The effect of dienogest treatment on anti-Mullerian hormone in patients with endometrioma: a 12-month follow-up study.

Objective: To assess the effect of dienogest treatment on endometrioma (OMA) size, serum anti-Mullerian hormone (AMH) levels and associated pain over a 12-month follow-up period. Material and Methods: A longitudinal cohort study of 104 patients with OMA who were treated with dienogest, between January 2017 and January 2020. Of the included patients, each had a 12-month follow-up period with transvaginal or pelvic ultrasound and measurement of serum AMH concentration at the sixth and twelfth months of follow-up. The alteration in OMA size in the sixth and twelfth months of treatment was the primary outcome measure and the alteration in AMH concentration over the same period was the secondary outcome measure. The only exclusion criterion was having surgical intervention for OMA during the follow-up period (n=44). In patients with bilateral OMA (n=21), the change in size of the largest OMA was considered in the analysis. Results: A total of 60 patients with a mean ± standard deviation (SD) age of 31.5±8.0 years were included. The mean ± SD OMA size on the day the dienogest was started was 46.3±17.4 mm and the mean AMH level was 3.6±2.4 ng/mL. After six months, the mean OMA size had decreased to 38.6±14.0 mm, with a median difference of 7.8 mm [95% confidence interval (CI): 3.0 to 12.6; p=0.003]. The mean AMH level was 3.3±2.7 ng/mL at 6 months follow-up (95% CI: -0.2 to 0.8; p=0.23) and the average difference was 0.3 ng/mL. At the 12th-month visit, when compared with the beginning of the treatment, OMA size had again significantly decreased by a median of -8.9 mm (95% CI: -2.9 to -14.9; p=0.005), and the decline in median AMH was also significant (-0.9 ng/mL, 95% CI: -0.1 to -1.7; p=0.045). The initial mean ± SD visual analog scale pain score at the commencement of dienogest treatment was 6.3±3.4. The mean values at the sixth and twelfth months of dienogest therapy were 1.08±1.8 and 0.75±1.5, respectively (both p<0.001 compared to baseline). Conclusion: At the sixth and twelfth months of dienogest treatment a significant decrease in OMA size and reported pain scores were observed, whereas the AMH concentrations did not change significantly.

Impact of clinicopathological variables on laparoscopic hysterectomy complications, a tertiary center experience.

OBJECTIVES: To analyze intraoperative and postoperative complications according to Clavian-Dindo Classification (CDC) and evaluate the influence of clinicopathological features on the feasibility and safety of total laparoscopic hysterectomy (TLH) in patients that underwent surgery in a tertiary center. MATERIAL AND METHODS: We retrospectively reviewed the database of 469 patients that underwent surgery for patients who underwent extra facial TLH from 2013 to 2020. RESULTS: A total of 86 (18.3%) peri-postoperative complications were observed. The incidence of intraoperative complications was 2% (n = 10). The overall conversion rate to open surgery was 1.9% (n = 9). A total of 76 postoperative complications were observed in 61 patients (14.3%). The incidence of minor (Grade I [n = 16, 3.4%] and II [n = 42, 8.9%]) and major complications (Grade III [n = 15, 3.2%], IV [n = 2, 0.4%] and V [n = 1, 0.2 %]) were 12.3% and 3.8%, respectively. A higher BMI and performing surgery at the first step of learning are found to be associated with intraoperative and postoperative complications (p < 0.05). Postoperative complications related to having a history of the cesarean section, additional comorbidities, and uterine weight ≥ 300 g (p < 0.05). CONCLUSIONS: The implementation of TLH by experienced surgeons appears to have remarkable advantages over open surgery. However, the risk factor for complications should be taken into account by surgeons in the learning curve in selecting the appropriate patient for surgery.

Hepatocyte proteomes reveal the role of protein disulfide isomerase 4 in alpha 1-antitrypsin deficiency.

BACKGROUND & AIMS: A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention. METHODS: Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease. RESULTS: We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease. CONCLUSIONS: PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD. LAY SUMMARY: Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease.

A Particular SORL1 Micro-haplotype May Prevent Severe Liver Disease in a French Cohort of Alpha 1-Antitrypsin-deficient Children.

ABSTRACT: The presence of modifier genes is now well recognized in severe liver disease outcome associated with alpha-1-antitrypsin deficiency (A1ATD) but their identification remains to be fully elucidated. To address this goal, we performed a candidate gene study with the SORL1 gene, already identified as risk gene in early-onset Alzheimer Disease families. A particular SORL1 micro-haplotype constituted with 3 SNPs (wild-type form TTG) was genotyped on 86 ZZ A1ATD children issued from 66 families. Interestingly, the mutated forms of this micro-haplotype (CAT most of the time) were associated with lower occurrence of severe liver disease and in cellulo studies showed that SORL1 influences Z-A1ATD cellular toxicity and biogenesis. These data suggest that the mutated CAT form of SORL1 micro-haplotype may partly prevent from severe liver disease in A1ATD children. Overall, these findings support a replication study on an independent cohort and additional in cellulo studies to confirm these promising results.

Assessment of Factors Affecting Breastfeeding Performance and Latch Score: A Prospective Cohort Study.

OBJECTIVE: To determine the risk factors that may affect LATCH scores. MATERIALS AND METHODS: We prospectively evaluated the LATCH scores and any relevant risk factors of patients who delivered at our institution during April and May 2020. All examinations were performed by the same physicians during the study period. LATCH scores were determined at initial breastfeeding session, and postnatal days 1 and 2. RESULTS: We analyzed 338 patients in this prospective study. Patients with high-risk pregnancies were found to have lower LATCH scores at each measurement (p: 0.002, 0.001, and 0.09, respectively). Skin-to-skin contact immediately after delivery and breastfeeding longer than 20 min in the first session did not improve LATCH scores (p>0.05). Breastfeeding within 30 min after delivery significantly improved LATCH scores at each session (p<0.01 for all). Odds ratios of having a LATCH score lower than 8 was 10.9 (95% CI: 4.22-28.37) for the patients breastfed after more than 30 min, while this ratio was 2.17 (95% CI: 1.34-3.50) and 6.5 (95% CI: 3.46-12.58) for the patients having a high-risk pregnancy and cesarean section, respectively. Furthermore, we also determined a positive statistically significant association between parity and all LATCH scores according to regression analyses (p: 0.005, 0.028, and 0.035 for LATCH scores at initial breastfeeding, postnatal day 1 and 2, respectively) CONCLUSION: High-risk pregnancies, patients who delivered by cesarean section, and patients not attempting to breastfeed within 30 min tend to have lower LATCH scores.

Comparison of term and preterm labor procalcitonin and leukocyte cell volume, conductivity and light scatter (VCS) parameters in order to demonstrate the impact of inflammation on the triggering mechanisms of preterm uterin contractions.

AIM: Comparison of mean channels of cell volume, conductivity and light scatter (VCS) parameters of neutrophil, monocyte and lymphocyte, procalcitonin (PCT) and white blood cell count (WBC) during term and preterm labor to evaluate the impact of inflammation on the triggering mechanisms of uterine contractions. METHODS: This study is consisted of 16 preterm and 60 term pregnancies at the beginning of the first stages of the labor. Leukocyte VCS parameters, PCT plasma levels and WBC count were evaluated. RESULTS: We could not demonstrate statistically significant difference in between leukocyte VCS parameters in preterm and term deliveries (P ˃ 0.050 for all). WBC counts were 10.6 and 11.8 × 103 /µL in the preterm and term groups respectively (P = 0.270). PCT levels were 0.04 and 0.03 ng/mL for preterm and term pregnancies (P = 0.062). CONCLUSION: Inflammation related markers such as leukocyte VCS parameters, PCT values and WBC count does not differentiate at the first stage of labor in preterm and term deliveries. These variables do not seem to have a prominent role at the biological events behind preterm contractions.

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways.

Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ΔF508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy.

Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by dominant alleles of the mitochondrial pro-fusion factor Mitofusin 2 (MFN2). To address the consequences of these mutations on mitofusin activity and neuronal function, we generate Drosophila models expressing in neurons the two most frequent substitutions (R94Q and R364W, the latter never studied before) and two others localizing to similar domains (T105M and L76P). All alleles trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism and increased mtDNA mutations, but they differently alter mitochondrial morphology and organization. Substitutions near or within the GTPase domain (R94Q, T105M) result in loss of function and provoke aggregation of unfused mitochondria. In contrast, mutations within helix bundle 1 (R364W, L76P) enhance mitochondrial fusion, as demonstrated by the rescue of mitochondrial alterations and locomotor deficits by over-expression of the fission factor DRP1. In conclusion, we show that both dominant negative and dominant active forms of mitofusin can cause CMT2A-associated defects and propose for the first time that excessive mitochondrial fusion drives CMT2A pathogenesis in a large number of patients.