[Value of surgery combined chemotherapy and radiation therapy in locally advanced neuroendocrine carcinoma of the cervix: a single-center retrospective cohort study].

Objective: To evaluate the surgery combined chemotherapy and radiation in locally advanced neuroendocrine carcinoma of the cervix (NECC) . Methods: This is a single-center retrospective cohort study. Locally advanced NECC patients admitted to Peking Union Medical College Hospital, Chinese Acadmy of Medical Sciences from January 2011 to April 2022 were enrolled. They were divided into concurrent chemoradiotherapy group, and surgery combined with chemotherapy and radiation group. The Kaplan-Meier method was used to analyze the progression free survival (PFS), overall survival (OS), recurrence rate, and mortality rate. Results: (1) Forty-six cases were included, 22 in concurrent chemoradiotherapy group, 24 in surgery combined chemotherapy and radiation group. With 16 patients (35%, 16/46) received neoadjuvant chemotherapy (NACT), the NACT effective rate was 15/16. (2) The median follow-up time was 27.5 months (range: 10-106 months), with 26 (57%, 26/46) experienced recurrences. There were 4 (9%, 4/46) pelvic recurrences and 25 (54%, 25/46) distant recurrences, and 3 (7%, 3/46) both pelvic and distant recurrences. Compared with concurrent chemoradiotherapy group, surgery combined chemotherapy and radiation group had lower pelvic recurrence rate [14% (3/22) vs 4% (1/24); χ2=1.296, P=0.255] but without statistic difference. Both groups had similar distant recurrence rate [55% (12/22) vs 54% (13/24); χ2=0.001, P=0.979] and overall recurrence rate [59% (13/22) vs 54% (13/24); χ2=0.113, P=0.736]. (3) During the follow-up period, 22 cases (48%, 22/46) died, with 11 cases (50%, 11/22) in concurrent chemoradiotherapy group and 11 cases (46%, 11/24) in surgery combined chemotherapy and radiation group, without significant difference (χ2=0.080, P=0.777). The postoperative 3-year and 5-year OS rates were 62.3% and 36.9%. Compared with concurrent chemoradiotherapy group, the patients in surgery combined chemotherapy and radiation group showed an extended trend in PFS (17.0 vs 32.0 months) and OS (37.0 vs 50.0 months) but without statistic differences (P=0.287, P=0.125). Both groups had similar 3-year OS rate (54.2% vs 69.9%; P=0.138) and 5-year OS rate (36.1% vs 38.8%; P=0.217). Conclusions: Our study supports the multi-modality treatment strategy (including surgery, chemotherapy and radiation) as an important component in the treatment of locally advanced NECC. The combination of surgery, chemotherapy and radiation seems to have advantages in the treatment of locally advanced NECC, but needs to be confirmed by further multicenter studies.

[Prognostic comparison of active surveillance and adjuvant chemotherapy in the treatment of patients with stage â ovarian immature teratoma after fertility-sparing surgery].

Objective: To compare the survival outcomes between surveillance and adjuvant chemotherapy in patients with stage Ⅰ ovarian immature teratoma (IMT) underwent fertility-sparing surgery. Methods: Clinical and pathological records of patients with stage Ⅰ ovarian IMT between Jan. 2011 to Feb. 2023 were collected from Peking Union Medical College Hospital, except stage Ⅰa grade 1. The consultation of risks and benefits regarding adjuvant chemotherapy was conducted by gynecologic oncologists. A shared decision about surveillance or chemotherapy was made by physician and patients or their guardians. Patients who finally decided to undergo surveillance were included in the surveillance group (n=40), the others were included in the adjuvant chemotherapy group (n=63). Clinical characteristics, treatment and survival outcomes were analyzed and compared between two groups. Results: A total of 103 patients were included. The median age of initial diagnosis was 20 years old (range: 3-39 years old), and the median follow-up time was 31 months (range: 1-254 months). The age, International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grade, surgical method, and preoperative and postoperative alpha-fetoprotein levels in the surveillance group and the adjuvant chemotherapy group were similar (all P>0.05). The surgical approach and maximum tumor diameter between two groups were significantly different (all P<0.05). Forty patients of the surveillance group were identified, only one patient with stage Ⅰa grade 2 IMT who underwent cystectomy had malignant recurrence on the same ovary. Another 63 patients received adjuvant chemotherapy after surgery, five patients had malignant recurrence, and two of them died of disease progression after relapsed. There were no significant differences in disease-free survival (DFS;20 vs 36 months) and overall survival (OS; 23 vs 39 months) between the surveillance group and the adjuvant chemotherapy group (follow-up time censored at 72 months; DFS: P=0.325, OS: P=0.278). Conclusions: There are no differences in survival outcomes between patients with stage Ⅰ ovarian IMT underwent adjuvant chemotherapy or not. Active surveillance might be safe and preferable in stage Ⅰ IMT patients underwent complete resection of tumor.

[Value of postoperative radiotherapy and analysis of prognostic factors in early-stage neuroendocrine carcinoma of cervix].

Objective: To evaluate the effect of postoperative radiotherapy and high-risk pathological factors on the prognosis of early-stage neuroendocrine carcinoma of cervix (NECC). Methods: A single-center retrospective cohort study of early-stage NECC in Peking Union Medical College Hospital from January 2011 to April 2022 were enrolled. The patients were treated with radical hysterectomy±adjuvant treatment. They were divided into postoperative non-radiation group and postoperative radiation group. The possible postoperative recurrence risk factors identified by univariate analysis were assessed using multivariate logistic regression. The Kaplan-Meier method was used to analyze the progression free survival (PFS), overall survival (OS), recurrence rate, and mortality rate. Results: (1) Sixty-two cases were included in the study, including 33 cases in postoperative non-radiation group and 29 cases in postoperative radiation group. (2) The median follow-up time was 37 months (ranged 12-116 months), with 23 cases (37%) experienced recurrences. There were 7 cases (11%) pelvic recurrences and 20 cases (32%) distant recurrences, in which including 4 cases (6%) both pelvic and distant recurrences. Compared with postoperative non-radiation group, the postoperative radiation group had a lower pelvic recurrence rate (18% vs 3%; P=0.074) but without statistic difference, a slightly elevated distant recurrence rate (24% vs 41%; P=0.150) and overall recurrence rate (33% vs 41%; P=0.513) without statistically significances. Univariate analysis showed that lymph-vascular space invasion and the depth of cervical stromal invasion≥1/2 were risk factors for postoperative recurrence (all P<0.05). Multivariate analysis showed lymph-vascular space invasion was an independent predictor for postoperative recurrence (OR=23.03, 95%CI: 3.55-149.39, P=0.001). (3) During the follow-up period, 18 cases (29%, 18/62) died with tumor, with 10 cases (30%, 10/33) in postoperative non-radiation group and 8 cases (28%, 8/29) in postoperative radiation group, without significant difference (P=0.814). The postoperative 3-year and 5-year survival rate was 79.2%, 60.8%. The depth of cervical stromal invasion≥1/2 was more common in postoperative radiation group (27% vs 64%; P=0.011), and postoperative radiation in such patients showed an extended trend in PFS (32.3 vs 53.9 months) and OS (39.4 vs 73.4 months) but without statistic differences (P=0.704, P=0.371). Compared with postoperative non-radiation group, the postoperative radiation did not improve PFS (54.5 vs 37.3 months; P=0.860) and OS (56.2 vs 62.4 months; P=0.550) in patients with lymph-vascular space invasion. Conclusions: Postoperative radiation in early-stage NECC patients has a trend to reduce pelvic recurrence but not appear to decrease distant recurrence and overall recurrence, and has not improved mortality. For patients with the depth of cervical stromal invasion≥1/2, postoperative radiation has a trend of prolonging OS and PFS but without statistic difference. Lymph-vascular space invasion is an independent predictor for postoperative recurrence, but postoperative radiation in such patients does not seem to have any survival benefits.

[Predictive value of net water uptake with respect to early neurological improvement after endovascular treatment in patients with acute anterior circulation large vessel occlusion stroke].

Objective: To investigate the value of net water uptake (NWU) for predicting early neurological improvement (ENI) after endovascular treatment in patients with acute anterior circulation large vessel occlusion stroke. Methods: A case-control study. A total of 132 patients (80 men, 52 women, median age 68 years) with acute anterior circulation large vessel occlusive stroke receiving endovascular treatment were retrospectively analyzed at Jinling Hospital from October 2014 to September 2019. Patients were divided into two groups based on the occurrence of ENI, which was defined as either an improvement of NIHSS score of ≥4 points, or an NIHSS score of 0 or 1 at 24 hours after endovascular treatment. The rank sum test, Chi square test, and other methods were used to compare differences in baseline characteristics between the two groups. Logistic regression analysis was used to investigate independent predictors of postoperative ENI. Receiver operating characteristic curve analysis used to assess the capacity of NWU to predict ENI. Results: Of the 132 patients in the study, ENI occurred in 47 and did not occur in 85. In multivariate logistic regression analysis age [odds ratio (OR)=0.940, 95% confidence interval (CI) 0.903-0.979, P=0.003], time from stroke onset to puncture (OR=0.995, 95%CI 0.991-0.999, P=0.025), time from puncture to recanalization/end of operation (OR=0.985, 95%CI 0.974-0.996, P=0.007), NWU (OR=0.762, 95%CI 0.620-0.937, P=0.010), and mTICI (OR=1.644, 95%CI 1.043-2.590, P=0.032) were predictive factors for ENI. Receiver operating characteristic curve analysis indicated that NWU could effectively predict ENI (area under the curve=0.642, 95%CI 0.543-0.741, P=0.007), and prediction accuracy was improved when it was combined with other clinical parameters. Conclusion: NWU is an independent predictor of ENI in patients with acute anterior circulation large vessel occlusive stroke undergoing endovascular treatment.

Association of non-alcoholic fatty liver disease with total testosterone in non-overweight/obese men with type 2 diabetes mellitus.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is considered as both a vital risk factor and a consequence of type 2 diabetes mellitus (T2DM). Low total testosterone (TT) is common in men with T2DM, contributing to increased risks of metabolic diseases. This study aimed to investigate the association between TT levels and the prevalence of NAFLD in men with T2DM. METHODS: In this cross-sectional study, 1005 men with T2DM were enrolled in National Metabolic Management Center (MMC) of First Affiliated Hospital of Wenzhou Medical University between January 2017 and August 2021. NAFLD was diagnosed using ultrasound as described by the Chinese Liver Disease Association. Overweight/obesity was defined as body mass index (BMI) ≥ 25 kg/m2 according to WHO BMI classifications. RESULTS: Individuals without NAFLD had higher serum TT levels than those with NAFLD. After adjustments for potential confounding factors, the top tertile was significantly associated with lower prevalence of NAFLD compared with the bottom tertile of TT level [odds ratio (OR) 0.303, 95% confidence interval (CI) 0.281-0.713; P < 0.001]. The association between TT with NAFLD in individuals with normal weight (OR 0.175, 95% CI 0.098-0.315; P < 0.001) was stronger than in individuals with overweight/obesity (OR 0.509, 95% CI 0.267-0.971; P = 0.040). There was a significant interaction of TT with overweight/obesity (P for interaction = 0.018 for NAFLD). CONCLUSION: Higher serum TT was significantly associated with a lower prevalence of NAFLD in men with T2DM. We found that the relationship of TT and NAFLD was stronger in individuals with non-overweight/obesity.

[Analysis of intestinal microbial diversity in Leopoldamys edwardsi based on illumina sequencing technique].

To explore the composition and diversity of the intestinal microflora of Leopoldamys edwardsi in Hainan Island. In November 2019, DNA was extracted from fecal samples of 25 adult Leopoldamys edwardsi (14 males and 11 females) in Hainan Island at the Joint Laboratory of tropical infectious diseases of Hainan Medical College and Hong Kong University. Based on the IonS5TMXL sequencing platform, single-end sequencing (Single-End) was used to construct a small fragment library for single-end sequencing. Based on Reads shear filtration and OTUs clustering. The species annotation and abundance analysis of OTUs were carried out by using mothur method and SSUrRNA database, and further conducted α diversity and ß diversity analysis. A total of 1481842 high quality sequences, belonging to 14 Phyla, 85 families and 186 Genera, were obtained from 25 intestinal excrement samples of Leopoldamys edwardsi. At the level of phyla classification, the main core biota of the Leopoldamys edwardsi contained Firmicutes (46.04%),Bacteroidetes (25.34%), Proteobacteria (17.09%), Tenericutes (7.38%) and Actinobacteria (1.67%), these five phyla account for 97.52% of all phyla. The ratio of Helicobacter which occupied the largest proportion at the genus level was 12.44%, followed by Lactobacillus (11.39%), Clostridium (6.19%),Mycoplasma (4.23%) and Flavonifractor (3.52%). High throughput sequencing analysis showed that the intestinal flora of Leopoldamys edwardsi in Hainan Island was complex and diverse, which had the significance of further research.

Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets.

Osteoarthritis (OA) is a multifactorial arthritic disease of weight-bearing joints concomitant with chronic and intolerable pain, loss of locomotion and impaired quality of life in the elderly population. Although the prevalence of OA increases with age, its specific mechanisms have not been elucidated and effective therapeutic disease-modifying drugs have not been developed. As essential organelles in chondrocytes, mitochondria supply energy and play vital roles in cellular metabolism, proliferation and apoptosis. Mitochondrial quality control (MQC) is the key mechanism to coordinate various mitochondrial biofunctions, primarily through mitochondrial biogenesis, dynamics, autophagy and the newly discovered mitocytosis. An increasing number of studies have revealed that a loss of MQC homeostasis contributes to the cartilage damage during the occurrence and development of OA. Several master MQC-associated signaling pathways and regulators exert chondroprotective roles in OA, while cartilage damage-related molecular mechanisms have been partially identified. In this review, we summarized known mechanisms mediated by dysregulated MQC in the pathogenesis of OA and latent bioactive ingredients and drugs for the prevention and treatment of OA through the maintenance of MQC.

MicroRNA-323-3p inhibits oxidative stress and apoptosis after myocardial infarction by targeting TGF-ß2/JNK pathway.

OBJECTIVE: Myocardial infarction (MI), which causes irreversible damage and loss of cardiomyocytes, is the most important cause of death in the world. MicroRNA is an important regulator of physiological and pathological activities of cardiovascular system. The aim of this research was to study the effect of microRNA-323-3p (miR-323-3p) on MI and its underlying mechanisms of action. MATERIALS AND METHODS: A rat model of MI was established to measure the expression of miR-323-3p, Bax, Bcl-2, SOD1, and SOD2 in ischemic myocardial tissue, and the cardiac function of rats were tested at seventh day after MI. H9c2 cells were divided into control group, miRNA negative control (NC) transfection group, miR-323-3p mimic (miR-323-3p min) transfection group, and then, treated with H2O2. Oxidative stress and apoptosis of H9c2 cells were observed by Western blot, Real Time-Polymerase Chain Reaction (RT-PCR), flow cytometry, SOD activity assay, TUNEL staining, DHR dye assay, etc. RESULTS: The level of miR-323-3p was decreased in ischemic myocardium, as well as H2O2-treated H9c2 cells. MiR-323-3p overexpression greatly decreased the level of Bax and increased the levels of SOD1, SOD2, and Bcl-2. After treated with miR-323-3p mimic, TUNEL positive cells were greatly reduced, and apoptosis rate of H9c2 cells was greatly decreased. Moreover, SOD levels significantly increased, while ROS production decreased after treatment of miR-323-3p. After intravenous injection of miR-323-3p agomir in rats with MI, the cardiac function of the rats was significantly improved. Western blot and Luciferase reporter gene experiments illustrated that miR-323-3p acts by targeting TGF-ß2. CONCLUSIONS: MiR-323-3p was downregulated in ischemic myocardium and H2O2-treated H9c2 cells, and miR-323-3p overexpression reduced oxidative stress and apoptosis of cardiomyocytes. The protective function was achieved via regulation of TGF-ß2/JNK pathway.

MiR-126 regulated myocardial autophagy on myocardial infarction.

OBJECTIVE: The aim of the study is to detect the effect of miR-126 in autophagy after acute myocardial infarction (AMI). MATERIALS AND METHODS: First, the changes of miR-126 and autophagy in myocardial infarction tissue and normal heart tissue were compared by establishing the myocardial infarction rat model, so as to clarify the relationship between miR-126 and changes of myocardial infarction and autophagy. Second, the regulation of miR-126 on autophagy related protein Beclin-1 and the role in myocardial infarction were studied to clarify whether miR-126 regulates autophagy through Beclin-1 and participates in the occurrence and development of myocardial infarction. Finally, the relationship between plasma miR-126 was observed. RESULTS: MiR-126 expression can regulate Beclin-1 expression and influence the cardiac function after AMI. The results are of great significance to reveal the new mechanism of myocardial infarction. CONCLUSIONS: The down-regulation of miR-126 will lead to the over-activation of myocardial autophagy induced by Beclin-1, which is an autophagy related protein. The plasm expression of miR-126 may be a clinical marker of autophagy after AMI.

[Clinical analysis of hypersensitivity reaction of platinum in ovarian cancer and cervical cancer patients].

Objective: To investigate the incidence, risk factors, management and prognosis of hypersensitivity reaction (HSR) of platinum-based chemotherapy in patients of ovarian cancer and cervical cancer. Methods: Cases from Peking Union Medical College Hospital from Jan. 2013 to Jan. 2016 were checked for patients' data of epithelial ovarian cancer treated with carboplatin/paclitaxel (every 3 weeks) and patients of cervical cancer treated with concurrent radiochemotherapy using cisplatin (every week). General characters, pathological features, treatment and prognosis of patients were analyzed to determine the severity, symptoms, outcomes and risk factors of HSR. Results: (1) Prevalence of HSR: there were 860 cases of ovarian cancer and 580 cases of cervical cancer, among which HSR occurred in 8.8% (76/860) and 5.9% (34/580) patients, respectively. (2) Grading for HSR: most HSR were grade 1 or 2, with 78.9%(60/76) in ovarian cancer and 82.4%(28/34) in cervical cancer patients. In ovarian cancer patients, there were 7 cases of grade 1 HSR and 53 cases of grade 2 HSR, and in cervical cancer patients, there were 11 cases of grade 1 HSR and 17 cases of grade 2 HSR. (3) Symptoms of HSR: most of HSR happened during intravenous infusion of platinum agents, with 98.7% (75/76) in ovarian cancer and 97.1% (33/34) in cervical cancer patients. In ovarian and cervical cancer patients, most common symptom were tight chest and dyspnea, which happened in 92.1% (70/76) and 97.1% (33/34) patients, respectively. Secondary common symptom were skin reactions, which happened in 53.9% (41/76) and 88.2% (30/34) patients respectively. (4) Treatment after HSR: of 76 ovarian cancer cases with HSR, there were no significant difference in the ratio of HSR recurrence among patients of different treatment after HSR (χ2=0.517, P=0.915): 1 of 4 patients applying prior chemotherapy, 4 of 13 cases receiving desensitization, 3 of 11 cases separating medicine, 2 of 11 patients switching to cisplatin. In 34 cervical cancer cases of HSR, there were also no significant difference in the ratio of HSR recurrence among patients of different treatment after HSR (χ2=0.079, P=1.000): 2 of 9 patients applying prior chemotherapy, 3 of 17 cases receiving desensitization. (5) Risk factors of HSR and patients prognosis: in ovarian cancer patients of HSR, risk factors included relapse (P=0.010), courses of chemotherapy reaching seven or nine for patients of primary treatment or reaching six or seven for recurrent patients (all P<0.05). There were no significant risk factors for cervical cancer patients of HSR (all P>0.05). HSR had no impact on the progression- free survival for ovarian cancer (P=0.144) or cervical cancer (P=0.782). Conclusions: In ovarian cancer patients treated with carboplatin and cervical cancer patients treated with concurrent radiochemotherapy using cisplatin, most HSR of platinum are mild and favorable outcomes. Relapse and longer chemotherapy courses are risk factors for HSR of carboplatin for epithelial ovarian cancer.

Sonic hedgehog through Gli2 and Gli3 is required for the proper development of placental labyrinth.

Sonic hedgehog (Shh) functions as a conserved morphogen in the development of various organs in metazoans ranging from Drosophila to humans. Here, we have investigated the potential roles and underlying mechanisms of Shh signaling in murine placentation. Immunostaining revealed the abundant expression of the main components of Shh pathway in both the trophectoderm of blastocysts and developing placentas. Disruption of Shh led to impaired vascularogenesis of yolk sac, less branching and malformation of placental labyrinth, thereby leading to a robust decrease in capacity of transplacental passages. Moreover, placenta-specific gene incorporation by lentiviral transduction of mouse blastocysts and blastocyst transplantation robustly knocked down the expression of Gli3 and Gli2 in placenta but not in embryos. Finally, Gli3 knockdown in Shh(-/-) placentas partially rescued the defects of both yolk sac and placental labyrinth, and robustly restored the capacity of transplacental passages. Gli2 knockdown in Shh(+/)(-) placentas affected neither the capacity of tranplacental passages nor the vascularogenesis of yolk sac, however, it partially phenocopied the labyrinthine defects of Shh(-/-) placentas. Taken together, these results uncover that both Shh/Gli2 and Shh/Gli3 signals are required for proper development of murine placentas and are possibly essential for pregnant maintenance.

Emerging epidemic in a growing industry: cigarette smoking among female micro-electronics workers in Taiwan.

OBJECTIVE: To explore the emerging tobacco epidemic in female workers in the growing micro-electronics industry of Taiwan. METHODS: Workers were surveyed regarding their smoking status, sociodemographics and work characteristics. In total, 1950 female employees in two large micro-electronics companies in Taiwan completed the survey. RESULTS: Approximately 9.3% of the female employees were occasional or daily smokers at the time of the survey. The prevalence of smoking was higher in those aged 16-19 years (20.9%), those not married (12.9%), those with a high school education or less (11.7%), those employed by Company A (11.7%), shift workers (14.3%), and those who had been in their present employment for 1 year or less (13.6%). Results of multivariate adjusted logistic regression indicated that younger age, lower level of education, shorter periods of employment with the company and shift working were the important factors in determining cigarette smoking among the study participants. The odds ratio of being a daily smoker was similar to that of being a current smoker. Marital status was the only significant variable when comparing former smokers with current smokers. CONCLUSIONS: Smoking prevalence in female workers in the two micro-electronics companies studied was much higher than previous reports have suggested about female smoking prevalence in Taiwan and China. We suggest that smoking is no longer a 'male problem' in Taiwan. Future smoking cessation and prevention programmes should target young working women as well as men.

Genetic basis of glycogen storage disease type 1a: prevalent mutations at the glucose-6-phosphatase locus.

Diagnosis of glycogen storage disease (GSD) type 1a currently is established by demonstrating the lack of glucose-6-phosphatase (G6Pase) activity in the patient's biopsied liver specimen. Recent cloning of the G6Pase gene and identification of mutations within the gene that causes GSD type 1a allow for the development of a DNA-based diagnostic method. Using SSCP analysis and DNA sequencing, we characterized the G6Pase gene of 70 unrelated patients with enzymatically confirmed diagnosis of GSD type 1a and detected mutations in all except 17 alleles (88%). Sixteen mutations were uncovered that were shown by expression to abolish or greatly reduce G6Pase activity and that therefore are responsible for the GSD type 1a disorder. R83C and Q347X are the most prevalent mutations found in Caucasians, 130X and R83C are most prevalent in Hispanics, and R83H is most prevalent in Chinese. The Q347X mutation has thus far been identified only in Caucasian patients, and the 130X mutation has been identified only in Hispanic patients. Our results demonstrate that the DNA-based analysis can accurately, rapidly, and noninvasively detect the majority of mutations in GSD type 1a. This DNA-based diagnosis now permits prenatal diagnosis among at-risk patients and serves as a database in screening and counseling patients clinically suspected of having this disease.

CD4+ beta islet cell-reactive T cell clones that suppress autoimmune diabetes in nonobese diabetic mice.

We report the isolation of a panel of CD4+ T helper type 1 autoreactive T cell clones from the spleen of unprimed nonobese diabetic mice, a murine model of human insulin-dependent diabetes mellitus. The T cell clones express a diverse repertoire of T cell receptors, three of which recognize beta islet cell autoantigen(s). The islet cell-reactive T cell clones inhibit adoptive transfer of insulin-dependent diabetes mellitus and intraislet lymphocytic infiltration. The protective capacity of the T cell clones correlates with their ability to produce a novel immunoregulatory activity that potently inhibits in vitro allogeneic mixed lymphocyte reaction. The partially purified activity significantly inhibited the adoptive transfer of diabetes. Our work provides evidence in support of the existence of T helper type 1, CD4+ T cells reactive to beta islet cell autoantigens that have acquired a protective instead of a diabetogenic effector function. These T cells mediate their protective action in part by production of an immunoregulatory activity capable of down-regulating immune responses, and they are likely to represent a population of regulatory T cells that normally plays a role in maintaining peripheral tolerance.

[Reproductive activities as a risk factor of endometriosis].

A case-control study, involving 203 cases of pelvic endometriosis and 406 randomly selected and age-matched community controls, was conducted. The results were as following: 1) A decreased risk for endometriosis was found to be related to pregnancy. The relative risk was 0.34 for para 1 and 0.08 for para 2 or more. A similar tendency was also showed in the analysis of gravidity, but this protective effect totally disappeared after adjustment for parity. Therefore, it may be revealed that it is the parity but not the gravidity which protects the women against the endometriosis. 2) There was an increased risk of 15.35 for endometriosis in women with infertility. 3) No relation emerged with age at first pregnancy to the occurrence of endometriosis as indicated in the literature. 4) The frequency of induced abortion was 42.4% in the cases and that was 63.7% in the controls. The association with the risk of the disease adjusted for education, menstruation, parity and contraception was not significant by a attentive stratification the data. 5) Two groups were relatively similar with respect to recorded condom and oral contraceptive use. However, more cases than controls did not use any contraception or only used rhythm method and coitus interruptus, and more controls than cases used an intrauterine device. The results of multivariate analysis did not approve of opinion that IUD is a risk factor of endometriosis. The results did not negate the likelihood of diminished chance of developing endometriosis in women with using oral contraceptives.

[Menstrual status as risk factors of endometriosis: a case-control study].

A case-control study, involving 203 cases of pelvic endometriosis and 406 randomly selected and age-matched community controls, was conducted. The results showed that women characterized by earlier menarche (< or = 12 years) and longer period (> 7 days) were associated with an elevated risk. Longer cycle (> 35 days) seemed to have a protective effect. There are a tendency to increasing risk for endometriosis associated with primary dysmenorrhea and energetic physical activities during menstruation. The results indicate that intensive treatment of primary dysmenorrhea and avoidance of strenuous exercise during menstruation may prevent pelvic endometriosis.

Regulation of the steady state level of Fc gamma RI mRNA by IFN-gamma and dexamethasone in human monocytes, neutrophils, and U-937 cells.

The high affinity IgG FcR Fc gamma RI, CD64, plays important roles in the immune response. Fc gamma RI is predominantly expressed on monocytes and macrophages, and barely detectable on neutrophils. rIFN-gamma markedly increases the expression of Fc gamma RI on neutrophils, monocytes, macrophages and myeloid cell lines such as U-937, HL-60, and THP-1. Glucocorticoids inhibit the augmentation of Fc gamma RI expression by rIFN-gamma on neutrophils and myeloid cell lines, but enhance the augmentation of Fc gamma RI expression by rIFN-gamma on monocytes. In this study, we examined the effect of rIFN-gamma and dexamethasone (Dex) on the steady state level of Fc gamma RI mRNA in U-937 cells, neutrophils, and monocytes by hybridizing total RNA with the Fc gamma RI cDNA probe, p135. We found that the amount of Fc gamma RI mRNA increased within 1 h of treatment with rIFN-gamma in all three cell types. This initial induction of Fc gamma RI mRNA by rIFN-gamma was completely blocked by an inhibitor of RNA synthesis, actinomycin D, suggesting that the rIFN-gamma-mediated induction of Fc gamma RI mRNA is dependent on gene transcription. Dex, used in combination with rIFN-gamma, partially blocked the induction of Fc gamma RI mRNA by rIFN-gamma in U-937 cells and neutrophils, but caused a synergistic increase in Fc gamma RI mRNA levels in monocytes. The inhibitory effect of Dex on the steady state level of Fc gamma RI mRNA in U-937 cells was blocked by an inhibitor of protein synthesis, cycloheximide, suggesting that Dex-induced proteins were involved in the regulation of Fc gamma RI expression. This study indicates that the regulation of Fc gamma RI expression on U-937 cells, neutrophils, and monocytes by rIFN-gamma and Dex occurs, at least in part, at the mRNA level. rIFN-gamma increases the steady state level of Fc gamma RI mRNA through a common pathway among U-937 cells, neutrophils, and monocytes, whereas the effect of Dex on rIFN-gamma-induced Fc gamma RI mRNA is cell-type specific.

Individual and combined tumoricidal effects of dexamethasone and interferons on human leukocyte cell lines.

We investigated the influence of glucocorticoids on two effects of interferons (IFNs) which are thought to relate to their antitumor actions: cytotoxic activity and induction of HLA antigen expression. We treated human myeloid cell lines (U-937, HL-60, THP-1, K-562, and KG-1a), and T-(MOLT-4) and B- (Daudi) lymphoblastic cell lines with concentrations of IFN-alpha, IFN-gamma, and dexamethasone (Dex) which are commonly achieved in the circulation following therapeutic administration. The results show that for every cell line except Daudi, the greatest inhibition of cell growth occurred when IFN-gamma and Dex treatments were combined. The advantage of combined IFN-gamma and Dex treatment over treatment with either agent alone was most dramatic for the three cell lines (U-937, HL-60, and THP-1) which have monocytoid characteristics. There was also more growth inhibition by the combination of IFN-alpha and Dex than by either agent alone for all seven cell lines tested. The induction of HLA antigen expression by IFN-alpha and IFN-gamma, an effect which could increase recognition of the tumor cells by the immune system, was as great or greater in the presence of Dex as in its absence. These results demonstrate that glucocorticoids do not inhibit, and in some cases enhance, two effects of IFNs that appear to be related to their antitumor actions: inhibition of tumor cell proliferation and enhancement of HLA antigen expression.