In-Vitro Diagnostic Reagent Evaluation of Commercially Available Cardiac Troponin I Assay Kits Using H/D Exchange Mass Spectrometry for Antibody-Epitope Mapping.

Cardiac troponin I (cTnI) is the biomarker of choice and considered a gold standard for the diagnosis of acute myocardial infarction. However, the quantitative results of cTnI assay kits from different manufacturers are not comparable. Based on the H/D exchange mass spectrometry (HDX-MS) workflow, we developed an in-vitro diagnostic reagent antibody evaluation strategy to analyze the interactions of epitopes and antibody cocktails─(R195, F12, S13) and (D1, D2, pAb2). The HDX results indicate that the quantitative result bias of the different reagents originates from the ability of antibodies to recognize various cTnI complex forms, such as free cTnI, hydrolyzed cTnI, and cTnI combined with cTnT or TnC as binary or ternary complexes (cTnIC, cTnTIC), in blood based on different epitopes. The data obtained from the peptide HDX of interest after treatment with various antibody cocktails clearly indicated epitope specificity. The consistency of quantitative results can be improved by a thorough investigation into the epitopes recognized by the antibodies of various diagnostic kits, which will lead to the standardization of cTnI diagnosis.

Active control of circular dichroism in a graphene-metal hybridized metamaterial driven by symmetry-protected bound states in the continuum.

Active control of chirality in plasmonic metamaterials is of great importance due to their potential for diverse applications in imaging, communication and spectroscopy. Recently, inspired by the concept of bound states in the continuum (BIC), strong chiroptical responses are constructed in metamaterials by introducing structural asymmetries. However, most of these chiral metamaterials are static and cannot be modulated. Herein, we theoretically demonstrate a novel approach for manipulating chiroptical responses with enhanced circular dichroism (CD) and large modulation depths in a graphene-metal hybridized metamaterial. By introducing a structured graphene and adjusting the Fermi energy (EF), the conversion between BIC and quasi-BIC states is achieved successfully. The proposed device demonstrates a tuneable CD in the range of 0.693-0.008 when EF is adjusted from 0.01 eV to 1.0 eV, which can be further improved by optimizing its geometry. The proposed graphene-metal hybridized metamaterial paves a new way for manipulating polarization states at terahertz frequencies and is of great potential for practical applications such as dynamic display and optoelectronic modulation.

Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet.

BACKGROUND: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.

Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systematic review and network meta-analysis.

BACKGROUND: Currently, 19 disease-modifying therapies (DMTs) have been approved for the treatment of patients with relapsing forms of multiple sclerosis (RMS). OBJECTIVE: The objective of this study was to conduct a systematic review and network meta-analysis to evaluate the efficacy and safety of DMTs in adults with RMS. METHODS: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the Food and Drug Administration, and European Medicines Agency websites for randomized controlled trials (RCTs) (from inception to July 2021). Eligible RCTs evaluated approved treatments for RMS as monotherapy and reported at least one of the primary outcome measures of interest. The primary outcome was efficacy (annualized relapse rate and 12-week confirmed disability progression) and safety (serious adverse events [AEs] and discontinuation due to AEs). We assessed the risk of bias (RoB) of included studies using the Cochrane RoB tool version 2.0 (https://www.bmj.com/content/343/bmj.d5928) for RCTs. Surface under the cumulative ranking (SUCRA) was used to rank therapies and to assess quality of general evidence, respectively. The Grading of Recommendations Assessment, Development and Evaluation framework was used to rank therapies and to assess quality of general evidence. RESULTS: A total of 43 records represent 45 RCTs selected for network meta-analysis. In total, 30,720 participants (median of 732; interquartile range: 248-931) were included, of which 67% were female. By SUCRA analysis, alemtuzumab (94.3%) presented the highest probability of being the best alternative for annualized relapse rate, whereas ofatumumab (93.5%) presented the highest probability of being the best alternative for 12-week confirmed disability progression. Interferon beta-1b subcutaneous (87.0%) presented the highest probability of the best safety among all DMTs for serious AEs, whereas alemtuzumab (92.4%) presented the highest probability of the best safety among all DMTs for discontinuation due to AEs. CONCLUSION: Network meta-analysis shows that alemtuzumab and ofatumumab present the highest efficacy among DMTs. Because there is little difference between these probabilities for many treatments, health professionals should use clinical shared decision making when formulating treatment plans with patients.

Association between hemoglobin level and cognitive profile in old adults: A cross-sectional survey.

OBJECTIVE: In the present study, the association between Hemoglobin (HGB) level and cognitive profile was investigated and whether it affected the dementia risk in older adults. METHODS: A cross-sectional population-based survey that included 3519 individuals ≥65 years of age was conducted in 2019. Basic demographic characteristics were collected. The neuropsychological assessments and blood tests were administered to evaluate cognition and HGB level. Generalized additive models were used to analyze the non-linear association between HGB levels and cognitive function. Logistics regression models were utilized to analyze the associations between HGB level and dementia risk. RESULTS: Overall, 459 (12.7%) participants were diagnosed with dementia and there were more females (54.7%) than males (45.3%). The number of subjects with anemia (3%) or hyperhemoglobinemia (5.2%) was higher than participants with normal HGB level. A visual representation of the relationship between HGB level and Mini-Mental State Examination (MMSE) score showed an inverted U-curve, which is more evident in female. Logistics regression models showed that anemia (odds ratio, OR = 1.826, 95% confidence interval, CI: 1.166-2.860, p < 0.01), but not hyperhemoglobinemia, significantly increased the risk of dementia. These trends were not the same for males and females. An abnormal HGB level had greater effects in females, resulting in higher risk of dementia for females with anemia or hyperhemoglobinemia than subjects with normal HGB level including males. CONCLUSION: Both low and high HGB levels can lead to cognitive decline in the incidence of dementia, indicating an inverted U-shaped curve association may exist between HGB level and global cognitive profile.

Nonsteroidal anti-inflammatory drugs associated acute kidney injury in hospitalized children: A systematic review and meta-analysis.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are regarded as nephrotoxins. Children commonly use NSAIDs and are susceptible to nephropathy, but the relationship between acute kidney injury (AKI) and use of NSAIDs is not well examined yet. OBJECTIVE: To evaluate the relationship between AKI and use of NSAIDs in hospitalized pediatric patients who are susceptible to nephropathy. METHODS: We conducted this systematic review and meta-analysis of observational studies by searching PubMed, Embase, and Cochrane Database for articles published up to June 1, 2020. Reports included involved children (age < 18 years) who used NSAIDs for various reasons and were admitted in the hospital. The main outcome measure was whether AKI occurred, and pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using generic inverse variance methods. RESULTS: Seven studies reporting risk of AKI in the hospitalized pediatric patients receiving NSAIDs were included applying a random-effects model. In the hospitalized pediatric population, the pooled OR of AKI for present NSAID exposure was 1.55 (95%CI 1.26-1.92). CONCLUSIONS: NSAID exposure was associated with an approximate 1.6-fold rise in the odds of developing AKI in hospitalized pediatric patients. Avoidance, cautious use of NSAIDs and further evidence are needed. This study was registered with PROSPERO (identifier: CRD42021219779).

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.

Research advances in hydrogen-deuterium exchange mass spectrometry for protein epitope mapping.

With the development of biomedical technology, epitope mapping of proteins has become critical for developing and evaluating new protein drugs. The application of hydrogen-deuterium exchange for protein epitope mapping holds great potential. Although several reviews addressed the hydrogen-deuterium exchange, to date, only a few systematic reviews have focused on epitope mapping using this technology. Here, we introduce the basic principles, development history, and review research progress in hydrogen-deuterium exchange epitope mapping technology and discuss its advantages. We summarize the main hurdles in applying hydrogen-deuterium exchange epitope mapping technology, combined with relevant examples to provide specific solutions. We describe the epitope mapping of virus assemblies, disease-associated proteins, and polyclonal antibodies as examples of pattern introduction. Finally, we discuss the outlook of hydrogen-deuterium exchange epitope mapping technology. This review will help researchers studying protein epitopes to gain a more comprehensive understanding of this technology.

Efficacy and Safety of Eculizumab for Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.

BACKGROUND: Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). This study aimed to evaluate the efficacy and safety of eculizumab in patients with PNH. METHODS: PubMed, EMBASE, The Cochrane Library, and ClinicalTrials.gov were searched for prospective interventional studies treating PNH with eculizumab. The primary outcome was the change in lactate dehydrogenase (LDH) levels, whereas secondary outcomes included the change in hemoglobin (Hb) levels, transfusion rates, and adverse drug events. RESULTS: Patients (n=235) from 6 studies were included in this meta-analysis. LDH and Hb levels and transfusion rates decreased significantly at 12, 26 weeks, 12, 15, and >15 months. The most frequent adverse events included nasopharyngitis (effect size [ES]: 0.53; 95% confidence intervals [CI]: 0.47 to 0.60; P=0.00), headache (ES: 0.47; 95% CI: 0.25 to 0.69; P=0.00), upper respiratory tract infection (ES: 0.37; 95% CI: 0.27 to 0.46; P=0.00), nausea (ES: 0.31; 95% CI: 0.24 to 0.38; P=0.00), fatigue, diarrhea, cough, pyrexia, abdominal pain, pain in extremities, and contusion. CONCLUSION: Eculizumab is an effective and well-tolerated treatment for patients with PNH. It is effective at decreasing LDH levels and transfusion rates while increasing Hb levels. Further studies are needed to explore the safety of eculizumab.

Precision and accuracy of commercial assays for vancomycin therapeutic drug monitoring: evaluation based on external quality assessment scheme.

BACKGROUND: Vancomycin remains a mainstay of the treatment of Gram-positive bacterial infections. It is crucial to accurately determine vancomycin serum concentration for adequate dose adjustment. OBJECTIVES: To evaluate the precision and accuracy of commercial assay techniques for vancomycin concentration and to assess the comparability of vancomycin detection methods in Chinese laboratories. METHODS: Human serum samples spiked with known concentrations of vancomycin were provided to laboratories participating in the external quality assessment scheme (EQAS). Assay methods included chemiluminescence, enzyme immunoassay (EIA) and so on. The dispersion of the measurements was analysed and the robust coefficient of variation (rCV), relative percentage difference (RPD) and satisfactory rate for method groups were calculated. Moreover, performance of the Chinese laboratories was assessed. RESULTS: A total of 657 results from 75 laboratories were collected, including 84 samples from 10 Chinese laboratories. The median rCV, median RPD and satisfactory rates classified by methods ranged from 1.85% to 15.87%, -14.75% to 13.34% and 94.59% to 100.00%, respectively. Significant differences were seen in precision, between kinetic interaction of microparticles in solution (KIMS) and other methods, and in accuracy, between enzyme-multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (FPIA) and other techniques. Vancomycin detection in China mainly depended on the chemiluminescence and EMIT methods, which tended to result in lower measurements. CONCLUSIONS: Although almost all assays in this study achieved an acceptable performance for vancomycin serum concentration monitoring, obvious inconsistencies between methods were still observed. Chinese laboratories were more likely to underestimate vancomycin concentrations. Thus, recognizing inconsistencies between methods and regular participation in vancomycin EQAS are essential.

The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: A meta-analysis.

AIMS: The aim of the present meta-analysis was to evaluate the efficacy and safety of fingolimod in patients with relapsing multiple sclerosis (RMS). METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for relevant studies. Two authors independently selected the studies, assessed the risk of bias, and extracted the data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. RESULTS: Ten studies met the inclusion criteria. In patients with RMS, fingolimod demonstrated a significantly lower annualized relapse rate (0.5 mg/d: mean difference [95% confidence interval] = -0.22 [-0.29 to -0.14]; 1.25 mg/d: -0.26 [-0.36 to -0.16]; 5 mg/d: -0.41 [-0.72 to -0.10]) than placebo. Fingolimod also exhibited a favorable performance on other magnetic resonance imaging outcomes and improved the quality of life in patients. No significant difference was noted in the prevalence of adverse events between the fingolimod treatment group and the placebo/disease-modifying therapy groups. CONCLUSIONS: Fingolimod may offer benefits for RMS patients and presents an acceptable safety profile.

Evaluation of Assays to Measure Aminoglycosides in Serum: Comparison of Accuracy and Precision Based on External Quality Assessment.

BACKGROUND: Aminoglycosides require highly accurate therapeutic drug monitoring owing to their narrow therapeutic windows and toxic side effects. Therapeutic drug monitoring varies in different laboratories, and this difference is mainly due to the use of different analytical techniques. This study aimed to compare the accuracy and precision of immunoassays for the measurement of gentamicin, tobramycin, and amikacin in serum. METHODS: Human plasma samples were spiked with known concentrations of amikacin, gentamicin, and tobramycin and dispatched to laboratories worldwide. The percentage deviation and coefficient of variation were calculated to compare the accuracy and precision among immunoassays and among antibiotics. RESULTS: We analyzed 273, 534, and 207 amikacin, gentamicin, and tobramycin measurement results, obtained satisfactory rates of 83.9%, 86.3%, and 93.7%, and coefficients of variation ranging from 1.1% to 15.6%, 2.9% to 25.2%, and 1.8% to 27.0%, respectively. The percentage deviation ranged from -7.5% to 6.6%, -20.8% to 18.7%, and -33.2% to 41.5% for amikacin, gentamicin, and tobramycin, respectively. Significant differences were observed in accuracy and precision among assays for all antibiotics. CONCLUSIONS: This study demonstrated high variations in results obtained from antibiotic assays conducted at different laboratories worldwide.

Combined therapy of somatostatin analogues with pegvisomant for the treatment of acromegaly: a meta-analysis of prospective studies.

BACKGROUND: Acromegaly is a rare, chronic and severe disease. Drug therapy including somatostatin analogues (SAs), dopamine receptor agonists and growth hormone receptor antagonists (pegvisomant, PEG) are commonly used to treat patients who do not respond to surgery. The use of combination therapy with PEG and SAs has become more common over the last decade. We performed this study to accurately evaluate the effect of combination therapy of SAs with PEG on acromegalic patients. METHODS: PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, Scopus, Web of Science, Chinese Biomedical Literature Database and Trip database were searched for relevant studies. Prospective clinical trials treating acromegaly with the co-administration of SAs and PEG were included. We performed a meta-analysis by using Stata 12.1. Sensitivity analysis was conducted to explore heterogeneity. RESULTS: Nine studies were included in this meta-analysis. The overall rate of serum insulin-like growth factor 1 (IGF-1) normalization was 66% (95% CI: 52-78%; I2 = 62.59%). The combination therapy did not significantly change patients' fasting plasma glucose (ES: 0.011 mmol*L- 1; 95% CI: - 0.374 to 0.397 mmol*L- 1; P = 0.954) or glycosylated haemoglobin (ES: - 0.074%; 95% CI: - 0.166 to 0.315%; P = 0.544) while decreasing the fasting plasma insulin (ES: - 21.487 pmol*L-1; 95% CI: - 35.713 to - 7.260 pmol*L-1; P = 0.003). Elevation of liver enzyme levels was found in 14% (95% CI: 8 to 21%) of the patients. There was no significant difference for serious adverse events and treatment discontinuation due to adverse event between SAs monotherapy group and combination therapy group. CONCLUSIONS: Combined therapy of SAs and PEG effectively normalized IGF-1 levels in most of the patients whose IGF-1 level was greater than the upper limit of normal after high dose SAs monotherapy. The therapy also decreased significantly FPI levels with a neutral effect on glucose parameters in acromegaly patients. Moreover, elevated liver enzyme levels were observed in a small number of patients, which suggests a need for liver function monitoring. TRIAL REGISTRATION: We have our protocol registered in PROSPERO. (Registration number: CRD42019115549 ).

Efficacy and safety of ketoconazole combined with calmodulin inhibitor in solid organ transplantation: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Calcineurin inhibitors (CNIs) can significantly improve the results of solid organ transplantation regarding graft and patient survival. However, the high cost, chronic nephrotoxicity and other side effects are major challenges for the long-term use of these drugs. Ketoconazole can significantly increase the plasma concentration of CNIs by inhibiting the activity of the cytochrome P450 enzyme. The combination of ketoconazole-CNIs can reduce the cost of medication for patients by reducing the dosage of CNIs, but its safety is still controversial. Therefore, this study was designed to assess the safety and efficacy of this combination. METHODS: We performed a systematic literature search in PubMed, Embase, Cochrane Library and clinicaltrials.gov for randomized controlled trials on ketoconazole and CNI (cyclosporin or tacrolimus) co-administration in solid organ transplantation. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019118796. RESULTS AND DISCUSSION: Five relevant trials with 326 patients were included. Compared with the controls, ketoconazole combined with CNIs can significantly reduce the dose of CNIs in patients receiving solid organ transplantation (WMD = -203.04 mg/day; 95% CI: -310.51 to -95.57, P = .0002). There was no significant difference in serum creatinine between the experimental group and the control group (WMD = -0.19 mg/mL; 95% CI: -0.52 to 0.14, P = .26). In addition, there was no significant difference in the number of rejections between the two groups (OR = 0.58; 95% CI: 0.27 to 1.22, P = .15). WHAT'S NEW AND CONCLUSION: The co-administration of ketoconazole and CNIs can significantly reduce the dose of CNIs. This combination may be safely used as a CNI-sparing agent from the time of solid organ transplantation with low-dose ketoconazole, based on the findings of this review.

Identification of differentially expressed proteins in the injured lung from zinc chloride smoke inhalation based on proteomics analysis.

BACKGROUND: Lung injury due to zinc chloride smoke inhalation is very common in military personnel and leads to a high incidence of pulmonary complications and mortality. The aim of this study was to uncover the underlying mechanisms of lung injury due to zinc chloride smoke inhalation using a rat model. METHODS: Histopathology analysis of rat lungs after zinc chloride smoke inhalation was performed by using haematoxylin and eosin (H&E) and Mallory staining. A lung injury rat model of zinc chloride smoke inhalation (smoke inhalation for 1, 2, 7 and 14 days) was developed. First, isobaric tags for relative and absolute quantization (iTRAQ) and weighted gene co-expression network analysis (WGCNA) were used to identify important differentially expressed proteins. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to study the biological functions of differentially expressed proteins. Then, analysis of lung injury repair-related differentially expressed proteins in the early (day 1 and day 2) and middle-late stages (day 7 and day 14) of lung injury after smoke inhalation was performed, followed by the protein-protein interaction (PPI) analysis of these differentially expressed proteins. Finally, the injury repair-related proteins PARK7 and FABP5 were validated by immunohistochemistry and western blot analysis. RESULTS: Morphological changes were observed in the lung tissues after zinc chloride smoke inhalation. A total of 27 common differentially expressed proteins were obtained on days 1, 2, 7 and 14 after smoke inhalation. WGCNA showed that the turquoise module (which involved 909 proteins) was most associated with smoke inhalation time. Myl3, Ckm, Adrm1 and Igfbp7 were identified in the early stages of lung injury repair. Gapdh, Acly, Tnni2, Acta1, Actn3, Pygm, Eno3 and Tpi1 (hub proteins in the PPI network) were identified in the middle-late stages of lung injury repair. Eno3 and Tpi1 were both involved in the glycolysis/gluconeogenesis signalling pathway. The expression of PARK7 and FABP5 was validated and was consistent with the proteomics analysis. CONCLUSION: The identified hub proteins and their related signalling pathways may play crucial roles in lung injury repair due to zinc chloride smoke inhalation.

Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials.

AIMS: The aim of the present meta-analysis was to evaluate the efficacy and safety of sapropterin dihydrochloride in phenylketonuria (PKU) patients. METHODS: The following databases were searched for randomized controlled trials (RCT) regarding PKU patients treated with sapropterin dihydrochloride: PubMed, Embase, Cochrane Library and clinicaltrials. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. RESULTS: Four studies met the inclusion criteria. In PKU patients with low blood phenylalanine (Phe) concentration, no significant difference was indicated for the decrease of Phe level (weighted mean difference (WMD) = -7.75 µmol L-1 ; 95% confidence intervals (CI): -82.63 to 67.13, P = 0.84, I2  = 0%), however, the dietary Phe tolerance was significantly improved in the sapropterin group (WMD = 19.89 mg kg-1  d-1 ; 95% CI: 10.26 to 29.52, P < 0.0001, I2  = 0%). In PKU patients with high blood Phe level, sapropterin showed a significant lowering in blood Phe concentration (WMD = -225.31 µmol L-1 ; 95% CI: -312.28 to -138.34, P < 0.00001, I2  = 0%). There was no significant difference for adverse events. CONCLUSIONS: Sapropterin could bring benefit for PKU patients with high or low Phe level, due to Phe reduction in a short time or dietary Phe tolerance improvement respectively. Sapropterin has an acceptable safety profile.

Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice.

BACKGROUND: Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. AIM: We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3. METHODS: Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 µg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. RESULTS: Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-ß, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups. CONCLUSION: Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.

Marked change in blood tacrolimus concentration levels due to grapefruit in a renal transplant patient.

WHAT IS KNOWN AND OBJECTIVE: Reveal the current status of grapefruit in the Chinese medical environment. CASE DESCRIPTION: An approximately 2-fold increase in blood tacrolimus concentration was observed on day 9 in the hospital despite no change in dose. The only possible cause is that the patient had consumed grapefruit during hospitalization, which is often mistakenly considered to be a fruit belonging to the West and uncommon in the medical environment in China. WHAT IS NEW AND CONCLUSION: This is the first report of grapefruit-induced blood tacrolimus concentration change. Chinese medical practitioners should re-evaluate the impact of grapefruit and food-drug interactions caused by it.

[Clinical characteristics of lung cancer complicated with pulmonary embolism].

OBJECTIVE: To investigate the clinical characteristics, risk factors, and survival time of patients with lung cancer (LC) and pulmonary embolism (PE). METHODS: A total of 17 LC patients complicated with PE admitted to this hospital from February 2012 to January 2014 were retrospectively reviewed. There were 13 males and 4 females, with an average age of (65±9) years (range, 38-82 years). Twenty LC patients, including 14 males and 6 females with an average age of (63±9) years (range, 34-81 years), and 10 PE patients , including 7 males and 3 females with an average age of (70±7) years (range, 42-85 years), were selected respectively as the LC control group and the PE control group. Logistic regression analysis was used to evaluate the risk factors for LC complicated with PE. The survival of these patients was compared with that of the control subjects by Kaplan-Meier analysis. RESULTS: In the 17 patients with LC and PE, the diagnosis of PE was made simultaneously with LC in 2, before the diagnosis of LC in 4, and after the diagnosis of LC in 11 patients. These patients showed a higher incidence of unexplained dyspnea (12 cases) than those with LC only (6 cases) (P<0.05). These patients also had a higher incidence of cough (11 cases) than those with PE only (2 cases) (P<0.05). The patients with both PE and LC had a lower PaO2 (67±18) mmHg (1 mmHg=0.133 kPa) than those with LC only (87±12) mmHg (P<0.05). They also showed higher WBC count (8.9±5.3) g/L and D-Dimer level (850±537) µg/L than those with LC only (4.5±3.0) g/L, (306±188) µg/L (P<0.05). Multi-factor analysis showed that Hb<100 g/L, WBC>11×10(9)/L, D-Dimer>500 µg/L, PO2<80 mmHg, adenocarcinoma, and high pathological grade (TNM grade) were the risk factors for LC with PE (odds ratio 1.58, 2.24, 3.06, 3.15, 3.44, 2.09, respectively). On January 31, 2014, the median survival time of patients with LC and PE was 8.7 months, which was significantly lower than that of patients with LC only (P<0.05). CONCLUSIONS: The common clinical manifestations in patients with both LC and PE included unexplained dyspnea, fever and cough. The most common pathological type was adenocarcinoma. The first 5 months after LC diagnosis were the peak time for PE. Patients with LC and PE had a shorter survival time. LC of grade III to IV, lower Hb, higher WBC, higher D-Dimer and hyoxemia were independent risk factors for LC complicated with PE.