Serum interleukin-4 is elevated in clinical drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) remains a challenging diagnosis due to an absence of specific biomarkers. DILI due to volatile anaesthetics (VA-DILI) is characterised by trifluoroacetyl and CYP2E1 antibodies, but may not be seen for weeks after injury. Interleukin-4 (IL-4) may be involved in the production of these antibodies and may serve as a clinically useful early biomarker of VA-DILI. AIM: To prospectively compare serum IL-4 levels between patients who develop VA-DILI and controls following exposure to the volatile anaesthetic. METHODS: A nested case-control study of patients exposed to VA during surgery was conducted. Thirteen DILI cases were identified from the original cohort, and 26 controls were matched according to age, sex and VA agent. Serum samples were collected before and 48-96 h after VA exposure, and analysed for IL-4 using quantitative enzyme-linked immunosorbent assay techniques. RESULTS: There was a statistically significant difference in serum IL-4 in post-VA samples between DILI cases and controls (control: 0.030 pg/mL, IQR: 0.030 - 0.030 pg/mL vs DILI: 0.044 pg/mL, IQR: 0.030 - 0.061 pg/mL; p = 0.039). A greater proportion of DILI cases had post-VA IL-4 levels above the assay lower limit of detection compared to controls (control: 23% vs DILI: 69%; p = 0.013). CONCLUSION: IL-4 is a potential biomarker of DILI. Clinical diagnosis and understanding of DILI disease mechanisms may be improved by further investigation of novel biomarkers, and this IL-4 signal in serum is important as proof of concept for prospective study designs.

[Femtosecond laser-assisted minimally invasive lamellar keratoplasty for advanced keratoconus].

Objective: To evaluate the initial safety and efficacy of femtosecond laser-assisted minimally invasive lamellar keratoplasty (FL-MILK) for advanced keratoconus. Methods: It was a case series study. Patients with advanced keratoconus who underwent FL-MILK between August 2017 and April 2020 at Shandong Eye Hospital were prospectively included. The femtosecond laser was used to create an intrastromal pocket in the recipient cornea and a lamellar cornea in the donor. The lamellar cornea was then gently inserted into the intrastromal pocket through the incision and flattened. Clinical measurements included best-corrected visual acuity, 3-mm anterior corneal mean keratometry, anterior and posterior central corneal elevation, central corneal thickness, corneal biomechanics, and endothelial cell density. The follow-up was conducted at 1 month, 12 months, and 24 months after the operation. Results: There were 33 patients (35 eyes) in the study. Twenty-six patients were male and 7 patients were female. The mean age was (20.34±5.24) years old. All patients completed 12 months of follow-up, and 25 patients (27 eyes) completed 24 months of follow-up. No epithelial ingrowth, infection, or allogeneic rejection was observed. Compared with the preoperative data, the anterior central corneal elevation significantly decreased (P<0.001), the mean keratometry significantly decreased (P<0.05), and the central corneal thickness significantly increased (P<0.001). The corneal biomechanical strength was significantly improved, with the deformation amplitude ratio at 2.0 mm decreasing from 1.39±0.14 preoperatively to 1.21±0.10 at 24 months postoperatively (P<0.001) and the stiffness parameter at the first applanation increasing from 41.49±11.47 preoperatively to 88.41±18.17 at 24 months postoperatively (P<0.001). There were no significant changes in the mean best-corrected visual acuity, posterior corneal elevation, mean spherical equivalent, and endothelial cell density (all P>0.05). Conclusions: FL-MILK may be a feasible option for advanced keratoconus. This procedure may provide a new resolution for keratoconus.

Downregulated FGFR3 Expression Inhibits In Vitro Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells of Mice with TBXT Gene Mutation.

We studied the effect of fibroblast growth factor receptor 3 (FGFR3) inhibitor BGJ-398 on the differentiation of bone marrow mesenchymal stem cells (BM MSC) into osteoblasts in wild type (wt) mice and in animals with mutation in TBXT gene (mt) and possible differences in the pluripotency of these cells. Cytology tests showed that the cultured BM MSC could differentiate into osteoblasts and adipocytes. The effect of different BGJ-398 concentrations on the expression of FGFR3, RUNX2, SMAD1, SMAD4, SMAD5, SMAD6, SMAD7, and SMAD8 were studied by quantitative reverse transcription PCR. The expression of RUNX2 protein was evaluated by Western blotting. BM MSC of mt and wt mice did not differ in pluripotency and expressed the same membrane marker antigens. BGJ-398 inhibitor reduced the expression of FGFR3 and RUNX2. In BM MSC from mt and wt mice have similar gene expression (and its changing) in FGFR3, RUNX2, SMAD1, SMAD4, SMAD5, SMAD6, SMAD7, and SMAD8 genes. Thus, our experiments confirmed the effect of decreased expression of FGFR3 on osteogenic differentiation of BM MSC from wt and mt mice. However, BM MSC from mt and wt mice did not differ in pluripotency and are an adequate model for laboratory research.

[Clinical phenotype and gene mutation analysis of 12 patients with hereditary protein C deficiency in different families].

Objective: To investigate the molecular pathogenesis and clinical features of unrelated 12 patients with inherited coagulation protein C (PC) deficiency in Chinese population. Methods: The PC activity (PC:A) and PC antigen (PC:Ag) were detected by chromogenic substrate and enzyme linked immunosorbent assay, respectively. The nine exons and flanking sequences of the protein C (PROC) gene were amplified by polymerase chain reaction with direct sequencing, and the suspected mutations were validated by reverse sequencing (clone sequencing for deletion mutations) . Results: The PC:A of the 12 probands decreased significantly, ranging from 18% to 55%, and the PC:Ag of the 10 probands decreased significantly. Eleven mutations were found, out of which four mutations [c.383G>A (p.Gly128Asp) , c.997G>A (p.Ala291Thr) , c.1318C>T (p.Arg398Cys) , and c.532G>C (p.Leu278Pro) ] were discovered for the first time. Six mutations were in the serine protease domain, four mutations were located in epidermal growth factor (EGF) -like domains, and one mutation was located in activation peptide. There were two deletion mutations (p.Met364Trp fsX15 and p.Lys192del) , and the rest were missense mutations. Mutations p.Phe181Val and p.Arg189Trp were identified in three unrelated families. All mutations may be inherited, and consanguineous marriages were reported in two families. Among the probands, nine cases had venous thrombosis, two cases had poor pregnancy manifestations, and one case had purpura. Conclusion: Patients with PC deficiency caused by PROC gene defects are prone to venous thrombosis, especially when there are other thrombotic factors present at the same time.

[Therapeutic effect of rigid permeable contact lenses on irregular astigmatism after keratoplasty].

Objective: To evaluate the clinical effect of rigid permeable contact lenses (RGPCL) in the correction of irregular astigmatism after keratoplasty. Methods: Retrospective case study. From June 2012 to December 2016, 31 patients (37 eyes) who underwent corneal transplantation were tested and fitted with RGPCL. The patients' data of primary disease, interval from keratoplasty to contact lens fitting, uncorrected visual acuity, best spectacle-corrected visual acuity, best RGPCL-corrected visual acuity, contrast visual acuity before and after RGPCL wear, corneal topography and corneal endothelium parameters before and after RGPCL wear were collected, including ocular complications and comfort of contact lenses. Results: Among the 31 patients, 24 were male and 7 were female, with age of (31.3±5.8) years. The mean interval between grafting and initial contact lens fitting was (4.6±2.3) years. Uncorrected visual acuity, best spectacle-corrected visual acuity, and best RGPCL-corrected visual acuity were 0.81±0.21, 0.54±0.13, and 0.10±0.07, respectively (t=7.170, 16.617, 17.866; all P<0.05). The average astigmatism was -5.76±2.23 D and -0.83±0.47 D before and after wearing RGPCL (t=8.531, P<0.05). After wearing RGPCL, the contrast visual acuity of 100%, 25%, 10%, and 5% was increased from 0.95±0.33, 1.18±0.21, 1.40±0.00, and 1.40±0.00 to 0.12±0.15, 0.37±0.17, 0.65±0.25, and 0.96±0.29, respectively (t=5.972, 8.473, 9.243, 5.104; all P<0. 05). There were no obvious changes of corneal endothelium parameters during the observation period. No obvious corneal allograft rejection or other complications occurred, and 94.6% (35/37) of the patients felt comfortable with wearing RGPCL. Conclusions: RGPCL wear is safe and effective in correcting irregular astigmatism after corneal transplantation. We can obtain good corrected vision and improve contrast visual acuity, especially for patients who can not wear spectacles. (Chin J Ophthalmol, 2019, 55: 413-418).

Randomized phase II trial comparing tumor bed alone with tumor bed and elective nodal postoperative radiotherapy in patients with locoregionally advanced thoracic esophageal squamous cell carcinoma.

This study compares the outcomes of different postoperative radiation fields for locoregionally advanced thoracic esophageal squamous cell carcinoma (ESCC) patients. This is a multi-institution randomized phase II trial and noninferior study. Patients with ESCC who had undergone esophagectomy (stage T3-4N0-3M0) were enrolled and randomized into the large-field irradiation arm (LFI; tumor bed and elective lymph node region) and small-field irradiation arm (SFI; tumor bed only). The primary endpoint was whether the disease-free survival (DFS) of SFI was not inferior to LFI. The secondary endpoint was to evaluate the rationality of the radiation target volume by analyzing failure patterns. One hundred twenty-one patients (64 patients for LFI and 57 patients for SFI, respectively) were eligible in this mid-time analysis. The 1- and 3-year DFS was 79.9%, 46.2% for LFI and 67.6%, 44.3% for SFI, respectively (P = 0.414). The locoregional recurrence-free survival (LRFS) of LFI was significantly better than that of SFI (P = 0.003). However, there were no significant differences in the distant metastasis-free survival and overall survival between the two arms (P = 0.332, P = 0.405, respectively). The failure patterns of the two arms were significantly different (P = 0.002). For pT3-4N0-3M0 ESCC patients, postoperative radiotherapy with SFI showed a similar survival outcome to LFI. However, the LRFS of patients with SFI was worse than that of patients with LFI.

Concurrent chemoradiotherapy for cervical esophageal squamous cell carcinoma: treatment results from a prospective observational study.

A prospective observational study was performed to evaluate the results of treatment with concurrent chemoradiotherapy (CCRT) in patients with cervical esophageal squamous cell carcinoma (CESCC). Patients had CESCC, no distant metastasis, were 18-75 years old, and had PS 0-2. Radiotherapy (RT) was administered as either three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) with a total dose of 60 Gy/30 fractions. All patients were treated with platinum-based doublet concurrent chemotherapeutic regimens. CCRT was followed by 2-3 cycles of consolidation chemotherapy. The endpoints were overall survival (OS), progression-free survival (PFS), toxicities, and failure patterns. Ninety-two patients were enrolled from March 2007 to July 2014. The median follow-up time was 34 months. For all patients, the 3-year OS was 49.8% (median OS: 36 months, 95% CI: 24.963-47.051), and the 3-year PFS was 42.1%, (median PFS: 25 months, 95% CI: 17.097-32.903). Treatment failures occurred in 54 patients, including 30 cases (32.6%) with locoregional failure alone, 14 cases (15.2%) with distant metastasis alone, and 10 cases (10.9%) with both locoregional failure and distant metastasis. There were 51 (55.4%) and 3 cases (3.3%) of grade 3 and grade 5 radiation esophagitis, respectively. One patient (1%) had grade 5 laryngeal edema. Overall, CCRT has tolerable acute toxicities, and this regimen is an option for the treatment of patients with CESCC.

[Eosinophilic esophagitis in children: analysis of 22 cases].

Objective: Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disease.The current domestic reports of EoE in children is rare.The aim of this study was to analyze the clinical features, the diagnosis and treatment advance of EoE in children by case analysis and literature review. Method: Clinical data of 22 children with EoE from January, 2011 to December, 2015 in Children's Hospital, Zhejiang University School of Medicine were recorded, retrospective analysis was performed on clinical presentation, gastroendoscopy and histopathological examination features and the treatment. Result: (1) Clinical data: EoE can occur at any age in children (5 months to 13 years). The most common clinical manifestations of EoE are vomiting and abdominal pain, 45% (10/22) and 41%(9/22) respectively. (2) Endoscopy and pathological features of esophageal mucosa: 11 cases with coarse mucous membrane (50%), 6 cases with congestion or erosion of esophageal membrane (27%), 5 cases with longitudinal crack (23%), 3 cases with ring uplift (14%), 3 cases with granular uplift (14%), 3 cases with normal mucosa(14%). Histopathologic manifestation is eosinophil infiltration and the eosinophil counts were all more than or equal to 15/HP. (3) Laboratory results: 13 cases had increasing eosinophil counts and eosinophils proportion (62%). (4)Allergy history: among 22 cases, 7 patients had allergy history (32%). (5) Situation of treatment and remission: 16 cases had clinical remission by oral omeprazole; 2 cases had clinical remission by oral Omeprazole and Montelukast sodium; 1 case acquired remission by elimination diet; 1 case acquired remission by elimination diet and oral prednisone. 2 cases dropped out; Only 2 patients received gastroendoscopy re-examination after 3 months and revealed esophageal mucosal histologic complete recovery. Conclusion: The clinical symptoms of EoE in children varies.Esophageal mucosal features of gastroendoscopy examination in children with EoE were longitudinal crack, white exudates or plaques, paper mucosa, ring uplift and granular uplift.Most patients could achieve remission by using proton-pump inhibitors, only few children needed elimination diet and change formula, or even oral glucocorticoids.

[Association between the C46T polymorphism of coagulation factor â « gene and the involvement of factor â « activity in patients with unexplained recurrent spontaneous abortion].

OBJECTIVE: To explore the association between the C46T polymorphism of coagulation factor Ⅻ (FⅫ) gene and the involvement of FⅫ activity (FⅫ:C) in patients with unexplained recurrent spontaneous abortion (URSA), and to elucidate its role in the pathogenesis of URSA. METHODS: This study included 203 patients with URSA (URSA group) and 171 healthy women with at least one child and no history of infertility or miscarriage (control group) in the southern area of Zhejiang Province. The C46T polymorphism of the FⅫ gene was analyzed with matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS) in all subjects. The values of prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, FⅫ:C and other coagulant parameters were determined. The frequency distribution of the wild-type (CC), heterozygote (CT), homozygote (TT) genotypes and C and T alleles were compared between the patients and controls. A comprehensive analysis of association was conducted between C46T genotypes and the FⅫ:C levels in URSA patients. RESULTS: The CC, CT, TT genotypes of the FⅫ gene were observed in 7 (3.4%, 7/203), 83 (40.9%, 83/203) and 113 (55.7%, 113/203) patients with URSA versus 7 (4.1%, 7/171), 46 (26.9%, 46/171) and 118 (69.0%, 118/171) controls. The frequency of CT in the patients with URSA was significantly higher than that in controls, but the frequency of TT in the patients was lower than that in controls (χ(2)=7.939, OR=1.884, 95%CI: 1.210-2.935, P<0.05). The frequencies of allele C and allele T were observed in 97 (23.9%, 97/406) and 309 (76.1%, 309/406) patients with URSA versus 60 (17.5%, 60/342) and 282 (82.5%, 282/342) controls. The distribution frequency of allele T in URSA group was lower than that in control group (χ(2)=4.510, OR=1.475, 95%CI: 1.029-2.115, P<0.05). The FⅫ: C levels in the patients were (102±13)% in CC genotype, (78±11)% in CT genotype and (59±9)% in TT genotype, respectively. The differences of the FⅫ: C levels between the CC and CT, CT and TT, CC and TT genotypes in the patients were significant (all P<0.05). CONCLUSIONS: The low level of FⅫ:C maybe result from the T allele of the FⅫ gene in URSA patients. The CT genotype might be relative to the pathogenesis of URSA in a Chinese Han female population from the southern area of Zhejiang province.

Hysteroscopic tubal catheterization and hydrotubation for treatment of infertile women with tubal obstruction.

We reported the efficacy of interval hysteroscopic tubal catherization and hydrotubation for three months in 54 infertile women with tubal obstruction (102 fallopian tubes). By comparison of HSGs before and after treatment, 86 of 102 tubes (84%) showed the improvement of tubal patency (P < 0.01). 56 tubes were patent (54.9%). This method is effective for partially patent tubes (87.5%), intramural tubal obstruction (62.5%), and the obstruction at the distal portion of the fallopian tube (13.3). One -12 month follow-up after treatment, 12 of 35 women whose tubes became completely patent achieved intrauterine pregnancies.