Heme Oxygenase-1/High Mobility Group Box 1 Pathway May Have a Possible Role in COVID-19 ARDS (Acute Respiratory Distress Syndrome): A Pilot Histological Study.

COVID-19 is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The persistent and excessive inflammatory response can build up a clinical picture that is difficult to manage and potentially fatal. Potent activators of inflammatory phenomena are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). HMGB1 is an intranuclear protein that is either passively released during hypoxia-related necrosis or actively released by macrophages. Heme oxygenase (HO-1) has an anti-inflammatory effect by inhibiting HMGB1, which could be a therapeutic target to reduce COVID-19 inflammation. In our study, we evaluated CD3, CD4, CD8, HMGB1 and HO-1 in the COVID-19 lung and correlated it to clinical data.

The resting metabolic rate in women with polycystic ovary syndrome and its relation to the hormonal milieu, insulin metabolism, and body fat distribution: a cohort study.

PURPOSE: To evaluate possible alterations of a major determinant of energy expenditure, the resting metabolic rate (RMR), in women with polycystic ovary syndrome (PCOS) compared with age-BMI similar controls. To assess whether the hormonal milieu, the body fat distribution and the insulin metabolism may affect energy consumption in these patients. METHODS: This is a monocentric observational prospective cohort study, including 109 Caucasian PCOS subjects and 31 healthy control women. (Median age PCOS 26.0 ± 9.2 years, controls 25.5 ± 8.5 years; median BMI-body mass index PCOS 26.4 ± 9.4 kg/m2, controls 27.2 ± 12.8 kg/m2). RMR was evaluated by the SenseWear Armband (SWA), a reliable and validated metabolic holter, never previously used in the PCOS population to this purpose. Hormonal assessment, insulin metabolism evaluated by HOMA-IR and OGTT, anthropometric features (BMI and WHR) were also assessed. RESULTS: Median RMR resulted similar in PCOS and control women: 1520.0 ± 248.00 kcal/day vs 1464.0 ± 332.70 kcal/day (p = 0.472), even after adjusting for BMI, fat distribution, insulin metabolism parameters. RMR resulted significantly correlated with BMI, WHR, estradiol levels, SHBG, total cholesterol, triglycerides, basal glycaemia, basal insulinemia, AUC insulin 240', and HOMA. In the subgroup of patients with WHR > 0.85, PCOS women showed a significantly lower RMR compared with controls. CONCLUSIONS: The higher prevalence of obesity, which negatively influences the reproductive and general health of PCOS women, could be related to factors other than an intrinsic alteration of the RMR. Further studies are needed to clarify the possible role of the visceral fat in modulating the energy balance in PCOS. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier NCT03132545.

Belimumab restores Treg/Th17 balance in patients with refractory systemic lupus erythematosus.

Belimumab, a specific inhibitor of the soluble B lymphocyte stimulator (BlyS), is the first biological drug approved by the United States Food and Drug Administration for the treatment of patients with active systemic lupus erythematosus (SLE) refractory to standard therapy. Given that an imbalance between regulatory T cells (Treg) and interleukin (IL)-17A-secreting T cells (Th17) has been reported in various autoimmune disorders, we assessed the frequency of both Treg and Th17 peripheral blood populations before and after belimumab administration in 20 patients with active SLE refractory to standard therapy. After six months of treatment, the mean SELENA-SLEDAI score as well as the mean anti-double-stranded DNA antibody titers were significantly decreased. In addition, we observed a significant increase in Treg percentages and a parallel, significant decrease in Th17 percentages, accompanied by significantly reduced serum levels of IL-21. In vitro studies showed that Treg purified from belimumab-treated patients were fully functional and displayed a suppressor function similar to that of Treg purified from healthy donors. Belimumab can restore Treg/Th17 balance in SLE patients with uncontrolled disease activity, and this results in decreased flare rate and reduced glucocorticoid dosage.

Mucine-1 Is Related to Cell-Mediated Immunoexpression and Blood Pressure in Pulmonary Artery in Pulmonary Arterial Hypertension (PAH): Preliminary Results.

BACKGROUND AND AIM: Mucine-1 (MUC1) increases in primary lung disease; however, no data are available on pulmonary arterial hypertension (PAH). Our aim was to analyze MUC1 in PAH and a possible link with pulmonary artery pressure (PAPs), PaO2, PaCO2 and cell-mediated immunity. METHODS: We studied nine PAH patients (four males and five females, aged 52 ± 21 years). The control groups were nine patients with pulmonary hypertensions due to lung disease (PPH; five males and four females, aged 63 ± 18 years) and 14 patients with left heart disease (HPH; four males and ten females, aged 73 ± 13 years). All underwent arterial gas analysis and echocardiography. A serum sample was collected to determine MUC1 and CD40L values on ELISA. RESULTS: No differences were found for PAPs and CD40L. MUC1 resulted in comparable values between PAH and HPH but decreased when compared to PPH (16.46 ± 4.12 vs 116.6 ± 47.08 U/ml, p = 0.049). pO2 was higher in PAH (PAH 83.18 ± 1.77 vs PPH 62.75 ± 3.23 mmHg, p = 0.003; vs HPH 65.83 ± 6.94 mmHg, p = 0.036). pCO2 was lower compared to PPH (36.15 ± 2.19 vs 45.83 ± 3.00 mmHg, p = 0.026) but not compared to HPH. In PAH patients the MUC1 correlated with pO2 (r = -0.91), pCO2 (r = 0.80), PAPs (r = 0.82) and CD40L (r = 0.72) while it did not in PPH and HPH. CONCLUSIONS: These preliminary data show a possible mechanism of immune stimulation in PAH patients. This may imply an association between lung parenchyma, immunity and increase in vascular resistance. Additional studies are required to confirm these findings.

Analysis of Aortic Remodeling and Stiffness in Patients with Obstructive Sleep Apnea Syndrome: Preliminary Results.

Obstructive sleep apnea (OSA) is a well-known risk factor for cardiovascular diseases. Several studies have shown that OSA is associated with vessel remodeling, but few studies have examined aorta. AIM: to analyse aortic remodelling in OSA. METHODS: Thirty consecutive OSA patients (22 males and 8 females, aged 58.5 ± 13.2 years) were studied. All patients underwent a morning blood gas analysis, a full cardiorespiratory evaluation, including nocturnal polygraphy and echocardiography, that assessed aortic root diameter (ARD) and aortic stiffness index (ASI). Patients were grouped as follows: Group 1, non-severe OSA (Apnea-Hypopnea Index; AHI <30, 14 patients); Group 2, severe OSA (AHI ≥30, 16 patients). RESULTS: No difference was found between the groups in ARD as absolute value (Group 1, 33.64 ± 0.91 mm; Group 2, 33.64 ± 1.02, p = ns) and as normalized value for the body surface area - ARDi (Group 1, 16.72 ± 0.63 mm/m2; Group 2, 16.09 ± 0.44, p = ns). Moreover, no difference was found in the ASI (Group 1, 14.04 ± 2.26; Group 2, 13.41 ± 2.22, p = ns). Considering all OSA patients, AHI showed an inverse correlation with ARDi (p = 0.018) and ASI (p = 0.0449). Moreover, the ASI showed a direct correlation with ARDi (p = 0.01) and morning PaO2 (p = 0.0349) as well as an inverse correlation with the oxygen desaturation index (ODI, p = 0.031) and total time with apnea and hypopnea (p = 0.039). CONCLUSION: No difference was found between severe and non-severe OSA in ARD. Surprisingly, the data show that the severity of OSA correlates inversely with the ASI and ARDi. The relation between PaO2 and stiffness might be explained by a feedback mechanism that tries to overcome the reduction of aortic elasticity due to night desaturation. These findings need to be investigated in further studies with a larger study population.

Expectant management may reduce overtreatment in women affected by unexplained infertility confirmed by diagnostic laparoscopy.

PURPOSE: To determine whether the mini-invasive surgery still play a role in the diagnostic workup and in the management of the couples affected by unexplained infertility. METHODS: 170 infertile women (age range 25-38 years) with documented normal ovarian, tubal and uterine function underwent combined hysteroscopic and laparoscopic surgery; 100 women refused surgery or ART treatment (control group) choosing expectant management. A retrospective assessment questionnaire was proposed to enrolled women to collect the rate of spontaneous or ART-induced pregnancies. RESULTS: The combined surgery revealed pelvic pathologies in 49.4% of patients, confirming the diagnosis of unexplained infertility only in 86 of studied patients. In this group of 86 selected women, 28 of them achieved a spontaneous pregnancy and 23 women obtained pregnancy after ART. The Chi-square analysis shows that the pregnancy rate was not influenced by the employment of ART. In the group of 100 control women, only 14 (14%) achieved a spontaneous pregnancy after 18 months of expectant management. CONCLUSIONS: Combined laparoscopy and hysteroscopy in women with unexplained infertility may reveal previously undiagnosed pathologies that could require ART, and in those without abnormal surgical finding, ART does not improve pregnancy rate.

Clinical efficacy and metabolic impact of two different dosages of ethinyl-estradiol in association with drospirenone in normal-weight women with polycystic ovary syndrome: a randomized study.

BACKGROUND: The estrogenic component of estro- progestin (EP) is responsible for a negative impact on the metabolic and lipid assessment in women with polycystic ovary syndrome (PCOS). AIM: To evaluate the risk/benefit ratio of two EP combinations, containing the same progestin (3 mg drospirenone) and a different dose of ethinyl-estradiol (EE) (20 vs 30 µg) and to compare their effects on the clinical and endocrine-metabolic parameters in normal-weight PCOS women. MATERIAL/SUBJECTS AND METHODS: In this randomized pilot study, we enrolled 30 young normal-weight PCOS women. Fifteen subjects were allocated to group A (20 µg EE) and 15 PCOS subjects to group B (30 µg EE). Hirsutism score, hormonal assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp and lipid profile were performed at baseline, and after 6 and 12 months of therapy. Main outcome measures were signs of hyperandrogenism, glucose and insulin metabolism, lipid profile. RESULTS: Both treatment regimens induced a significant improvement in hirsutism score, testosterone, DHEAS, and SHBG levels. Androstenedione significantly dropped only in patients of Group A, while 17(OH)P only in those from Group B. Both the formulations did not significantly modify gluco-insulinemic metabolism. Total cholesterol, LDL cholesterol, and HDL cholesterol levels significantly increased in both groups. Triglycerides levels, which increased as well, resulted more markedly influenced by the formulation with 30 µg EE. CONCLUSIONS: In association with drospirenone, 20 µg EE results as effective as 30 µg in improving clinical and hormonal features of normal-weight PCOS women, while exhibiting a milder influence on lipidic parameters.

Bamlanivimab and Etesevimab administered in an outpatient setting for SARS-CoV-2 infection.

The early administration of anti-SARS-CoV-2 monoclonal antibodies (mAb) could decrease the risk of severe disease and the need of inpatients care. Herein, our clinical experience with Bamlanivimab/Etesevimab for the treatment of early SARS-CoV-2 infection through an outpatient service was described. Patients with confirmed COVID-19 were selected by General Practitioners (GPs) if eligible to mAb administration, according to manufacturer and AIFA (Agenzia-Italiana-del-Farmaco) criteria. If suitability was confirmed by the Multidisciplinary Team, the patient was evaluated within the next 48-72 hours. Then, all patients underwent a medical evaluation, followed by mAb infusion or hospitalization if the medical condition had worsened. Overall, from March 29th to June 4th, 2021, 106 patients with confirmed COVID-19 were identified by GPs; 26 were considered not eligible and then excluded, while 9 refused treatment. Among the 71 remaining, 6 were not treated because of worsening of symptoms soon after selection. Finally, 65 received mAb therapy. All treated patients survived. However, 2/65 developed adverse events (allergic reaction and atrial fibrillation, respectively) and 6/65 needed hospitalization. By performing univariate logistic regression analysis, diabetes was the only risk factor for hospitalization after mAb administration [aOR = 9.34, 95%CI = 1.31-66.49, p= .026]. Importantly, subjects who worsened awaiting mAb were more frequently obese (OR = 16.66, 95%CI = 1.80-153.9, p= .013) and received home corticosteroid therapy for COVID-19 (OR = 14.11, 95%CI = 1.53-129.6, p= .019). Establishing a network among GPs and COVID units could be an effective strategy to provide mAb treatment to patients with early SARS-CoV-2 infection to reduce hospitalizations and pressure on healthcare systems.

[Hemorheology and microcirculation in some pathologies of internal medicine]. / Alterazioni emoreologiche e microcircolatorie in alcune patologie di interesse internistico.

AIM: It is very interesting in physiopathology to evaluate the blood flow in the microvasculature of patients affected by diabetes, arterial hypertension, lipoproteinosis, peripheral occlusive arterial disease (POAD) and liver failure. METHODS: We studied 4 groups. Group 1: controls formed by 25 healthy subjects (15 males and 10 females aged 36+/-3 years); group 2: diabetes, including 32 patients (group 2A, 20 subjects with diabetes type 1: 12 males and 8 females aged 43+/-4 years and group 2B, 12 subjects with diabetes type 2: 6 males and 6 females aged 45+/-3 years); group 3: liver failure, formed by 6 subjects (3 males and 3 females aged 44+/-5 years); group 4: hypertensives, 50 subjects (group 4A, 28 smokers 12 males and 16 females aged 40+/-4 years and group 4B, 22 non-smokers: 12 males and 10 females aged 38+/-3 years). We evaluated the capillary morphology using computerized videocapillaroscopy, the hemorheology (red blood cell RBC deformability and aggregability) using LORCA (Laser assisted Optical Rotational Red Cell Analyzer) and tissue oxygenation using transcutaneous oxymeter (Periflux 5000 Perimed). Statistical analysis were performed using the Student t-test. RESULTS: The capillary loops in patients with diabetic microangiopathy had in 50% of the patients studied an image such as ''deer horns'', as ''elephant nose'' in 72% and as ''cork screw'' in 44%. In diabetics we found also a capillary rarefaction in 28% of them. An improvement in perfusion was observed in patients with liver failure one week after liver transplantation from cadaver in 83% of them. Morphological alterations were present in hypertensives (27% in non-smokers, 46% in smokers). The RBC deformability evaluated as elongation index (EI) and RBC aggregability (t1/2 expressed in seconds) were detected using LORCA. Group 1: EI 0.59+/-0.02, t1/2 3+/-1 s; group 2A: EI 0.55+/-0.01; t1/2 2+/-0.5 s p<0.05 vs controls; group 2B: EI 0.56+/-0.01; t1/2 2+/-0.2 s p<0.04 vs controls; group 3: EI 0.56+/-0.02, t1/2 2+/-0.4 s p<0.04; group 4A: EI 0.56+/-0.02, t1/2 2+/-0.6 s p<0.03; group 4B: 0.57+/-0.02, t1/2 2+/-0.6 s p<0.04. We evaluated also the TcpO2 at the dorsum of the right foot expressed in mmHg: group 1, 96+/-11 mmHg; group 2A, 74+/-9 p<0.05 vs controls; group 2B, 76+/-8 mmHg p<0.05; group 3, 69+/-6 mmHg p<0.05; group 4A, 70+/-5 mmHg p<0.05; group 4B, 77+/-9 mmHg p<0.05. CONCLUSION: This study indicates an interesting and complete methodology in order to evaluate the microcirculation condition in different pathologies inducing microvasculature alterations.

Data on glycerol/tartaric acid-based copolymer containing ciprofloxacin for wound healing applications.

This data article is related to our recently published research paper "Exploiting a new glycerol-based copolymer as a route to wound healing: synthesis, characterization and biocompatibility assessment", De Giglio et al. (Colloids and Surfaces B: Biointerfaces 136 (2015) 600-611) [1]. The latter described a new copolymer derived from glycerol and tartaric acid (PGT). Herein, an investigation about the PGT-ciprofloxacin (CIP) interactions by means of Fourier Transform Infrared Spectroscopy (FT-IR) acquired in Attenuated Total Reflectance (ATR) mode and Differential Scanning Calorimetry (DSC) was reported. Moreover, CIP release experiments on CIP-PGT patches were performed by High Performance Liquid Chromatography (HPLC) at different pH values.

The Role of Anti-Müllerian Hormone in the Characterization of the Different Polycystic Ovary Syndrome Phenotypes.

Rotterdam criteria identified 4 polycystic ovary syndrome (PCOS) phenotypes based on the combination of anovulation (ANOV), hyperandrogenism (HA), and polycystic ovaries (PCOs): phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO), and phenotype 4 (ANOV + PCO). Anti-Müllerian hormone (AMH) was suggested to play a pathophysiologic and diagnostic role in this syndrome. The aim of this study was to compare AMH levels among the different phenotypes in relation to clinical, endocrine, and metabolic features. We enrolled 117 women with PCOS (body mass index: 25.89 ± 6.20 kg/m(2), age range: 18-37 years) and 24 controls. Anthropometric characteristics, hirsutism score, ultrasound ovarian features, and hormonal parameters, including AMH, were evaluated. Each participant also underwent an oral glucose tolerance test and an euglycemic-hyperinsulinemic clamp. The prevalence of phenotypes 1 to 4 was 62.4%, 8.6%, 11.1%, and 17.9%, respectively. Body mass index and insulin resistance indexes were similar among the groups. Phenotype 1 showed the highest luteinizing hormone, androgens levels, ovarian volume, and AMH concentrations (9.27 ± 8.17 ng/mL,P< .05) versus phenotype 2 and controls. Phenotype 2 women were hirsute, showed an intermediate free androgen index value, low ovarian volume, and low AMH levels (4.05 ± 4.12 ng/mL). Phenotype 3 showed an intermediate state of HA and slightly augmented AMH levels (5.87 ± 4.35 ng/mL). The clinical and endocrine characteristics of phenotype 4 resembled those of controls, except for higher ovarian volume and AMH levels (7.62 ± 3.85 ng/mL;P< .05). Our results highlight the heterogeneity of the association between increased AMH levels, menstrual dysfunction, and HA in the different PCOS phenotypes, thus offering a key to an understanding of the current controversy on the value of AMH measurement in PCOS.

Exploiting a new glycerol-based copolymer as a route to wound healing: Synthesis, characterization and biocompatibility assessment.

The use of biocompatible materials based on naturally derived monomers plays a key role in pharmaceutical and cosmetic industries. In this paper we describe the synthesis of a new low molecular weight copolymer, based on glycerol and l-tartaric acid, useful to develop biocompatible dermal patches with drug delivery properties. The copolymer's chemical composition was assessed by FT-IR (Fourier transform infrared spectroscopy), (1)H NMR ((1)H Nuclear Magnetic Resonance) and XPS (X-ray photoelectron spectroscopy), while its molecular weight distribution was estimated by SEC (size exclusion chromatography). Copolymer thermal properties were studied by TGA (thermogravimetric analysis). Biological evaluations by MTT assay and SEM (scanning electron microscopy) observations performed with murine fibroblasts and human keratinocytes (HaCaT) revealed a good compatibility of the proposed copolymer. Ciprofloxacin was selected as model drug and its release was evaluated by HPLC (high performance liquid chromatography), showing that the new copolymer supplied promising results as drug delivery system for wound healing applications. Furthermore, investigations on Skin-Mesenchymal stem cells (S-MSCs) behaviour and gene expression showed that the copolymer and its combination with ciprofloxacin did not affect their stemness. In this regard, the fabrication of dermal patches with new, low cost materials for local treatment of skin infections represents an attractive strategy in order to bypass the worrying side effects of systemic antibiotic therapy. Overall, the performed physico-chemical characterization, drug release test and biological evaluations showed that this new copolymer could be a promising tool for the in situ delivery of bioactive molecules during skin lesions treatment.

The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome.

CONTEXT: In the adult ovary, antimullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles and negatively regulates folliculogenesis. AMH is overproduced in the polycystic ovary and was recently proposed to play a role in the ovulatory dysfunction of polycystic ovary syndrome (PCOS). OBJECTIVE: The aim of the study was to investigate the effects of metformin administration on AMH levels in relation with the clinical and endocrine-metabolic parameters in obese women with PCOS. DESIGN AND SETTING: We conducted a pilot prospective study in an academic research environment. PATIENTS: We studied 28 obese PCOS women. INTERVENTIONS: We performed ultrasonographic pelvic exams, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and lipid profile at baseline and after 6 months of metformin treatment (850 mg twice a day orally). MAIN OUTCOME MEASURES: We measured AMH, hormonal assays, ultrasound aspect of the ovaries, and indexes of glucose and insulin metabolism. RESULTS: Insulin secretion and body mass index significantly decreased after treatment. Almost 70% of subjects experienced an amelioration of menstrual irregularities. Mean androstenedione, testosterone, and 17-hydroxyprogesterone levels and hirsutism score were significantly improved by metformin. However, no significant changes in AMH levels occurred. Data were further analyzed after dividing patients on the basis of pretreatment insulinemic response to the oral glucose tolerance test; metformin was effective in reducing insulin secretion, AMH levels, and, interestingly, ovarian volume exclusively in PCOS patients with hyperinsulinism; none of these changes occurred in the normoinsulinemic group. CONCLUSIONS: Metformin differentially affects the interplay between insulin and the ovarian function in obese PCOS women; the presence of hyperinsulinemia seems to be predictive of the efficacy of the treatment.