Quantitative Analysis of Vitamin D2 and Ergosterol in Yeast-Based Supplements Using High-Performance Liquid Chromatography with Ultraviolet Detection.

Owing to ergosterol content, after UV irradiation yeast become a well-known source of ergocalciferol (vitamin D2). Additionally, pharmaceutical yeast-based supplements may represent a suitable option for treating hypovitaminosis, especially in patients adhering to a vegan diet. Using the high-performance liquid chromatography-ultraviolet (HPLC-UV) methodology our study sought to analyse three commercially available yeast-based vitamin D2 supplements while comparing the effect of UV-C irradiation (254 nm) on yeast biomass derived from the brewing process and pure ergosterol. The two compounds were precisely separated under the described conditions in an efficient and quick manner with a retention time (Rt) of 4.152 ± 0.018 minutes for vitamin D2 and 5.097 ± 0.013 minutes for ergosterol. However, when approaching the quantitative analysis, based on our findings, it appears that the pharmaceutical supplements deviate from the declared amount of substance indicated on the label. 15 minutes of UV-C irradiation generates vitamin D2 in yeast biomass with a conversion rate of 1.78%. Also, high content of ergosterol, beside vitamin D2 formation after irradiation, may trigger the appearance of secondary products such as tachysterol.

Endometrial Osseous Metaplasia-A Rare Cause of Infertility with Unknown Etiology.

Background: Osseous tissue in the endometrium is a rare find, and it is most often discovered when the patient presents with infertility. It is frequently associated with dysmenorrhea and abnormal menstrual bleedings. Although its etiology remains unclear, in almost all described cases until now, the patient has an obstetrical history. Case report: In this report, we present a unique case of endometrial osseous metaplasia in a 27-year-old primary infertile patient. The transvaginal ultrasound revealed a 18/13/7 mm hyperechoic endometrial mass with posterior acoustic shadowing and no flow on color Doppler. A hysteroscopic examination found a polygonal calcification on the endometrial posterior face of the uterine cavity, in the corporeal isthmic region, which was extracted. The histopathological evaluation revealed microscopic elements compatible with endometrial calcification. The patient had a good postoperative course and the complex endocrinologic, immunologic and electrolytical investigation failed to prove any abnormality. Follow-up transvaginal ultrasound examinations revealed no modifications. Three years later, the patient conceived spontaneously, had an uneventful pregnancy and delivered a full-term fetus. Conclusion: We assumed that this entity can be a serious cause of infertility since the patient had a long history of (primary) infertility and its resection made the pregnancy's occurrence possible. Finally, since neither history of abortion or chronic inflammation nor any abnormal laboratory test were noticed, we concluded that the etiology of this entity remained unclear.

Maternal Steroids on Fetal Doppler Indices, in Growth-Restricted Fetuses with Abnormal Umbilical Flow from Pregnancies Complicated with Early-Onset Severe Preeclampsia.

Corticoids are largely used for fetal interest in expected preterm deliveries. This study went further, evaluating the effect of maternal administration of dexamethasone (Dex) on the umbilical artery (UA), middle cerebral artery (MCA), and ductus venous (DV) spectrum, in growth-restricted fetuses, with the absent end-diastolic flow (AEDF) in UA, from singleton early-onset severe preeclamptic pregnancies. Supplementary, the impact on both uterine arteries (UTAs) flow was also evaluated. In 68.7% of cases, the EDF was transiently restored (trAEDF group), in the rest of 31.2% remained persistent absent (prAEDF group). UA-PI significantly decreased in the first day after Dex (day 1/0; p < 0.05), reaching its minimum during day 2 (day 2/1; p > 0.05), revealing a significant recovery to day 4 (day 4/2; p < 0.05), in both groups. The MCA-PI decreased from day 1 until day 3 in both groups, but significantly only in the trAEDF group (p = 0.030 vs. p = 0.227. The DV-PI's decrease (during day 1) and the CPR's increase (between days 0 and 2) were not significant in both groups. UTAs-PIs did not vary. The prAEDF group had a significantly increased rate of antenatal worsening Doppler and a poorer perinatal outcome compared with the trAEDF group. In conclusion, Dex transiently restored the AEDF in UA in the majority of cases, a "positive" effect being a useful marker for better perinatal prognosis. UA-PI significantly decreased in all cases. The improvement in umbilical circulation probably was responsible for the short but not significant DV-PI reduction. MCA-PI decreased only in sensitive cases, probably due to an already cerebral "full" vasodilation in the prAEDF group. Furthermore, the CPR's nonsignificant improvement was the result of a stronger effect of Dex on UA-PI than on MCA-PI. Finally, despite the same etiology, it was only a weak correlation between the severity of the umbilical and uterine abnormal spectrum.

CYP27B1 Enzyme in Psoriasis: A Preliminary Study of Immunohistochemical Observations.

Connections between vitamin D and psoriasis have been a matter of interest for the past decades, with its active metabolite, 1,25(OH)2 vitamin D, being valued for antiproliferative and immunomodulatory effects. However, none of vitamin D's actions could be possible without the CYP27B1 enzyme that bio-activates this metabolite of interest. In order to see if there is any link between the enzyme expression and the disease's particularities, we conducted a preliminary study that involved 11 skin biopsies of patients with mild (n = 4) or moderate to severe psoriasis (n = 7). The cell proliferation antigen Ki67 and the CD45RO+ marker were also assessed. Compared with healthy skin, in psoriasis, it is reported that the enzyme's expression seems to be more ubiquitous, but a clear correlation between the disease's severity and the CYP27B1 expression was, to our knowledge, lacking. We found that, in patients with very mild psoriasis, the enzyme expression was observed in the epidermal stratum basale in a similar manner as in healthy skin specimens. Contrary, for higher severity scores, a divergent result was observed, with the enzyme being either variably spread in the epidermal stratum spinosum or completely absent. Unlike malignant diseases, a significant connection between CYP27B1 and Ki67 (p = 0.313) or CYP27B1 and CD45RO+ (p = 0.657) does not seem to be relevant in psoriasis.

Cabergoline Failure and a Spontaneous Pregnancy in a Microprolactinoma with High Prolactin Levels.

We report a particular case of a spontaneously occurring pregnancy in a long-term amenorrheic patient due to a prolactinoma with high serum prolactin (PRL) following the failure of dopamine agonist therapy (DA) for infertility. Initially, clinical, laboratory, and genital ultrasounds were normal, but the serum PRL was 10,074 µIU/mL (n.v.: 127−637 µIU/mL), the PEG fraction was 71% (laboratory cut-off > 60%), and luteinizing hormone (LH) was significantly lower. An MRI revealed a pituitary tumor of 12.8/10 mm with a subacute intratumoral hemorrhage. DA was initiated, and menstrual bleeding reappeared with a reduction in the tumor's volume to 1.9/2.2 mm at 12 months. Two years later, the patient renounced DA and follow-ups. After another 2 years, she became spontaneously pregnant. Serum PRL was 18,325 µIU/mL, and an MRI revealed a microprolactinoma of 2.1/2 mm. The patient gave birth to a normal baby at term, and she breastfed for six months, after which she asked for ablactation, and DA was administered. This case highlights the possibility of the occurrence of a normal pregnancy during a long period of amenorrhea induced by a microprolactinoma with a high level of serum PRL, even if DA fails to correct infertility. There was no compulsory relationship between the tumoral volume's evolution and the evolution of its lactophore activity. The hypogonadotrophic hypogonadism induced by high PRL was mainly manifested by low LH, and in this situation, normal levels of FSH and estradiol do not always induce follicle recruitment and development without abnormalities in the ovary ultrasound.

Vitamin D May Be Connected with Health-Related Quality of Life in Psoriasis Patients Treated with Biologics.

Suboptimal states of vitamin D may play a role in psoriasis evolution, but the interconnections have been studied over the past years with controversial results. Although a peerless therapy among moderate to severe types of psoriasis, the therapeutic effectiveness of biological therapy may vary unforeseeably between patients and leads to biologics switch. We conducted a pilot study in patients diagnosed with psoriasis and treated with biologics, the purpose of which was to explore the prevalence of suboptimal states of vitamin D, especially in the group of patients characterized by the failure of previous biologics, and to investigate the associations between vitamin D levels and psoriasis, regarding aspects such the severity of the disease and quality of life. Their current result of latent tuberculosis infection (LTBI) was also considered concerning a feasible relationship with vitamin D levels. From July to December 2021, 45 patients corresponding to our inclusion criteria were assessed. Variables such as Psoriasis Area and Severity Index (PASI) score and the Dermatology Life Quality Index (DLQI) score, as well as vitamin D serum concentrations and their LTBI result, were recorded for them. Lower serum concentrations of vitamin D were not more common in patients characterized by failure to previous biologics (p = 0.443), but we concluded a weak correlation between the DLQI score and vitamin D (rho = -0.345, p-value = 0.020), although a statistically insignificant result was obtained between vitamin D and the PASI score (rho = -0.280, p-value = 0.062), and with the LTBI result (rho = -0.053, p-value = 0.728). These results establish a connection between higher levels of vitamin D and a better outcome of psoriasis from the perspective of the patient's quality of life, with no significant association with psoriasis severity and no significant prevalence of suboptimal states among patients that failed previous biologics compared to those with a continuously good response.

The Future in Standards of Care for Gynecologic Laparoscopic Surgery to Improve Training and Education.

Standards of care offer doctors and patients the confidence that an established quality, evidence-based, care is provided, and represent a tool for optimal responding to the population's needs. It is expected that they will increasingly express a multimodal relationship with gynecologic laparoscopy. Laparoscopy is, now, a standard procedure in operative gynecology, standards are embedded in many laparoscopic procedures, standardization of the skills/competency assessment has been progressively developed, and the proof of competency in laparoscopy may become a standard of care. A continuous development of surgical education includes standard equipment (that may bring value for future advance), standardized training, testing (and performance) assessment, educational process and outcome monitoring/evaluation, patients' care, and protection, etc. Standards of care and training have a reciprocally sustaining relationship, as training is an essential component of standards of care while care is provided at higher standards after a structured training and as credentialing/certification reunites the two. It is envisaged that through development and implementation, the European wide standards of care in laparoscopic surgery (in close harmonization with personalized medicine) would lead to effective delivery of better clinical services and provide excellent training and education.

The Effect of Switching to Long-Acting Injection (LAI) Antipsychotic Therapy on Patients with Schizophrenia.

MATERIAL AND METHOD: We analyzed 362 patients with schizophrenia admitted during 2016 in an acute psychiatric ward and in a chronic psychiatric ward, diagnosed with paranoid or other schizophrenia, according to DSM-IV-TR, which, after remission of the symptoms of the acute episode, they benefited from antipsychotic therapy only in oral formulation. For some of these patients we instituted maintenance therapy with depot formulas. Patients were followed for up to two years. RESULTS: Comparing the level of adherence to therapy, we found a statistically significant improvement, from 42.96% to 76.30%. Although we estimate that adherence to LAI therapy is over 90%, almost a quarter of patients have given up this type of treatment at some point due to side effects. Carrying out the comparative analysis of the number of hospitalizations per year, from the past and from the follow-up period, as well as of the scores registered at the scales used (PANSS, CGI, GAS, WHOQOL), in dynamics, we demonstrated the appearance of statistically significant changes. CONCLUSIONS: the administration of antipsychotic therapy through LAI-type depot formulas can improve the therapeutic adherence of the patient with schizophrenia, thus improving the evolution of the disease and the quality of life.

Dexamethasone on absent end-diastolic flow in umbilical artery, in growth restricted fetuses from early-onset preeclamptic pregnancies and the perinatal outcome.

BACKGROUND: Absent end-diastolic flow (AEDF) in the umbilical artery (UA) worsens the already poor prognosis of growth-restricted fetuses (GRFs) in pregnancies complicated by early-onset preeclampsia with severe features (ESP). METHOD: We assessed the correlation between the effect of maternal dexamethasone (Dex) on AEDF in the UA and perinatal outcomes, in 59 GRFs from EPS-complicated pregnancies. The maternal outcome was also evaluated. RESULTS: The mean maternal age at inclusion was 22.4 ± 5.9 years. Dex transiently restored EDF in the UA in 38 (64.4%) cases (trAEDF group), but in 21 (35.6%) patients, the flow was persistently absent (prAEDF group). The effect lasted up to the 4th day.The gestational age at diagnosis, number of days from admission until delivery, and fetal weight were significantly lower in the prAEDF group than in the trAEDF group (p < .05). The same group had a significantly increased rate of fetal proximal deterioration, low APGAR scores, neonatal hypoxia, assisted ventilation, mild intraventricular haemorrhage (I/II), and respiratory distress syndrome, as well as maternal deterioration, especially in cases of resistant hypertension (p < .05). Although the rates of fetal acidemia and perinatal mortality in the prAEDF group were respectively three times and two times higher, the differences were not significant (p > .05). CONCLUSIONS: The Dex no-effect on UA Doppler in GRFs with AEDF in the UA, in EPS-complicated pregnancies, can be a useful marker for a higher risk of proximal fetal deterioration, poor state at delivery, neonatal hypoxic complications, and worsening maternal condition, but not for perinatal mortality. The findings also highlight the alarmingly younger age of patients with EPS. Finally, all these pregnancies should be monitored in a complex multidisciplinary manner in tertiary referral units.Key messageThe effect of dexamethasone on absent end-diastolic flow in the umbilical artery in growth-restricted fetuses from pregnancies complicated by early-onset preeclampsia with severe features can be a useful prognostic factor for perinatal outcomes.

Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth.

The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective ß-arrestin-biased signaling (ß-arr-BS). As these overlapping processes are initiated by the ß-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and ß-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced ß-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated ß-arr-BS. In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between ß-arrestin isoforms; in low ligand conditions, PX favored ß-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. SIGNIFICANCE: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1R-targeted therapy in cancer.

New insights into IL-17/IL-23 signaling in ankylosing spondylitis (Review).

Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life.

JAK/STAT pathway in pathology of rheumatoid arthritis (Review).

Rheumatoid arthritis (RA) is classified as an inflammatory, chronic autoimmune and disabling disease based on the intricate interplay between environmental and genetic factors. With a prevalence ranging from 0.3 to 1%, RA is the most prevalent inflammatory joint disease observed in adults. Disruption of immune tolerance becomes evident when abnormal stimulation of the innate and adaptive immune system occurs. This cascade of events causes persistent joint inflammation, proliferative synovitis and, ultimately, damage of the underlying cartilage as well as the subchondral bone, leading to permanent joint destruction, deformity and subsequent loss of function. With cytokines being the key to a multitude of biological processes, including inflammation, hematopoiesis and overall immune response, one must inevitably look at the main pathways through which a significant number of those molecules exert their function. Janus kinase/signal transducers and activators of transcription (JAK/STATs) represent one such pathway and, recently, JAK inhibitors (JAKinibs) have shown promise in the treatment of several inflammatory diseases, including RA. This narrative review focuses on the intricate signaling pathways involved as well as on the clinical aspects and safety profiles of JAKinibs approved for the treatment of RA.

Is there a relationship in-between ovarian endometriosis and ovarian cancer? Immunohistochemical profile of four cases with coexisting ovarian endometriosis and cancer.

Endometriosis (EMs) is a benign disease characterized by the presence of endometrial tissue outside the uterine cavity. EMs associated with ovarian cancer (OC) has a relative low incidence (5% to 10%), sometimes with evidence of a transition stage through atypical EMs (1.6% cases). We have assessed 135 consecutive patients with either EMs or OC and, out of them, our study reports on four cases of ovarian EMs and OC: two cases with endometrioid OC and two cases with high-grade serous OC (HGSOC). Cases with EMs and HGSOC are extremely rarely reported in the literature - we could find not more than 30 cases. The main objective of our research was to observe the possible similarities between EMs and OC. Secondly, we analyzed the differences between EMs associated with endometrioid OC and EMs associated with HGSOC. We evaluated them in terms of clinical status (age, stages of EMs and OC) and immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR), Ki67, p53, p16, Wilms' tumor 1 (WT1), cluster of differentiation (CD) 34 and CD10 immunomarkers - we could not find in the literature all these markers assessed, in the same time, to such samples. Our results indicated that there are no similarities between EMs and OC and no atypical EMs was identified in our cases. We recorded higher values of ER expression in EMs associated with HGSOC than in EMs associated with endometrioid OC. Higher values of ER expression were also recorded in OC than in endometriotic foci. There were no differences in proliferative rate of endometriotic foci associated with endometrioid OC, compared to EMs associated with HGSOC. An aberrant IHC expression for p53 protein and p16 protein was noted only in HGSOC. Also, a positive immunostaining for Wilms' tumor 1 (WT1) was identified only in HGSOC. Higher values of microvessel density were recorded in OC but not in endometriotic foci. We concluded that there were no similarities between EMs and OC for the cases included in our study, but we noticed differences in terms of Ki67 index and also between hormonal receptors expression in EMs associated with HGSOC, comparing with EMs associated with endometrioid OCs. These results may represent a "brick" for future researches on the less understood EMs associated with type II of OCs, especially with HGSOC. Identifying the best marker, which can predict the risk of developing OC for the patients with EMs, may lead to discover new specific therapeutic agents and, therefore, a better, tailored, therapy.

A unique case of recurrent fetal cystic hygroma: first fetus with an inherited heteromorphism of chromosome 1 (1qh+) and the second fetus with 69XXX triploidy.

The authors report a unique recurrent septated cystic hygroma (CH), on two successive pregnancies, at five years interval. The chromosome analysis of the first fetus showed an increase in length of heterochromatin on the long arm of chromosome 1 - 1qh+, a chromosomal polymorphism inherited from mother, 46XX,1qh+,14ps+,21ps+. The karyotype of the second CH, with more severe ultrasound (US) imaging, showed a 69XXX triploidy. The patient took no risk and underwent each time a termination of pregnancy (TOP). The first karyotype is generally considered "normal", although there are few reports linking 1qh+ with low fertility, but this was not the case, the patient having, from a previous marriage, a healthy boy and two TOPs. So, this "particular", but "healthy" karyotype was not a cause for the first CH. The second karyotype highlights a possible causality between the 69XXX triploidy, usually associated with partial hydatidiform mole, and a more severe septated CH in the last fetus. Neither the CHs' appearance nor their recurrence seemed to be family linked, as the two CHs had distinct genetic profiles. We recommend that, once CH is diagnosed, a careful US examination is compulsory for the determination of subcutaneous edema, ascites, pleural and pericardial effusions and cardiac or renal abnormalities; an early genetic work-up is mandatory, by chorionic villus sampling or amniocentesis. However, a "healthy" karyotype does not exclude a severe form, as in our first case of CH. Due to the very poor outcome of fetuses with CH, the patient must be thoroughly informed about the short and the long-term fetal prognosis.

Effects of VPAC1 activation in nucleus ambiguus neurons.

The pituitary adenylyl cyclase-activating polypeptide (PACAP) and its G protein-coupled receptors, PAC1, VPAC1 and VPAC2 form a system involved in a variety of biological processes. Although some sympathetic stimulatory effects of this system have been reported, its central cardiovascular regulatory properties are poorly characterized. VPAC1 receptors are expressed in the nucleus ambiguus (nAmb), a key center controlling cardiac parasympathetic tone. In this study, we report that selective VPAC1 activation in rhodamine-labeled cardiac vagal preganglionic neurons of the rat nAmb produces inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization, membrane depolarization and activation of P/Q-type Ca2+ channels. In vivo, this pathway converges onto transient reduction in heart rate of conscious rats. Therefore we demonstrate a VPAC1-dependent mechanism in the central parasympathetic regulation of the heart rate, adding to the complexity of PACAP-mediated cardiovascular modulation.

Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

GPER and ERα expression in abnormal endometrial proliferations.

UNLABELLED: G-protein coupled estrogen receptor 1 (GPER), a particular extranuclear estrogen receptor (ER), seems not to be significantly involved in normal female phenotype development but especially associated with severe genital malignancies. This study investigated the GPER expression in different types of normal and abnormal proliferative endometrium, and the correlation with the presence of ERα. GPER was much highly expressed in cytoplasm (than onto cell membrane), contrary to ERα, which was almost exclusively located in the nucleus. Both ERs' densities were higher in columnar epithelial then in stromal cells, according with higher estrogen-sensitivity of epithelial cells. GPER and ERα density decreased as follows: complex endometrial hyperplasia (CEH) > simple endometrial hyperplasia (SHE) > normal proliferative endometrium (NPE) > atypical endometrial hyperplasia (AEH), ERα' density being constantly higher. In endometrial adenocarcinomas, both ERs were significant lower expressed, and widely varied, but GPER÷ERα ratio was significantly increased in high-grade lesions. CONCLUSIONS: The nuclear ERα is responsible for the genomic (the most important) mechanism of action of estrogens, involved in cell growth and multiplication. In normal and benign proliferations, ERα expression is increased as an evidence of its effects on cells with conserved architecture, in atypical and especially in malignant cells ERα's (and GPER's) density being much lower. Cytoplasmic GPER probably interfere with different tyrosine÷protein kinases signaling pathways, also involved in cell growth and proliferation. In benign endometrial lesions, GPER's presence is, at least partially, the result of an inductor effect of ERα on GPER gene transcription. In high-grade lesions, GPER÷ERα ratio was increased, demonstrating that GPER is involved per se in malignant endometrial proliferations.

Ovarian teratomas in a patient with Bardet-Biedl syndrome, a rare association.

Bardet-Biedl syndrome (BBS) represents a rare ciliopathy recessive autosomal inherited. The main clinical features are retinal dystrophy, postaxial polydactyly, obesity, different degrees of cognitive deficit, renal impairment, hypogonadism and genital malformations. The genetic explanation consists in BBS genes mutations, which encode modified proteins, altering the function of the immotile cilia. As a multitude of BBS genes mutations were described, the phenotypic aspect of these disorders varies according to that. We present the case of a 22 years old female patient, known with BBS since the age of 11 and which was diagnosed and operated for bilateral ovarian dermoid cysts, at the age of 21. We did not find a similar case in literature, regarding the association between the two disorders. We consider that our case points towards the importance of periodic imagistic evaluations [magnetic resonance imaging (MRI), computed tomography (CT) or ultrasound] of these patients, not only clinical and biological. Usually, the moment they are diagnosed with hypogonadism or genital malformations (in childhood or adolescence), the genital evaluation is neglected thereafter. We also consider that our therapeutic approach can be helpful in other similar clinical situations. Another important conclusion is represented by the importance of genetic counseling of the relatives of a BBS patient, unfortunately insufficiently provided in our region.

Salivary and serum biomarkers for the study of side effects of aripiprazole coprescribed with mirtazapine in rats.

The aim of this study was to investigate whether the co-administration of aripiprazole and mirtazapine could determine weight gain and lipid metabolism disorders in Wistar rats, compared to the same side effects produced by mirtazapine alone, and the risk of hepatotoxicity due to the combination of the two substances. Tumor necrosis factor alpha (TNF-α), liver fatty acid binding protein (L-FABP/FABP1) and repulsive guidance molecule C/hemojuvelin (RGM-C/HJV) levels were determined in serum and in saliva. Also, serum levels for total cholesterol (TC), low and high-density lipoprotein (LDL, HDL), triglycerides (TG), aspartate aminotransferase (ASAT) and alanine amino transferase (ALAT) were assessed. We found positive and statistically significant correlations between serum and salivary levels of TNF-α, L-FABP/FABP1 and RGM-C/HJV. Mirtazapine determined significantly differences of TNF-α and L-FABP serum levels; final body weight; TC and LDL levels, leading to higher concentrations than its association with aripiprazole. Although not statistically significant, mirtazapine group experienced higher values for salivary levels of TNF-α, TG and ASAT, and lower values for HDL, compared to aripiprazole + mirtazapine group. The results suggest that aripiprazole might improve some of the disturbances caused by mirtazapine, and that the two drugs combination cause no additional alterations in liver function. Also, the findings indicate that TNF-α, L-FABP/FABP1 and RGM-C/HJV levels can be helpful as biomarkers for metabolic disturbances and impaired function of hepatocytes, and that their salivary determination can replace serum determination.

Perfusion deficits, inflammation and aging precipitate depressive behaviour.

Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therapeutic interventions.