Markers of ovarian reserve are associated with reproductive age acceleration in granulosa cells from IVF patients.

STUDY QUESTION: Is reproductive aging in granulosa cells associated with markers of ovarian reserve? SUMMARY ANSWER: Age acceleration was associated with anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), oocyte yield and maturity, and the number of successfully fertilized embryos. WHAT IS KNOWN ALREADY: The rate of reproductive aging varies among women of the same age. DNA methylation can be used to predict epigenetic age in a variety of tissues. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study of 70 women at the time of oocyte retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 70 participants were recruited for this study at an academic medical center and they provided follicular fluid samples at the time of oocyte retrieval. Granulosa cells were isolated and assessed on the MethylationEPIC array. Linear regression was used to evaluate the associations between DNA methylation-based age predictions from granulosa cells and chronological age. Age acceleration was calculated as the residual of regressing DNA methylation-based age on chronological age. Linear regressions were used to determine the associations between age acceleration and markers of ovarian reserve and IVF cycle outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Participants were a mean of 36.7 ± 3.9 years old. In regards to race, 54% were white, 19% were African American and 27% were of another background. Age acceleration was normally distributed and not associated with chronological age. Age acceleration was negatively associated with AMH levels (t = -3.1, P = 0.003) and AFC (t = -4.0, P = 0.0001), such that women with a higher age acceleration had a lower ovarian reserve. Age acceleration was also negatively correlated with the total number of oocytes retrieved (t = -3.9, P = 0.0002), the number of mature oocytes (t = -3.8, P = 0.0003) and the number of fertilized oocytes or two-pronuclear oocytes (t = -2.8, P = 0.008) in the main analysis. LIMITATIONS, REASONS FOR CAUTION: This study used pooled follicular fluid, which does not allow for the investigation of individual follicles. Infertility patients may also be different from the general population, but, as we used granulosa cells, the participants had to be from an IVF population. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that epigenetic age and age acceleration can be calculated from granulosa cells collected at the time of oocyte retrieval. GrimAge most strongly predicted chronological age, and GrimAge acceleration was associated with baseline and cycle characteristics as well as cycle outcomes, which indicates its potential clinical relevance in evaluating both oocyte quantity and quality. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Institutes of Health (UL1TR002378) and the Building Interdisciplinary Research Careers in Women's Health Program (K12HD085850) to A.K.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding source had no role in any aspect of this study. J.B.S. serves as Vice Chair for the American Society for Reproductive Medicine Education Committee, is a Medical Committee Advisor for the Jewish Fertility Foundation and works with Jscreen. J.B.S. has received funding from Georgia Clinical Translational Research Alliance. H.S.H., J.B.S. and A.K.S. have received NIH funding for other projects. A.K.K., S.A.G., S.G., Q.S.K., L.J.M. and W.S. have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Immunodeficiencies.

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

Performance evaluation of a miniature ion mobility spectrometer drift cell for application in hand-held explosives detection ion mobility spectrometers.

The implementation of hand-held ion mobility spectrometers (IMS) requires the development and evaluation of miniature drift cells providing high sensitivity while maintaining reasonable resolution. This manuscript describes the construction of a miniature IMS designed for such an application and its characterization by evaluation of the detection limits and resolution of the system with seven explosive compounds including trinitrotoluene (TNT), cyclotrimethylenetrinitramine (RDX), pentaerythritol tetranitrate (PETN), 2,4,6-trinitrophenyl-N-methylnitramine (Tetryl), nitroglycerin (NG), 2,4-dinitrotoluene (2,4 DNT), and 2,6-dinitrotoluene (2,6 DNT).

Read-noise characterization of focal plane array detectors via mean-variance analysis.

Mean-variance analysis is described as a method for characterization of the read-noise and gain of focal plane array (FPA) detectors, including charge-coupled devices (CCDs), charge-injection devices (CIDs), and complementary metal-oxide-semiconductor (CMOS) multiplexers (infrared arrays). Practical FPA detector characterization is outlined. The nondestructive readout capability available in some CIDs and FPA devices is discussed as a means for signal-to-noise ratio improvement. Derivations of the equations are fully presented to unify understanding of this method by the spectroscopic community.

Frequent false positive beta human chorionic gonadotropin tests in immunoglobulin A deficiency.

A patient with IgA deficiency had a series of positive serum pregnancy tests which led to medical and surgical procedures for suspected molar pregnancy. These tests were found to be falsely positive due to heterophile antibody. The aim of this study was to determine the frequency of false positive betahCG assays in sera of IgA deficient patients. Sera from a panel of IgA deficient (IgA < 7 mg/dl) patients were tested for the presence of betaHCG using three different assays, and also for IgG anti-goat and anti-mouse antibodies. Patients were seen at Mount Sinai Medical Center and included 54 patients (ages 1-80 years, 32 females, 22 males) with IgA deficiency. Thirty percent of 54 IgA deficient patient sera yielded positive pregnancy tests by one or more of the three betahCG assays, however, none of the patients were pregnant. In comparison to sera of normal controls, 39% of the patient sera contained significant amounts of anti-goat antibody and 18% contained significant amounts of anti-mouse antibody. While heterophile antibodies are common in IgA deficient serum, false positive assays for betahCG in IgA deficient serum have not been previously reported. The possibility of false positive test results should be considered prior to invasive procedures in IgA deficient patients.

Benz[f]isoquinoline analogues as high-affinity sigma ligands.

This paper describes the synthesis of some conformationally restricted 4-phenylpiperidine analogues and their affinities for the guinea pig cerebellum sigma recognition site ([3H]-DTG) and the rat striatum dopamine D2 receptor ([3H]-(-)-sulpiride) in order to develop potent selective sigma ligands as tools in the investigation of this site in psychosis. It was found that both hexa- and octahydrobenz[f]isoquinolines with lipophilic N-substituents had high affinities for the sigma site. Notably, trans-3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline (26) had an affinity of 0.25 nM making it the highest affinity sigma ligand reported to date. Moreover, it is at least 10,000-fold selective over the D2 receptor and could prove to be a valuable tool in the study of sigma sites. Other analogues such as 1H-indeno[2,1-c]pyridines and 1H-benzo[3,4]cyclohepta[1,2-c]pyridines also displayed high sigma site affinity.

Spiropiperidines as high-affinity, selective sigma ligands.

A variety of achiral conformationally restricted spirocyclic piperidines have been prepared in an attempt to investigate the functional role of the central sigma recognition site. All the compounds possessed a lipophilic N-substituent incorporating either a tetralin, indan, or benzocycloheptane skeleton. Their in vitro affinity at the sigma site was assessed in radioligand displacement experiments with guinea pig cerebellum homogenates using the sigma-specific radioligand [3H]-N,N'-di-o-tolylguanidine ([3H]-DTG, [3H]-6). A study of the structure-activity relationships identified the N-butyl and N-dimethylallyl substituents as the optimum groups for high affinity and selectivity at the sigma site (e.g., 3,4-dihydro-1'-(3-methylbut-2-enyl)spiro[1H-indene-1,4'-piperidine ] (48), pIC50 = 8.9 vs [3H]-6 and greater than 10,000-fold selective over the dopamine D2 receptor). Such compounds are amongst the highest affinity sigma ligands reported to date, with excellent selectivity over the dopamine D2 receptor, and may serve as a useful tool for exploring the physiological role of the sigma site.