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BackgroundThere are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences.MethodsWe used Translating Ribosome Affinity Purification (TRAP) sequencing and behavioral pharmacology to test the hypothesis that nociceptor (Nav1.8 expressing neurons) translatomes would differ by sex.ResultsWe found 66 genes whose mRNA were sex-differentially bound to nociceptor ribosomes. Many of these genes have known neuronal functions but have not been explored in sex differences in pain. We focused on Ptgds, which was increased in female mice. The mRNA encodes the prostaglandin D2 (PGD2) synthesizing enzyme. We observed increased Ptgds protein and PGD2 in female mouse DRG. The Ptgds inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in females. Conversely, female mice responded more robustly to another major prostaglandin, PGE2, than did male mice. Ptgds protein expression was also higher in female cortical neurons, suggesting DRG findings may be generalizable to other nervous system structures.ConclusionsNociceptor TRAP sequencing (TRAP-seq) reveals unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins. Our results demonstrate that translatome analysis reveals physiologically relevant sex differences important for fundamental protective behaviors driven by nociceptors.

Background Topical prostaglandin analogs (PGAs) are widely approved and preferred first-line options for glaucoma and elevated intraocular pressure (IOP). However, prostaglandin-associated periorbitopathy syndrome (PAPS) is now a well-recognized clinical and cosmetic concern for patients receiving PGAs, especially during long-term and unilateral therapy. PGA-associated periocular changes occur in a substantial proportion of patients, with older patients (>60 years) at greater risk of clinical presentation. PAPS may hinder long-term management of glaucoma, including treatment adherence, ophthalmic surgery outcomes, and reliable IOP measurements. Recommendation New therapeutic approaches may address this unmet clinical need. Omidenepag isopropyl (OMDI) is a novel, non-prostaglandin, selective EP2 receptor agonist in ongoing development, which provides a unique pharmacological mechanism of action. OMDI appears to provide IOP reductions comparable to PGAs, but without PAPS-related undesirable effects. OMDI may offer a suitable long-term option for patients who demonstrate decreased efficacy, or failure, of PGAs, plus patients with significant PAPS, while fulfilling international guidelines.

Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see ‘Data availability’ section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19., New results shed light on the molecular mechanisms of dexamethasone action, underlying its therapeutic benefit in patients with severe COVID-19.

The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals.One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin FConcentrations of PGEOur findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

After reviewing the current definitions and classification of pulmonary hypertension (PH) associated with congenital heart disease (CHD), based on an analysis of 59 clinical trials (of which 14 are randomized controlled trials) drugs registered in the Russian Federation, the evidence base for PH therapy in adults with CHD is provided. The presence of a randomized controlled trial of bosentan BREATHE-5 and uncontrolled trials of other drugs became the basis for a higher class and level of evidence of bosentan (IB) compared to other drugs (IIaC) for Eisenmenger syndrome in the current European (ERS/ESC 2015) and updated Russian (2020) guidelines. According to the updated European (ESC 2020) guidelines for congenital heart disease in adults, in Eisenmenger patients with reduced exercise capacity (6MWT distance 450 m), a treatment strategy with initial endothelin receptor antagonist monotherapy should be considered followed by combination therapy if patients fail to improve (IIaB), in low- and intermediate-risk patients with repaired simple lesions and pre-capillary PH, initial oral combination therapy or sequential combination therapy is recommended and high-risk patients should be treated with initial combination therapy including parenteral prostanoids (IA) and endothelin receptor antagonists and phosphodiesterase 5 inhibitors may be considered in selected patients with elevated pulmonary pressure/resistance in the absence of elevated ventricular end diastolic pressure (IIbC). Only three (bosentan, macitentan and selexipag) out of seven specific pulmonary vasodilators registered in the Russian Federation have indications for pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome or pulmonary arterial hypertension associated with corrected simple congenital heart disease in the instructions for use.После рассмотрения современных определений и классификации легочной гипертензии (ЛГ), ассоциированной с врожденными пороками сердца (ВПС), на основе анализа 59 клинических исследований (из них 14 рандомизированные контролируемые исследования) зарегистрированных в Российской Федерации препаратов приводится доказательная база терапии ЛГ у взрослых с ВПС. Наличие рандомизированного контролируемого исследования бозентана BREATHE-5 и неконтролируемых исследований других препаратов стало основанием для более высокого класса и уровня доказательности бозентана (IB) по сравнению с другими препаратами (IIaС) при синдроме Эйзенменгера в действующих Европейских (ERS/ESC 2015) и обновленных Российских (2020 г.) рекомендациях по ЛГ. Согласно обновленным Европейским (ESC 2020) рекомендациям по ВПС у взрослых пациентам с синдромом Эйзенменгера и сниженной переносимостью физической нагрузки (дистанция теста 6-минутной ходьбы 450 м) показана монотерапия антагонистами рецепторов эндотелина, а при отсутствии эффективности комбинированная терапия (IIaB), пациентам низкого и промежуточного риска с корригированными простыми ВПС и прекапиллярной ЛГ рекомендуется пероральная начальная или последовательная комбинированная терапия, пациентов же высокого риска следует лечить начальной комбинацией, включающей парентеральные простаноиды (IA), и антагонисты рецепторов эндотелина и ингибиторы фосфодиэстеразы 5 могут быть рассмотрены у отдельных пациентов после операции Фонтена с повышенным давлением в легочной артерии/легочным сосудистым сопротивлением при отсутствии повышения конечного диастолического давления системного желудочка (IIbC). Лишь 3 (бозентан, мацитентан и селексипаг) из 7 зарегистрированных в РФ специфических легочных вазодилататоров имеют показания легочная артериальная гипертензия, ассоциированная с ВПС и синдромом Эйзенменгера, или легочная артериальная гипертензия, ассоциированная с корригированными простыми ВПС, в инструкциях по применению.

The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunction, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways.

Introduction Systemic sclerosis (SSc) is a systemic multi-organ disease. Raynaud’s phenomenon (RP) and digital ulcers (DUs) in SSc patients can be resistant to usual treatments. We studied the clinical benefits, capillaroscopy changes, and cost-effectiveness of local injection of botulinum toxin-A (BTX-A) and intravenous prostaglandin analogs (iloprost/alprostadil) in patients with SSc with resistant DUs. Method In a clinical trial study, we evaluated 26 patients fulfilling the ACR/EULAR SSc criteria with resistant DUs. Visual analog scale of pain and RP, skin color and type of ulcers, and capillaroscopy were assessed before and 1 month after treatment. In the first group, 20 units of BTX-A was injected at the base of each involved fingers by a dermatologist. In the second group, 20 µg iloprost or 60 µg alprostadil was infused daily. The cost of these treatments was compared. Result In 26 patients (43 fingers), there were 16 patients (22 fingers) in the BTX-A and 10 patients (21 fingers) in the prostaglandin group. In 95.5% of the BTX-A and 90.5% of the prostaglandin group, the ulcers were healed. In both groups, a significant decrease in pain was seen (p

Functional hyperemia is fundamental to provide enhanced oxygen delivery during exercise in skeletal muscle. Different mechanisms are suggested to contribute, mediators from skeletal muscle, transmitter spillover from the neuromuscular synapse as well as endothelium-related dilators. We hypothesized that redundant mechanisms that invoke adenosine, endothelial autacoids, and KATP channels mediate the dilation of intramuscular arterioles in mice. Arterioles (maximal diameter: 20–42 µm, n = 65) were studied in the cremaster by intravital microscopy during electrical stimulation of the motor nerve to induce twitch or tetanic skeletal muscle contractions (10 or 100 Hz). Stimulation for 1–60 s dilated arterioles rapidly up to 65% of dilator capacity. Blockade of nicotinergic receptors blocked muscle contraction and arteriolar dilation. Exclusive blockade of adenosine receptors (1,3-dipropyl-8-(p-sulfophenyl)xanthine) or of NO and prostaglandins (nitro-L-arginine and indomethacin, LN + Indo) exerted only a minor attenuation. Combination of these blockers, however, reduced the dilation by roughly one-third during longer stimulation periods (> 1 s at 100 Hz). Blockade of KATP channels (glibenclamide) which strongly reduced adenosine-induced dilation reduced responses upon electrical stimulation only moderately. The attenuation was strongly enhanced if glibenclamide was combined with LN + Indo and even observed during brief stimulation. LN was more efficient than indomethacin to abrogate dilations if combined with glibenclamide. Arteriolar dilations induced by electrical stimulation of motor nerves require muscular contractions and are not elicited by acetylcholine spillover from neuromuscular synapses. The dilations are mediated by redundant mechanisms, mainly activation of KATP channels and release of NO. The contribution of K+ channels and hyperpolarization sets the stage for ascending dilations that are crucial for a coordinated response in the network.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 × 10-5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F2α (vs. control), and these effects are stronger than that of LA (3 × 10-5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl2-induced ileal and colonic LSM contractions in Ca2+-free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF2α, and CaCl2 were completely suppressed by verapamil (10-5 M), a voltage-gated/dependent Ca2+ channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

Background Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. Method Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. Results All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. Conclusions Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.

To examine the effect of switching from a prostanoid FP receptor agonists to EP2 receptor agonist (omidenepag isopropyl) on the deepening of the upper eyelid sulcus (DUES) and intraocular pressure (IOP) in Japanese glaucoma patients over 3 months post treatment. Prospective observational study. Patients with glaucoma who received FP receptor agonists treatment and had complained of DUES-related reduction in quality of life were included. Their FP receptor agonists was switched to omidenepag isopropyl without a drug holiday. At baseline and 1 and 3 months post-switch, photographs were taken and the changes in DUES were assessed by three independent observers. IOP and adverse events were also assessed. The study included 23 eyes of 23 patients (6 men, 17 women; average age, 60.6 years). After switching, DUES improved in 12 eyes at 1 month and in 16 eyes at 3 months; eyes in the remaining patients showed no worsening of the condition. The mean IOP before switching was 15.3 ± 3.3 mmHg (95% confidence interval 13.9–16.7 mmHg). Following the switch, the mean IOP values were 15.6 ± 3.3 mmHg (14.1–17.0 mmHg) at 1 month and 15.5 ± 3.3 mmHg (14.1–16.9 mmHg) at 3 months (P = 1.0 at 1 month, P = 1.0 at 3 months; both adjusted by Bonferroni correction). No adverse effects were observed. Omidenepag isopropyl improved DUES while maintaining IOP in over 70% of Japanese patients with glaucoma who exhibited DUES caused by FP receptor agonists; the improvement was observed within 3 months after switching from FP receptor agonists.

The physiological pattern of hormonal and signaling molecules associated with labor induction is not fully clear. We conducted a preliminary study in order to investigate hormonal changes during labor induction in women with previous cesarean section. Eighty-seven women at term, with previous cesarean section, were randomized to undergo induction of labor by breast stimulation or intracervical balloon and compared with spontaneous labor (controls). Maternal serum levels of oxytocin, prostaglandin F2α, prostaglandin E2, prolactin, estradiol, and cortisol were analyzed at 0, 3, and 6 h post-induction initiation. Fetal umbilical cord hormones were measured. No significant difference was found in the induction-to-delivery time or mode of delivery between the induction groups. Maternal serum oxytocin levels decreased to a lesser extent in the breast stimulation group vs. the control group (p=0.003, p

Preterm infants experience frequent arterial oxygen desaturations during oxygen therapy, or intermittent hypoxia (IH). Neonatal IH increases oxidative distress which contributes to neuroinflammation and brain injury. We tested the hypotheses that exposure to neonatal IH is detrimental to the immature brain and that early supplementation with antioxidants and/or omega 3 polyunsaturated fatty acids (n-3 PUFAs) combined with non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Newborn rats were exposed to brief hypoxia (12% O2 ) during hyperoxia (50% O2 ) from the first day of life (P0) until P14 during which they received daily oral supplementation with antioxidants, namely coenzyme Q10 (CoQ10) or glutathione nanoparticles (nGSH), n-3 PUFAs and/or topical ocular ketorolac. Placebo controls received daily oral olive oil and topical ocular saline. Room air (RA) littermates remained in 21% O2 from birth to P21 with all treatments identical. At P14 animals were allowed to recover in RA until P21 with no further treatment. Whole brains were harvested for histopathology and morphometric analyses, and assessed for biomarkers of oxidative stress and inflammation, as well as myelin injury. Neonatal IH resulted in higher brain/body weight ratios, an effect that was reversed with n-3 PUFAs and n-3 PUFAs+CoQ10 with or without ketorolac. Neonatal IH was also associated with hemorrhage, oxidative stress, and elevations in inflammatory prostanoids. Supplementation with n-3 PUFAs and nGSH with and without ketorolac were most beneficial for myelin growth and integrity when administered in RA. However, the benefit of n-3 PUFAs was significantly curtailed in neonatal IH. Neonatal IH during a critical time of brain development causes inflammation and oxidative injury. Loss of therapeutic benefits of n-3 PUFAs suggest its susceptibility to oxidation in neonatal IH and therefore indicate that co-administration with antioxidants may be necessary to sustain its efficacy.

PURPOSE To determine the effect of chronic topical use of prostaglandin analogs for glaucoma on lower eyelid tension. METHODS A prospective case-control study was performed. Lower eyelid tension was measured in a group of glaucoma patients (73 eyelids) using prostaglandin analogs and a paired control group (87 eyelids). Seven glaucoma patients with unilateral use of prostaglandin analogs had the lower eyelid tension of the exposed side compared with the contralateral eyelid. Eyelid tension was digitally measured in photographs in neutral position and after manual downward traction in the center of the eyelid (modified distraction test). Duration of drug exposition, age, use of other topical medication and other prostaglandin-associated periorbitopathy signs as long eyelashes, eyelid hyperemia, eyelid pigmentation, and deepening of upper eyelid sulcus were recorded for analysis. RESULTS Mean lower eyelid tension in prostaglandin group was significantly higher than in control group: distraction 5.26 mm (SD 1.52) versus 6.80 mm (SD 1.29) (p < 0.001). On the unilateral prostaglandin use intragroup comparison, mean lower eyelid distraction in prostaglandin side was 4.24 mm (SD 1.80) and in control side was 6.79 mm (SD 1.63) (p < 0.012). Beta blocker and carbonic anhydrase inhibitor concomitant use was associated with lower eyelid tension measures in prostaglandin users. Presence of long eyelashes was associated with higher eyelid tension. All other measured variables did not demonstrate interaction with eyelid tension. CONCLUSIONS Chronic topical use of prostaglandin analogs for glaucoma is associated with lower eyelid tightening.

Supplemental Digital Content is Available in the Text. Targeted lipids and inflammation modulators were analyzed in abdominal fluid and serum revealing an association between endocannabinoids (2-AG and AEA) and gynecological pain., Endocannabinoid (eCB) levels fluctuate in inflammatory conditions and as such may take part in endometriosis-associated pain or even in endometriosis pathogenesis. In this case–control (23 cases and 19 controls) study, targeted lipids were measured in the serum and peritoneal fluid collected during laparoscopy. Endometriosis was confirmed histologically. Dysmenorrhea, abdominal pain, and dyspareunia were assessed using the Numeric Rating Scale for pain. Steroids, eCBs, and related lipids were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Tumor necrosis factor alpha, IL-8, PAPP-A, PP14, RANTES, OPG, MIDKINE, MCP-1, VEGF, leptin, and defensins were quantified by ELISA. We found that eCB levels were significantly influenced by both noncyclic and cyclic abdominal pain. Specifically, women suffering from noncyclic abdominal pain were characterized by a higher 2-AG level in the peritoneal fluid throughout the menstrual cycle, whereas women suffering from dysmenorrhea had higher 2-AG levels and lower AEA levels during the proliferative phase alone. In addition, 2-AG positively correlated with prostaglandin E2 (PGE2), and the ratio AEA/2-AG positively correlated with defensins, suggesting a possible link between endocannabinoids system and inflammatory pain. The results of the current study indicate that the eCB system may play a role in endometriosis-associated pain, but additional studies are needed to investigate the causal relationship.

Background and Purpose: To evaluate the use of prostaglandins and oxytocin in labour induction according to different indications. Perinatal outcomes, rate of vaginal delivery and complation of labour were studied and compared. Methods: Cross-sectional descriptive study from January 2012 to December 2012. 530 women who required labour induction were included. Seven groups were created according to the methods of induction. Women with twin pregnancies, induction of dead foetus, two previous caesarean sections or an incomplete clinical history were excluded. Results: The rate of vaginal deliveries in women that only received prostaglandins the first day was 84.6%; similar in women with prolonged pregnancies, 85.2%. The induction with oxytocin directly showed the highest rate of caesarean section. The rate of vaginal deliveries was 50% in women with previous caesarean section. Conclusions: A high rate of vaginal deliveries with a single dose of prostaglandin and within 24 hours of beginning induction. Administration of prostaglandins must be used when cervix is unfavorable and previous to oxytocin stymulation.

Robert English Jnr, Sophia Ruiz Perfect Hair Health, San Francisco, CA, 94115, USACorrespondence: Robert English JnrPerfect Hair Health, 2021 Fillmore Ste # 98, San Francisco, CA, 94115, USAEmail Rob@perfecthairhealth.comAbstract: Despite decades of study, debate persists over the role of inflammation, fibrosis, and prostaglandins in the histopathology of androgenic alopecia (AGA). This brief review proposes that inconsistent findings across histological studies are a consequence of three inadequately controlled variables: 1) biopsy location, 2) hair diameter diversity (HDD), and 3) relative hair follicle miniaturization (HFM) within and across subjects. We suggest new methodological considerations to improve AGA histopathological research, as well as a novel classification system to quantify HFM by its stages. Finally, we hypothesize a dynamic relationship between inflammation, fibrosis, and prostaglandin activity dependent on relative HFM.Keywords: androgenic alopecia, hair diameter diversity, inflammation, fibrosis, prostaglandins

Summary: Background: The extent of arterial disease in patients with erectile dysfunction (ED) non-responsive to intracavernosal injection of Alprostadil is of importance for therapeutic options. However, published evidence, in particular angiographically validated is scarce. Here we investigated arterial lesion patterns in this specific patient cohort by selective angiography. Patients and methods: A cohort of 239 patients received a clinical and duplex-sonographic workup for ED of suspected vascular origin. Duplex ultrasound of the cavernosal arteries was performed after intracavernosal injection of 10 μg Alprostadil. Consequently, standardized workup included grading of the erectile and determination of peak systolic velocity (PSV) and end-diastolic velocity (EDV) in both cavernosal arteries. PSV-values below 30 cm/sec indicated reduced arterial flow, whereas EDV-values above 15 cm/sec indicated a venous leak of the pudendal veins. All patients with suspected arterial ED based on duplex sonography underwent contrast-enhanced computed tomography. Endovascular therapy was carried out in ED patients not responsive or with significant side effects to PDE-5-inhibitors or Alprostadil by selective angiographic depiction of erection-related arteries. Results: 54 patients with a mean age of 61.2 (±9.8) years underwent angioplasty of erectionr elated arteries. Out of these 48/54 (89%) patients presented with an erection considered insufficient for penetration (E0-E3) subsequent to intracavernous application of 10 μg Alprostadil. 14/48 (29%) patients had bilateral arterial obstructions and 34/48 (71%) had unilateral disease. Commonly affected was the internal pudendal artery (n = 31, 65%), followed closely by the common penile artery (n = 30, 64%). The least affected arteries were the dorsal penile (n = 6, 13%), hypogastric (n = 4, 8%), common iliac (n = 4, 8%), cavernosal (n = 4, 8%), and inferior gluteal (n = 1, 2%) arteries. Conclusions: Arterial obstructions amenable to endovascular revascularization are frequent in patients non-responsive to intracavernosal prostaglandin administration. Therapeutic strategies in ED patients non-responsive to conservative measures should therefore consider endovascular treatment opportunities.

Growth hormone (GH) and insulin-like growth factor 1 (IGF1) are crucial for female reproductive functions. The cyclic regulation of the local GH/IGF1 axis in the oviduct and its involvement in oviductal contraction in cattle has not been investigated. Thus, the messenger RNA (mRNA) expression for GH receptor (GHR), IGF1, IGF1 receptor (IGF1R) in the whole oviducts, as well as in cultured bovine oviductal epithelial cells (BOECs) were evaluated. The GHR, IGF1, and IGF1R mRNA expression was significantly higher during postovulatory phase. The luteinizing hormone (LH), estradiol-17β (E2), and LH + E2 treatments significantly increased GHR and IGF1 mRNA expression in cultured BOECs. Further, GH and combination of GH with LH and E2 upregulated IGF1 mRNA expression in the BOECs. Moreover, IGF1 + LH and combined IGF1 + LH + E2 treatments significantly increased prostaglandin synthesis cascade enzyme mRNA expression in the BOECs. An ex vivo microdialysis assay revealed that GH and IGF1 induced the release of oviductal contraction related prostaglandins, endothelin-1, and angiotensin II in follicular and postovulatory phases. Together, the findings strongly suggest that the presence of the active GH/IGF1 axis during the peri-ovulatory period, regulating the local system for the release of oviductal contraction related substances, which may provide the optimal oviductal environment for gametes and early embryo.

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of N(G)-monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBF(AUC))] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBF(AUC): 271 ± 97 mL, P > 0.05) or sPLM (LBF(AUC): 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests. NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.

Heterogeneous flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC) responses have been reported between upper- and lower-limb arteries. Radial artery L-FMC, but not FMD, responses are blunted when endothelial-derived hyperpolarizing factors (EDHFs) or prostaglandin production is inhibited in young adults. However, it is unknown if these mechanisms similarly impact endothelial-dependent responses in the brachial (BA) and popliteal (POP) arteries. We tested whether BA- and POP-L-FMC and FMD would be influenced by independent EDHF and prostaglandin inhibition. Eighteen participants (23 ± 3 yr; 6♀) completed three randomized and double-blinded ultrasound assessments following ingestion of an opaque capsule containing maltodextrin (control), 150 mg of fluconazole (EDHF inhibition), or 500 mg of aspirin (prostaglandin inhibition). POP resting diameter was reduced following fluconazole administration (6.13 ± 0.63 mm vs. 6.19 ± 0.65 mm in control

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model.

Aim. The aim of the study was to evaluate the progression of changes in the visual fields in patients with hypertensive glaucoma (HTG) and normotensive glaucoma (NTG) following administration of prostaglandins and beta blockers, as well as also in NTG without ophthalmological therapy. Methodos. The HTG group included 12 patients (mean age 66 years) with approximately the same changes in the visual field and central corneal thickness (CCT-568um) treated with prostaglandins, and 12 patients (mean age 60 years, CCT=544um) treated with beta-blockers. The IOP ranged from 12 to 18mmHg for the whole follow-up period. The NTG group consisted of three subgroups. The first subgroup consisted of 14 patients (mean age 58 years) who were treated with prostaglandins. The second subgroup consisted of 10 patients (mean age 57 years) who were treated with beta blockers. The third subgroup consisted of 18 patients (mean age 57 years) who underwent no ophthalmological therapy. IOP was within the range of 8-12 mmHg over the whole follow-up period. In all patients, we monitored the pattern defect (PD) and overall defect (OD) within a period of five years. The treatment was not modified during the treatment period. All patients were compensated for cardiovascular status and had no other internal or neurological disease. Visual acuity was 1.0 with a possible correction (less than 3 dioptres) in all patients. Results. There was no statistically significant difference in HTG during the treatment with prostaglandins in PD (P=0.35) and OD (P=0.09) or beta blockers (P=0.37 and 0.23, respectively). In NTG, the greatest changes occurred in PD (P=0.0001) in untreated patients. OD showed no statistically significant changes (P=0.25). Similarly, the patients on prostaglandins had a statistically significant difference in PD (P=0.04), while OD did not show statistically significant changes (P=0.4). We did not find statistically significant differences in progression in patients with NTG treated with beta blockers PD (P=0.7), OD (P=0.4). Conclusion. Treatment of glaucoma with prostaglandins and beta blockers has a significant importance in HTG. However, beta blockers have a higher protective effect on the visual field. This is not true in NTG, where we demonstrated this effect only following the administration of beta blockers.

Vasomotor reactions of prostacyclin (prostaglandin I2 ; PGI2 ) can be collectively modulated by thromboxane prostanoid receptor (TP), E-prostanoid receptor-3 (EP3), and the vasodilator I prostanoid receptor (IP). This study aimed to determine the direct effect of PGI2 on renal arteries and/or the whole renal vasculature and how each of these receptors is involved. Experiments were performed on vessels or perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP-/- ) and/or EP3. Here we show that PGI2 did not evoke relaxation, but instead resulted in contraction of main renal arteries (from ~0.001-0.01 µM) or reduction of flow in perfused kidneys (from ~1 µM); either of them was reversed into a dilator response in TP-/- /EP3-/- counterparts. Also, we found that in renal arteries although it has a lesser effect than TP-/- on the maximal contraction to PGI2 (10 µM), EP3-/- but not TP-/- resulted in relaxation to the prostanoid at 0.01-1 µM. Meanwhile, TP-/- only significantly reduced the contractile activity evoked by PGI2 at ≥0.1 µM. These results demonstrate that PGI2 may evoke an overall vasoconstrictor response in the mouse renal vasculature, reflecting activities of TP and EP3 outweighing that of the vasodilator IP. Also, our results suggest that EP3, on which PGI2 can have a potency similar to that on IP, plays a major role in the vasoconstrictor effect of the prostanoid of low concentrations (≤1 µM), while TP, on which PGI2 has a lower potency but higher efficacy, accounts for a larger part of its maximal contractile activity.

Background: Androgenetic alopecia [AGA] one of the common scalp hair loss disorders affecting males. Androgenetic alopecia is characterized by progressive miniaturization of hair follicles in the scalp and gradual transformation of terminal hairs into vellus hairs leading to progressive decrease in hair density. The pattern of loss follows the scale developed by Hamilton and later extended by Norwood. Aim of Work: Evaluation of the efficacy of topical cetirizine 1% for the treatment of androgenetic alopecia in male patients. Patients and methods: This case-controlled study included 30 male patients treated by topical cetirizine1%and 30 male patients as a control group treated by placebo for 6 months recruited from dermatology outpatient clinic of Damietta Hospital and Al-Sarou hospital during the period from September 2018 to August 2019. For each patient, the trichoscopic evaluation was performed before the beginning of treatment and after 6 months of treatment. Results: Treatment with topical cetirizine 1% in male patients with AGA showed that according to number of new up growing hairs, the majority [56.7%] of cases had no new growing hair, 20.0%, 16.7% &6.7% had one, two and three new hair respectively. On the other hands, all control had no new hair after 6 months of treatment. Conclusion: Topical cetirizine is effective in the treatment of Androgenetic alopecia in men.

Inflammatory bowel diseases (IBD), namely, Crohn’s disease (CD) and ulcerative colitis (UC) are idiopathic chronic, relapsing, inflammatory diseases of the gastrointestinal (GI) tract. Triggers for disease flares include medications, infection, acute stress, and the menstrual cycle. Varying ovarian hormone levels i.e. prostaglandins and progesterone may exaggerate GI symptoms in IBD. We aimed to determine the relationship between quality of life, endoscopic and clinical disease activity and the menstrual cycle among females with IBD through a questionnaire based cross-sectional study. The first 75 women of child-bearing age seen at IBD clinic completed a questionnaire incorporating the short IBD questionnaire (SIBDQ). Menstrual symptoms were evaluated using the validated Moos Menstrual Distress Questionnaire (MDQ) to measure cyclical peri-menstrual symptoms. Endoscopic disease severity was assessed using the Rutgeert’s score (post ileo-cecal resection patients) or Simple Endoscopic Score for CD and the Mayo score for UC. There was a statistically negative correlation between MDQ and SIBDQ scores (p

The objectives of this study were to evaluate in horse testes the expression of kisspeptin (KiSS) and GnRH1 neuropeptides and their cognate receptors, KiSS1R and GnRH1R, as well as their action on testosterone, GnRH1, prostaglandin F2α (PGF2α), and PGE2 synthesis and cyclooxygenase 1 (COX1) and COX2 activity by Leydig cells in vitro. Testes were obtained from 9 sexually mature horses by surgical castration. Immunohistochemistry, evidenced the presence of KiSS, KiSS1R, GnRH, and GnRH1R in Leydig cells, whereas germinal and Sertoli cells were positive only for GnRH1. Transcripts for both neuropeptides and their cognate receptors were revealed in isolated Leydig cells by RT-PCR. Isolated and purified Leydig cells were in vitro cultured with agonists and antagonists of KiSS (KiSS-10 and KiSS-234, respectively) and GnRH1 (buserelin and antide, respectively). KiSS-10 and buserelin increased (P 0.01) COX1 activity and testosterone and PGF2α basal secretion, while decreased (P 0.01) that of PGE2. KiSS-10 and buserelin did not affect COX2 activity. GnRH1 basal production was increased (P 0.01) by KiSS-10, but not by buserelin. Antide counteracted the KiSS and GnRH1 effects, whereas KiSS-234 influence only those of KiSS. Summarizing, the KiSS/GnRH1 system is present in horse Leydig cells and modulates their endocrine activity. In particular, the endocrine effects of KiSS are mediated by GnRH1, so suggesting that hypothalamic-like interaction between KiSS and GnRH1 occurs also in Leydig cells.

Aim. The aim of the work is to study the interleukin and prostaglandin status of patients with shingles depending on the severity of the disease. Materials and methods. We examined the blood of 27 patients with shingles, aged from 52 to 69 years, with 11 women (40.7 %) and 16 men (59.3 %) among them. Mild shingles was observed in 7 patients (25.9 %), moderate shingles was observed in 12 patients (44.4 %) and severe shingles was observed in 8 patients (29.6 %). The control group consisted of 12 practically healthy people (7 men and 5 women aged from 50 to 67 years old), who had not been ill with shingles before, but had suffered from chickenpox in childhood. Determination of the quantitative content of interleukins (IL), tumor necrosis factor α (TNFa), prostaglandins (PG), thromboxane (TXB2) and matrix metalloproteinase-8 (MMR-8) in blood serum was performed using a solid-phase enzyme immunoassay. Statistical processing of the study results was performed using the Mann-Whitney test and the program Statistica v. 10.0. Results. Clinical manifestation of shingles is accompanied by the increase of concentrations of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNFα), prostanoids (PGE2, PGF2α, 6KPGF1α, TXB2) and matrix proteinase-8 (MMR-8) in blood serum. The degree of change in interleukin and prostaglandin status depends on the severity of shingles, and it is the lowest in its mild course, and the highest in its severe course. In interleukin status of patients with shingles the degree of increased concentrations of proinflammatory cytokines (IL-1β, IL-6, IL-8, TNFα) prevails over the degrees of increasing of cytokines with anti-inflammatory properties (IL-2, IL-4, IL-10). In the acute period of shingles in prostaglandin status of patients, there is an imbalance in the PGE2/PGF2α and 6KPGF1α/TXB2 systems with a predominance of concentrations of PGE2 over PGF2α, and TXB2 over 6KPGF1α in the blood serum. Conclusions. The degree of violation of the interleukin and prostaglandin status of patients with shingles progressively increases as the severity of the disease increases.

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg–maximum ( N = 131 pretreated patients) and placebo ( N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: –8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

Introduction: Induction of labor (IOL) is used to improve the outcome of pregnancy for mother and child. Since 2013, oral misoprostol has been used for IOL at Aarhus University Hospital, Denmark. The purpose of the present paper is to describe our experience of the use of a new, 25-µg misoprostol tablet commercially manufactured for the purpose of IOL regarding efficacy and outcome for mother and neonate in both an inpatient and an outpatient regimen. Material and methods: We performed an audit from 1 April 2016, including data on all IOL in women with singleton pregnancies until 1000 consecutive women were registered. Data from 976 consecutive women with gestational age ≥37+0 weeks induced in accordance with the “Aarhus protocol” were included in the present analyses. All inductions were by oral misoprostol. Outpatient induction is standard procedure in low-risk pregnancies, that is, pregnancies with a healthy mother and no signs of placental insufficiency. In the outpatient IOL, the first dose of misoprostol is administered after a normal cardiotocography registration at the hospital. Subsequent doses are taken at home according to a predefined regimen. Following delivery, data on baseline variables and outcome variables for the mother and neonate were retrieved from the medical records. Results: In 71.9% of cases, the women were induced in an outpatient regimen. Delivery within 24 hours was achieved in 38.8% of women (nulliparous 32.3%, multiparous 50.9%) and within 48 hours in 70.1% (nulliparous 66.2%, multiparous 77.2%). Hyperstimulation during induction occurred in 0.6%. The mode of delivery was spontaneous vaginal in 75.5% of cases. The cesarean section rate was 14.9% (nulliparous 20.7%, multiparous 4.1%). Apgar

Утеротоники широко используются в акушерстве для преиндукции и индукции родов, профилактики и лечения послеродовых кровотечений. Для профилактики послеродовых кровотечений в качестве утеротонических средств используют окситоцин, карбетоцин и мизопростол, а для лечения – окситоцин, эргометрин, синтометрин и мизопростол. При соблюдении принципа активного ведения третьего периода родов профилактическое применение утеротоников на 60% снижает риск послеродовых гипотонических кровотечений. В обзоре приведены современные данные о фармакокинетике, дозах, режимах применения и возможных осложнениях при использовании препаратов окситоцина, аналогов простагландинов Е1 и Е2, алкалоидов спорыньи в акушерской практике. Представлены последние рекомендации Международного консенсуса об использовании утеротоников во время кесарева сечения 2019 г. с учетом различий между потребностями в их дозе при плановом и ургентном кесаревом сечении. Помимо утеротонического действия, окситоцин осуществляет парасимпатическую нейромодуляцию, вызывает вазодилатацию, отрицательные инотропный и хронотропный эффекты, снижает артериальное давление, однако в больших дозах и при быстром введении может оказывать негативное воздействие на плод. Автор подчеркивает, что если введение окситоцина/карбетоцина не дает хорошего тонуса матки, утеротоники второго ряда следует рассматривать по возможности раньше, при этом помня о том, что сочетанное применение окситоцина с эргометрином усиливает риски развития кардиальных осложнений. Введение метилэргометрина может приводить к повышению центрального венозного и артериального давления, в некоторых случаях может спровоцировать ишемию и некроз сердечной мышцы. Мизопростол применяется при преиндукции, индукции родов, а также для профилактики и лечения послеродовых кровотечений вне официальных показаний. При использовании мизопростола увеличивается риск гиперстимуляции матки и учащения сердечных сокращений у плода, повышается температура тела матери. Поэтому залогом эффективности и безопасности применения утеротоников являются правильный способ, доза, путь и скорость введения, учет показаний и противопоказаний, тщательный контроль за состоянием беременной, плода, роженицы и родильницы, соблюдение рекомендуемых условий хранения препаратов.

IMPORTANCE Long-term data are needed regarding effective and safe glaucoma treatment modalities. BACKGROUND This study evaluated 4-year outcomes of second-generation trabecular micro-bypass stent implantation (iStent inject) combined with topical travoprost in open-angle glaucoma (OAG). DESIGN Prospective, non-randomized, multi-surgeon study at a tertiary care ophthalmology centre. PARTICIPANTS OAG subjects with preoperative intraocular pressure (IOP) 18 to 30 mmHg on two medications and 22 to 38 mmHg post-washout. METHODS Subjects (n = 53) underwent standalone iStent inject implantation and started travoprost on postoperative Day 1. Measures included IOP, medications, comprehensive ophthalmic examinations and testing, and adverse events (AEs). Annual medication washouts were performed. MAIN OUTCOME MEASURES Mean medicated and unmedicated IOP; and proportions of eyes with IOP ≤18mmHg, ≤15 mmHg, or ≥20% reduced while on travoprost vs screening IOP on two medications. RESULTS At 48 months postoperative, 85% of eyes reduced IOP ≥20% on travoprost vs screening IOP on 2 medications; 92% of eyes had IOP ≤18 mmHg on travoprost; and 83% had IOP ≤15 mmHg on travoprost. At Month 49 (post-washout), 90% of eyes reduced IOP ≥20% vs preoperative washout IOP. Throughout follow-up, mean IOP on travoprost was 11.9 to 13.0 mmHg (34%-40% reduced vs 19.7 mmHg on 2 medications preoperatively; P

Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naive T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D2 and thromboxane B2, a metabolite of thromboxane A2, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naive T cells in the thymus.

Introduction: Androgenetic alopecia is a common hair loss disorder affecting up to 80% of males by the age of 80. It is characterized by androgen related progressive thinning of hair in a defined pattern. It results in diminished self-esteem, reduced confidence and distress in affected men, irrespective of age or stage of baldness. An effective treatment for hair baldness is needed.Areas covered: In androgenetic alopecia, hair follicles undergo progressive miniaturization. Genetic factors and androgens are key role-players in disease pathogenesis. Herein the authors review the pharmacologic treatment of androgenetic alopecia, which involves 5 alpha reductase inhibitors, minoxidil and prostaglandins. Non-pharmacologic approaches are also explored.Expert opinion: Androgenetic alopecia progresses over time and although the current available medical treatments like finasteride and minoxidil are effective in arresting the progression of the disease, they allow only partial regrowth of hair at its best. Early treatment achieves a more optimal outcome. Non-pharmacologic treatments like PRP can be considered in patients refractory to medical treatment.Abbreviations: MPHL: male pattern hair loss; AGA: androgenetic alopecia; DHT: dihydrotestosterone; 5AR: 5-alpha-reductase; VEGF: vascular endothelial growth factor; PG's: prostaglandins (PG's); PGD2R: prostaglandin D2 receptor; VPA: valproic aid; SR: Serenoa Repens; PRP: platelet-rich plasma; PDGF: platelet derived growth factor; TGF: transforming growth factor; ERK: extracellular signal-regulated kinase; PKB: protein kinase B; LLLT: low-level laser therapy; ROS: reactive oxygen species; RCT: randomized control trial; SFRP1: secreted frizzled related protein 1; DP: dermal papilla; PDE5: phosphodiesterase 5.

Oral mucositis (OM) is a painful condition caused by chemotherapeutic or radiotherapeutic cancer treatments, occurring in patients with different tumour characteristics and locations. OM greatly impacts a patient’s quality of life and cancer recovery. Current OM management strategies are not providing sufficient prevention and treatment; new approaches to injury management are needed. Studies on the benefit of omega-3 free fatty acids (FFA) in human health have increased significantly in recent years. FFA properties have been studied extensively, including their potential therapeutic use in inflammatory conditions. However, omega-3 FFA’s use as a supplementary treatment for OM has not been clinically tested. Preliminary evidence suggests that utilising FFA to manage OM could be a useful strategy for lesion management, assisting with healthy oral mucosa recovery. This review will describe the incidence, risk factors, biology of OM and the current treatment strategies, leading to a discussion of the utility of omega-3 FFA as a novel therapeutic agent for OM.

Background Recently there has been increased interest in a possible association between mast cell activation (MCA) disorder and postural orthostatic tachycardia syndrome (POTS). This study examined the frequency with which symptoms and laboratory findings suggesting MCA disorder occurred in patients diagnosed with POTS. Methods and Results Data were obtained from patients in whom symptoms and orthostatic testing were consistent with a POTS diagnosis. Individuals with Conclusions Laboratory findings suggesting MCA disorder were relatively common in patients diagnosed with POTS and who present with additional nonorthostatic gastrointestinal, cutaneous, and allergic symptoms. While solitary abnormal laboratory findings are not definitive, they favor MCA disorder being considered in such cases.

Simple Summary A article proved that, in rats with PTU-induced hypothyroidism, the E2 level as well as the expression of the uterine-receptivity factors homeobox A10 and osteopontin was decreased. Additionally, we observed changes in the expression of PGE2, PGF2α, and PGI2 signaling pathway elements, and changes in the concentrations of those prostaglandins in uterine tissue. The results suggest that hypothyroidism may interfere with the prostaglandin signaling pathway, which may further result in a reduction in uterine receptivity. Abstract Thyroid hormones control the functions of almost all body systems. Reproductive dysfunctions, such as abnormal sexual development, infertility, or irregularities in the reproductive cycle, might be associated with thyroid disorders. Uterine receptivity is the period when the uterus is receptive to the implantation of an embryo. During the receptivity period (implantation window), a newly formed blastocyst is incorporated into the uterine epithelium. Prostaglandins are well-known primary mediators of pathological conditions such as inflammation and cancer but are also essential for the physiology of female reproduction. The aim of this study was to evaluate the possible relationship between hypothyroidism and changes in the prostaglandin signaling pathways in the uterus and in the process of uterine receptivity in a rat model. The results show that hypothyroidism impaired uterine receptivity by decreasing the level of E2 as well as decreasing the expression of the uterine-receptivity factors homeobox A10 and osteopontin. Moreover, hypothyroidism caused changes in the expression of elements of the prostaglandin E2, F2α, and I2 signaling pathways and changed the levels of those prostaglandins in the uterine tissue. The results suggest that the mechanisms by which hypothyroidism affects female reproductive abnormalities might involve the prostaglandin signaling pathway, resulting in a subsequent reduction in uterine receptivity.

Quercetin is a polyphenolic flavonoid occurring in leaves, stems, flowers and fruits of many plants. In traditional Chinese medicine, it is used as a natural therapeutic agent with a broad spectrum of activities (antioxidant, neuroprotective, anti-inflammatory, anticancer, antibacterial and antiviral). Moreover, quercetin affects function of the reproductive tract, however the knowledge of this activity is still fragmentary. Therefore, this study aimed to determine the influence of quercetin on the contractile activity of the porcine myometrium collected from immature (n = 6), cyclic (n = 6) and early pregnant (n = 6) gilts. Strips of the myometrium (comprising longitudinal and circular layer) were resected from the middle part of the uterine horns and the isometric contractions were recorded. After 60–90 min of preincubation, the strips were stimulated with quercetin in increasing (10−13–10−1 M) concentrations and the changes in the tension amplitude and frequency of contractions were measured. Quercetin decreased (P−11–10−1 M and 10−10–10−1 M in cyclic and early pregnant groups, respectively. The frequency of contractions decreased in all groups but was the highest (at concentrations 10−11–10−1 M; P−5–10−1 M; P−6–10−1 M; P

Although lynxes and domestic cats are both felids, their luteal life cycles differ. As in many species, corpora lutea (CLs) of domestic cats regress after pregnancy or pseudopregnancy. By contrast, CLs of lynxes do not functionally regress following the cycle of their formation. They stay physiologically active and persist for several years. To obtain an improved understanding of the life cycle of both species, we comparatively studied the CLs of these species in detail. In this review, we summarize the similarities and differences of their CLs regarding sex steroid and prostaglandin generation and receptors. The most evident differences were visible in the CLs of lynxes, which persist from previous cycles, compared with CLs of lynxes and domestic cats from the recent luteal cycle. We assume that these differences could indicate processes ensuring long-term luteal survival and functionality, for example, by high estrogen production/metabolism or by antioxidative effects.

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.

Prostacyclins are the mainstay treatment for patients with severe pulmonary arterial hypertension. This case highlights the transition from selexipag to oral treprostinil. Our patient improved both subjectively and objectively. Cardiac output and index, as measured by the echocardiogram, improved 12% and 7.7%, respectively. Invasive hemodynamic data revealed greater improvements: cardiac output improved by 25% and cardiac index by 28%. Mixed venous oxygen saturation improved from 65% to 71%. A possible explanation is that selexipag has a maximal dose, whereas there is no recommended maximum dose of oral treprostinil. Another theory is oral treprostinil has higher affinity to the IP receptor, though selexipag has a higher specificity. However, there are no bio-equivalency data, and data comparing pharmacodynamics of both drugs are lacking. Furthermore, no head-to-head trials comparing these agents exist.

Objective After globally acceptance of planned vaginal birth after cesarean section (VBAC), the mode of induction is still a matter of debate and requires further discussion. We aimed to study obstetric outcomes in post-cesarean patients undergoing induction of labor with prostaglandin gel compared with patients who developed spontaneous labor pains. Methods All patients at 34 weeks or more of gestation with previous one cesarean section eligible for trial of labor after cesarean section admitted in a labor room within one year were divided in 2 groups. Group one consisted of patients who experienced the spontaneous onset of labor pains and group 2 consisted of patients who underwent induction of labor with prostaglandin gel. They were analyzed for maternofetal outcomes. Descriptive statistics, independent sample t-test, and chi-square test were applied using SPSS 20 software for statistical analysis. Results Both groups were comparable in maternal age, parity, and fetal weight, but different in bishop score, mode of delivery, and neonatal outcome. Admisson bishop score was 6.61±2.51 in group 1 and 3.15±1.27 in group 2 (P

Introduction Receptor tyrosine kinases have been implicated in various vascular remodeling processes and cardiovascular disease. However, their role in the regulation of vascular tone is poorly understood. Herein, we evaluate the contribution of c-Kit signaling to vasoactive responses. Methods The vascular reactivity of mesenteric arteries was assessed under isobaric conditions in c-Kit deficient (KitW/W−v) and littermate control mice (Kit+/+) using pressure myography. Protein levels of soluble guanylyl cyclase beta 1 (sGCβ1) were quantified by Western blot. Mean arterial pressure was measured after high salt (8% NaCl) diet treatment using the tail-cuff method. Results Smooth muscle cells (SMCs) from c-Kit deficient mice showed a 5-fold downregulation of sGCβ1 compared to controls. Endothelium-dependent relaxation of mesenteric arteries demonstrated a predominance of prostanoid vs. nitric oxide (NO) signaling in both animal groups. The dependence on prostanoid-induced dilation was higher in c-Kit mutant mice than in controls, as indicated by a significant impairment in vasorelaxation with indomethacin with respect to the latter. Endothelium-independent relaxation showed significant dysfunction of NO signaling in c-Kit deficient SMCs compared to controls. Mesenteric artery dilation was rescued by addition of a cGMP analog, but not with a NO donor, indicating a deficiency in cGMP production in c-Kit deficient SMCs. Finally, c-Kit deficient mice developed higher blood pressure on an 8% NaCl diet compared to their control littermates. Conclusion c-Kit deficiency inhibits NO signaling in SMCs. The existence of this c-Kit/sGC signaling axis may be relevant for vascular reactivity and remodeling.

Renal cell carcinomas (RCC), constitute 80– 85% of primary renal neoplasms. The classic triad of RCC (flank pain, hematuria, and a palpable abdominal renal mass) occurs in approximately 9% of patients; it strongly suggests locally advanced disease. RCC may also be associated with a number of paraneoplastic syndromes. These are typically due to ectopic production of various hormones. We present a 69-year-old male patient previously healthy presented to the emergency department with recurrent persistent cough. A non-metastatic RCC was incidentally discovered. Eventually, he underwent left radical nephrectomy. One year has passed with no cough. This is a rare and unusual presentation of RCC that falls under the category of paraneoplastic syndrome with review of similar reported cases and summary of all paraneoplastic syndromes associated with RCC in literature.

Background : Sixty percent of the mammalian brain is composed of lipids including arachidonic acid (AA). AA released from cell membranes is metabolised in the cyclooxygenase (COX) pathway to prostanoids – biologically active substances involved in the regulation of many processes including inflammation. It has been shown that long-term exposure to fluoride in pre and neonatal period is dangerous because this element is able to penetrate through the placenta and to cross the blood-brain barrier. Exposure to fluoride during the development affects metabolism and physiology of neurons and glia which results in the impairment of cognitive functions but the exact mechanisms of fluoride neurotoxicity are not clearly defined. Objective : The aim of this study was to determine whether exposure to fluoride during the development affects COXes activity and the synthesis of prostanoids. Material and methods : Pre- and postnatal toxicity model in Wistar rats was used. Experimental animals received 50 mg/L of NaF in drinking water ad libitum, while control animals received tap water. In cerebral cortex, hippocampus, cerebellum and striatum were measured fluoride concentration, COX1 and COX2 genes expression, immunolocalization of the enzymatic proteins and concentration of PGE2 and TXB2. Results : of this study showed statistically significant changes in the concentration of fluoride in brain structures between study group and control animals. Moreover, significant changes in the expression level of COX1 and COX2, and in the concentration of PGE2 and TXB2 were observed. Conclusion : Exposure to fluoride in the prenatal and neonatal period result in the increase in COX2 activity and increase in PGE2 concentration in rats brain, which may lead to disturbances in central nervous system homeostasis.‬‬

Objective. The aim of this study was to assess and compare morning vs. midnight initiation of induction of labor (IOL) on time of birth and perinatal outcome.Study Design. A retrospective study performed at University Hospital Merkur, Zagreb, Croatia; in period between 2006 to 2017. The participants were low-risk nulliparous women with gestational age over 41 weeks who had labor induced by a prostaglandin E2 analogue dinoprostone applied intracervically. Two groups were compared; the first one had IOL initiated in the morning and the second one at midnight.Results. A total of 206 pregnant women were included in the study. Women with IOL starting at midnight (n=103) gave birth more often during daytime (7am-6.59pm) compared to women with IOL starting in the morning (n=103) (p

Increased salt (NaCl) consumption triggers chronic diseases such as hypertension or osteopenia. Its impact on orthodontic tooth movement and periodontitis, however, has not been investigated, although both processes are related to the immune system, with periodontal ligament fibroblasts (PDLFs) playing a key mediating role. Here, we investigated the impact of NaCl on the expression pattern of PDLFs in a model of simulated compressive orthodontic strain. Periodontal ligament fibroblasts were preincubated for 24 h with additional 0 or 40 mM NaCl and concurrently treated for another 48 h with or without compressive strain of 2 g cm-2 . We analyzed the expression of genes and proteins involved in orthodontic tooth movement by reverse transcription quantitative polymerase chain reaction (RT-qPCR), ELISA, and immunoblot. Co-culture experiments were performed to observe PDLF-mediated osteoclastogenesis. A higher (40 mM) concentration of NaCl in the culture medium resulted in increased secretion of prostaglandin, expression of alkaline phosphatase, and expression of genes involved in extracellular matrix remodeling, but decreased compression-induced expression of the interleukin-6 (IL6) gene. The 40 mM concentration of NaCl also enhanced receptor activator of nuclear factor kappa-B ligand (RANKL) but reduced that of osteoprotegerin (OPG), resulting in upregulated PDLF-mediated osteoclastogenesis. A high NaCl concentration in the periodontal ligament, corresponding to a high-salt diet in vivo, may influence orthodontic tooth movement and periodontitis through increased secretion of prostaglandins by PDLFs and upregulated PDLF-mediated osteoclastogenesis, possibly accelerating orthodontic tooth movement and propagating periodontitis and periodontal bone loss.

We aimed to analyze whether a diet supplemented with a standard dose of copper (Cu) in the form of nanoparticles, as an alternative to carbonate, exerts beneficial effects within the vasculature and improves the blood antioxidant status. Male Wistar rats were fed for 8 weeks with a diet supplemented with Cu (6.5 mg Cu/kg in the diet) either as nanoparticles (40 nm diameter) or carbonate — the control group. Moreover, a negative control was not supplemented with Cu. At 12 weeks of age, blood samples, internal organs and thoracic aorta were taken for further analysis. Blood antioxidant mechanism was measured together with Cu and Zn. Diet with Cu as nanoparticles resulted in an elevated catalase activity and ferric reducing ability of plasma, however decreased Cu (plasma), and ceruloplasmin (Cp) compared to carbonate. The participation of vasoconstrictor prostanoid was increased, as indomethacin did not modify the acetylcholine (ACh)-induced response. Arteries from Cu nanoparticle and carbonate rats exhibited a reduced maximal contraction to potassium chloride and an increased response to noradrenaline. The endothelium-dependent vasodilation to ACh was enhanced while exogenous NO donor, sodium nitroprusside, did not modify the vascular response. Down-regulation of BKCa channels influenced hyperpolarizing mechanism. The superoxide dismutase and HDL-cholesterol were decreased opposite to an increased lipid hydroperoxides, malondialdehyde, Cu (plasma and liver) and Cp. Despite the increased antioxidant capacity in blood of Cu nanoparticle fed rats, vasoconstrictor prostanoids and NO are involved in vascular regulation.

To evaluate 5-year safety and efficacy of 2 trabecular micro-bypass stents versus prostaglandin as initial stand-alone treatment for newly diagnosed, treatment-naive primary open-angle glaucoma (POAG).Prospective, randomized, controlled, multi-surgeon clinical trial.Enrolled eyes (n = 101) were phakic and had a confirmed POAG diagnosis, normal angle anatomy, mean diurnal intraocular pressure (IOP) 21 to 40 mmHg, and vertical cup-to-disc (C:D) ratio ≤0.9.Eyes were randomized (1:1) to receive either 2 stents (iStent trabecular micro-bypass; Glaukos Corporation, San Clemente, CA) or once-daily topical travoprost.The primary and secondary efficacy end points were the change from screening in mean diurnal IOP at months 12 and 24, respectively, without glaucoma surgery or add-on medication (any medication in stent eyes or a second medication in travoprost eyes). Two additional secondary end points were the proportion of eyes achieving treatment success at months 12 and 24, defined as IOP 6 to 18 mmHg without additional medication or glaucoma surgery. This report shows these efficacy measures through 60 months. Safety measures included best-corrected visual acuity, C:D ratio, visual field, pachymetry, complications, and adverse events.Of 101 enrolled eyes (54 stent eyes, 47 travoprost eyes), 90 eyes (49 stent eyes, 41 travoprost eyes) completed 5-year follow-up. Five-year mean diurnal IOP was 16.5±1.2 mmHg in stent eyes (35.3% reduced vs. 25.5±2.5 mmHg preoperatively; P0.0001) and 16.3±1.9 mmHg in travoprost eyes (35.1% reduced vs. 25.1±4.6 mmHg preoperatively; P0.0001). During follow-up, add-on medication was initiated in 12 stent eyes (22.2% of the initial 54-eyes) and 18 travoprost eyes (38.3% of the initial 47-eyes). By 5 years, 17% (6/35) of stent eyes and 44% (14/32) of travoprost eyes needed add-on medication to control IOP (P = 0.017). Treatment success was achieved in 77% (27/35) of stent eyes and 53% (17/32) of travoprost eyes (P = 0.04). Both groups exhibited excellent safety.This prospective randomized trial demonstrates 5-year effectiveness and safety of 2 trabecular bypass stents in patients with newly diagnosed, treatment-naive POAG, with comparably favorable outcomes as topical prostaglandin.