Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.

Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.

Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1 A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.

Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature.

BACKGROUND: The pandemic the coronavirus disease 2019 (COVID-19) has created a global health crisis. Although Paxlovid is recommended for the early-stage treatment of mild-to-moderate COVID-19 in patients at increased risk of progression to severe COVID-19, more and more cases are reported a COVID-19 rebound after Paxlovid treatment. Currently, information on the additional treatment for COVID-19 rebound following Paxlovid treatment is limited. CASE REPORT: Here, we present four cases with COVID-19 who were mild on admission. All cases experienced a COVID-19 rebound and progressed to severe COVID-19, following treatment with Paxlovid (300 mg of nirmatrelvir with 100 mg ritonavir, twice daily for 5 days). After being treated with proxalutamide (300 mg/day), all cases finally turned real-time reverse transcription polymerase chain reaction (RT-PCR) negative. CONCLUSION: Our cases suggested that proxalutamide might be an effective remedial treatment option for patients experiencing a COVID-19 rebound after Paxlovid treatment.

Identify nitrogen transport paths and sources contribution in karst valley depression area using isotopic approach.

Karst groundwater provides drinking water for a quarter of Earth's population. However, in intensive agricultural regions worldwide, karst water is commonly polluted by nitrate (NO3-), particularly in the valley depression areas with well hydrological connectivity. The valley depression aquifers are particularly vulnerable to anthropogenic pollution because their pipes and sinkholes respond quickly to rainfall events and anthropogenic inputs. Identifying nitrate sources and transport paths in the valley depression areas is key to understanding the nitrogen cycle and effectively preventing and controlling NO3- pollution. This study collected high-resolution samples at four sites including one surface stream-SS, two sinkholes-SH and reservoir-Re, during the wet season in the headwater sub-catchment. The chemical component concentrations and stable isotopes (δ15N-NO3- and δ18O-NO3-) were analyzed. The stable isotope analysis model in R language (SIAR) was used to quantitatively analyze the contribution rate of NO3- sources. The results showed that the down section site (Re) has the highest [NO3--N], followed by SH and the lowest SS. The sources calculation of SIAR demonstrated that, during the non-rainfall period, soil organic nitrogen was the primary source of the down section site, followed by fertilizer and the upper reaches sinkholes. During the rainfall period, fertilizer was the primary source of the down section site, followed by soil organic nitrogen and from upper reaches sinkholes. Rainfall events accelerated fertilizer-leaching into the groundwater. Slight denitrification may have occurred at the sampling sites but the assimilation of Re and SH could not occur. In conclusion, agricultural activities were still the primary influencing factor of [NO3--N] in the study area. Therefore, the focus of NO3- prevention and control in the valley depression areas should consider the methods and timing of fertilization and the spatial distribution of sinkholes. To reduce nitrogen flux in the valley depression area, effective management policy should consider, e.g., prolongation of water residence time by wetland, and blocking nitrogen loss paths by sinkholes.

The efficacy of hydrogen/oxygen therapy favored the recovery of omicron SARS-CoV-2 variant infection: results of a multicenter, randomized, controlled trial.

Clinical studies had found that hydrogen/oxygen mixed inhalation was beneficial to ameliorate the respiratory symptoms in the adjuvant treatment of patients with COVID-19. We aimed to explore the efficacy of hydrogen/oxygen therapy in favoring the recovery of Omicron SARS-CoV-2 variant infection. There were 64 patients who randomly assigned to receive hydrogen/oxygen inhalation (32 patients) and oxygen inhalation (32 patients). The average shedding duration of Omicron in hydrogen/oxygen group was shorter than oxygen group. The trend of cumulative negative conversion rate of Omicron increased gradually after the third day. The IL-6 levels in hydrogen/oxygen group decreased by 22.8% compared with the baseline. After hydrogen/oxygen mixed gas inhalation, the lymphocyte count increased to 61.1% of the baseline on the 3rd day in the hydrogen/oxygen group. More patients in the hydrogen/oxygen group had resolution of pulmonary lesions. Our study showed the beneficial trends of molecular hydrogen in treating patients with COVID-19, which may offer a prospective solution to adjuvant therapy for COVID-19 Patients.

[Academic characteristics of contemporary famous traditional Chinese medicine experts and schools in treatment of chronic renal failure based on SrTO].

According to the systematic review of text and opinion(SrTO) developed by the Joanna Briggs Institute(JBI), this study integrated the evidence of the medical cases, papers, medical experience, and other related research of famous experts and schools on the treatment of chronic renal failure in the field of traditional Chinese medicine(TCM) nephropathy, analyzed the academic characteristics and influencing factors from the aspects of the principle, method, recipe, and medicines, and explored the internal logic and law of inheritance and innovation in TCM nephropathy. A total of 36 famous TCM experts and 4 schools were included. The work areas are concentrated in North and South China. 94.0% of the famous TCM experts have experienced master-disciple teaching. 27.8% have studied TCM through family succession. 38.9% have been taught by multiple famous teachers. And 5.6% have not experienced master-disciple teaching. In terms of principle, method, recipe, and medicines, many innovations have been made, with 30.6% of famous TCM experts proposing new theories, 11.1% advocating staged treatment of chronic renal failure, and 47.2% summarizing the treatment methods. The formation of the academic thoughts of contemporary famous TCM experts and schools on the treatment of chronic renal failure is closely related to the learning mode, era, and work area. Contemporary famous TCM experts and schools have the academic characteristics of combining classical and clinical theories and paying more attention to TCM with western medicine supplemented. The field of TCM nephropathy has the characteristics of simultaneous inheritance and innovation. On the basis of inheriting the classical theories of TCM, it absorbs modern medical theories, combines clinical diagnosis with the syndrome and treatment law of contemporary diseases, and makes innovations in principle, method, recipe, and medicines, which has significant clinical efficacy in the treatment of chronic renal failure.

Single-Component White Light Emission from a Metal-Coordinated Cyclotriveratrylene-Based Coordination Polymer.

A coordination polymer, namely, [Cd3L(H2O)3]·DMA·4H2O (1) (DMA = N,N-dimethylacetamide), was prepared by the solvothermal reaction of cyclotriveratrylene-based ligand 5,6,12,13,19,20-hexacarboxy-methoxy-cyclotriveratrylene (H6L) and Cd(NO3)2·4H2O. In 1, a two-dimensional structure was constructed by the connection of hexanuclear Cd-O clusters and L6- anions. Photoluminescence measurements indicated that 1 displayed tunable photoluminescence through the variation of the excitation wavelength. Significantly, the white light emission of 1 can be observed with a broad excitation wavelength range from 320 to 385 nm. When 1 is excited by 385 nm light, its chromatic coordinate is (0.29, 0.34), which is located very close to the pure white light region (0.33, 0.33). Meanwhile, the color temperature (CCT) is 7994 K, which corresponds well to "cold" white light.

The presence and co-incidence of geriatric syndromes in older patients with mild-moderate Lewy body dementia.

INTRODUCTION: Geriatric symptoms are common in dementia cases, while few studies have focused on these symptoms in Lewy body dementia (LBD). The purpose of this study is to investigate the distributions of Apolipoprotein E (APOE) ε4 and geriatric symptoms, and explore their associaitons in Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: A retrospective study with 185 mild-moderate probable DLB (n = 93) and PDD (n = 92) patients was assigned. Demographic and clinical characteristics, neuropsychological assessments, and APOE genotypes were recorded. Description, correlation and logistic regression models were used to analyze the presence of geriatric symptom complaints and their associations with APOE ε4. RESULTS: DLB patients displayed more frequency of fluctuating cognition, visual hallucination, rapid eye movement sleep behavior disorder, delusion, depression, anxiety, apathy, and loss of appetite, whereas the PDD cases had constipation, fear of falling, and insomnia more frequently. The APOE ε4 allele was more common in DLB than PDD (29.9% vs. 7.0%, p < 0.001), and the patients with DLB + APOE ε4 (+) were presented more delusions (p = 0.005) and apathy (p = 0.007) than patients with PDD + APOE ε4 (+). We also found that the APOE ε4 allele was significantly associated with hyperhidrosis (OR = 3.472, 95%CI: 1.082-11.144, p = 0.036) and depression (OR = 3.002, 95%CI: 1.079-8.353, p = 0.035) in DLB patients, while there were no significant associations between APOE ε4 allele and the age at visit, the age at onset, scores of MDS-UPDRS III, H&Y stage, ADL, MMSE, MOCA and NPI, as well as the presences of fluctuating cognition, VH, parkinsonism and RBD in both groups. CONCLUSION: The presence and co-incidence of geriatric symptoms are common in patients with mild-moderate LBD. The presence of APOE ε4 allele is associated with hyperhidrosis and depression, but not global cognition, activitives of daily life, motor function and other neuropsychitric symptoms in DLB. These findings improve the awareness of geriatric symptoms, and contribute to the healthcare management of mild-moderate DLB and PDD.

Survival and causes of death among people with clinically diagnosed dementia with Lewy bodies: A multicenter cohort study.

OBJECTIVE: A comprehensive study of the survival and causes of death of people with clinically diagnosed Dementia with Lewy bodies (DLB) were few. The aim of our study was to investigate the survival and causes of death of DLB. METHODS: The patients diagnosed with probable DLB were consecutively enrolled from five memory clinics in China across a 5-year period (2017-2021) with mortality data updated to December 2021. The endpoint was all-cause death. Survival analysis including Cox regression by groups (time both from disease onset and the first visit to death) and causes of death were evaluated. RESULTS: Of the 108 patients with DLB, 54 (50%) were men and the time from onset of disease to the first visit to the memory clinic (lag time) was 24 (12-48) months. During follow-up, 28.7% (n = 31) of the patients died. The median survival time both from disease onset and the first visit were 81 (95% cognitive impairment (CI) 69.09-92.91) and 45 (95% CI 34.78-55.22) months, respectively. The use of antipsychotic drugs (HR 0.15, 95% CI: 0.03-0.75), moderate to severe dementia (Clinical Dementia Rating [CDR]) at the first visit (HR 0.22, 95% CI 0.78 to 0.62) and the longer lag time (HR 0.943, 95% CI 0.92-0.97) predicted a shorter survival. Failure to thrive (stopped eating, drinking) or multiple organ dysfunction syndrome (MODS) maybe the most common cause of death (41.7%), followed by pneumonia or aspiration (29.2%). CONCLUSIONS: The factors associated with survival time were disease severity level, antipsychotic drug use and lag time to seek medical advice. Failure to thrive or MODS and pneumonia were probably the most common cause of death. The long-term outcomes of DLB patients may be helpful to guide clinicians counseling patients and caregivers.

Association between marital status and cognitive impairment based on a cross-sectional study in China.

BACKGROUND: Marital status may have an impact on the elderly population's health, but few studies in China discussed about the association between marital status and cognitive impairment. OBJECTIVE: To investigate the relationship between marital status and cognitive impairment. To compare the influences of marital status on dementia between men and women. METHODS: This study was based on a representative national cross-sectional epidemiological survey in China. We randomly selected 13 provinces and municipalities and included 19,276 participants aged 65 years or older in our study. Data was collected by interviewing the participants about their sociodemographic characteristics, and neuropsychological testing was administered to the participants by neurologists. To analyze the association between marital status and cognitive impairment, multiple logistic regression was based on a series of models. RESULTS: Among the 19,276 subjects, about 77.2% were married, 1.6% were single, 21.2% were divorced/separated or widowed. The odds ratios (OR) of dementia were higher in single (OR: 2.13, CI: 1.53-2.97; p < 0.001), divorced/separated/widowed when they were ≤55 years old (OR: 1.75, CI: 1.30-2.35; p < 0.001), and divorced/separated/widowed when they were >55 years old (OR: 1.16, CI: 1.03-1.31; p < 0.001) participants than in married ones. Divorced/separated/widowed ≤55 men had about 2.75 times increase in dementia risk than married men. CONCLUSION: People with long-term divorced/separated/widowed status would be associated to cognitive impairment more than those with short-term divorced/separated/widowed status. Men may be affected by marriage disruption more than women in terms of increasing the risk of dementia.

Time interval between alfentanil and rocuronium administration necessary to prevent rocuronium-induced withdrawal movement.

BACKGROUND: We aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50). METHODS: A total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 µg/mL. Then, alfentanil 15 µg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon's up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection. RESULTS: The TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2-7.6 s) and 20.3 s (95% CI, 7.7-26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7-25.3 s) and 35.0 s (95% CI, 28.1-95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P < 0.001). Compared with the T0, MAP and HR decreased significantly at T1 and T2 in both groups. CONCLUSION: The TimeAR50 required for preventing rocuronium-induced withdrawal movement were 4.7 s and 20.3 s in male and female patients, respectively. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trials Registry on April 7, 2021 (URL: http://www.chictr.org.cn . Registry number: ChiCTR2100045137 ) .

Intracranial drainage versus extracranial shunt in the treatment of intracranial arachnoid cysts: a meta-analysis.

OBJECTIVE: To review the literature and analyze the efficacy and safety of two surgery procedures, intracranial drainage and extracranial shunt, for intracranial arachnoid cysts. METHODS: We searched the online Medlars, PubMed, and Cochrane Central electronic databases and collected studies of patients with intracranial arachnoid cysts treated with two surgical methods. RESULTS: The meta-analysis results shows that there were not statistically significant in clinical symptoms improvement, cyst reduction, the improvement of epilepsy, epidural hematoma, cerebrospinal fluid leak, and recurrence rate (P > 0.05, with RR values are 0.99, 0.94, 1.00, 0.94, 1.21, and 0.75 respectively). There was statistically significant in the occurrence rate of intracranial infection (P = 0.0004, RR = 0.28). The intracranial drainage group was lower than extracranial shunt group. CONCLUSION: The results indicated that the efficacy and safety of two surgery procedures are similar in the treatment of intracranial arachnoid cysts, but the intracranial drainage was better than extracranial shunt in reducing the risk of intracranial infection.

Twenty-four-week interim outcomes of bedaquiline-containing regimens in treatment of adolescents with rifampicin-resistant tuberculosis: A retrospective cohort study in China.

AIM: To evaluate the 24-week interim outcomes of bedaquiline-containing regimens in the treatment of adolescents with rifampicin-resistant tuberculosis (RR-TB) in China. METHODS: Adolescents with RR-TB from two hospitals were included in this retrospective study. All patients received the longer regimen containing bedaquiline. Sputum culture, chest computed tomography, blood tests and electrocardiography were performed regularly, and the outcomes after 24 weeks of treatment were reported. RESULTS: Four male and six female adolescents aged 11 to 17 years old were included. Among them, four (40.0%), four (40.0%) and two (20.0%) were confirmed to have RR-TB, multidrug-resistant TB and extensively drug-resistant TB, respectively. The most common companion drugs included linezolid (100.0%), cycloserine (90.0%), pyrazinamide (80.0%), moxifloxacin (50.0%) and levofloxacin (40.0%). Culture conversion rates of 80.0%, 100.0% and 100.0% were observed at weeks 2, 4 and 24, respectively. The mean maximum drug concentration of bedaquiline at weeks 2, 12 and 24 was 3.29 ± 0.66, 1.78 ± 0.81 and 1.93 ± 0.74 µg/mL, respectively. Six adverse events including leukopenia (50.0%), Fridericia-corrected QT (QTcF) interval prolongation (16.7%), anaemia (16.7%) and peripheral neuropathy (16.7%) were observed in five (50.0%) patients. No patient discontinued bedaquiline owing to QTcF interval prolongation. Meanwhile, no deaths, reversions or serious adverse events were reported during 24 weeks of treatment. CONCLUSION: A longer regimen containing bedaquiline was effective and well tolerated in Chinese adolescents with RR-TB. The combination of bedaquiline and linezolid may be a favourable choice for this population.

Prevalence and risk factors of stroke in a rural area of northern China: a 10-year comparative study.

BACKGROUND AND AIMS: Stroke is currently the leading cause of death in China; however, the past decade has produced no new epidemiological studies of stroke. Therefore, the current study aimed to compare the prevalence and risk factors of stroke between 2010 and 2019. METHODS: A comparative study was used to analyze the prevalence of risk factors for stroke in a population aged 65 years or older between 2010 and 2019. Demographic characteristics, risk factors, medical history, and other clinical characteristics were collected for all participants via door-to-door interviews and inpatient hospital records. RESULTS: The standardized prevalence of stroke was 7.9% in 2010 and 14.2% in 2019 (p < 0.001). The prevalence of stroke was significantly higher in men than in women (p < 0.05) for all age groups. The risk factors of stroke were being male, hypertension, and diabetes mellitus in both 2010 and 2019. When comparing the risk factors between 2010 and 2019, these risk factors were statistically significantly more strongly associated with stroke in 2019 than in 2010. CONCLUSION: The current study suggests that the prevalence of stroke increased nearly by twofold in a population aged 65 years or older within the past 10 years. Hypertension, diabetes mellitus, and being male were the primary risk factors. In addition, these factors were more significantly associated with stroke in 2019 compared to 2010.

Application of Dexmedetomidine combined with Propofol Intravenous Anesthesia in Laparoscopic Day Surgery in Pediatric Urology.

OBJECTIVES: To evaluate the sedative and analgesic effects of dexmedetomidine combined with propofol intravenous anesthesia in laparoscopic day surgery in pediatric urology. METHODS: Eighty male children with cryptorchidism and hydrocele who underwent laparoscopic daytime surgery in our hospital from January 2019 to January 2021 were selected and randomly divided into two groups: the experimental group and the control group. Children in the experimental group ranged in age from 5.7 to 11.3, with an average of 8.52±2.17 years old, while those in the control group ranged in age from 5.3 to 12.0, with an average of 8.60±2.07 years old. There were 12 cases of cryptorchidism and 28 cases of hydrocele in the experimental group, and 14 cases of cryptorchidism and 26 cases of hydrocele in the control group. Children in the control group received conventional propofol intravenous combined anesthesia, while those in the experimental group were given dexmedetomidine (2-5 ug/kg) intranasally on the basis of conventional propofol intravenous anesthesia. The anesthetic effect, analgesic effect, serum levels of inflammatory cytokines before and after surgery and adverse drug reactions in the two groups were compared and analyzed. RESULTS: The awakening time, extubation time and retention time in the resuscitation room of the experimental group were shorter than those of the control group, with a statistically significant difference (P<0.05); The VAS pain scores of the experimental group were significantly lower than those of the control group at 15minutes, 12hour and 24hour after awakening, with a statistically significant difference (P<0.05). In addition, the levels of TNF-a, CRP, IL-6 and other inflammatory factors in the control group were significantly higher compared with those in the experimental group 24h after surgery, with a statistical significance (TNF-a, P=0.02; CRP, P=0.00; IL-6, P=0.03); The incidence of adverse drug reactions in the experimental group was 17.5%, while that in the control group was 12.5%, which was not statistically significant (P=0.53). CONCLUSION: Dexmedetomidine combined with intravenous propofol anesthesia may be helpful to shorten the extubation time, the recovery time and the stay time in the anesthesia resuscative room, improve the analgesic effect, and may reduce the inflammatory response and the expression of serum inflammatory cytokines, with no significant increase in side effects.

Observation on the clinical effect of high-dose Intravenous Immunoglobulin combined with low-dose prednisone acetate in the treatment of patients with Kawasaki Disease.

OBJECTIVE: To evaluate the clinical effect of high-dose intravenous immunoglobulin (HDIVIG) single dose and pulse therapy combined with small-dose prednisone acetate in the treatment of patients with Kawasaki disease (KD). METHODS: Eighty patients with KD from Baoding Children's Hospital, China, were randomly divided into two groups: the experimental group and the control group, each with 40 cases. Patients in the experimental group were treated with HDIVIG single dose, pulse therapy combined with low-dose prednisone acetate, while patients in the control group were treated with conventional-dose immunoglobulin. Patients in both groups were treated with aspirin orally, and given symptomatic treatment including anti-inflammatory, nutritional support, correction of water and electrolyte disturbance and acid-base balance. Peripheral venous blood samples were drawn from all patients at the time of admission, Day-1, Day-7 and Day-14 after treatment, and in the basic state of getting up in the morning, and then the levels of tumor necrosis factor (TNF-a), C-reactive protein (CRP), interleukin-6 (IL-6) and other inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The time of body temperature falling to normal, lymph node swelling recovery, hands and feet swelling, mucosal hyperemia regression after treatment in the two groups was recorded, and the treatment effect of the two groups was comprehensively evaluated. RESULTS: After treatment, the levels of inflammatory factors such as TNF-a, CRP, IL-6 in the experimental group were significantly lower than those in the control group, with a statistically significant difference (P<0.05). In addition, the time of body temperature falling to normal, lymph node swelling recovery, hands and feet swelling, and mucosal hyperemia regression in the experimental group was significantly shorter than that in the control group (p=0.00). The effective rate of the experimental group was 95% and that of the control group was 80%, with a statistically significant difference (p=0.04). CONCLUSION: HDIVIG single dose, pulse therapy combined with small-dose prednisone acetate has a favourable therapeutic effect in the treatment of patients with KD, by which the inflammatory factors can be significantly improved, clinical symptoms and weight can be quickly ameliorated, and therapeutic effect can be enhanced.

The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer's Disease: A Preclinical Study in APP/PS1 Transgenic Mice.

BACKGROUND: Depression is highly related to Alzheimer's disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. METHODS: Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. RESULTS: In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin-eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. CONCLUSIONS: Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

Gemfibrozil improves lipid metabolism in Nile tilapia Oreochromis niloticus fed a high-carbohydrate diet through peroxisome proliferator activated receptor-α activation.

High carbohydrate diet (HCD) can induce lipid metabolism disorder, characterized by excessive lipid in farmed fish. Peroxisome proliferator activated receptor-α (PPARα) plays an important role in lipid homeostasis. In this study, we hypothesize that PPARα can improve lipid metabolism in fish fed HCD. Fish (3.03 ± 0.11 g) were fed with three diets: control (30% carbohydrate), HCD (45% carbohydrate) and HCG (HCD supplemented with 200 mg/kg gemfibrozil, an agonist of PPARα) for eight weeks. The fish fed HCG had higher growth rate and protein effiency than those fed the HCD diet, whereas the opposite trend was observed in feed conversion ratio, hepatosomatic index and mesenteric fat index. Additionally, fish fed HCG significantly decreased lipid accumulation in the whole body, liver and adipose tissues compared to those fed the HCD diet. Furthermore, fish in the HCG group significantly increased the mRNA and protein expression and protein dephosphorylation of PPARα. The HCG group also significantly increased the mRNA level of the downstream target genes of PPARα, whereas the opposite trend occured in the mRNA level of lipolysis-related genes compared to the HCD group. Besides, fish in the HCG group remarkably decreased the contents of alanine aminotransferase, aspartate aminotransferase and malondialdehyde, whereas the opposite occured in the activities of antioxidative enzymes and anti-inflammatory cytokine genes compared to the HCD group. This study indicates that gemfibrozil can improve lipid metabolism and maintain high antioxidant and anti-inflammatory capacity through activating PPARα in Nile tilapia fed a high carbohydrate diet.

Functional rs6265 polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in posttraumatic stress disorder among Chinese patients with hepatocellular carcinoma.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that plagues trauma survivors. Evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the occurrence and development of PTSD. Here we tried to demonstrate whether BDNF gene polymorphisms are correlated with neurocognitive function following PTSD in patients with hepatocellular carcinoma (HCC). This study included 102 patients with HCC complicated with PTSD, 146 HCC patients, and 152 healthy volunteers. Initially, we evaluated the neurocognitive function of the study subjects. Next, we measured BDNF G11757C and rs6265 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. The correlation of BDNF polymorphisms and BDNF level with HCC complicated with PTSD was evaluated. The results revealed that HCC complicated with PTSD showed decreased serum BDNF level and Mini-mental state examination (MMSE) score. Serum BDNF level of HCC and HCC complicated with PTSD was positively correlated with MMSE score. GA + AA allele and A allele of rs6265 increased the risk of PTSD among patients with HCC. GA and AA genotypes of rs6265 were correlated with the decreased MMSE score of HCC complicated with PTSD. Haplotype GA of rs6265 and G11757C increased the risk of PTSD for HCC, while haplotype CG decreased this risk. Lastly, the logistic regression analysis suggested that low BDNF level was a contributor to HCC complicated with PTSD, while GG genotype of rs6265 served as a protective factor. Collectively, this study defines the GG genotype of BDNF rs6265 polymorphism as a protector to HCC complicated with PTSD. In addition, these results provided a promising target for PTSD prevention in patients with HCC.

Tacrolimus Levels in the Prophylaxis of Acute Graft-Versus-Host Disease in the Chinese Early After Hematopoietic Stem Cell Transplantation.

BACKGROUND: Tacrolimus has been widely accepted as the backbone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (alloHSCT). The present work evaluated whether tacrolimus concentrations early after transplant correlate with the incidence of aGVHD in Chinese alloHSCT recipients. METHODS: One hundred four Chinese alloHSCT recipients were included in this retrospective study. All patients received standard prophylaxis with tacrolimus and short-term methotrexate. Blood samples were taken at steady-state for those on i.v. tacrolimus (Cv) or predose (C0) and 2 hours after the last oral dose (C2). RESULTS: In the first 8 weeks after alloHSCT, significant variability in Cv, C0, and C2 of Chinese patients was observed. It was found that higher tacrolimus C0 and C2 values tended to be associated with a reduced risk of aGVHD, although this was a nonsignificant trend due to the small sample size involved. Receiver operating characteristic curve analysis indicated that Cv levels of ≥16.52 ng/mL, C0 levels of ≥5.56 ng/mL, and C2 levels of ≥7.83 ng/mL minimized the incidence of treatment failure during weeks 3-4 with intravenous administration and weeks 5-6 with oral administration. There was no statistically significant association of the patient liver and kidney function with the blood concentration of tacrolimus in the desired range of 5-20 ng/mL. CONCLUSIONS: Tacrolimus therapeutic drug monitoring improved treatment outcomes of Chinese alloHSCT recipients. Cv measurements during weeks 3-4 and C0 or C2 measurements during weeks 5-6 better predicted aGVHD (I-IV) than the concentrations measured at other time points during the first 6 weeks after alloHSCT.