Michigan Reproductive Medicine

Disrupted gonadotropin-releasing hormone (GnRH) secretion patterns can impair fertility as in polycystic ovary syndrome (PCOS).We used prenatally androgenized (PNA) female mice, which recapitulate neuroendocrine abnormalities observed in PCOS patients, to study how changes in GnRH neuron intrinsic properties during development (prepubertal 3-week-old versus adult females) and with PNA treatment shape their postsynaptic response to GABAergic input. The properties of isolated GABAergic postsynaptic currents in GnRH neurons were used to generate representative model conductances of 1, 2, 5, and 10 nS, with decay time constants representing prepubertal and adult mice (7 vs. 10 ms). These conductances were applied to GnRH neurons from each experimental group using dynamic clamp, and response was measured. Neither development nor PNA altered the response of GnRH neurons to small conductances (1 or 2 nS), and these conductances did not initiate action potentials. In response to the 5 nS conductance, dynamic-clamp-induced postsynaptic potentials were larger in 3-week-old controls versus 3-week-old PNA mice at the 7 ms decay time constant and larger than vehicle-treated (VEH) adults at the 10 ms decay time constant. In response to larger conductances, only seven of 78 GnRH neurons from adults generated action potentials, whereas 14 of 73 GnRH neurons from 3-week-old females did. Interestingly, an altered action potential waveform was observed only in 3-week-old PNA females. The changes in GnRH neuron intrinsic properties occurring with development and PNA treatment result in differential responses to the same physiologic GABA input and may contribute to the action potential firing changes previously reported in this model.

This project aims to model an optimal scanning environment for breast magnetic resonance imaging (MRI) screening based on real-life data to identify to what extent the logistics of breast MRI can be optimized. A novel concept for a breast MRI screening facility was developed considering layout of the building, workflow steps, used resources, and MRI protocols. The envisioned screening facility is person centered and aims for an efficient workflow-oriented design. Real-life data, collected from existing breast MRI screening workflows, during 62 scans in 3 different hospitals, were imported into a 3D simulation software for designing and testing new concepts. The model provided several realistic, virtual, logistical pathways for MRI screening and their outcome measures: throughput, waiting times, and other relevant variables. The total average appointment time in the baseline scenario was 25:54 minutes, with 19:06 minutes of MRI room occupation. Simulated improvements consisted of optimizing processes and resources, facility layout, and scanning protocol. In the simulation, time spent in the MRI room was reduced by introducing an optimized facility layout, dockable tables, and adoption of an abbreviated MRI scanning protocol. The total average appointment time was reduced to 19:36 minutes, and in this scenario, the MRI room was occupied for 06:21 minutes. In the most promising scenario, screening of about 68 people per day (10 hours) on a single MRI scanner could be feasible, compared with 36 people per day in the baseline scenario. This study suggests that by optimizing workflow MRI for breast screening total appointment duration and MRI occupation can be reduced. A throughput of up to 6 people per hour may be achieved, compared with 3 people per hour in the current setup.

In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status, and may under- or overestimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Posttreatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.

It is proposed that the first follicular phase in the lamb is initiated when responsiveness to oestradiol inhibition of LH secretion decreases sufficiently to permit the expression of an inherent hourly LH pulse rhythm. The hourly LH pulse rhythm is believed to drive oestradiol production to levels that induce the first LH surge. This hypothesis is based upon several considerations. First, pulsatile LH secretion invariably occurs at low frequencies in immature lambs whereas hourly pulses are manifest in postpubertal lambs and mature ewes during the follicular phase of the oestrous cycle. Second, intravenous administration of LH at hourly intervals to immature lambs results in an increase in follicular size, induction of an LH surge, ovulation and corpus luteum formation. Third, hourly LH pulses will occur in the immature female if the ovaries are removed; the hourly frequency in the immature ovariectomized lamb can be reduced by exogenous oestradiol. Fourth, in the chronically oestradiol-treated ovariectomized lamb, responsiveness to oestradiol inhibition of LH secretion becomes markedly decreased during the pubertal period, and the hourly LH pulse rhythm is expressed. It is further proposed that a minimum body weight and short daylengths are necessary for the reduction in oestradiol negative feedback. With regard to photoperiod, the delay in onset of cyclicity in lambs born in the wrong season (autumn) may be due to retarded maturation or post-maturational seasonal anoestrus.

Linezolid is an effective and well-tolerated antibiotic for the treatment of Gram-positive infections, including hospital and community-acquired pneumonia and complicated and uncomplicated skin and skin structure infections. In adults linezolid treatment for >/=2 weeks has been associated with reversible hematopoietic suppression, primarily thrombocytopenia. To evaluate the occurrence of hematologic effects in children with Gram-positive infections in an open label study of linezolid vs. vancomycin. Detailed analyses of hematologic data, including reported hematologic adverse events, complete blood counts, reticulocyte index (RI) and iron studies (serum iron and transferrin saturation), were conducted in both groups at baseline and during and after treatment with the use of an intent-to-treat analysis. Three hundred sixteen patients (median age, 1.65 yr) randomized 2:1 to linezolid (n = 215) or vancomycin (n = 101) were treated. Total treatment durations were similar in the vancomycin group (12.2 +/- 6.4 days; median, 11.0 days) and the linezolid group (11.3 +/- 5.0 days; median, 11.0 days) (P = 0.20). No significant differences were noted in drug-related hematologic events, such as thrombocytopenia (linezolid, 1.9% vs. vancomycin, 0%; P = 0.170), anemia (linezolid, 1.4% vs. vancomycin, 1.0%; P = 0.771) or neutropenia (linezolid, 0% vs. vancomycin, 0%). Hemoglobin values also were similar between treatment groups when assessed by shifts from baseline to lowest recorded value. Frequency of occurrence of any substantially abnormal value for hemoglobin (15.7% vs. 12.4%), platelets (12.9% vs. 13.4%) and neutrophils (5.9% vs. 4.3%) were similar in the linezolid and vancomycin groups. No clinically relevant changes in RI or iron studies were noted between treatment groups, and parallel increases in RI occurred with both linezolid and vancomycin. No significant differences in hematologic profiles between linezolid and vancomycin occurred in this pediatric population.

Nosocomial infections, particularly hospital-acquired pneumonia (HAP) and bacteremia, are an increasing concern in pediatric hospitals and pediatric intensive care units. Gram-positive pathogens are a leading cause of these infections in children. Linezolid is well-tolerated and as effective as vancomycin in the treatment of these infections in adults. To evaluate the clinical effectiveness and safety of iv/oral linezolid and iv vancomycin in children with resistant Gram-positive HAP or bacteremia. Hospitalized children <12 years of age were randomized 2:1 to linezolid or vancomycin. Patients received linezolid 10 mg/kg iv every 8 h with the option to change treatment to oral linezolid suspension 10 mg/kg every 8 h or iv vancomycin 10 to 15 mg/kg every 6 to 24 h. Clinical response was evaluated at follow-up. Results from an analysis of patients with HAP or bacteremia are presented. Thirty-nine patients (linezolid, 23; vancomycin, 16) with HAP and 113 patients with bacteremia (linezolid, 81; vancomycin, 32) were included in the intent-to-treat group. Clinical cure rates for clinically evaluable patients with HAP did not differ between treatment groups (linezolid, 90.0% and vancomycin, 100%; P = 0.305). No significant difference was seen in clinical cure rates in the clinically evaluable population between the linezolid and vancomycin groups for patients with catheter-related bacteremia (84.8 and 80.0%, respectively; P = 0.716) or patients with bacteremia of unknown source (79.2 and 69.2%, respectively; P = 0.501). In this subset fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19.4% vs. 28.3%; P = 0.230). Similar percentages of patients with laboratory abnormalities, including selected hematologic parameters, were seen in both treatment groups. Intravenous/oral linezolid was well-tolerated and as effective as vancomycin in treating children with resistant Gram-positive HAP or bacteremia.