Reduction of pancreatic β-cells mass, major secondary to increased β-cells apoptosis, is increasingly recognized as one of the main contributing factors to the pathogenesis of type 2 diabetes (T2D), and saturated free fatty acid palmitate has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting β-cells apoptosis. Recent literature suggests that valproate, a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder, can inhibit glycogen synthase kinase-3β (GSK-3β) activity and has cytoprotective effects in neuronal cells and HepG2 cells. Thus, we hypothesized that valproate may protect INS-1 β-cells from palmitate-induced apoptosis via inhibiting GSK-3β.Valproate pretreatment remarkable prevented palmitate-mediated cytotoxicity and apoptosis (lipotoxicity) as well as ER distension. Furthermore, palmitate triggered ER stress as evidenced by increased mRNA levels of C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) in a time-dependent fashion. However, valproate not only reduced the mRNA and protein expression of CHOP but also inhibited GSK-3β and caspase-3 activity induced by palmitate, whereas, the mRNA expression of ATF4 was not affected. Interestingly, TDZD-8, a specific GSK-3β inhibitor, also showed the similar effect on lipotoxicity and ER stress as valproate in INS-1 cells. Finally, compared with CHOP knockdown, valproate displayed better cytoprotection against palmitate.Valproate may protect β-cells from palmitate-induced apoptosis and ER stress via GSK-3β inhibition, independent of ATF4/CHOP pathway. Besides, GSK-3β, rather than CHOP, may be a more promising therapeutic target for T2D.
Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Interestingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions.
Some patients with psoriasis experience relapses shortly after discontinuation of biologics. However, there is a lack of risk prediction tools to identify those at high risk of relapse.
The impact of smoking on tuberculosis outcome was evaluated in a territory-wide treatment programme. 16,345 consecutive patients undergoing chemotherapy for active tuberculosis in government chest clinics in Hong Kong from 2001 to 2003 were followed up prospectively for 2 years for treatment outcome and subsequently tracked through the territory-wide tuberculosis notification registry for relapse until the end of 2012. Smoking was associated with more extensive lung disease, lung cavitation and positive sputum smear and culture at the baseline. In both current smokers and ex-smokers, sputum smears and cultures were significantly more likely to remain positive after 2 months of treatment. Both categories of smokers were significantly less likely to achieve cure or treatment completion within 2 years. Overall, 16.7% of unsuccessful treatment outcomes were attributable to smoking, with the key contributor being default in current smokers and death in ex-smokers. Among successful treatment completers, there was a clear gradient (hazard ratios of 1.00, 1.33 and 1.63) of relapse risk from never-smokers to ex-smokers and current smokers, with an overall population attributable risk of 19.4% (current smokers: 12.2%; ex-smokers: 7.2%). Smoking adversely affects baseline disease severity, bacteriological response, treatment outcome and relapse in tuberculosis. Smoking cessation likely reduces relapse and secondary transmission.
Objective
To compare the curative effect of laparoscopic and small incision surgery on pediatric indirect inguinal hernia.
Methods
A retrospective analysis was conducted on 456 patients with indirect inguinal hernia in Padiatric Surgery of Anqing Hospital Affiliated to Anhui Medical University from September 2011 to March 2013. In which 230 patients were treated with laparoscopic procedure (laparoscopic group) and 226 patients were treated by small incision surgery (traditional operation group). The treatment efficacies of two kinds of operation mode were analyzed retrospectively.
Results
In laparoscopic group, 62 patients (26.56%, 62/230) with contralateral processus vaginalis were detected intraoperatively and high ligated simultaneously. There was no case converted to laparotomy, and all of the incision healed in stage Ⅰ with no obvious scar in laparoscopic group. The unilateral and bilateral repair operative time of laparoscopic procedure were (19.3±5.4)min and (26.8±6.2)min, respectively. In laparoscopic group, there were 3 patients of postoperative swelling of the scrotum, and no cases with scrotal hematoma and iatrogenic cryptorchidism, 2 patients of recurrence in the follow-up of 3-21 months. The unilateral and bilateral repair operative time in small incision surgery group were (20.8±6.5)min and(28.6±7.8)min, respectively. There were 3 patients with incision effusion and 1 patients of wound infection after operation. In traditional operation group, there were 202 patients of postoperative swelling of the scrotum, 9 patients with scrotal hematoma, and 2 patients with iatrogenic cryptorchidism, 4 patients of homolateral and 7 patients of contralateral recurrence in the follow-up of 3-21 months. There was no significant difference between two groups in the operation time and the rate of incision infection, iatrogenic cryptorchidism and recurrence after operation (all P values>0.05). The rate of scrotum swelling, scrotal hematoma and contralateral recurrence was lower in laparoscopic group, complication rates had significant difference (all P values<0.05).
Conclusions
Compared with traditional small incision surgery, laparoscopic procedure is superior in the beauty of incision, lower rate of postoperative scrotum swelling, scrotal hematoma, and contralateral recurrence. Contralateral occult hemia can be detected and ligated intraoperatively. The laparoscopic herniotomy is a safe, reliable and effective option for the treatment of pediatric indirect inguinal hernia.
Key words:
Hernia, inguinal; Laparoscopic; Child
Background: Dynein, axonemal, heavy chain 1 (DNAH1) gene mutations have been found to be related to primary ciliary dyskinesia (PCD) and the DNAH1 gene is associated with abnormal flagellar morphology in spermatozoa. Infertility is a common condition in women presenting with primary ovarian insufficiency (POI) characterized by hypergonadotropic hypogonadism. The purpose of this study was to explore the clinical significance of genetic diagnostics in several Chinese primary infertile women with atypical POI. Methods: Four atypical POI patients and 100 healthy subjects were recruited, genetic pathogenicityc factors were investigated by whole exome sequencing (WES). Results: WES revealed a homozygous deletion mutation in the DNAH1 gene (NM_015512.5; c.11726_11727delCT, p.Pro3909Argfs*33) in one of the four POI patients. The 31-year-old affected woman presented with a normal menstrual cycle and elevated plasma levels of FSH, around the postmenopausal range, but had a normal antral follicle count and normal anti-Müllerian hormone levels. The patient, after two failed ovulation cycles, became pregnant in the third IVF cycle and delivered a healthy girl at term. Conclusions: The homozygous deletion mutation in the DNAH1 gene suggested that the patient might have a cilia movement disorder of the fallopian tubes, which is a known infertility factor. Moreover, the significantly elevated plasma level of FSH in this patient is likely one of the most important factors leading to her decreased fertility.
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