NB-ACB) complex causing invasive diseases in Korean children. Methods: ACB complexes isolated from sterile body fluid of children in three referral hospitals were prospectively collected. Colistin susceptibility was additionally tested via broth microdilution. Whole genome sequencing was performed and antibiotic resistance genes were analyzed. Results: During January 2015 to December 2020, a total of 67 ACB complexes were isolated from sterile body fluid of children in three referral hospitals. The median age of the patients was 0.6 (interquartile range, 0.1-7.2) years old. Among all the isolates, 73.1% (n=49) were confirmed as AB and others as NB-ACB complex by whole genome sequencing. Among the AB isolates, only 22.4% susceptible to carbapenem. In particular, all clonal complex (CC) 92 AB (n=33) showed multi-drug resistance, whereas 31.3% in non-CC92 AB (n=16) (P<0.001). NB-ACB showed 100% susceptibility to all classes of antibiotics except 3rd generation cephalosporin (72.2%). The main mechanism of carbapenem resistance in AB was the bla oxa23 gene with ISAba1 insertion sequence upstream. Presence of pmr gene and/or mutation of lpxA/C gene were not correlated with the phenotype of colistin resistance of ACB. All AB and NB-ACB isolates carried the abe and ade multidrug efflux pumps. Conclusions: In conclusion, monitoring and research for resistome in ACB complex is needed to identify and manage drug-resistant AB, particularly CC92 AB carrying the bla oxa23 gene.

Effect of Low-Intensity Transcranial Focused Ultrasound Stimulation in Patients With Major Depressive Disorder: A Randomized, Double-Blind, Sham-Controlled Clinical Trial.

OBJECTIVE: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. METHODS: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. CONCLUSION: Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.

Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca²âº dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood. We found that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca²âº handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca²âº dysregulation caused an impairment of post-tetanic potentiation in mossy fiber-CA3 synapses. The alteration of cellular Ca²âº clearance in Tg2576 mice is region-specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca²âº clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca²âº uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes.

Neural evidence for emotional involvement in pathological alcohol craving.

AIMS: Reducing craving is a key to success in the treatment of alcohol dependence. The emotion circuit may be involved in pathological craving for alcohol. In this study, we investigated neural correlates of emotional involvement in craving in alcohol dependence. METHODS: The study included 17 detoxified alcoholic patients and 25 social drinkers. We used functional magnetic resonance imaging to examine brain activation (blood oxygen level-dependent signals) while participants reported craving and emotion in response to visually presented, alcohol-related stimuli and emotional stimuli. RESULTS: In the craving-rating paradigm, negative emotional stimuli as well as alcohol cues activated craving-related brain regions in alcoholic patients. Activations of the inferior parietal lobule and dorsolateral prefrontal cortex by negative emotional stimuli were negatively correlated with craving; meanwhile limbic activation was positively correlated with craving. For the emotion paradigm, greater limbic activation was evident by alcohol-related stimuli in the alcohol-dependent group. CONCLUSIONS: Our findings constitute neural evidence for emotional involvement in pathological craving for alcohol, underscoring the importance of emotion management in abstinent alcoholic patients for relapse prevention.

Reevaluation of patients with bipolar disorder on manic episode: improving the diagnosing of mixed episode.

Mixed manic/depressive episodes in patients with bipolar disorder are underdiagnosed because of restrictive diagnostic criteria. Using the broader definition of a mixed episode represented by the Cincinnati criteria, we reevaluated the medical records of patients with bipolar disorder hospitalized for a manic episode. We also examined the predictive power of previously unrecognized depressive symptoms. Of 520 inpatients with mania, we retrospectively diagnosed 59 (11.3%) as having a probable mixed episode. Compared with the patients with pure mania, the patients with mixed episodes were more likely to have a family history of psychiatric illness, comorbid personality disorder, and a history of suicide attempts. Binary logistic regression revealed that loss of interest, loss of energy, feelings of worthlessness, and feelings of helplessness had good positive predictive value (>0.7) for mixed episodes. Accurate diagnosis of mixed episodes may require a broadening of diagnostic criteria and emphasis on symptoms such as loss of interest, loss of energy, and feelings of worthlessness and helplessness.