Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone

Plasma LH is commonly elevated in women with the polycystic ovary syndrome (PCOS), but the underlying mechanisms are uncertain. We tested the hypothesis that the elevated LH in part reflects a reduced sensitivity of the hypothalamic GnRH pulse generator to suppression by estradiol (E2) and progesterone (P). In an initial protocol, normal controls (beginning on cycle days 8-10) and women with PCOS were given E2 transdermally and P by vaginal suppository (three times daily), to achieve plasma concentrations similar to those in the midluteal phase of an ovulatory cycle, for 21 days. Blood was obtained at 10-min intervals for 12 h before and on days 5, 10, 20, and 28 (7 days after E2 and P were discontinued). LH pulse amplitude and LH pulse frequency were suppressed in both PCOS and normal controls, but LH pulse frequency fell more rapidly in controls and was lower by day 10 (P < 0.05). Based on this time course a dose-response study was performed, in which E2 in constant dosage and varying concentrations of P were administered for 7 days. Pulsatile LH release was appraised on days 1 and 7. The frequency of LH pulse secretion was reduced in controls and was lower than that in patients with PCOS on day 7 (P < 0.0001). Plasma P concentrations of 13-15 ng/mL suppressed LH pulse frequency to a similar degree in PCOS and controls. In contrast, lower concentrations (P < 10 ng/mL) were more effective in suppressing GnRH/LH pulse frequency in controls (by > 45% of basal) than in PCOS (< 40%; P < 0.01). The data indicate that E2 and P can inhibit the activity of the hypothalamic GnRH pulse generator in women with PCOS. However, higher plasma concentrations of P were required to reduce GnRH/LH pulse frequency in PCOS compared to controls, suggesting an insensitivity of the GnRH pulse generator to suppression by E2 and P. These results suggest that an abnormality in the regulation of hypothalamic GnRH secretion is present in PCOS and may be a factor in the etiology of the disorder in adolescence.     

A survey of current clinical practice of permanent prostate brachytherapy in the United States

PURPOSE: To help establish standards of care for transperineal interstitial permanent prostate brachytherapy (TIPPB) by obtaining data regarding current clinical practice among the most experienced TIPPB brachytherapists in the United States. METHODS AND MATERIALS: The 70 brachytherapists who performed the greatest number of TIPPB cases in 1995 in the U.S. were surveyed. Each received a comprehensive four page questionnaire that included sections on training and experience, patient and isotope selection criteria, manpower, technique, and follow-up. Thirty-five (50%) surveys were ultimately returned after three mailings and follow-up phone calls. The cumulative experience of the 35 respondents represented approximately 45% of the total TIPPB volume in the U.S. for 1995. Respondents included 29 from the private sector and six from academic programs. RESULTS: The median physician experience with TIPPB was reported as 4.9 years. Each performed an average of 73 TIPPB procedures in 1995 (range 40-300). This represented an increase in volume for most (74%) of the respondents. Sixty-three percent of the respondents attended a formal training course, 54% had TIPPB-specific residency training, and 31% had been proctored (16 had received two or more types of training experience). The most commonly reported selection criteria for implant alone was on Gleason score < or = 7, PSA < 15, < or = Stage T2a, and gland size < or = 60 cc, although no clear consensus was found. Fifty-four percent considered a history of TURP to be a relative contraindication, while 34% considered TURP to have no impact on patient selection. Eighty-six percent of respondents combine brachytherapy with external beam radiation in an average of 32% of their patients. Boosts were given with both 125I prescribed to 120 Gy (75%) or 103Pd to 90 Gy (50%). Sixty percent reported using a Mick applicator, 46% prefer using preloaded needles, and (11%) use both techniques. Real-time imaging was usually performed with ultrasound (94%); most included fluoroscopy (60%). Definitions of PSA control varied widely. CONCLUSIONS: TIPPB clinical practice in the U.S. demonstrates similarities in technique, but differences in patient selection and definitions of biochemical control. It is, therefore, incumbent on those beginning TIPPB programs to carefully review the specific practice details of those institutions with a broad experience.     

Cloning of zebrafish neurofilament cDNAs for plasticin and gefiltin: increased mRNA expression in ganglion cells after optic nerve injury

During retinal growth and optic axon regeneration, the differential expression of the neuronal intermediate filament proteins, plasticin and gefiltin, in the goldfish visual pathway suggests that these proteins support programmed axonal growth. To investigate plasticin and gefiltin during axonogenesis, we turned to the zebrafish, a system that is more amenable to mutational analysis. As a first step, we demonstrated that the intermediate filament compositions of goldfish and zebrafish are similar. In addition, the cDNAs for zebrafish plasticin and gefiltin were cloned and characterized. Using in situ hybridization in retina, we show increased mRNA levels for these proteins following optic nerve crush. Zebrafish plasticin and gefiltin peak and return to baseline levels of expression more rapidly than in goldfish. Furthermore, in the unoperated eye of experimental fish, there was a moderate increase in the levels of plasticin and gefiltin mRNA, suggesting that soluble factors influence the expression of these proteins. The successive expression of plasticin and gefiltin suggests that these neuronal intermediate filament proteins are integral components of axonogenesis. The cloning and characterization of cDNAs for plasticin and gefiltin permit mutational analyses of these proteins during zebrafish axonogenesis.     

10 Gbit/s transmission over 50 km nonzero dispersion-shifted fibreusing 1.3 μm directly modulated uncooled transmitters

A 1.3 μm uncooled transmitter with wide-open eye diagrams at laser temperatures of 20, 50, and 85°C is presented. Using this transmitter, it is demonstrated that 10 Gbit/s transmission is possible over a 50 km nonzero dispersion-shifted Lucent TrueWave-RS fibre. This result is compared with transmission over a 55 km standard singlemode fibre     

Spatially resolved protein hydrogen exchange measured by matrix-assisted laser desorption ionization in-source decay

Mass spectrometry has become a powerful tool for measuring protein hydrogen exchange and thereby reveal the structural dynamics of proteins in solution. Here we describe the successful application of a matrix-assisted laser desorption ionization (MALDI) mass spectrometry approach based on in-source decay (ISD) to measure spatially resolved amide backbone hydrogen exchange. By irradiating deuterated protein molecules in a crystalline matrix with a high laser fluence, they undergo prompt fragmentation. Spatially resolved deuteration levels are readily obtained by mass analysis of consecutive fragment ions. MALDI ISD analysis of deuterated cytochrome c yielded an extensive series of c-fragment ions which originate from cleavage of nearly all N-C(α) bonds (Cys17 to Glu104) allowing for a detailed analysis of the deuterium content of the backbone amides. While hydrogen scrambling can be major concern when using mass spectrometric fragmentation to obtain detailed information on protein hydrogen exchange, we show that the level of hydrogen scrambling in our MALDI ISD measurements is negligible and that the known dynamic behavior of cytochrome c in solution is accurately reflected in the deuterium contents of the fragment ions. The developed method combines several attractive features from a practical point of view as it is simple to perform and it readily provides a detailed mapping of the dynamic structure of a protein in solution.     

Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response,Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.     

From Single Molecules to Thin Film Electronics,Nanofibers, e‐Textiles and Power Cables: Bridging Length Scales with Organic Semiconductors

Organic semiconductors are the centerpiece of several vibrant research fields from single‐molecule to organic electronics, and they are finding increasing use in bioelectronics and even classical polymer technology. The versatile chemistry and broad range of electronic functionalities of conjugated materials enable the bridging of length scales 15 orders of magnitude apart, ranging from a single nanometer (10^?9 m) to the size of continents (10⁶ m). This work provides a taste of the diverse applications that can be realized with organic semiconductors. The reader will embark on a journey from single molecular junctions to thin film organic electronics, supramolecular assemblies, biomaterials such as amyloid fibrils and nanofibrillated cellulose, conducting fibers and yarns for e‐textiles, and finally to power cables that shuffle power across thousands of kilometers.     

The production of interleukin-1 alpha immunoreactivity by human oviductal cells in a coculture system

PURPOSE: The aim of this study was to determine the concentration of interleukin-1 alpha in human embryo culture medium with or without oviductal cell coculture and to correlate the interleukin-1 alpha levels with pregnancy. METHODS: Culture media from 32 in vitro fertilization and embryo transfer cycles were assayed for interleukin-1 alpha by immunoassay technique. Human embryos were cultured in Earles' balanced salt solution supplemented with 15% preovulatory serum (sEBSS) in 16 of these cycles, while embryos in the rest of the cycles were cocultured with human oviductal cells in sEBSS. RESULTS: Both sEBSS and spent sEBSS after embryo culture contained low or undetectable levels of interleukin-1 alpha in the pregnant and nonpregnant cycles. On the other hand, oviductal cells significantly increased the amount of interleukin-1 alpha immunoreactivity in the conventional culture medium or coculture medium (P < 0.001, Mann-Whitney rank sum test). The concentrations of interleukin-1 alpha in the spent sEBSS after oviductal cell culture and after coculture with human embryos were 1.5 +/- 1.0 and 1.3 +/- 0.9 pg/ml, respectively. There was no difference in the interleukin-1 alpha concentration between the pregnant and the nonpregnant coculture cycles. CONCLUSIONS: These data showed that human oviductal cells produced interleukin-1 alpha immunoreactivity in a coculture system. However, this production could not be used as a marker for successful embryo implantation.