Successful use of tofacitinib in epidermolysis bullosa pruriginosa.

This case report describes 26-year-old woman who had multiple clusters of pale-pink lichenoid papules since childhood and the accompanying itching was intense. Skin biopsy revealed obvious fissures had formed under the epidermis. The patient was diagnosed with epidermolysis bullosa pruriginosa and was successfully treated with tofacitinib.

Circular RNA circ_0000034 upregulates STX17 level to promote human retinoblastoma development via inhibiting miR-361-3p.

OBJECTIVE: Retinoblastoma (RB) is a common intraocular tumor of infancy and childhood. Circular RNAs (circRNAs) are related to the development of RB. The purpose of this research was to reveal the functional mechanism of circRNA circ_0000034 in RB. MATERIALS AND METHODS: Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot were applied to determine the levels of genes. MTT assay and flow cytometry were employed to assess cell proliferation and apoptosis rate, respectively. Furthermore, cell migratory and invasive abilities were measured using the transwell assay. Mouse xenograft was conducted to analyze the effect of circ_0000034 on tumor growth in vivo. Besides, the interaction between miR-361-3p and circ_0000034 or syntaxin 17 (STX17) was predicted by starBase, and then, confirmed by the Dual-Luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS: The levels of circ_0000034 and STX17 were increased and miR-361-3p level was decreased in RB tissues and cells. Circ_0000034 knockdown suppressed cell proliferation, migration, invasion, autophagy, and tumor growth, and induced apoptosis in RB. Circ_0000034 targeted miR-361-3p and miR-361-3p bound to STX17. Circ_0000034 overexpression and miR-361-3p knockdown reversed the effect of miR-361-3p upregulation and STX17 depletion on the growth of RB cells, respectively. Besides, circ_0000034 elevated STX17 level by repressing miR-361-3p expression. CONCLUSIONS: We demonstrated that circ_0000034 knockdown suppressed the development of RB by the modulation of miR-361-3p/STX17 axis. Our findings provided a theoretical basis for the treatment of RB.

Does the use of monopolar energy as the preferred mode of dissection effectively reduce seroma formation in laparoscopic total extra peritoneal hernioplasty? A prospective double-blinded randomized control trial.

INTRODUCTION: Seroma is a commonly encountered sequela after hernia repair. Tremendous effort has been spent to investigate the effective way to prevent this "complication" including the modification of surgical technique, use of per-peritoneal drainage, etc. There were debates about the use of monopolar diathermy versus blunt dissection in laparoscopic TEP in the prevention of seroma formation. This randomized study aims to compare the effects of using 2 techniques in laparoscopic TEP on pre-peritoneal drain output and seroma formation. METHOD: From 1.9.2018 to 30.9.2019, all male and female patients presented with the first occurrence, unilateral inguinal hernia anticipated for laparoscopic TEP were enrolled into the study after informed consent. Patients were randomized into "monopolar dissection preferred" (MDP) group and "blunt dissection-preferred" (BDP) group just before commencing of operation after general anesthesia. Surgeons were instructed to use monopolar energy as main dissection method for the whole operation if possible (MDP), whereas blunt dissection is the preferred choice in BDP group, but the use of monopolar energy was allowed if needed. Total energy time was measured by a specially designed homemade device attaching to the monopolar pedals as accurate as to millisecond (ms). Pre-peritoneal drains were inserted for drainage and removed 23 h after operation. Drainage output, total operating time, energy time, clinical and ultrasonic seroma sizes at day 1, day 6, 1-month post operations, recurrence are compared between 2 groups. RESULTS: A total of 103 patients where included. There was no significant difference in age, gender, co-morbidities, side of hernia, mean defect size, operating time, fixation adjuncts, or postoperative stay. The drain volume in BDP group is 71.13 ± 31.42 mL while it in MDP group is 56.36 ± 21.46 mL. The MDP group had significantly fewer drain output at 23 h post operation (p = 0.007) and lower seroma incidence on days 6 (p = 0.036). Overall incidence of seroma formation was 12% on postoperative day 1, 11% on postoperative day 7. No statistically differences in postoperative pain score or complications were observed at the first week, 1- and 3-months' post operation. There was no correlation with energy time to the drain output. No recurrence was found in subsequent follow-up. CONCLUSION: Pre-peritoneal drainage is clinically safe in laparoscopic totally extra-peritoneal hernioplasty and can effectively reduce the size and incidence of seroma. The seroma formation can be further reduced by appropriate use of monopolar energy as preferred dissection approach in lap TEP. Due to limitation in measuring the actual energy time, the result should be further validated by randomized multi-centers trial on its potential benefit in hernia repair by a more accurate measuring device on energy used.

[Effect of different medication time prior to corneal refractive surgery on tear film stability].

Objective: To investigate the effect of different medication time prior to corneal refractive surgery on tear film stability. Methods: Prospective cohort study. A total of 60 patients (60 eyes), including 38 males (63.3%) and 22 females (37.7%) with an average age of (24.2±5.1) years (form 18 to 37 years), who had planned for corneal refractive surgery with normal ocular surface disease index score were included in this study. The patients were divided into 1d group (medication of 1 day, 30 eyes) and 3d group (medication of 3 days, 30 eyes) randomly. The first tear break up time (FBUT), the average tear break up time (AVBUT) and the dry eye grade score were recorded on the examination day and the operation day with Keratograph 5M. The difference of FBUT and AVBUI between the two groups was compared with the independent sample t test. The difference of FBUT and AVBUT between the examination day and the operation day was compared with the paired t test. The difference of the dry eye classification between the two groups was compared using chi-square test. Results: The FBUT and AVBUT of 1d group and 3d group were (10.89±5.19)s and (10.88±6.82)s, (16.24±3.62)s and (16.21±4.74)s respectively in preoperative examination, and (10.65±6.03)s and (8.14±5.75)s, (15.14±5.30)s and (12.86±5.92)s respectively in operation day. There was no significant difference in FBUT and AVBUT between the two groups (t=0.01, 1,47, 0.02, 1.44; P>0.05). However, in the 3d group, the AVBUT of operation day decreased as compared with that of the examination day, and the difference was statistically significant (t=2.31, P<0.05). There was no significant difference in the distribution of dry eye classification between the two groups (χ(2)=0.07, 3.36; P>0.05). Conclusion: Both of medication of 1 day and medication of 3 days prior to corneal refractive surgery can provide a similar tear film stability, however more attention should be paid to the medication for patients with asymptomatic but abnormal BUT. (Chin J Ophthalmol, 2018, 54: 744-747).

Factors related to skeletal relapse in the two-jaw surgery treatment of mandibular prognathism.

This study identified factors contributing to skeletal relapse in the two-jaw surgery treatment of mandibular prognathism. A set of three standardized lateral cephalograms (T1: before surgery, T2: immediately after surgery, T3: final follow-up after surgery) were obtained from 35 patients. The surgical changes were defined as follows: postsurgical immediate change (T2-T1), postoperative stability (T3-T2) and the final surgical change (T3-T1). The occlusal plane and gonial angles were also measured. Relapse was defined as the reverse movements of the menton point (Me) and point A, with the null hypothesis stating that Me and point A do not significantly change at the postoperative stability (T3-T2). A paired t test and Pearson's correlation were used for statistical analysis. The immediate postoperative changes (T2-T1) in Me and point A were significant, and were measured to be 8.5mm backward and 3.0mm forward, respectively. Additionally, the occlusal plane and gonial angles significantly increased by 2° and decreased by 2°, respectively. The final postoperative changes (T3-T1) in Me and point A were also significant, and were measured to be 5.2mm backward and 2.5 forward, respectively; the occlusal plane and gonial angles also increased nonsignificantly by 0.6° and 0.7°, respectively. Upon investigating postoperative stability (T3-T2), Me was measured to be significantly 3.3mm forward and 1.4mm upward, whereas point A was measured to be nonsignificantly 0.5mm backward and 0.9mm upward. Therefore, the null hypothesis was rejected. Pearson's correlation showed that horizontal Me (T3-T2) and point A (T3-T2) were significantly correlated with the amounts of setback Me (T2-T1) and advancement A (T2-T1), respectively. In conclusion, skeletal relapses are significantly correlated with the amounts of mandibular setback and maxillary advancement.

The impact of hepatitis B virus infection and vaccination on the development of non-Hodgkin lymphoma.

Hepatitis B virus (HBV) infection has been documented as a risk factor for non-Hodgkin lymphoma (NHL). However, there are few large cohort studies, and there is no report about the impact of HBV vaccination. We conducted this study to evaluate these issues. We used the nationwide cohort of the Taiwan National Health Insurance Research Database for 1997-2013. We compared the incidence and the risk of developing NHL and CD20+ aggressive lymphoma between HBV and non-HBV cohorts. The hazard ratios (HRs) were computed using Cox proportional hazards models. We matched these two large cohorts to reconfirm the data. We also compared the incidence of NHL between cohorts born before and after the inception of universal HBV vaccination. We found that HBV infection increased the risk for developing NHL and CD20+ aggressive lymphoma, with HRs of 4.14 and 5.52, with a higher incidence of 17.07 and 13.9 per 100 000 person-years, respectively, compared to the non-HBV cohort. The incidence of NHL in the cohort born in the era before universal HBV vaccination was higher with 1.85 per 100 000 person-years compared to 0.74 in the cohort born later aged younger than 20. Our study confirms that HBV confers a greater risk for developing NHL, especially CD20+ aggressive lymphoma. The impact of HBV vaccination is protective against lymphoma development in the teenagers in an endemic area, but longer follow-up is needed for older age.

Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes.

PURPOSE: To evaluate the refractive outcomes in children treated after intravitreal injection of bevacizumab (IVB) for retinopathy of prematurity (ROP). METHODS: A retrospective, bi-centre study of 34 patients (64 eyes) was conducted. The patients were divided into three groups, patients received intravitreal IVB (IVB group), patients received combined IVB and laser treatment (IVB + Laser group), or patients received lens-sparing vitrectomy (IVB + LSV group). Cycloplegic refraction and axial length (AXL) were evaluated at 2 years old. RESULTS: The prevalences of myopia and high myopia were 47.5 and 10.0% in the IVB group, respectively, which were lower than those in the IVB + Laser (82.4 and 29.4%) and IVB + LSV (all 100%) groups (P = 0.001 and P < 0.001). The prevalences of emmetropia in the IVB group, IVB + Laser group, and IVB + LSV group were 50, 5.9, and 0% (P = 0.001). The AXL were similar among all groups. CONCLUSIONS: At the 2-year follow-up, severe ROP patients treated with IVB alone were more likely to remain emmetropic and had lower prevalences of myopia and high myopia. The development of high myopia in severe ROP patients could not be explained by AXL changes but may be associated with abnormalities in the anterior segment.

Association of IGF1R polymorphisms with the development of HBV-related hepatocellular carcinoma.

Although the involvement of insulin-like signaling in cancer has been well documented in various types of cancers, the association between the genetic variants in the insulin-like signaling and the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. In this study, a total of 498 individuals including 173 HBV related cirrhosis patients, 171 HBV-related HCC patients, and 154 healthy controls were enrolled. Sixteen single nucleotide polymorphisms (SNPs) in IGF1, IGF2, IGF1R and IGF2R have been genotyped by employing SNaPshot assays. We found A/A genotype at rs3743251 of IGF1R was negatively associated with HBV related HCC [odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.20-0.72, P = 0.037]; A/G genotype decreased the risk of portal vein thrombosis (OR = 0.38, 95%CI = 0.18-0.82, P = 0.01). These results indicate that rs3743251 polymorphism in IGF1R is associated with the susceptibility of HBV-related HCC.

Use of twin dorsal middle phalangeal finger flaps for thumb or index finger reconstruction.

Amputation or degloving injuries of the thumb or index finger are highly disabling. We describe the use of twin dorsal middle finger flaps harvested from the dorsal aspects of the middle and ring fingers, and based on one palmar proper digital artery, its venae comitantes, and the dorsal branches of the palmar digital nerves of the middle and ring fingers, respectively. These flaps offer advantages when large soft tissue defects of the thumb or index finger are present. In this study, twin dorsal middle finger flaps were used in nine patients (six thumbs, three index fingers). All flaps completely survived. At the mean follow-up of 20 months, the appearance of the reconstructed thumbs or index fingers was acceptable, the length was maintained, and the mean static 2-point discrimination values were 10 mm in the palmar flap and 13 mm in the dorsal flap of the reconstructed digit. All patients were satisfied with the appearance and mobility of the donor fingers. All but one donor finger showed normal finger pulp sensibility, with a static 2-point discrimination between 3 and 6 mm.

Intravitreal triamcinolone acetonide vs bevacizumab for treatment of macular oedema secondary to branch retinal vein occlusion.

PURPOSE: To compare the short-term visual and morphological results of intravitreal triamcinolone acetonide vsintravitreal bevacizumab for eyes with macular oedema secondary to branch retinal vein occlusion (BRVO). DESIGN: Retrospective interventional consecutive case series. METHODS: We reviewed the clinical records of 29 patients (29 eyes) who had macular oedema due to BRVO with minimum follow-up of 6 months. A total of 16 patients were treated with intravitreal injection of 4 mg/0.1ml triamcinolone acetonide. The other 13 patients received intravitreal bevacizumab of 1.25 mg in 0.05 ml. Baseline visual acuity, macular thickness, and intraocular pressure were recorded. Final visual acuity, final macular thickness, intraocular pressure, and adverse events were also recorded throughout the follow-up. RESULTS: All patients completed at least 6 months of follow-up. There were significant improvement in visual acuity and showed significant macular oedema decrease in optical coherence tomography examination in both the two groups postoperatively. However the therapeutic effects showed no statistically significant difference between these two groups with regard to visual results (F=6.012, P=0.083) and macular thickness decline (F=0.007, P=0.570). Seven eyes developed recurrent macular oedema and received reinjections of triamcinolone acetonide or bevacizumab. CONCLUSION: These short-term results indicate that intravitreal injection of triamcinolone acetonide or bevacizumab can both improve visual acuity and decrease macular oedema temporarily in eyes with BRVO. However, the therapeutic effects of intravitreal triamcinolone acetonide showed no significant differences compared with intravitreal bevacizumab with regard to anatomical and functional outcomes but seemed to cause more adverse events than bevacizumab.

Beta-cell failure as a complication of diabetes.

Type 2 diabetes mellitus is a complex disease characterized by beta-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic beta-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact beta-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect beta-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of beta-cell mass during normal conditions. Then, we will discuss the mechanisms of beta-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of beta-cell failure and thus identify possible novel therapeutic targets. Type 2 diabetes mellitus is a multifactorial disease that has greatly risen in prevalence in part due to the obesity and inactivity that characterize the modern Western lifestyle. Pancreatic beta-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states of nutrient excess and increased insulin demand. beta-cell response to nutrient excess occurs by several mechanisms, including hypertrophy and proliferation of existing beta-cells, increased insulin production and secretion, and formation of new beta-cells from progenitor cells [1, 2]. Failure of pancreatic beta-cells to adequately expand in settings of increased insulin demand results in hyperglycemia and diabetes. In this review, we will first discuss the factors involved in beta-cell growth and then discuss the mechanisms by which beta-cell expansion fails and leads to beta-cell failure and diabetes (Fig. 1).

Sesquiterpenes from the Formosan stolonifer Tubipora musica.

Eight new sesquiterpenes, tubipolides A-G (1-7) and tubiporone (8) (novel carbon skeleton), and a known sesquiterpene, spirotubipolide, have been isolated from the Formosan stolonifer Tubipora musica. The structures of compounds 1-8 were determined by 1D and 2D NMR spectral analysis.

Nitration and hydroxylation of aromatic amino acid and guanine by the air pollutant peroxyacetyl nitrate.

Peroxyacetyl nitrate (PAN) is a common gaseous photochemical compound in polluted air and cigarette smog. The toxicity of PAN has been found to depend on three pathways: (1) its oxidizing property that mimics peroxide or peroxynitrite; (2) its nitrating and hydroxylating properties similar to peroxynitrite; and (3) its acetylating property like acetic anhydride. The present investigations were intended to focus on the reactions of PAN with aromatic amino acids and guanine. When PAN interacted with tyrosine and guanine the major products were 3-nitrotyrosine, 3, 5-dinitrotyrosine, 8-hydroxyguanine and 8-nitroguanine. These compounds have been used as indicators for the presence of peroxynitrite in previous studies. When PAN interacted with phenylalanine, the products were 3-nitrotyrosine, 4-nitrophenylalanine, p-tyrosine, o-tyrosine and m-tyrosine. 5-Hydroxytryptophan is produced from the reaction of PAN with tryptophan. Furthermore, the formation of nitrated tyrosines was also found in the PAN-treated HL-60 cells. A high yield of dityrosine was formed when PAN and peroxynitrite were reacted with tyrosine, probably through free radical oxidation. We also found that peroxynitrite and PAN are similar in their oxidizing activity. From these findings, we suggest that peroxynitrite may be considered as the reactive intermediate of PAN.

Peroxyacetyl nitrate-induced apoptosis through generation of reactive oxygen species in HL-60 cells.

Peroxyacetyl nitrate (PAN), an ubiquitous air pollutant, induced apoptosis in human leukemia HL-60, human chronic myelogenous leukemia K-562, and mouse monocyte-macrophage RAW 264.7 cell lines. In the HL 60 cells, characteristic apoptosis morphology could be observed 4 h after the cells were treated with 50 microM PAN. Exposure of HL-60 cells to increasing concentrations of PAN (from 1 microM to 100 microM) confirmed the concentration dependence of apoptosis as evidenced by DNA fragmentation in HL-60 cells, chromatin condensation by acridine-orange staining, and the appearance of the DNA apoptotic peak in flow cytometry. During apoptosis in HL-60 cells, 3-nitrotyrosine and 3,5-dinitrotyrosine were detected by high-performance liquid chromatography and liquid chromatography-mass spectrometry-mass spectrometry. We hypothesized that PAN might induce cell death in human leukemia cells by releasing peroxynitrite and other reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Moreover, exogenous superoxide dismutase promoted PAN-induced apoptosis, and in contrast, a combination of superoxide dismutase and catalase suppressed this apoptosis. We also hypothesize that the generation of ROS during PAN-induced apoptosis in HL-60 cells could activate stress-activated protein kinase/jun N-terminal kinase activity. The formation of H2O2 produced from the dismutation of PAN-elicited superoxide anion contributed to the apoptotic mechanism in HL-60 cells through ROS pathways. These findings suggested that induction of apoptosis by the air pollutant PAN might occur as a result of the release of ROS.

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.