The effect of mitochondria-targeted slow hydrogen sulfide releasing donor AP39-treatment on airway inflammation.

Mitochondrial dysfunction has been shown to contribute to the pathophysiology of airway diseases. Therefore, mitochondria are targeted in the development of new therapeutic approaches. Hydrogen sulfide (H2S) has been shown to be involved in the pathophysiological processes of airway inflammation. We aimed to evaluate the effect of mitochondria-targeted slow H2S releasing donor AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl)triphenylphosphoniumbromide)] on lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS was applied to female Balb/c mice by intranasal (i.n.) route to induce airway inflammation and the subgroups of mice were treated with i.n. AP39 (250-1000 nmol/kg). 48 h after LPS administration airway reactivity was evaluated in vivo, then bronchoalveolar lavage (BAL) fluid and lungs were collected. LPS application led to bronchial hyperreactivity and neutrophil infiltration into the lung tissues along with increased TNF-α, IL-1ß and IL-6 levels in BAL fluid. LPS also induced an increase in the rate of glycolysis, glycogenolysis and Krebs-cycle. AP39 treatment prevented the LPS-induced bronchial hyperreactivity and reversed the increase in TNF-α and IL-6 levels in BAL fluid. The increase in neutrophil numbers in BAL fluid was also prevented by AP39 treatment at the highest dose. Our results indicate that AP39 can prevent bronchial hyperreactivity and decrease airway inflammation. Targeting H2S to the mitochondria may be a new therapeutic approach in airway inflammation.

Endocannabinoid metabolism inhibition ameliorates ovalbumin-induced allergic airway inflammation and hyperreactivity in Guinea pigs.

AIMS: Endocannabinoids are biologically active cannabinoid-related substances endogenously synthesized in many mammalian tissues. Mainly two enzymes carry out their degradation; Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL). Endocannabinoids are shown to affect the modulation of inflammatory processes and airway responsiveness. In the present study, we investigated the effects of FAAH and MAGL inhibitor treatments in experimental allergic airway inflammation in guinea pigs. MATERIALS AND METHODS: Guinea pigs were sensitized and challenged by ovalbumin to induce an allergic asthma model. Then, the effects of FAAH inhibitor URB597, MAGL inhibitor JZL184, and dual (FAAH/MAGL) inhibitor JZL195 on airway inflammation and hyperreactivity were evaluated. KEY FINDINGS: Ovalbumin challenge increased airway reactivity, IgE in serum, IL-4, and IL-13, and the percentage of eosinophils in bronchoalveolar lavage (BAL). In addition, inhibition of FAAH or MAGL enzymes leads to an increase in endocannabinoid levels. The selective inhibition of the FAAH enzyme prevented inflammation indicators such as cytokine production and inflammatory cell infiltration but had a negligible effect on airway hyperreactivity. However, the inhibition of the MAGL enzyme or dual inhibition of both FAAH and MAGL enzymes tent to moderate both pulmonary inflammation and airway hyperreactivity. SIGNIFICANCE: We have previously demonstrated that modulation of endocannabinoid levels in the airways by FAAH or MAGL inhibition can be useful in preventing acute lung inflammation. The results of the present study further suggest that FAAH and MAGL inhibitor treatment can also be a promising strategy for bronchial hyperreactivity and airway inflammation in allergic asthma.

Prediction of clinical outcomes in women with placenta accreta spectrum using machine learning models: an international multicenter study.

INTRODUCTION: Placenta accreta spectrum is a major obstetric disorder that is associated with significant morbidity and mortality. The objective of this study is to establish a prediction model of clinical outcomes in these women. MATERIALS AND METHODS: PAS-ID is an international multicenter study that comprises 11 centers from 9 countries. Women who were diagnosed with PAS and were managed in the recruiting centers between 1 January 2010 and 31 December 2019 were included. Data were reanalyzed using machine learning (ML) models, and 2 models were created to predict outcomes using antepartum and perioperative features. ML model was conducted using python® programing language. The primary outcome was massive PAS-associated perioperative blood loss (intraoperative blood loss ≥2500 ml, triggering massive transfusion protocol, or complicated by disseminated intravascular coagulopathy). Other outcomes include prolonged hospitalization >7 days and admission to the intensive care unit (ICU). RESULTS: 727 women with PAS were included. The area under curve (AUC) for ML antepartum prediction model was 0.84, 0.81, and 0.82 for massive blood loss, prolonged hospitalization, and admission to ICU, respectively. Significant contributors to this model were parity, placental site, method of diagnosis, and antepartum hemoglobin. Combining baseline and perioperative variables, the ML model performed at 0.86, 0.90, and 0.86 for study outcomes, respectively. Ethnicity, pelvic invasion, and uterine incision were the most predictive factors in this model. DISCUSSION: ML models can be used to calculate the individualized risk of morbidity in women with PAS. Model-based risk assessment facilitates a priori delineation of management.

Hydrogen sulfide donors prevent lipopolysaccharide-induced airway hyperreactivity in an in vitro model of chronic inflammation in mice.

We aimed to investigate and compare the effects of rapid (NaHS) and slow (GYY4137 and AP39) hydrogen sulfide (H2 S) releasing donors on LPS-induced tracheal hyperreactivity and pro-inflammatory cytokine levels in lung tissues of mice. Tissues were isolated from male BALB/c mice and incubated with LPS (10 µg/mL) in tissue culture. The subgroups were incubated with NaHS, GYY4137 and mitochondria-targeted donor AP39. LPS incubation did not alter contraction response to carbachol, but enhanced 5-HT and bradykinin-induced contractions in tracheal rings, and elevated IL-1ß, IL-6 and TNF-α levels in lung homogenates. NaHS at 300 µmol/L and 1000 µmol/L, GYY4137 at 30 µmol/L and 100 µmol/L, and AP39 at 30 nmol/L concentrations inhibited the tracheal hyperreactivity to 5-HT, whereas none of these donors affected the enhanced contraction to bradykinin. GYY4137 was also effective to inhibit 5-HT hyperreactivity acutely. In lung tissues, NaHS prevented the elevation of IL-1ß level at 1000 µmol/L, and IL-6 and TNF-α levels at 100 µmol/L concentrations. Incubation with GYY4137 (100 µmol/L) and AP39 (30 nmol/L and 300 nmol/L) inhibited the increase in IL-6 and TNF-α levels, but not IL-1ß at concentrations that they affected tracheal hyperreactivity. These results indicate that H2 S donors can decrease inflammation and prevent airway hyperreactivity.

Prediction of success of uterus-preserving management in women with placenta accreta spectrum (CON-PAS score): A multicenter international study.

OBJECTIVE: To create a model for prediction of success of uterine-preserving procedures in women with placenta accreta spectrum (PAS). METHODS: PAS-ID is a multicenter study that included 11 centers from 9 countries. Women with PAS, who were managed between January 1, 2010 and December 31, 2019, were retrospectively included. Data were split into model development and validation cohorts, and a prediction model was created using logistic regression. Main outcome was success of uterine preservation. RESULTS: Out of 797 women with PAS, 587 were eligible. Uterus-preserving procedures were successful in 469 patients (79.9%). Number of previous cesarean sections (CS) was inversely associated with management success (adjusted odds ratio [aOR] 0.02, 95% confidence interval [CI] 0.001-3.63 with five previous CS). Other variables were complete placental invasion (aOR 0.14, 95% CI 0.05-0.43), type of CS incision (aOR 0.04, 95% CI 0.01-0.25 for classical incision), compression sutures (aOR 2.48, 95% CI 1.00-6.16), accreta type (aOR 3.76, 95% CI 1.13-12.53), incising away from placenta (aOR 5.09, 95% CI 1.52-16.97), and uterine resection (aOR 102.57, 95% CI 3.97-2652.74). CONCLUSION: The present study provides a prediction model for success of uterine preservation, which may assist preoperative and intraoperative decisions, and promote incorporation of uterine preservation procedures in comprehensive PAS protocols.

Effects of intranasal treatment with slow (GYY4137) and rapid (NaHS) donors of hydrogen sulfide in lipopolysaccharide-induced airway inflammation in mice.

We have investigated the effects of slow (GYY4137) and rapid (NaHS) hydrogen sulfide (H2S) releasing donors in lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS (0.1 mg/ml) in 60 µl PBS was administered by the intranasal (i.n.) route and control group received vehicle, whereas the subgroups of mice were treated with i.n. GYY4137 or NaHS. The tracheal reactivity, inflammatory cell count in bronchoalveolar lavage (BAL) fluid and lung histopathology were evaluated in all groups 48 h after LPS/PBS applications. 5-Hydroxytryptamine (5-HT)-induced contraction response in isolated tracheas was enhanced after LPS treatment but carbachol response was not altered. Incubation with atropine (10-6 M), 5-HT2A receptor antagonist ketanserin (10-9-10-7 M) and 5-HT3 receptor antagonist alosetron (10-8 and 10-7 M) prevented 5-HT-induced hyperreactivity whereas 5-HT4 receptor antagonist GR113808 (10-7 M, 10-6 M) did not have any effect in LPS-treated group. Electrical field stimulation (EFS) of isolated tracheas elicited frequency-dependent contractile response, which was not altered by LPS treatment alone but was enhanced in the presence of 5-HT (10-9-10-4 M). This data indicated that 5-HT2A and 5-HT3 receptors, and acetylcholine released from cholinergic nerves were contributing to 5-HT-induced hyperreactivity in the present experiments. The increase in neutrophil count along with cytokine (IL-1ß, TNF-α) levels in bronchoalveolar lavage (BAL) fluid and histopathological changes like paranchymal inflammation and interalveolar thickening were determined in LPS-treated mice. H2S production in lung homogenates were determined by the methylene blue assay, and found to be similar in both LPS and control groups. The experiments conducted after i.n. treatment with H2S donors has shown that only GYY4137 (1 mg/kg) inhibited 5-HT-induced hyperreactivity, and both GYY4137 and NaHS (1 mg/kg) prevented the neutrophil increase in BAL fluid in LPS-induced airway inflammation. IL-1ß increase in BAL fluid was abolished by both GYY4137 and NaHS treatments whereas TNF-α levels remained unchanged. Furthermore, GYY4137 treatment did not have any effect in LPS-induced changes of lung pathology whereas NaHS prevented the paranchymal inflammation. The different H2S releasing pattern of these donors may explain the difference of their effects in this model. Compounds that provide stable H2S levels via local application may be a new therapeutic approach in airway inflammation.

What should the optimal intrauterine pressure be during outpatient diagnostic hysteroscopy? A randomized comparative study.

AIM: The aim of this study was to evaluate and compare lower and higher uterine filling pressures during outpatient diagnostic hysteroscopy. METHODS: One hundred and seventy-five women eligible for outpatient diagnostic hysteroscopy were included in this randomized double blind comparative study. The subjects were randomized into two groups. Group 1 (n = 80) underwent surgery with lower intrauterine filling pressures (30, 40, and 50 mmHg) and group 2 (n = 81) underwent surgery with higher filling pressures (70, 80, and 100 mmHg). The primary outcome measure was adequate visibility during the procedure. The secondary outcome measure was pain perceived by the patient during and 30 min after the procedure. RESULTS: In total, 161 patients completed the trial. Group 2 had significantly higher adequate visibility than group 1 (71/80, 88.75% in group 1 and 79/81, 97.5% in group 2, P = 0.008). There was a trend toward increase in pain scores with higher pressures during the procedure. However, there were no significant differences between the two groups in terms of visual analog scale pain scores measured 30 min after the procedure. CONCLUSION: Lower uterine filling pressure was associated with lower pain scores with a higher trend towards inadequate visibility. It appears that higher filling pressure can be used for performing office hysteroscopy, but it is associated with higher pain scores.

Ovarian Torsion in the Normal Ovary: A Diagnostic Challenge in Postmenarchal Adolescent Girls in the Emergency Department.

BACKGROUND Ovarian torsion can be seen in the otherwise-normal ovary and is a challenging issue in the emergency department. The aims were (1) to evaluate and compare the surgically verified ovarian torsion cases in otherwise-normal ovaries and ovaries including a mass or cyst and (2) to investigate whether the normal-appearing ovaries on ultrasound examination affected the diagnosis of ovarian torsion or not. MATERIAL AND METHODS A retrospective cohort study design was used. The medical records of all postmenarchal adolescent girls with surgically verified ovarian torsion treated in a university hospital from 2010 to 2016 were reviewed. RESULTS Twenty-nine post-menarchal girls were identified. The subjects were divided into two groups. Eight girls (group 1) had ovarian torsion in a normal ovary, and twenty-one girls (group 2) had ovarian torsion including a mass or cyst. The median ages of group 1 and 2 were 13 and 14 years, respectively. Abdominal pain was the main presenting symptom for all cases in both groups. Doppler flow studies were abnormal in 6/9 (66.6%) in group 1 and 12/21 (57.1%) in group 2. The time from first admission to the operation was statistically longer in group 1 than in group 2 (34.5±24.3 hours vs. 19.5±9.2 hours, respectively; p=0.001). The longitudinal axis of uterine size was significantly shorter in group 1 than in group 2 (34.3±2.9 mm vs. 47.6±4.5 mm, respectively; p=0.001). CONCLUSIONS Ovarian torsion in adolescent girls can be seen within the otherwise-normal ovary. The normal-appearing ovaries on ultrasound in the emergency department may lead to delay in the diagnosis of ovarian torsion in adolescent girls.

Evaluation of hemoglobin A1c levels in endometrial cancer patients: a retrospective study in Turkey.

BACKGROUND: Hemoglobin A1c(HgA1c) is a marker of poor gylcemic control and elevation HgA1c is associated with increased risk of many cancers. We aimed to determine the HgA1c levels in endometrial cancer cases and any relationship with stage and grade of disease. MATERIALS AND METHODS: A retrospective data review was performed between June 2011 and October 2012 at a tertiary referral center in Turkey. The study included 35 surgically staged endometrial cancer patients and 40 healthy controls. Preoperative HgA1c levels drawn within 3 months before surgery were compared. Also the relationships between HgA1c levels and stage, grade and hystologic type of cancer cases were evaluated. RESULTS: The mean HgA1c levels were statistically significantly higher at 6.19 ± 1.44 in endometrial cancer cases than the 5.61 ± 0.58 in controls (p=0.027). With endometrial cancer cases, the mean HgA1c level was found to be 6.62 ± 1.40 for stage I and 6.88 ± 1.15 for stages II-IV (p=0.07). The figures were 6.74 ± 1.65 for endometrioid and 6.63 ± 1.41 for non-endometrioid type tumors (p=0.56). Mean HgA1c levels of 6.72 ± 1.14 for grade 1 and 6.62 ± 1.42 for grade 2-3 were observed (p=0.57). CONCLUSIONS: HgA1c levels in endometrial cancer patients were statistically higher than healthy controls. However, HgA1c did not show any significant correlation with stage, grade and histologic type in endometrial cancer cases.

Abdominal nonparenchymatous cystic lesions and their mimics in children.

Abdominal cystic lesions in children may originate from parenchymatous organs or from nonparencyhmatous structures. Although these lesions have well-described imaging features, proper diagnosis usually depends on the accurate determination of the origin of the lesion. Because large lesions may resemble each other it is difficult to identify the site of origin, which results in a diagnostic dilemma. In this pictorial essay we describe abdominal nonparenchymatous cystic lesions and their mimics arising from parenchymatous organs in children.

Maternal serum CA-125 level is elevated in severe preeclampsia.

AIM: The aim of this study was to determine the relationship between serum concentrations of cancer antigen-125 (CA-125) and pre-eclampsia severity. METHODS: We evaluated 91 females with a singleton pregnancy. Serum CA-125 levels were measured in subjects with severe pre-eclampsia (n=34) and those with mild pre-eclampsia (n=24). Females with healthy pregnancies (n=31) served as the control group. The three study groups were statistically similar in terms of maternal age, gestational age, and body mass index. RESULTS: The CA-125 level was significantly higher in the severe pre-eclampsia group than that in the mild pre-eclampsia and control groups (p<0.05). No significant difference in CA-125 levels between the mild pre-eclampsia and control groups was observed. CA-125 level was positively correlated with proteinuria (r=0.489, p=0.000), systolic blood pressure (r=0.503, p=0.018), and diastolic blood pressure (r=0.532, p=0.000). In contrast, CA-125 was negatively correlated with birth weight (r=0.266, p=0.012) and gestational age at birth (r=0.250, p=0.018). CONCLUSIONS: CA-125 level increased in severe pre-eclampsia, which reflected abnormal trophoblastic invasion and chronic inflammation. Elevated levels of CA-125 in pre-eclamptic patients may be a marker of the disease severity.

An uncommon case of neurofibromatosis type 2: a tribute to the intracranial calcifications.

Neurofibromatosis Type 2 (NF2) is a genetic disorder associated with schwannomas, meningiomas, and ependymomas. Intracranial calcifications, either tumoral or non-tumoral, are relatively lesser known features of NF2. Here, we present a case of NF2, in which the diagnosis was suspected due to the presence of choroid plexus and subependymal calcifications, although no obvious schwannoma or meningioma was detected initially on standard computed tomography or magnetic resonance imaging. This case highlights the importance of further evaluation with appropriate imaging techniques.