STAT3 gene polymorphism in chronic obstructive pulmonary disease.

OBJECTIVE: The aim of this study was to explore the correlation between rs8069115, rs41289087, and rs11079042 polymorphisms of the signal transducer and activator of transcription 3 (STAT3) gene and chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: A total of 200 patients diagnosed with COPD were enrolled in the disease group. Meanwhile, 200 normal subjects were selected as the control group. Peripheral blood was collected from subjects in the disease group and control group. Subsequently, nucleated cells were isolated for determination of STAT3 gene polymorphisms. Quantitative Polymerase Chain Reaction (qPCR) was utilized to detect the expression level of STAT3. Samples from 12 patients with differences in STAT3 haplotypes and 12 cases with no difference were collected and treated with transcriptome sequencing to analyze pathways enriched with differentially expressed genes. RESULTS: There were statistically significant differences in allele distributions at rs8069115 between the disease group and control group (p=0.000), and the allele frequency of G was higher in disease group. Genotype distributions of rs8069115 (p=0.000) and rs41289087 (p=0.000) of the STAT3 gene in disease group were significantly different in comparison with the control group. The frequency of rs8069115 GG genotype was remarkably higher, while the frequency of rs41289087 TG genotype was lower in the disease group (p<0.05). In addition, compared with the control group, the distributions of the dominant model (p=0.002) and recessive model (p=0.004) of rs8069115 of the STAT3 gene were markedly different in the disease group. A significantly higher frequency of dominant model GG+GA and lower frequency of recessive model GA+AA were observed at rs8069115 in the disease group (p<0.05). Moreover, the haplotype distributions of AGC (p=0.002), ATC (p=0.001), GTA (p=0.010), and GTC (p=0.035) at rs8069115, rs41289087, and rs11079042 were different between the disease group and control group. Besides, rs8069115 locus and rs11079042 locus were linked to each other (D'=0.523). There was a remarkable association between rs11079042 polymorphism of the STAT3 gene and gene expression (p<0.05). STAT3 was highly expressed in patients with genotype CC (p<0.05). Furthermore, changes in transcriptome levels among different haplotype populations (haplotype with different distributions vs. haplotype with no difference in distribution) were analyzed. The results demonstrated that multiple pathways, such as ECM-receptor interactions, cell cycle checkpoints, and protein processing were notably enriched (p<0.05). CONCLUSIONS: According to our results, we confirmed that the polymorphisms (rs8069115, rs41289087, and rs11079042) of STAT3 gene are noticeably correlated with the occurrence and progression of COPD.

Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as early biomarkers for predicting vancomycin-associated acute kidney injury: a prospective study.

OBJECTIVE: Previous studies have demonstrated that urinary kidney injury molecule-1 (uKIM-1) and neutrophil gelatinase-associated lipocalin (uNGAL) were superior to serum creatinine (Scr) in detecting acute kidney injury (AKI), but their ability to predict clinical vancomycin-associated AKI has not been investigated. This study aimed to investigate the abilities of uKIM-1 and uNGAL individually and in combination to predict vancomycin-associated AKI. PATIENTS AND METHODS: Scr, uKIM-1, and uNGAL were measured on the day before and days 1, 2, and 3 of vancomycin therapy in a generalized adult population. Levels of these biomarkers between AKI and non-AKI groups were comparatively analyzed. Predictive performances were evaluated by receiver operating characteristic curve (ROC) analysis. RESULTS: A total of 87 patients were enrolled, and among them, 11 (12.6%) patients developed AKI. Urinary KIM-1 and NGAL levels in the AKI group were higher than in the non-AKI group at all time points (p < 0.05), and the areas under the receiver operating characteristic curves (AUC) were 0.849 (95% confidence interval [CI] 0.750-0.948) for uKIM-1 and 0.824 (95% CI 0.726-0.922) for uNGAL, with cut-off values of 1.72 ng/mL and 9.07 ng/mL respectively. The AUC of uKIM-1 and uNGAL combined was 0.852 (95% CI 0.754-0.949), and the sensitivity and specificity were 90.9% and 75.0%, respectively. CONCLUSIONS: Urinary KIM-1 and NGAL could efficiently discriminate patients with or without vancomycin-associated AKI earlier than Scr, and the combined urinary biomarkers showed fair discrimination compared with the individual biomarkers.

[Correlation study of blood drug concentration and nephrotoxicity on high dose methotrexate therapy in suggestion of diagnosis and treatment of childhood acute lymphoblastic leukemia in the 4th revised edition].

Objective: To explore the influence of the 4th revised treatment recommendations in childhood acute lymphoblastic leukemia (ALL) on high dose methotrexate(HD-MTX)-induced nephrotoxicity and MTX blood concentrations. Method: The clinical data from 330 ALL children who received 1 242 courses of HD-MTX therapies from September 2012 to November 2016 was collected. The courses were divided into two groups based on the chemotherapies: original scheme group was treated with the 3rd revised regimen, and new scheme group was treated with the 4th revised regimen. The two groups in acute kidney injury (AKI) and MTX blood concentrations were compared. Result: The incidences of AKI with low risk (LR) and intermediate risk (IR) in new scheme group were significantly lower than those in original scheme group (1.3%(3/229) vs. 7.9%(24/303), 4.9%(10/204) vs. 12.8%(26/203), χ(2)=11.831 and 7.888 respectively, both P<0.05). There was no significant difference in the incidence of AKI with high risk (HR) in the two groups (15.2%(10/66) vs. 10.5%(25/237), χ(2)=1.071, P>0.05). The 48h MTX blood concentrations and the interphase from onste to MTX concentrations decreased to the safe level with LR and IR children in new scheme group were significantly lower than those in original scheme group (0.36(0.08-4.00) vs. 0.44(0.06-32.00) µmol/L, 0.49(0.22-33.00) vs. 0.60(0.18-83.00) µmol/L, 3(2-6) vs. 3(2-11) d, 3(2-11) vs. 3(2-19) d, Z=-5.953, -2.658, -4.490 and -4.729 respectively, all P<0.05). The differences with HR were not observed between the two groups (0.61(0.14-36.00) vs. 0.71(0.11-68.00) µmol/L, 3(2-15) vs. 3(2-13) d, Z=-1.465 and -1.179 respectively, both P>0.05). Conclusion: Decreased renal toxicity and acceleration of MTX excretion may occur when childhood ALL with LR and IR were treated with the 4th revised regimen. However, nephrotoxicity and MTX blood concentrations have no significant differences with HR in the two regimens, and close monitoring are necessary.

Retrospective analysis of vancomycin treatment outcomes in Chinese paediatric patients with suspected Gram-positive infection.

WHAT IS KNOWN AND OBJECTIVE: Vancomycin is one of the most widely used antibiotics for treating serious Gram-positive infections in children. Few clinical studies have examined the potential risk factors for treatment failure in children receiving vancomycin. The objectives of this study were to evaluate the relationships between vancomycin trough concentration and treatment outcomes in Chinese paediatric patients with suspected Gram-positive infections and to identify baseline characteristics that may affect treatment failure associated with vancomycin use. METHODS: A retrospective cohort study was conducted from April 2007 to October 2015. Patients were included in this study if they were <18 years old, had received vancomycin for at least 72 h and had at least one bacterial culture and one serum steady-state vancomycin trough concentration. Treatment outcomes were defined as success or failure. Nephrotoxicity was defined as a serum creatinine (Scr) increase ≥44·2 µmol/L or a ≥50% increase in baseline Scr for at least two consecutive days. Univariate and multivariate logistic regression analyses were performed to identify risk factors for treatment failure with vancomycin. RESULTS AND DISCUSSION: One hundred and eighty-two patients were included. Vancomycin treatment failure occurred in 52 patients (28·6%), and the incidence of nephrotoxicity was low. No significant difference was observed in the vancomycin trough concentrations between the treatment success and failure groups. Multivariate logistic regression analyses showed that the vancomycin trough concentration [odds ratio (OR), 1·046; 95% confidence interval (CI), 0·979-1·118; P = 0·179, statistical power: 62·04%)] was not associated with treatment outcome, and only intensive care unit (ICU) admission (OR, 3·808; 95% CI, 1·714-8·465; P = 0·001, statistical power: 90·40%) was found to be independently associated with vancomycin treatment failure. WHAT IS NEW AND CONCLUSION: Our findings suggest that the vancomycin trough concentration is not associated with treatment outcome. ICU admission is an independent predictor of treatment failure.

Single-nucleotide polymorphism microarray-based preimplantation genetic diagnosis is likely to improve the clinical outcome for translocation carriers.

STUDY QUESTION: Is preimplantation genetic diagnosis (PGD) for translocation carriers more effective when done with a single-nucleotide polymorphism (SNP) array using trophectoderm (TE) biopsy and frozen embryo transfer (FET) compared with traditional PGD based on fluorescence in situ hybridization (FISH-PGD) using blastomere biopsy and fresh embryo transfer? SUMMARY ANSWER: The procedure using the SNP array combined with TE biopsy and FET significantly improves the clinical pregnancy rate for translocation carriers. The miscarriage rate also slightly decreases. WHAT IS KNOWN ALREADY: FISH-PGD has been widely used in translocation carriers but the clinical outcomes have not been ideal. SNP arrays can detect both chromosome segmental imbalances and aneuploidy, and may overcome the limitations of FISH in PGD for translocation carriers. STUDY DESIGN, SIZE AND DURATION: This was a retrospective study of 575 couples with chromosomal translocations, including 169 couples treated by SNP-PGD between October 2011 and August 2012, and 406 couples treated by FISH-PGD between January 2005 and October 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was set in an IVF center at the Reproductive and Genetic Hospital of CITIC-Xiangya, China. In total, 169 couples underwent SNP analysis, including 52 Robertsonian translocation carriers and 117 carriers of reciprocal translocations. Blastocysts (n = 773) were biopsied and FET was carried out on the balanced embryos. Four hundred and six couples underwent FISH-PGD, including 149 Robertsonian translocation carriers and 257 reciprocal translocation carriers. In total, 3968 embryos were biopsied and balanced embryos were transferred fresh. The SNP-PGD results and clinical outcomes were compared with those of FISH-PGD. MAIN RESULTS AND THE ROLE OF CHANCE: Reliable SNP-PGD results were obtained for 717 out of 773 (92.8%) biopsied blastocysts. The proportions of normal/balanced embryos, embryos with translocation-related and translocation-unrelated abnormalities, the median number of embryos per patient, the ongoing pregnancy rate per embryo transfer and the miscarriage rate were 58, 23, 19, 2, 69 and 12%, respectively, for Robertsonian translocation carriers and 36, 52, 12, 1, 74 and 11%, respectively, in reciprocal translocation carriers. Reliable FISH-PGD results were obtained for 3452 out of 3968 (87.0%) biopsied embryos. The proportions of normal/balanced embryos, unbalanced embryos, the median number of embryos per patient, the ongoing pregnancy rate per transfer and the miscarriage were 36, 64, 3, 38 and 17%, respectively, for Robertsonian translocation carriers and 20, 80, 1, 39 and 16%, respectively, for reciprocal translocation carriers. Thus, SNP-PGD achieved a higher pregnancy rate but a lower miscarriage rate than FISH-PGD. There were no significant differences in maternal age, basal endocrine level and the average number of retrieved oocytes and good-quality D3 embryos in the SNP-PGD group compared with the FISH-PGD group. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study with the two groups treated in different periods; therefore, there is a chance of sample bias and a possibility that the results were influenced by other factors that changed over time. Furthermore, the two treatment protocols differ in several respects and we cannot say which makes the greatest contribution to the difference in success. Complete pregnancy outcomes of SNP-PGD have not been obtained as some embryos have not been transferred yet. We cannot exclude differences between the final data and the data in the present manuscript. WIDER IMPLICATIONS OF THE FINDINGS: The adoption of SNP-PGD combined with TE biopsy and FET may significantly improve the clinical pregnancy rate, and decrease the miscarriage rate after PGD for translocation carriers.

Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities.

Comparative effects of cholinesterase inhibitors (ChEI) huperzine A with E2020 and tacrine on the radial maze performance in ethylcholine mustard aziridinium ion (AF64A)-treated rat and inhibition of cholinesterase activity were studied. The intracerebroventricular (i.c.v.) injection of AF64A (3 nmol/side) caused significant impairment in the rat's ability to fulfill the partially baited maze paradigm. Oral huperzine A (0.5-0.8 mg/kg), E2020 (1.0-2.0 mg/kg), and tacrine (8.0 mg/kg) effectively reversed AF64A-induced working memory deficit. The doses that improved AF64A-induced memory deficit were correlated to about 25-30% (huperzine A) and less than 10% (E2020, tacrine) inhibition of acetylcholinesterase (AChE) activity in the cortex and hippocampus. Huperzine A, E2020 and tacrine all produced dose-dependent inhibition of brain AChE following i.c.v. and oral administration. Oral huperzine A exhibited higher efficacy on the inhibition of AChE in the cortex and hippocampus than those of E2020 and tacrine. Tacrine was more effective in inhibiting plasma butyrylcholinesterase (BuChE) than it was brain AChE. Conversely, the BuChE activity was less affected by huperzine A and E2020. The results showed that huperzine A had high bioavailability and more selective inhibition on AChE activity in cortex and hippocampus. Huperzine A fits more closely with the established criteria for an ideal AChE inhibitor to be used in clinical studies.

Effects of huperzine A on nucleus basalis magnocellularis lesion-induced spatial working memory deficit.

AIM: To study the effects of huperzine A on nucleus basalis magnocellularis (NBM) lesion-induced spatial working memory impairment. METHODS: A delayed-non-match-to-sample radial arm maze task was used to study spatial working memory. The choline acetyltransferase (ChAT) activity was determined by the conversion of [3H]acetyl-CoA to [3H]ACh. RESULTS: Unilateral NBM lesion by kainic acid 0.02 mumol impaired rat's ability to perform this working memory task as evidenced by fewer correct choices after different delay intervals and more total errors to complete the task. This behavioral impairment associated with a decrease in the activity of ChAT by about 40% in the ipsilateral cerebral cortex. Huperzine A (0.2 mg.kg-1 i.p. 30 min before testing) ameliorated this spatial working memory impairment. Physostigmine (0.2-0.3 mg.kg-1 i.p. 20 min before testing) also attenuated the NBM lesion-induced memory deficit. CONCLUSION: The integrity of NBM is critical for spatial working memory processing, and this working memory impairment induced by NBM lesion can be ameliorated by huperzine A and physostigmine.

Huperzine A, a novel promising acetylcholinesterase inhibitor.

The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease.

A pharmacokinetic and pharmacodynamic study of a 'visiting pill' containing norethisterone.

The pharmacokinetics and pharmacodynamic effects of two doses of norethisterone (5mg and 3mg) used as a 'visiting pill' were investigated. There were no significant differences in the pharmacokinetics of the two doses except for the peak concentration achieved and the bioavailability as assessed by the area under the serum norethisterone concentration - time curve. Both doses were rapidly absorbed. Pharmacodynamic effects were minor. No change occurred in serum concentrations of total cholesterol, total triglycerides or HDL-cholesterol. The area under the serum glucose concentration--time curve and particularly the area under the serum insulin concentration--time curve were significantly increased as a result of treatment but no change occurred in the serum levels of glycosylated haemoglobin. SHBG concentrations in serum decreased on treatment whereas those of ceruloplasmin increased.

Stimulation of bone growth by periosteal stripping. A clinical study.

Periosteal stripping in the long lower limb bones of thirty children with shortening after poliomyelitis was performed. All have been followed up for five years. A relative increase in length attributable to the periosteal stripping procedure was seen in the majority. The conclusions are that this simple procedure is indicated in minor degrees of limb inequality in growing children, but that the haphazare response precludes any accurate estimation of the final outcome of such a procedure.