Comparison of intravenous paracetamol infusion versus intramuscular tramadol as labor analgesia: a randomized control trial.

PURPOSE: Labor pain is one of the most agonizing pains experienced by all delivered women. Many pharmacological agents used in labor analgesia require intense monitoring facilities, which are not available in routine obstetric practice in low-resource settings. This study aimed to compare the efficacy of intravenous (IV) paracetamol and intramuscular (IM) tramadol on labor pain relief, labor progression, and maternal and neonatal outcomes. METHODS: This randomized drug trial was carried out on 110 women divided into two groups. Group A women received 1000 mg of IV paracetamol, and Group B women received 100 mg of IM tramadol during the active phase of labor. Pain intensity was assessed by the Visual Analogue Scale (VAS) at intervals till 120 min of delivery. The maternal and neonatal outcomes were recorded. RESULTS: There was a statistically significant fall in pain score till 180 min of drug administration in the paracetamol group and 120 min in the tramadol group. At 180 min and 240 min, paracetamol is more effective than tramadol (p value 0.004 at 180 min and 0.0119 at 240 min). There were significantly low pain score levels at 60 min of delivery in the paracetamol group (p value-0.004). Nausea and vomiting were significantly higher in the tramadol group (p value 0.000013). CONCLUSION: Compared to IM tramadol, IV paracetamol has a longer duration of action and fewer maternal side effects, making it suitable for parenteral analgesia in labor. Due to a better safety profile, there is no need for intense maternal and fetal monitoring with IV paracetamol. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI registration number-CTRI /2019/05/019244).

Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF. METHODS AND RESULTS: Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness. CONCLUSIONS: Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.

The impact of patient sex on the response to intramyocardial mesenchymal stem cell administration in patients with non-ischaemic dilated cardiomyopathy.

AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups. CONCLUSION: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.

EEG Spectral Features in Sleep of Autism Spectrum Disorders in Children with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a multisystem disorder with increased prevalence of autism spectrum disorders (ASDs). This project aimed to characterize the autism phenotype of TSC and identify biomarkers of risk for ASD. Because abnormalities of EEG during sleep are tied to neurodevelopment in children, we compared electroencephalographic (EEG) measures during Stage II sleep in TSC children who either did (ASD+) or did not (ASD-) exhibit symptoms of ASD over 36-month follow up. Relative alpha band power was significantly elevated in the ASD+ group at 24 months of age with smaller differences at younger ages, suggesting this may arise from differences in brain development. These findings suggest that EEG features could enhance the detection of risk for ASD.

Pexy of intraperitoneal LVAD driveline to relieve small bowel obstruction.

BACKGROUND: Left ventricular assist device (LVAD) implantation is a lifesaving intervention in advanced heart failure. However, LVAD is not without complication. In this case, an inadvertent intraperitoneal driveline caused small bowel obstruction, subsequently requiring pexy of the driveline to the abdominal wall to avoid future complications. CASE PRESENTATION: A 37-year-old male with worsening, nonischemic, dilated cardiomyopathy underwent LVAD implantation. Postoperative day (POD) 15 he developed small bowel obstruction, and abdominal exploration showed transition point at an inadvertently placed intraperitoneal LVAD driveline. The patient was LVAD-dependent precluding removal, so the driveline was secured to the anterior abdominal wall. He subsequently improved and was discharged. CONCLUSIONS: While LVAD is increasingly common for heart failure patients, the tunneled driveline may inadvertently enter the peritoneal cavity where it can cause significant morbidity. In this case, we propose securing the driveline to the abdominal wall to prevent complications when LVAD removal is not an option.

Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions.

Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products.

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done. METHODS AND RESULTS: We conducted a subanalysis of 3 single-center, randomized, and blinded clinical trials: (1) TAC-HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1-year cardiac structure and function and quality-of-life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within-group, P=0.002) compared to ICM (1.5%; within-group, P=0.14; between-group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (-0.2 mL; P=0.73; between-group, P=0.02). End-diastolic volume improved only in ICM (10.6 mL; P=0.04) and end-systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (-0.04; P=0.0002). End-diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (-4.1 g; P=0.34; between-group, P=0.007). The 6-minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between-group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between-group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (-19.5; P=0.002) and ICM (-6.4; P=0.03; δ between-group difference P=0.042) patients. CONCLUSIONS: Mesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: TAC-HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON-DCM: NCT01392625.

A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration.

BACKGROUND: The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES: This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS: Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS: Both ACCT and allo-MSCs reduced scar size by -11.1 ± 4.8% (p = 0.012) and -9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS: ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study).

RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07). CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Granular cell tumor of the stellate ganglion presenting with Horner's syndrome.

We report a granular cell tumor (GCT) that occurred within the stellate ganglion of a 26-year-old woman who initially presented with a unilateral Horner's syndrome and progressive right upper extremity pain. We also review the literature related to the differential diagnoses of such a cervicothoracic tumor, with particular emphasis on the embryologic origin of these possibilities. GCT are rare tumors of Schwann cell origin which are more often found in subcutaneous locations than in relation to neural elements. In this woman, a mass identified on preoperative imaging was positioned anterolateral to the T1 vertebral body and displaced the vertebral artery anteriorly. During surgery, the lesion was observed within the sympathetic chain in the area of the stellate ganglion. The sympathetic chain was transected above and below the mass in order to achieve an adequate resection. The pathology demonstrated polygonal cells with diffuse eosinophilic granular cytoplasm positive for CD68 (a marker of lysosomes) and S-100 (a marker of neural crest derivatives) which established the diagnosis of GCT. This is the first patient, to our knowledge, with a granular cell tumor arising from the stellate ganglion.

Molecular structure, vibrational analysis (FT-IR, FT-Raman), NMR, UV, NBO and HOMO-LUMO analysis of N,N-Diphenyl Formamide based on DFT calculations.

In this work, the vibrational spectral analysis is carried out by using Raman and infrared spectroscopy in the range 4000-400 cm(-1) and 4000-50 cm(-1) respectively for N,N-Diphenyl Formamide (DPF) molecule. The optimized molecular structures, vibrational frequencies and corresponding vibrational assignments, nuclear magnetic resonance (NMR) and ultraviolet-visible (UV-VIS) spectra of the title molecule are evaluated using density functional theory (DFT) with standard B3LYP/6-31G(d,p) basis set. The harmonic vibrational frequencies are calculated and the scaled values have been compared with experimental FT-IR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The stability of the molecule arising from hyper conjugative interactions and the charge delocalization has been analyzed using natural bond (NBO) analysis. The possible electronic transitions are determined by HOMO-LUMO orbital shapes and their energies. Thermodynamic properties (heat capacity, entropy and enthalpy) and the first hyperpolarizability of the title compound are calculated. The Mulliken charges and electric dipole moment of the molecule are computed using DFT calculations. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shift of the molecules are calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results.

Impact of medication and psychological behaviour assessment by community pharmacists in type 2 diabetes mellitus patients after hospital stay.

BACKGROUND: Drug related problem (DRPs) is a key factor which will affect the outcome of therapy and safety. OBJECTIVE: To assess the DRPs in type 2 diabetes mellitus (T2DM) patients and psychological aspects of patients by community pharmacists to observe the rate of DRP. METHODS: Prospective randomized controlled intervention study involved T2DM patients and conducted in two community pharmacies at Kanpur from January 2012 to December 2012. The assessment of DRPs was based on the PCNE. Changes in glycosylated hemoglobin (HBA1c), low density lipoproteins (LDL), blood pressure(BP), foot examinations, changes medical and medication utilization were studied. Using as control group, received usual care, and interventional group provided, intervened with use of the standard treatment guidelines (STG). Researcher provided the knowledge to community pharmacists and patients. Baseline and interventional data were collected at 0,3,6,9 and 12 months. RESULTS: Over the 12 month study, participants' average HBA1C reduced from 8.9% at initial visit to 7.5%. During this time, the eye examination rate was raised from 31% to 48%, and the foot examination rate was raised from 35% to 50%. CONCLUSION: The intervention of pharmacists showed little influence on any of the intermediate health outcomes in T2DM.

Acute appendicitis: a disease severity score for the acute care surgeon.

BACKGROUND: Analogous to organ injury scales developed for trauma, a scoring system is needed for acute care surgery. The purpose of this study was to develop a disease severity score (DSS) for acute appendicitis, the most common surgical emergency. METHODS: A panel of acute care surgery experts reviewed the literature and developed a DSS for acute appendicitis as follows: grade 1, inflamed; Grade 2, gangrenous; Grade 3, perforated with localized free fluid; Grade 4, perforated with a regional abscess; and Grade 5, perforated with diffuse peritonitis. We applied the DSS to 1,000 consecutive patients undergoing appendectomy from 1999 to 2009 and examined its association with outcomes (mortality, length of hospital stay, incidence of in-hospital, and postdischarge complications). Of the 1,000 patients, 82 were excluded owing to negative or interval appendectomy or advanced end-stage renal disease. RESULTS: Among 918 eligible patients, the DSS distribution was Grade 1 at 62.4%, Grade 2 at 13.0%, Grade 3 at 18.7%, Grade 4 at 4.4%, and Grade 5 at 1.5%. Statistical analyses indicated a stepwise risk increase in adverse outcomes with higher DSS grades (c statistics ≥ 0.75 for all outcomes). Covariates (age, sex, and type of surgical access) did not add to the predictive power of DSS. CONCLUSION: Based on this single-institution study, the proposed appendicitis DSS seems to be a useful tool. This DSS can inform future, national efforts, which can build on the knowledge provided by the present investigation. This DSS may be useful for comparing therapeutic modalities, planning resource use, improving programs, and adjusting reimbursement LEVEL OF EVIDENCE: Epidemiologic study, level III.

Ammonia-oxidizing archaea and nitrite-oxidizing nitrospiras in the biofilter of a shrimp recirculating aquaculture system.

This study analysed the nitrifier community in the biofilter of a zero discharge, recirculating aquaculture system (RAS) for the production of marine shrimp in a low density (low ammonium production) system. The ammonia-oxidizing populations were examined by targeting 16S rRNA and amoA genes of ammonia-oxidizing bacteria (AOB) and archaea (AOA). The nitrite-oxidizing bacteria (NOB) were investigated by targeting the 16S rRNA gene. Archaeal amoA genes were more abundant in all compartments of the RAS than bacterial amoA genes. Analysis of bacterial and archaeal amoA gene sequences revealed that most ammonia oxidizers were related to Nitrosomonas marina and Nitrosopumilus maritimus. The NOB detected were related to Nitrospira marina and Nitrospira moscoviensis, and Nitrospira marina-type NOB were more abundant than N. moscoviensis-type NOB. Water quality and biofilm attachment media played a role in the competitiveness of AOA over AOB and Nitrospira marina-over N. moscoviensis-type NOB.

Antagonistic properties of seagrass associated Streptomyces sp. RAUACT-1: a source for anthraquinone rich compound.

OBJECTIVE: To identify the antibacterial potential of seagrass (Syringodium isoetifolium) associate microbes against bacterial pathogens. METHODS: Eumeration of microbial associates were analyzed with leaf and root samples of Syringodium isoetifolium. MIC and MBC were calculated for bacterial pathogens with microbial associates. Phylogenetic and GC-MS analysis were calculated for Actinomycetes sp. (Act01) which was the most potent. RESULTS: Of the isolated microbial associates phosphatase producing bacterial isolates were identified as maximum [(261.78±35.09) CFU×10(4)/g] counts in root sample. Of the selected microbial isolates Actinomycete sp (Act01) showed broad spectrum of antibacterial activity against antibiotic resistant and fish bacterial pathogens. Phylogenetic analysis of Act01 showed maximum identities (99%) with the Streptomyces sp. (GU5500072). The 16s rDNA secondary structure of Act01 showed the free energy values as -366.3 kkal/mol. The GC-MS analysis Act01 showed maximum retention value with 23.742 RT and the corresponding chemical class was identified as 1, 4-dihydroxy-2-(3-hydroxybutyl)-9, 10-anthraquinone 9, 10-anthrac. CONCLUSIONS: In conclusion, Streptomyces sp. (GU045544.1) from Syringodium isoetifolium could be used as potential antibacterial agent.

Age at menarche and parity are independently associated with Anti-Müllerian hormone, a marker of ovarian reserve, in Filipino young adult women.

OBJECTIVES: Despite ample evidence of variation in timing of menopause, little is known about the extent or underlying causes of individual variation in ovarian reserve and age-related follicular decline. Anti-Müllerian hormone (AMH), a hormonal marker of ovarian reserve, may be a useful tool to clarify these questions. We describe AMH in a cohort of Filipino young adult women, and evaluate whether ovarian reserve in early adulthood relates to measures of life history scheduling (menarcheal age) and reproductive effort (parity). METHODS: Data and samples are obtained from 294 nonpregnant participants (21.5 years ± 0.3) in the Cebu Longitudinal Health and Nutrition Survey. Plasma AMH was assayed using an enzyme immunoassay and relationships between AMH, menarcheal age, and parity were examined. RESULTS: Mean AMH was 4.3 ng/mL. In multiple regression models, women who experienced menarche earlier had significantly higher AMH as young adults (P < 0.05). Women with two (P < 0.05) and three or more (P < 0.01) children had significantly lower AMH than those with no children. These associations were independent of age, smoking, and body mass index. CONCLUSIONS: These findings suggest that individual variation in life history scheduling and reproductive history could contribute to variation in ovarian reserve. Moreover, they demonstrate the utility of AMH as a tool for human reproductive ecology, and highlight the need for further research clarifying the extent of human population variation in ovarian reserve and the behavioral and ecological influences underlying this variation.

The role of estrogen receptor α and ß in regulating vascular smooth muscle cell proliferation is based on sex.

BACKGROUND: We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) in mediating proliferation in male and female VSMC. MATERIALS AND METHODS: Proliferation was assessed in primary rat aortic male and female VSMC using (3)H-thymidine incorporation in the presence or absence of ER alpha (α) inhibitor methyl-piperidino-pyrazole, the ER beta (ß) inhibitor (R,R)-5,11-Diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol, the combined ERαß inhibitor ICI 182,780, and/or the NO donor DETA/NO. Proliferation was also assessed in primary aortic mouse VSMC harvested from wildtype (WT), ERα knockout (ERα KO), and ERß knockout (ERß KO) mice in the presence or absence of DETA/NO and the ERα, ERß, and ERαß inhibitors. Protein levels were assessed using Western blot analysis. RESULTS: Protein expression of ERα and ERß was present and equal in male and female VSMC, and did not change after exposure to NO. Inhibition of either ERα or ERß had no effect on VSMC proliferation in the presence or absence of NO in either sex. However, inhibition of ERαß in rat VSMC mitigated NO-mediated inhibition in female but not male VSMC (P < 0.05). Evaluation of proliferation in the knockout mice revealed distinct patterns. Male ERαKO and ERßKO VSMC proliferated faster than male WT VSMC (P < 0.05). Female ERßKO proliferated faster than female WT VSMC (P < 0.05), but female ERαKO VSMC proliferated slower than female WT VSMC (P < 0.05). Last, we evaluated the effect of combined inhibition of ERα and ERß in these knockout strains. Combined ERαß inhibition abrogated NO-mediated inhibition of VSMC proliferation in female WT and knockout VSMC (P < 0.05), but not in male VSMC. CONCLUSIONS: These data clearly demonstrate a role for the ER in mediating VSMC proliferation in both sexes. However, these data suggest that the antiproliferative effects of NO may be regulated by the ER in females but not males.

Adventitial contributions of the extracellular signal-regulated kinase and Akt pathways to neointimal hyperplasia.

BACKGROUND: We recently reported that the efficacy of nitric oxide (NO) appears to be based on both sex and hormone status. The mechanism responsible for this differential efficacy is unknown. The aim of this study was to characterize the effect of sex, hormones, and NO on the extracellular signal-regulated kinase (ERK) and Akt signaling pathways after arterial injury. METHODS: Male and female Sprague-Dawley rats underwent castration or sham surgery. Two weeks later, they underwent carotid artery balloon injury. Treatment groups included the following: control, injury, and injury + 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO) (n = 5 per group). Arteries were harvested 2 weeks after injury and assessed for phospho-ERK (pERK) and phospho-Akt (pAkt) expression. RESULTS: After injury, more pERK and pAkt activity was seen in the adventitia than media in both sexes, regardless of hormone status (P < .05). In hormonally intact males, NO further increased pERK (44%) and pAkt (120%) after injury (P < .001). Castration attenuated the effects of NO. In hormonally intact females, NO caused the opposite pattern with pERK activity but did not affect pAkt activity. CONCLUSIONS: After arterial injury, ERK and Akt activity is significantly greater in the adventitia than the media, and depends on sex, hormone status, and NO. Understanding adventitial regulation of proliferative signaling pathways will allow the development of targeted therapies for neointimal hyperplasia.

FUS (16p11) gene rearrangement as detected by fluorescence in-situ hybridization in cutaneous low-grade fibromyxoid sarcoma: a potential diagnostic tool.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare, typically deep-seated soft tissue neoplasm with deceptively bland cytology and metastatic potential. A t(7;16)(q34;p11) translocation, yielding a FUS/CREB3L2 fusion gene, has been identified in approximately 80%-90% of deep soft tissue LGFMS. Cutaneous fibromyxoid neoplasms occur not infrequently; dermatopathologists rarely consider LGFMS in the differential diagnosis, as this lesion is uncommon in the skin. We identified a group of superficial LGFMS and a spectrum of other cutaneous fibromyxoid neoplasms and performed fluorescence in situ hybridization (FISH) to assess the frequency of FUS rearrangement. FISH for the chromosomal rearrangement of FUS (16p11), using a dual-color, break-apart probe (Abbott Molecular/Vysis, Des Plaines, IL), was performed on formalin-fixed paraffin-embedded tissue sections from superficial LGFMS (n = 6), myxomas (n = 10), and myxofibrosarcoma/myxoid malignant fibrous histiocytomas (myxoid MFH) (n = 5). One hundred nonoverlapping tumor nuclei per case were evaluated for either fused (normal) or split (translocated) signals. Of the LGFMS, 4 of 6 (67%) showed a rearrangement of FUS (range: 72%-80% positive nuclei per 100 nuclei). The other neoplasms within the differential diagnosis were devoid of any rearrangement involving FUS (range: 0%-2% positive nuclei per 100 nuclei). Our observed frequency of FUS rearrangement in superficial LGFMS is consistent with those published in the literature for more deeply seated lesions. When applied to suspicious superficial myxoid or fibromyxoid neoplasms, the FUS FISH probe in formalin-fixed paraffin-embedded tissue can be a useful ancillary technique for diagnosis of this uncommon and deceptively bland tumor.