Targeting TYK2 for Fighting Diseases: Recent Advance of TYK2 Inhibitors.

TYK2 (tyrosine-protein kinase 2) is a non-receptor protein kinase belonging to the JAK family and is closely associated with various diseases, such as psoriasis, inflammatory bowel disease, systemic lupus erythematosus. TYK2 activates the downstream proteins STAT1-5 by participating in the signal transduction of immune factors such as IL-12, IL-23, and IL-10, resulting in immune expression. The activity of the inhibitor TYK2 can effectively block the transduction of excessive immune signals and treat diseases. TYK2 inhibitors are divided into two types of inhibitors according to the different binding sites. One is a TYK2 inhibitor that binds to JH2 and inhibits its activity through an allosteric mechanism. The representative inhibitor is BMS-986165, developed by Bristol-Myers Squibb. The other class binds to the JH1 adenosine triphosphate (ATP) site and prevents the catalytic activity of the kinase by blocking ATP and downstream phosphorylation. This paper mainly introduces the protein structure, signaling pathway, synthesis, structure-activity relationship and clinical research of TYK2 inhibitors.

Balancing Act: Exploring the Gut Microbiota-Brown Adipose Tissue Axis in PCOS Pathogenesis and Therapeutic Frontiers.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive, endocrine, and metabolic disease that affects 5-18% of women worldwide, with a rising incidence. Hyperandrogenemia and insulin resistance are two key pathophysiological factors that contribute to PCOS, both of which contribute to a variety of health issues such as menstrual irregularities, obesity, dysfunctional glucose and lipid homeostasis, infertility, mental disorders, and cardiovascular and cerebrovascular diseases. Despite ongoing studies, the origin and pathogenesis of PCOS remain elusive; there is also a clinical need for simpler, more effective, longer lasting, and more comprehensive treatments for women with PCOS. The gut-fat axis, a critical regulatory route for metabolism, endocrine function, and immune response, has received considerable interest in recent years in the research of the etiology and treatment of metabolic illnesses such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. The latest research in PCOS has revealed significant alterations in the homogeneity and phylogenetic diversity of the gut microbiota. Animal research using fecal microbiota transplantation has confirmed the importance of gut microbiota in regulating insulin sensitivity and sex hormone balance in PCOS. Furthermore, studies have shown a decrease in the volume and/or activity of brown adipose tissue (BAT) in PCOS patients, a change that alters adipokine release, leading to insulin resistance and hyperandrogenemia, aggravating PCOS progression. Given the function of BAT in increasing energy expenditure and alleviating metabolic parameters, efforts to activate BAT or induce browning of white adipose tissue have emerged as possible treatments for PCOS. Recent research has suggested that the gut microbiota can influence BAT creation and activity via metabolites such as short-chain fatty acids and bile acids, as well as the gut-brain axis. Cold exposure, healthy dieting, metformin, bariatric surgery, glucagon-like peptide 1 receptor agonists and melatonin have all been shown in basic and clinical studies to modulate BAT activity by influencing the gut microbiota, demonstrating significant clinical potential. However, more studies into the regulation mechanisms of the gut-BAT axis are required to produce more effective, comfortable, and safe tailored therapeutics for PCOS.

Ionic Diffusive Nanomemristors with Dendritic Competition and Cooperation Functions for Ultralow Voltage Neuromorphic Computing.

Realization of dendric signal processing in the human brain is of great significance for spatiotemporal neuromorphic engineering. Here, we proposed an ionic dendrite device with multichannel communication, which could realize synaptic behaviors even under an ultralow action potential of 80 mV. The device not only could simulate one-to-one information transfer of axons but also achieve a many-to-one modulation mode of dendrites. By the adjustment of two presynapses, Pavlov's dog conditioning experiment was learned successfully. Furthermore, the device also could emulate the biological synaptic competition and synaptic cooperation phenomenon through the comodulation of three presynapses, which are crucial for artificial neural network (ANN) implementation. Finally, an ANN was further constructed to realize highly efficient and anti-interference recognition of fashion patterns. By introducing the cooperative device, synaptic weight updates could be improved for higher linearity and larger dynamic regulation range in neuromorphic computing, resulting in higher recognition accuracy and efficiency. Such an artificial dendric device has great application prospects in the processing of more complex information and the construction of an ANN system with more functions.

Case report: Heterozygous mutation in HTRA1 causing typical cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive disorder characterized by baldness, recurrent ischemic stroke, lumbago, headache, and dementia which is closely related to homozygous mutations of the high-temperature requirement serine peptidase A1 (HTRA1) gene. Heterozygous mutations of HTRA1 are usually considered to be non-pathogenic. Although it has been revealed that only a few patients with heterozygous mutations could present some manifestations, their clinical symptoms were atypical, milder, and always with a lower frequency of extra-neurological features. Here, a rare patient with heterozygous mutation of HTRA1 who had all typical features of CARASIL as well as severe clinical symptoms and rapid progression was initially reported in our study. Case presentation: A 43-year-old female patient presented with a gradual onset of headache and cognitive decline. As time progressed, her headache intensified and symptoms of dementia began to manifest gradually. During her early years, she had thinning hair and subsequently experienced two occurrences of ischemic strokes in her thirties. Furthermore, she also had a history of lumbago and urinary retention before visiting our hospital. The patient's magnetic resonance imaging revealed the presence of widespread white matter lesions, infarctions, and microbleeds, in addition to lumbar disc herniation and degenerative lesions. The observed clinical characteristics had a strong correlation with CARASIL, and the patient was diagnosed with a heterozygous missense mutation of 905G>A (Arg302Gln) in the HTRA1 gene. The patient has been under continuous follow-up for a duration exceeding 3 years subsequent to her release from the hospital. She underwent cystostomy, and symptoms of bulbar paralysis developed in a progressive way. Currently, there has been a notable decrease in motor function and activities of daily living, resulting in the individual being confined to bed for a duration exceeding 1 year. Conclusion: This case suggests that patients carrying a heterozygous mutation in G905A may also have typical clinical features of CARASIL, which allows us to have a more comprehensive understanding of CARASIL.

Study on the Antioxidant Effect of Shikonin-Loaded ß-Cyclodextrin Forming Host-Guest Complexes That Prevent Skin from Photoaging.

When the skin is overexposed to ultraviolet rays, free radicals will accumulate in the skin, causing lipid damage and even inducing photoaging of the skin. Combination therapy with antioxidant drugs is a good choice for topical treatment of skin photoaging due to its special physiological structure. In this paper, shikonin was encapsulated in ß-cyclodextrin (SH-ß-CD) by the precipitation crystallization method, which delayed the release of the drug and increased drug solubility. The average diameter of SH-ß-CD was 203.0 ± 21.27 nm with a zeta potential of -14.4 ± 0.5 mV. The encapsulation efficiency (EE%) was 65.9 ± 7.13%. The results of the in vitro permeation across the dialysis membrane and ex vivo transdermal release rates were 52.98 ± 1.21% and 88.25 ± 3.26%, respectively. In vitro antioxidant and antilipid peroxidation model assay revealed the antioxidant potential of SH and SH-ß-CD. In the mice model of skin photoaging, SH and SH-ß-CD had a recovery effect on the skin damage of mice, which could significantly increase the superoxide dismutase (SOD) activity in the skin. Briefly, SH-ß-CD had an obvious therapeutic effect on the skin photoaging of mice caused by UV, and it is promising in skin disease treatment and skin care.

Brown adipose tissue-derived exosomes delay fertility decline in aging mice.

Introduction: Ovarian aging has steadily grown to be a significant health issue for women as a result of the increase in average life expectancy and the postponement of reproductive age. One of the important pathological foundations of ovarian aging is formed by mitochondrial dysfunction, which causes decreases in follicle quantity and oocyte quality. In recent years, brown adipose tissue (BAT) transplantation has been proven as an effective treatment for aging-related diseases, such as ovarian aging. However, BAT transplantation is an invasive operation with long-term risks. Therefore, we need to find an alternative strategy. Methods: We injected BAT-derived exosomes into eight-month-old C57BL/6 female mice. The fertility was detected by the estrous cycle and mating test. The changes of ovary and oocyte were measured by ovarian volume, organ coefficient, follicle counting, and oocyte maturation rate. ROS level, mitochondrial membrane potential and ATP level were measured to analyze the mitochondrial function of oocytes. The changes in metabolism were explored by cold stimulation test, body weight and blood sugar. The possible molecular mechanism was further investigated by RNA sequencing. Results: In terms of fertility, the estrous cycle of aging mice after BAT-derived exosome intervention was more regular, and the number of progenies and litters was increased. At the tissue level, the ovaries in the BAT-exosome group were larger, and the number of primordial follicles, secondary follicles, antral follicles and total follicles increased. At the cellular level, BAT-derived exosomes improved the maturation of oocytes in vivo and in vitro, increased the mitochondrial membrane potential and ATP levels of oocytes, and decreased ROS levels. Besides, BAT-derived exosomes ameliorated the metabolism and viability of aging mice. Furthermore, mRNA sequencing showed that BAT exosomes altered the expression levels of genes related to metabolism and the quality of oocytes. Conclusion: BAT-derived exosomes enhanced mitochondrial function, promoted follicle survival, improved fertility, and extended ovarian lifespan in aging mice.

Efficacy and safety of acupuncture in the treatment of stroke complicated with sleep apnea syndrome: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: stroke patients often have a combination of sleep apnea syndrome, which is an important and modifiable risk factor for stroke prognosis. Acupuncture is one of the measures for sleep apnea syndrome, and it is also widely used in stroke. However, we are concerned that its efficacy and safety in the treatment of stroke with sleep apnea syndrome are not yet clear. METHODS: This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses schema and was registered with INPLASY (registration number: INPLASY202250113). The following 8 databases were searched: PubMed, Cochrane Library (CENTRAL), Embase, Web of Science, China National Knowledge Infrastructure, Chongqing VIP Information, WanFang Data, and China Biomedical Literature Database limited from the establishment of each database to May 4, 2022. Subject headings, free words, and keywords were used for retrieval. Relevant literature was supplemented by consulting other resources. We assessed the risk of bias in the included studies using the Cochrane risk of bias tool. RevMan 5.4 software (The Cochrane Collaboration, 2020) was used to perform the meta-analysis. RESULTS: Six records were included, including a total of 513 participants: 256 in the experimental group and 257 in the control group. The results showed that the total effective rate (relative risk = 1.23, 95% confidence interval (CI): 1.13, 1.34, P < .00001), apnea-hypopnea index (mean difference (MD) = -8.39, 95% CI: -9.19, -7.59, P < .00001), Epworth Sleepiness Scale score (MD = -1.59, 95% CI: -2.66, -0.52, P = .004), minimal oxygen saturation (MD = 4.99, 95% CI: 3.5, 6.47, P < .00001), longest duration of apnea (MD = -7.47, 95% CI: -8.97, -5.97, P < .00001), longest duration of apnea (MD = -6.48, 95% CI: -8.60, -4.35, P < .00001), and S100ß levels (standard mean difference = -1.52, 95% CI: -1.87, -1.18, P < .00001) were better in the experimental group than in the control group. Simultaneously, the effect of reducing the neuron-specific enolase level in the experimental group was comparable to that in the control group (MD = -3.40, 95% CI: -9.08, 2.29, P = .24). CONCLUSIONS: Acupuncture can improve the clinical symptoms and related laboratory indicators for sleep apnea syndrome in patients with stroke. More high-quality trials remain urgently needed.

Effects of sodium tanshinone IIA sulfonate injection on inflammatory factors and vascular endothelial function in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A systematic review and meta-analysis of randomized clinical trials.

Background: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) therapy may experience further damage to the vascular endothelium, leading to increased inflammatory response and in-stent thrombosis. In many clinical studies, sodium tanshinone IIA sulfonate injection (STS) has been found to reduce inflammatory factors and enhance vascular endothelial function in patients with ACS while improving the prognosis of PCI. However, to date, there has been no systematic review assessing the effectiveness and safety of STS on inflammatory factors and vascular endothelial function. Purpose: The aim of this study is to systematically review the effects of STS on inflammatory factors and endothelial function in patients with ACS treated with PCI. Methods: Until October 2022, eight literature databases and two clinical trial registries were searched for randomized controlled trials (RCTs) investigating STS treatment for ACS patients undergoing PCI. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool 2.0. Meta-analysis was performed using RevMan 5.4 software. Results: Seventeen trials met the eligibility criteria, including 1,802 ACS patients undergoing PCI. The meta-analysis showed that STS significantly reduced high-sensitivity C-reactive protein (hs-CRP) levels (mean difference [MD = -2.35, 95% CI (-3.84, -0.86), p = 0.002], tumor necrosis factor-alpha (TNF-α) levels (standard mean difference [SMD = -3.29, 95%CI (-5.15, -1.42), p = 0,006], matrix metalloproteinase-9 (MMP-9) levels [MD = -16.24, 95%CI (-17.24, -15.24), p < 0.00001], and lipid peroxidation (LPO) levels [MD = -2.32, 95%CI (-2.70, -1.93), p < 0.00001], and increased superoxide dismutase (SOD) levels [SMD = 1.46, 95%CI (0.43, 2.49), p = 0,006] in patients with ACS. In addition, STS significantly decreased the incidence of major adverse cardiovascular events (relative risk = 0.54, 95%CI [0.44, 0.66], p < 0.00001). The quality of evidence for the outcomes was assessed to be very low to medium. Conclusion: STS can safely and effectively reduce the levels of hs-CRP, TNF-α, MMP-9, and LPO and increase the level of SOD in patients with ACS treated with PCI. It can also reduce the incidence of adverse cardiovascular events. However, these findings require careful consideration due to the small number of included studies, high risk of bias, and low to moderate evidence. In the future, more large-scale and high-quality RCTs will be needed as evidence in clinical practice.

Identification of circRNA-miRNA-mRNA Regulatory Network and Crucial Signaling Pathway Axis Involved in Tetralogy of Fallot.

Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases (CHD) worldwide; however, its pathogenesis remains unclear. Recent studies have shown that circular RNAs (circRNAs) act as "sponges" for microRNAs (miRNAs) to compete for endogenous RNA (ceRNA) and play important roles in regulating gene transcription and biological processes. However, the mechanism of ceRNA in TOF remains unclear. To explore the crucial regulatory connections and pathways of TOF, we obtained the human TOF gene, miRNA, and circRNA expression profiling datasets from the Gene Expression Omnibus (GEO) database. After data pretreatment, differentially expressed mRNAs (DEmRNAs), microRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified between the TOF and healthy groups, and a global triple ceRNA regulatory network, including circRNAs, miRNAs, and mRNAs based on the integrated data, was constructed. A functional enrichment analysis was performed on the Metascape website to explore the biological functions of the selected genes. Then, we constructed a protein-protein interaction (PPI) network and identified seven hub genes using the cytoHubba and MCODE plug-ins in the Cytoscape software, including BCL2L11, PIK3R1, SOCS3, OSMR, STAT3, RUNX3, and IL6R. Additionally, a circRNA-miRNA-hub gene subnetwork was established, and its enrichment analysis results indicated that the extrinsic apoptotic signaling pathway, JAK-STAT signaling pathway and PI3K-Akt signaling pathway may be involved in the pathogenesis of TOF. We further identified the hsa_circ_000601/hsa-miR-148a/BCL2L11 axis as a crucial signaling pathway axis from the subnetwork. This study provides a novel regulatory network for the pathogenesis of TOF, revealing the possible molecular mechanisms and crucial regulatory pathways that may provide new strategies for candidate diagnostic biomarkers or potential therapeutic targets for TOF.

Photoinduced large polaron transport and dynamics in organic-inorganic hybrid lead halide perovskite with terahertz probes.

Organic-inorganic hybrid metal halide perovskites (MHPs) have attracted tremendous attention for optoelectronic applications. The long photocarrier lifetime and moderate carrier mobility have been proposed as results of the large polaron formation in MHPs. However, it is challenging to measure the effective mass and carrier scattering parameters of the photogenerated large polarons in the ultrafast carrier recombination dynamics. Here, we show, in a one-step spectroscopic method, that the optical-pump and terahertz-electromagnetic probe (OPTP) technique allows us to access the nature of interplay of photoexcited unbound charge carriers and optical phonons in polycrystalline CH3NH3PbI3 (MAPbI3) of about 10 µm grain size. Firstly, we demonstrate a direct spectral evidence of the large polarons in polycrystalline MAPbI3. Using the Drude-Smith-Lorentz model along with the FrÓ§hlich-type electron-phonon (e-ph) coupling, we determine the effective mass and scattering parameters of photogenerated polaronic carriers. We discover that the resulting moderate polaronic carrier mobility is mainly influenced by the enhanced carrier scattering, rather than the polaron mass enhancement. While, the formation of large polarons in MAPbI3 polycrystalline grains results in a long charge carrier lifetime at room temperature. Our results provide crucial information about the photo-physics of MAPbI3 and are indispensable for optoelectronic device development with better performance.

Ultralow Power Wearable Organic Ferroelectric Device for Optoelectronic Neuromorphic Computing.

In order to imitate brain-inspired biological information processing systems, various neuromorphic computing devices have been proposed, most of which were prepared on rigid substrates and have energy consumption levels several orders of magnitude higher than those of biological synapses (∼10 fJ per spike). Herein, a new type of wearable organic ferroelectric artificial synapse is proposed, which has two modulation modes (optical and electrical modulation). Because of the high photosensitivity of organic semiconductors and the ultrafast polarization switching of ferroelectric materials, the synaptic device has an ultrafast operation speed of 30 ns and an ultralow power consumption of 0.0675 aJ per synaptic event. Under combined photoelectric modulation, the artificial synapse realizes associative learning. The proposed artificial synapse with ultralow power consumption demonstrates good synaptic plasticity under different bending strains. This provides new avenues for the construction of ultralow power artificial intelligence system and the development of future wearable devices.

A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients.

BACKGROUND: Few models to predict antiviral response of peginterferon were used in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients and the prediction efficacy was unsatisfied. Quantitative antibody to hepatitis B core antigen (anti-HBc) is a new predictor of treatment response. We aimed to develop a new model to identify HBeAg-positive Chinese patients who were more likely to respond to peginterferon. METHODS: Data from 140 peginterferon recipients with HBeAg-positive were applied with generalized additive models and multiple logistic regression analysis to develop a baseline scoring system to predict serological response (SR: HBeAg loss and HBeAg seroconversion 24 weeks post-treatment) and combined response (CR: SR plus serum HBV DNA levels <2000 IU/mL 24 weeks post-treatment). RESULTS: Anti-HBc levels, alanine aminotransferase ratio, and HBeAg were retained in the final model. The new model scored from 0 to 3. Among patients with scores of 0, 1, or ≥2, SR was achieved in 6.45% (2/31), 13.21% (7/51), and 55.36% (31/56), respectively, and CR in 3.23% (1/31), 9.43% (5/53), and 25.00% (14/56), respectively. Our model has a higher AUROC for SR comparing to Chan's (Z = 2.77 > 1.96, p < 0.05) and Lampertico's (Z = 2.06 > 1.96, p < 0.05) model. The negative predictive value for SR and CR were both 100% in patients with score 0 and hepatitis B surface antigen ≥20,000 IU/mL at week 12. CONCLUSIONS: Patients with higher scores at baseline were more likely to respond to peginterferon. This new model may predict the treatment response.

Emodin relieves hypoxia-triggered injury via elevation of microRNA-25 in PC-12 cells.

Emodin (EMO) possesses extensive pharmacological activities, which has been proven to exert the protective impact in diverse nervous system diseases. Nonetheless, whether EMO emerges a neuro-protective activity in hypoxic-evoked ischemic brain injury is still further probed. The intention of the research is to disclose whether EMO emerges neuro-protective activity in hypoxic-evoked ischemic brain injury. PC-12 received hypoxia administration, and then cell viability, apoptosis and autophagy were estimated. After EMO disposition, the above-involved cellular processes were evaluated again. MiR-25 functions in EMO-affected cells were also estimated. The interrelation between miR-25 and neurofilament light-chain polypeptide gene (NEFL) and the conceivable roles of NEFL in hypoxia-disposed cells were investigated. The latent mechanism was uncovered by mTOR and Notch pathways determination. Hypoxia triumphantly triggered apoptosis and autophagy, but EMO repressed these functions in PC-12 cells. Increased miR-25 was induced by EMO, and inhibited miR-25 abated the impacts of EMO on hypoxia-disposed PC-12 cells. NEFL as a neoteric target gene of miR-25 was predicated, and overexpressed NEFL annulled the functions of EMO in hypoxia-injured cells. EMO activated mTOR and Notch pathways through repressing NEFL. The investigations corroborated that EMO weakened hypoxia-triggered injury via elevating miR-25 by targeting NEFL in PC-12 cells.

Compound heterozygous mutations in PARK2 causing early-onset Parkinson disease: A case report.

RATIONALE: Parkinson disease (PD) is a complex neurodegenerative movement disorder characterized by resting tremor, muscular rigidity, bradykinesia, and so on. Genetics has been regarded as an important role in the development of PD. PARK2, an autosomal recessive gene, is the most common one referring to early-onset Parkinson disease (EOPD). Strangely, only a single heterozygous mutation in PARK2 was found in a small minority of patients with PD, which has been reported quite rarely and is difficult to explain. PATIENT CONCERNS: We described a case of 36-year-old male patient, complaining of progressive tremor for 10 years. He 1st presented uncontrolled resting tremor of his left arm. Besides, he also had trouble in completing fine motor tasks such as writing and buttoning. Six years later, tremor of the ipsilateral leg gradually occurred. On neurologic examinations, pronounced parkinsonian symptoms were noted, including resting tremor, body bradykinesia, and hypomimia. The positron emission tomography-computed tomography showed the distribution of dopamine transporter in both putamens decreased obviously. No family history was indentified. He came to hospital because his disease aggravated in the past 4 months. DIAGNOSIS: This patient was diagnosed with PD according to the movement disorder society clinical diagnostic criteria for PD. INTERVENTIONS AND OUTCOMES: With regard to the sequencing of this patient, a heterozygous point mutation of G403C in PARK2 was detected, which was inherited from his unaffected mother, leading to an amino acid alternation of glycine to arginine. Furthermore, deletion mutation of exon 6 in PARK2 was also found in this patient, which was inherited from his normal father. He accepted madopar and benzhexol and showed stable efficacy. To our knowledge, it is the 1st case report to explain the synergistic action of both heterozygous pathogenic point mutation in PARK2 and deletion mutation of exon 6 leading to EOPD. LESSONS: Compound heterozygous mutations in PARK2 with point mutation of G403C and deletion mutation of exon 6 might contribute to the development of EOPD.

A case report of intraventricular tigecycline therapy for intracranial infection with extremely drug resistant Acinetobacter baumannii.

RATIONALE: Intracranial infection with Acinetobacter baumannii is a tough problem due to the presence of multiresistance and drugs poor penetration through the blood brain barrier (BBB). Tigecycline is effective to cure A baumannii, but it can only be used intravenously which is also difficult to pass BBB. So, it will be a breakthrough if intraventricular (IVT) tigecycline is used in the clinical therapy. However, this treatment has been reported quite rarely until now. PATIENT CONCERNS: We described a case of a 50-year-old male worker whose clinical futures were high fever and cerebral rigidity after neurosurgery. DIAGNOSES: Intracranial infection with extensive drug resistant (XDR) A baumannii. INTERVENTIONS: The patient was treated with IVT tigecycline. OUTCOMES: The symptoms of intracranial infection disappeared. The temperature of this patient decreased to normal and cerebral rigidity disappeared. The cerebrospinal fluid culture became negative, with normal levels of white blood cell, glucose and chlorine. LESSONS: IVT tigecycline therapy maybe effective to intracranial infection with XDR A baumannii. However, more studies will further demonstrate the therapeutic values of IVT tigecycline to intracranial infection, and not only restricted to A baumannii infections.

A seventeen-year observation of the antimicrobial susceptibility of clinical Campylobacter jejuni and the molecular mechanisms of erythromycin-resistant isolates in Beijing, China.

OBJECTIVES: To investigate the dynamic development of the antimicrobial resistance of Campylobacter jejuni isolated from human diarrhea in Beijing, China, between 1994 and 2010, and to further analyze the molecular mechanisms of erythromycin-resistant strains. METHODS: Susceptibility tests were performed on 203 non-duplicate clinical C. jejuni strains against eight common antibiotics using the standard agar dilution method. The molecular determinants were further studied in the erythromycin (ERY) non-susceptible strains. The analysis focused on the 23S rRNA gene, the rplD and rplV ribosomal genes, the ermB gene, and the regulatory region of the CmeABC efflux pump. RESULTS: The rates of resistance of C. jejuni to ciprofloxacin (CIP), nalidixic acid (NAL), doxycycline (DOX), tetracycline (TET), florfenicol (FFC), and chloramphenicol (CHL) increased significantly over the period studied (all p<0.05). Similarly, the proportions of resistant patterns (CIP-NAL-DOX-TET, CIP-NAL-DOX-TET-FFC, and CIP-NAL-DOX-TET-CHL) increased remarkably. In this study, 4.4% (9/203) of C. jejuni strains were ERY non-susceptible. The A2075G mutation in the 23S rRNA was found in all of the resistant strains except cj8091, which harbored the ermB gene. Interestingly, the ermB gene was also detected in intermediately resistant isolates, and the earliest ermB-positive strain cj94473 was derived in 1994. Moreover, none of the ribosomal rplD or rplV genes harbored mutations that have been described to confer resistance to macrolides. Different mutations affecting the regulatory region of the CmeABC efflux pump were also found. CONCLUSIONS: This is the first comprehensive study on the recent trend in antimicrobial resistance and the molecular mechanisms of macrolide resistance in clinical C. jejuni strains isolated in China. More stringent monitoring and regulation of human and animal antimicrobial use are warranted.

Antibody to hepatitis B core antigen levels in the natural history of chronic hepatitis B: a prospective observational study.

Previous studies have revealed antibody to hepatitis B core antigen (anti-HBc) levels as a predictor of treatment response in hepatitis B early antigen (HBeAg)-positive chronic hepatitis B (CHB) patients in both interferon and nucleos(t)ide analog therapy cohorts. However, there is no information about anti-HBc levels in the natural history of CHB. This study aimed to define anti-HBc levels of different phases in the natural history of CHB. Two hundred eleven treatment-naive CHB patients were included in the study. They were classified into 4 phases: immune tolerance (IT) phase (n = 39), immune clearance (IC) phase (n = 48), low or no-replicative (LR) phase (n = 55), and HBeAg-negative hepatitis (ENH, n = 69). Fifty patients who were HBsAg negative and anti-HBc positive were also recruited as past HBV infection (PBI) control group. Anti-HBc levels were measured by a newly developed double-sandwich immunoassay. Correlation of anti-HBc levels with alanine aminotransferase (ALT) and other HBV-related markers within each phase was performed. Serum anti-HBc levels were statistically significant between patients in different phases of CHB (P < 0.001). The median anti-HBc levels were: IT (3.17 log 10 IU/mL), IC (4.39 log 10 IU/mL), LR (3.29 log 10 IU/mL), ENH (4.12 log 10 IU/mL), and PBI (0.61 log 10 IU/mL). There existed a strong correlation in IC (r = 0.489, P < 0.001), a poor correlation in ENH (r = 0.275, P = 0.042), and no correlation in patients with ALT reached 5 times upper limit of normal (r = 0.120, P = 0.616). Anti-HBc levels show significant differences during the natural course of CHB. These results may provide some potentially useful insights into hepatitis B pathogenesis and immune activation against hepatitis B virus.

Case-control study on prednisolone combined with ursodeoxycholic acid and azathioprine in pure primary biliary cirrhosis with high levels of immunoglobulin G and transaminases: efficacy and safety analysis.

To the best of our knowledge, this is the first study to address the use of glucocorticoids in the comparatively special population of pure primary biliary cirrhosis (PBC) patients who have high levels of immunoglobulin G (IgG) and transaminases but do not have PBC-autoimmune hepatitis overlap syndrome. Ursodeoxycholic acid (UDCA) is now assumed to be the standard therapy for PBC patients. However, patients treated with UDCA still have a risk of progression to cirrhosis and end-stage liver disease. The most recent European Association for the Study of the Liver guidelines of 2009 declared that further studies on glucocorticoid therapy in this disease should be a priority. Therefore, we designed this 3-year longitudinal retrospective study, which might provide deep insight into the treatment for PBC.The aim of this study was to assess whether the combination of prednisolone, UDCA, and azathioprine was superior to UDCA alone in these PBC patients.Sixty patients were enrolled in this study. Thirty-one patients underwent UDCA monotherapy, and 29 patients were treated with prednisolone, UDCA, and azathioprine. We analyzed their biochemistries, immune parameters, liver synthetic function, and noninvasive assessments of liver fibrosis, as well as treatment efficacy and adverse effects at baseline and at 1, 3, 6, 12, 24, and 36 months.Alkaline phosphatase (ALP), γ-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase levels and the aspartate aminotransferase-to-platelet ratio index (APRI) and S-index improved dramatically in both groups, whereas IgG levels only decreased in the combination group (all P < 0.05). Albumin (ALB) levels decreased in the UDCA group but increased with the combination treatment at 36 months. Significant differences between the 2 groups were observed at 36 months in ALP (P = 0.005), IgG (P = 0.002), ALB (P = 0.002), APRI (P = 0.015), and S-index (P = 0.020). Prednisolone combined with UDCA and azathioprine showed a higher efficacy based on our new criteria.The combination of prednisolone, UDCA, and azathioprine is superior to UDCA alone for the treatment of pure PBC patients with high levels of IgG and transaminases. Side effects were minimal or absent.

[Correlation of hepatocyte expression of hepatitis B viral core antigen and the clinicopathological characters in chronic hepatitis B patients].

OBJECTIVE: To investigate the relationship between the expression of hepatitis B virus (HBV) core antigen and viral replication and liver tissue inflammation damage in chronic hepatitis B (CHB) patients, and to analyze the relationship of core antigen expression differences with clinical and pathological features in e antigen-negative and e antigen-positive CHB patients. METHODS: Sixty-three treatment-naive patients diagnosed with CHB who underwent liver biopsy were included in this retrospective analysis. Liver pathology was assessed, and the karyotype, pulp type, and pulp karyotype were determined. Core and e antigen expression was quantitatively determined by automated immunoassay. Blood samples were used to determine the amount of peripheral lymphocytes or monocytes and HBV DNA load. Results The median titer of HBV DNA was significantly higher in the CHB patients with e antigen positivity (n = 48) than those with e antigen negativity (n = 15) (5.4 * 106 copies/ml vs. 5.4 * 104 copies/ml, P = 0.003). The core antigen positive expression rate was significantly higher in the e antigen-positive CHB patients than in the e antigen-negative CHB patients (80.33% vs. 53.33%, P = 0.042). For the e antigen-positive CHB patients, the HBV DNA titer in karyotype core antigen cases was higher than that in the pulp karyotype mixed-type cases (P = 0.008) and in the negative cases (P = 0.013); in addition, the karyotype patients showed higher titer than the plasma patients (P = 0.019). Also for the e antigen-positive CHB patients, the HBV DNA titer was positively correlated with the rank level of pulp karyotype in core antigen expression (r = 0.589, P = 0.003) but negatively correlated with lobular inflammation, interface inflammation, and fibrosis level (r = -0.552, P = 0.000; r = -0.381, P = 0.008; r = -0.555, P = 0.000); in addition, the level of peripheral blood lymphocytes was negatively correlated with lobular inflammation and fibrosis level (r = -0.361, P = 0.012; r = -0.356, P = 0.013). For the e antigen-negative CHB patients, the level of peripheral blood lymphocytes was negatively correlated with lobular inflammation and interface inflammation (r = -0.702, P = 0.004; r = -0.578, P = 0.024), while the level of peripheral blood mononuclear cells was negatively correlated with lobular inflammation, interface inflammation, and fibrosis level (r = -0.682, P = 0.005; r = -0.620, P = 0.014; r = -0.527, P = 0.044); in addition, age positively correlated with interface inflammation (r = 0.690, P = 0.004). CONCLUSION: The pulp karyotype mixed-type of core antigen expression may reflect the level of HBV replication. Negative expression of core antigen may be associated with variation in pre-C or C zone. The monocyte-macrophage system may be involved in the pathogenesis of e antigen-negative CHB, while the mechanism of immune escape may play an important role in increasing HBV DNA titer in an e-antigen-negative CHB condition.