Previous studies investigating the relationship between systemic lupus erythematosus (SLE) and primary ovarian failure (POF) generated conflicting results. To data, no mendelian randomization study ...has been applied to examine this association. In this study, genetic instruments for exposure (SLE) were selected from a GWAS study with 5201 cases and 9066 noncases. Outcome data for POF and three reproductive traits (age at menarche, age at menopause, and age at first live birth) were obtained from other eligible GWASs. To estimate causal association, the inverse-variance weighted (IVW) method (the main analyse), MR Egger test, weighted median, simple mode, and weighted mode were applied. Moreover, sensitivity analyses were conducted to ensure the robustness of the results. Estimated by the IVW method, SLE was suggested to be causally related to the risk of POF (OR = 1.166, 95% CI 1.055-1.289, P = 0.003) and delayed age at first live birth (OR = 1.006, 95% CI 1.002-1.010, P = 0.007), with no evidence of a causal association between SLE and age at menopause or menarche. The estimates were robust according to sensitivity analysis. In conclusion, the two-sample MR study supported a causal association between SLE and POF from a genetic aspect.
Systemic lupus erythematosus (SLE) is often associated with adverse reproductive outcomes. But it's currently unclear regarding the role of SLE in oocyte and embryonic development. Also, it's ...controversial whether SLE has an adverse effect on fertility. There is a lack of comprehensive understanding and assessment of fertility in patients with SLE.
This study was aim to investigate oocyte and embryonic development as well as ovarian reserve, and clinical outcomes in SLE patients during
fertilization (IVF) treatment. By combining data on embryonic and gamete development in SLE patients, we hope to provide new insights into a comprehensive assessment of fertility in SLE patients.
In this study, we collected data from 34 SLE patients who were previously diagnosed and in remission for a total of 44 IVF cycles and matched 102 infertile women with a total of 148 IVF cycles by Propensity Score Matching (PSM) of 1:3 ratio. We then evaluated baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical outcomes between the two groups.
After PSM matching, baseline characteristics including age, infertility types, and duration, as well as infertility causes overall coincided between the two groups. Anti-müllerian hormone (AMH) was significantly lower in the SLE group
comparison (1.9
. 3.3 ng/mL,
=0.001). The SLE group performed a significant reduction in available embryo rate (76.6%
. 86.0%,
=0.001), good-quality blastocyst formation rate (35.1%
. 47.0%,
=0.003), and blastocyst formation rate (51.0%
. 67.7%,
=0.001) compared to the comparison. As for clinical outcomes, the implantation rate in the SLE group was notably lower (37.9%
. 54.9%,
=0.022). The CLBR following every embryo-transfer procedure was distinctly lower (41.2%
64.7%,
=0.016) in the SLE group
comparison. Also, the conservative and optimal CLBRs following every complete cycle procedure were significantly reduced in the SLE group
the comparison (
=0.001, both).
Patients with SLE present worse outcomes in oocyte and embryonic development, thus yielding compromised female fertility and clinical pregnancy. Individualized fertility assessment and early fertility guidance are necessary for these special groups.
The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of ...physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.
Primary Sjögren syndrome (pSS) is often related to adverse neonatal outcomes. But it's currently controversial whether pSS has an adverse effect on female fertility and clinical pregnancy condition. ...More importantly, it's unclear regarding the role of pSS in oocyte and embryonic development. There is a lack of comprehensive understanding and evaluation of fertility in pSS patients.
This study aimed to investigate oocyte and embryonic development, ovarian reserve, and clinical pregnancy outcomes in Primary Sjögren syndrome (pSS) patients during in vitro fertilization (IVF) treatment from multi-IVF centers.
We performed a muti-central retrospective cohort study overall evaluating the baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical pregnancy outcomes between the pSS patients and control patients who were matched by Propensity Score Matching.
Following PSM matching, baseline characteristics generally coincided between the two groups. Ovarian reserve including anti-müllerian hormone (AMH) and antral follicle counting (AFC) were significantly lower in the pSS group vs comparison (0.8 vs. 2.9 ng/mL, P < 0.001; 6.0 vs. 10.0, P < 0.001, respectively). The pSS group performed significant reductions in numbers of large follicles, oocytes retrieved and MII oocytes. Additionally, pSS patients exhibited obviously deteriorate rates of oocyte maturation, 2PN cleavage, D3 good-quality embryo, and blastocyst formation compared to comparison. As for clinical pregnancy, notable decrease was found in implantation rate (37.9% vs. 54.9%, P = 0.022). The cumulative live birth rate (CLBR) following every embryo-transfer procedure was distinctly lower in the pSS group, and the conservative and optimal CLBRs following every complete cycle procedure were also significantly reduced in the pSS group. Lastly, the gestational weeks of the newborns in pSS group were distinctly early vs comparison.
Patients with pSS exhibit worse conditions in terms of female fertility and clinical pregnancy, notably accompanied with deteriorate oocyte and embryo development. Individualized fertility evaluation and early fertility guidance are essential for these special patients.
Background
Previous studies have shown that lipopolysaccharide (LPS)-activated bone marrow-derived dendritic cells (DClps) might induce tolerance in autoimmune and cancer models
in vivo
, whereas it ...remains unclear whether DClps could play a role in allergic disease model. Herein, we aimed to elucidate the potential effects of DClps on OVA-sensitized/challenged airway inflammation in a mouse model, which may help facilitate the application of specific tolerogenic dendritic cells (tolDC) in allergic asthma in the future.
Methods
The phenotype and function of immature DC (DCia), DClps or IL-10-activated-DC (DC10) were determined. OVA-sensitized/challenged mice were treated with OVA-pulsed DCia or DClps or DC10. We assessed the changes of histopathology, serum total IgE level, pulmonary signal transducers and activators of transcription (STAT), pulmonary regulatory T cells (Tregs), and airway recall responses to OVA rechallenge, including proliferation and cytokine secretory function of pulmonary memory CD4
+
T cells in the treated mice.
Results
DClps exhibited low levels of CD80 and MHCII and increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β. Additionally, DClps treatment dramatically diminished infiltration of inflammatory cells, eosinophilia, serum IgE and STAT6 phosphorylation level, increased the number of pulmonary Tregs. In addition, DClps treatment decreased the proliferation of pulmonary memory CD4
+
T cells, which further rendered the downregulation of Th2 cytokines
in vitro
.
Conclusion
LPS stimulation may lead to a tolerogenic phenotype on DC, and thereby alleviated the Th2 immune response of asthmatic mice, possibly by secreting anti-inflammatory cytokines, inhibiting pulmonary memory CD4
+
T cells, downregulating pulmonary STAT6 phosphorylation level and increasing pulmonary Tregs.
To investigate the prognostic value of quantitative analysis of CT among patients with idiopathic pulmonary fibrosis (IPF) by quantifying the fibrosis extent and to attempt to provide precise ...medium-long term prognostic predictions for individual patients.
This was a retrospective cohort study that included 95 IPF patients in Zhongshan Hospital, Fudan University. 64 patients firstly diagnosed with IPF from 2009 to 2015 was included as the derivation cohort. Information regarding sex, age, the Gender-Age-Physiology (GAP) index, high-resolution computed tomography (HRCT) images, survival status, and pulmonary function parameters including forced vital capacity (FVC), FVC percent predicted (FVC%pred), diffusing capacity of carbon monoxide (DLCO), DLCO percent predicted (DLCO%pred), carbon monoxide transfer coefficient (KCO), KCO percent predicted (KCO%pred) were collected. 31 patients were included in the validation cohort. The Synapse 3D software was used to quantify the fibrotic lung volume (FLV) and total lung volume (TLV). The ratio of FLV to TLV was calculated and labeled CT
, reflecting the extent of fibrosis. All the physiological variants and CT
were analyzed for the dimension of survival through both univariate analysis and multivariate analysis. Formulas for predicting the probability of death based on the baseline CT
were calculated by logistic regression, and validated by the validation cohort.
The univariate analysis indicated that CT
along with DLCO%pred, KCO%pred and GAP index were significantly correlated with survival. However, only CT
was meaningful in the multivariate analysis for prognostic prediction (HR 1.114, 95% CI 1.047-1.184, P = 0.0006), and the best cutoff was 11%, based on receiver operating characteristic (ROC) curve analysis. The survival times for the CT
≤ 11% and CT
> 11% groups were significantly different. Given the CT
data, the death probability of a patient at 1 year, 3 years and 5 years could be calculated by using a particular formula. The formulas were tested by the validation cohort, showed high sensitivity (88.2%), specificity (92.8%) and accuracy (90.3%).
Quantitative volume analysis of CT might be useful for evaluating the extent of fibrosis in the lung. The CT
could be a valuable biomarker for precisely predicting the medium-long term prognosis of individual patients with IPF.
Multiple morphological abnormalities of the sperm flagella (MMAF) is characterized by abnormal flagellar phenotypes, which is a particular kind of asthenoteratozoospermia. Previous studies have ...reported a comparable intracytoplasmic sperm injection (ICSI) outcome in terms of fertilization rate and clinical pregnancy rate in patients with MMAF compared with those with no MMAF; however, others have conflicting opinions. Assisted reproductive technology (ART) outcomes in individuals with MMAF are still controversial and open to debate.
A total of 38 patients with MMAF treated at an academic reproductive center between January 2014 and July 2022 were evaluated in the current retrospective cohort study and followed up until January 2023. Propensity score matching was used to adjust for the baseline clinical characteristics of the patients and to create a comparable control group. The genetic pathogenesis of MMAF was confirmed by whole exome sequencing. The main outcomes were the embryo developmental potential, the cumulative pregnancy rate (CLPR), and the cumulative live birth rate (CLBR).
Pathogenic variants in known genes of
,
,
,
, and
were identified in patients with MMAF. Laboratory outcomes, including the fertilization rate, 2PN cleavage rate, blastocyst formation rate, and available blastocyst rate, followed a trend of decline in the MMAF group (
< 0.05). Moreover, according to the embryo transfer times and complete cycles, the CLPR in the cohort of MMAF was lower compared with the oligoasthenospermia pool (
= 0.033 and
= 0.020, respectively), while no statistical differences were observed in the neonatal outcomes.
The current study presented decreased embryo developmental potential and compromised clinical outcomes in the MMAF cohort. These findings may provide clinicians with evidence to support genetic counseling and clinical guidance in specific patients with MMAF.
Airway dendritic cells (DCs) are recognized as important factors in the mechanisms of allergic inflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) is involved in regulating the ...functions of T cells and macrophages, but the roles of SOCS3-expressing DCs in the pathogeneses of allergic inflammatory diseases are still controversial. We compared the effects of adoptively transferred SOCS3
and SOCS3
bone marrow-derived DCs (BMDCs) on airway inflammation in ovalbumin (OVA)-sensitized asthmatic mice. Adoptive transfer of mature DCs (lipopolysaccharide LPS-induced DCs, DClps) with or without SOCS3 gene expression significantly ameliorated allergic airway inflammation. SOCS3
DCs slightly attenuated BMDC-induced immunogenic tolerance. DClps migrated to OVA-sensitized lungs with higher efficiency than immature DCs (DCim). DClps with or without SOCS3 greatly improved lung pathology scores and alleviated airway inflammatory cell infiltration after adoptive transfer into mice; they also increased interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production and inhibited signal transducer and activator of transcription (STAT) 4 and STAT6 signaling in the lungs after OVA sensitization. In conclusion, the BMDC adoptive transfer-induced immunogenic tolerance in OVA-sensitized mice might not be due to SOCS3 gene depletion. BMDC adoptive transfer may be developed into a new approach that alleviates asthma by modulating the balance between immune tolerance and inflammation.
Background
Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the ...development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown.
Methods
We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 patients with severe asthma, and 12 control subjects). H
2
O
2
was used to stimulate the human macrophage line U937 to mimic the oxidative stress status in severe asthma. The ability of candidate compounds, namely, azithromycin, PI3K inhibitors (BEZ235 and LY294002) and a p38 MAPK inhibitor (BIRB796), to ameliorate GC insensitivity in severe asthma was evaluated.
Results
PBMCs from patients with severe asthma exhibited dose-dependent and time-dependent GC insensitivity, which correlated with reduced activity of histone deacetylase 2 (HDAC2) (p < 0.05) and elevated expression of proinflammatory genes nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) (p < 0.01) compared with these parameters in the control group. The PI3K inhibitors (BZE235 and LY294002) significantly restored the GC sensitivity of PBMCs from patients with severe asthma. In vitro, the PI3K inhibitors (BZE235 and LY294002) ameliorated GC insensitivity in H
2
O
2
/TNFα-induced IL-8 release from U937 cells by independently restoring the activity of HDAC2 or inhibiting the activation of transcription factors.
Conclusions
This study demonstrates that PI3K inhibitors ameliorate GC insensitivity in severe asthma by restoring HDAC2 activity and inhibiting the phosphorylation of nuclear signaling transcription factors.
It is known that small airway disease is present across all asthma severities; however, its prevalence and clinical characteristics in cough variant asthma (CVA) have not been fully illuminated.
A ...total of 77 CVA patients with preserved proximal airway function (FEV1/FVC > 70%) were enrolled in this study. The correlation between forced expiratory flow at 50% (FEF
) and FEF
in the CVA population was first evaluated. FEF
was determined to be an easy and feasible parameter for identifying small airway disease. CVA with small airway disease is defined as FEF
< 70%, whereas CVA with normal small airways is identified as FEF
> 70%. Demographic features, clinical characteristics, lung function and induced sputum test results were determined at the initial visit and at the final visit 1 year later.
FEF
is a good marker for small airway disease. The cutoff value of 70% is more sensitive than the previously published 60% for identifying more patients with small airway problems early. Nearly half of the CVA population (45.4%) in our cohort had small airway disease. In both group, symptoms improved greatly after anti-asthmatic treatment. Interestingly, the changes in symptom scores Asthma Control Test (ACT) and ACQ were even greater in the CVA with small airway disease group than in the control group because of the higher medication usage in this subpopulation in real life. However anti-asthmatic therapy can not reverse small airway dysfunction. At last visit, FEF
of CVA with small airway diseases was 57.2% ± 10.5%, still much lower than the control group (FEF
= 92.6% ± 16.5%).
In our cohort, nearly half of the CVA population had small airway disease. Their demographic features, clinical characteristics, airway eosinophils and drug responsiveness were quite similar between two groups, which means these indices can not be used as markers to identify small airway obstruction. We found FEF
is an easy and feasible marker for early identification. Regular anti-asthmatic medication helped to improve clinical scores in patients with small airway disease, but the obstruction could not be reversed over 1-year period.
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