Safety and acceptability of intravaginal rings releasing estradiol and progesterone.

OBJECTIVE: This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17ß-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause. DESIGN: DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 µg/day E2 + 4 mg/day P4 (IVR1) or 160 µg/day E2 + 8 mg/day P4 (IVR2) compared with oral E2 1 mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment emergent adverse events (TEAEs). To determine acceptability, at the end of treatment IVR users completed a questionnaire assessing tolerability and usability. RESULTS: Enrolled women (n = 34) were randomized to use IVR1 (n = 10), IVR2 (n = 12) or oral (n = 12). Thirty-one participants (IVR1 = 10, IVR2 = 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups were similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4 mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4 mm at screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable. CONCLUSIONS: Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.

Description and comparison of brain distribution of oxytocin receptors in Rhabdomys pumillio and Rhabdomys dilectus.

Oxytocin receptor (OXTR) distribution in the brain has been associated with different reproductive and social strategies of species. Rhabdomys pumilio (R. pumilio) and Rhabdomys dilectus (R. dilectus) are two sister rodent species that live in large/medium (but flexible) or small (mostly solitary) social groups respectively. In this study, we describe and compare the distribution of OXTR in these two species. OXTR binding in the brain of R. pumilio (8 females and 5 males) and R. dilectus (8 females and 5 males) adults was determined using autoradiography. Our results revealed significant differences in the nucleus accumbens, diagonal band, medial preoptic area, lateral habenula, superior colliculus, periaqueductal area and anterior paraventricular nucleus (higher in R. dilectus), and the dorsal lateral septum and anterior bed nucleus of the stria terminalis (higher in R. pumilio). OXTR density in other brain regions, such as the amygdala nuclei and hippocampus, did not differ between the two species. Sex differences were found in the medial preoptic area and ventral region of the lateral septum in R. pumilio (OXTR density higher in males) and in the anterior paraventricular thalamic nucleus, ventromedial nucleus of the hypothalamus and basolateral amygdala of R. dilectus (OXTR density higher in females). A sex difference in the density of OXTR was also found in the posterior region of the bed nucleus of the stria terminalis, where it was higher in males than in females of both species. This study shows species-specific brain distribution of OXTR in R. pumilio and R. dilectus that are unique, but with similarities with other polygynous or promiscuous rodent species that live in variable size groups, such as R. norvergicus, C. sociabilis, S. teguina and M. musculus.

WHY WOULDN'T I JOIN IMS?.

in January, I had the pleasure of speaking at the annual meeting of the Scott County Medical Society (SMCS), my home county and local medical society. It was great to see colleagues and friends I've known for many years, but equally nice was meeting new physicians and their spouses. Several physicians, including one of my partners, were honored for 25 consecutive years of commitment and service to SCMS. In another time, a continuous 25 year commitment to organized medicine was common; not only was membership a way to stay connected and involved in the medical community, it was a privilege of our profession. Times have changed and many physicians no longer feel that sense of professional responsibility to organized medicine. I can't help but ponder the impact on our medical society - both at the state and county levels - the cost to our profession, and the reasons behind the apathy.

Development of temperature correction equations for bioelectrical impedance analysis models for brook trout Salvelinus fontinalis.

The objective of this study was to establish the relationships between bioelectrical impedance analysis (BIA) measures (resistance and reactance) and temperature and to determine if corrections improve BIA models for brook trout Salvelinus fontinalis when used over a wide range of temperatures. Both resistance and reactance significantly decreased as temperature increased. Application of temperature corrections to BIA models attempting to predict per cent dry mass reduced root-mean-squared error by an average of 32%. Researchers taking BIA measures on fishes in the field where temperature varies will need to correct resistance and reactance to the temperature at which the BIA model was developed for successful predictions of per cent dry mass to be possible. This study presents a clear description of methods that can be used to developed temperature correction equations so that future researchers can use BIA in any field setting and increase the accuracy of BIA-based estimates of per cent dry mass.

Viral hemorrhagic septicemia IVb status in the United States: inferences from surveillance activities and regional context.

The United States (U.S.) response to viral hemorrhagic septicemia virus (VHSV) IVb emergence in the Laurentian Great Lakes (GL) included risk-based surveillance for cost-effective decision support regarding the health of fish populations in open systems. All U.S. VHSV IVb isolations to date derive from free-ranging fish from GL States. Most originate in the region designated by US Geological Survey hydrologic unit code (HUC) 04, with the exception of two detections in neighboring Upper Mississippi (HUC 05) and Ohio (HUC 07) regions. For States outside the GL system, disease probability was assessed using multiple evidence sources. None substantiated VHSV IVb absence using surveillance alone, in part due to the limited temporal relevance of data in open systems. However, Bayesian odds risk-based analysis of surveillance and population context, coupled with exclusions where water temperatures likely preclude viral replication, achieved VHSV IVb freedom assurance for 14 non-GL States by the end of 2012, with partial evidence obtained for another 17 States. The non-GL region (defined as the aggregate of 4-digit HUCs located outside of GL States) met disease freedom targets for 2012 and is projected to maintain this status through 2016 without additional active surveillance. Projections hinge on continued basic biosecurity conditions such as movement restrictions and passive surveillance. Areas with navigable waterway connections to VHSV IVb-affected HUCs (and conducive water temperatures) should receive priority for resources in future surveillance or capacity building efforts. However, 6 years of absence of detections in non-GL States suggests that existing controls limit pathogen spread, and that even spread via natural pathways (e.g., water movement or migratory fish) appears contained to the Great Lakes system. This report exemplifies the cost-effective use of risk-based surveillance in decision support to assess and manage aquatic animal population health in open systems.

Low intensity conduction states in FeS2: implications for absorption, open-circuit voltage and surface recombination.

Pyrite (FeS2), being a promising material for future solar technologies, has so far exhibited in experiments an open-circuit voltage (OCV) of around 0.2 V, which is much lower than the frequently quoted 'accepted' value for the fundamental bandgap of ∼0.95 eV. Absorption experiments show large subgap absorption, commonly attributed to defects or structural disorder. However, computations using density functional theory with a semi-local functional predict that the bottom of the conduction band consists of a very low intensity sulfur p-band that may be easily overlooked in experiments because of the high intensity onset that appears 0.5 eV higher in energy. The intensity of absorption into the sulfur p-band is found to be of the same magnitude as contributions from defects and disorder. Our findings suggest the need to re-examine the value of the fundamental bandgap of pyrite presently in use in the literature. If the contribution from the p-band has so far been overlooked, the substantially lowered bandgap would partly explain the discrepancy with the OCV. Furthermore, we show that more states appear on the surface within the low energy sulfur p-band, which suggests a mechanism of thermalization into those states that would further prevent extracting electrons at higher energy levels through the surface. Finally, we speculate on whether misidentified states at the conduction band onset may be present in other materials.

A novel HLA-A*03 allele, HLA-A*03:71.

A novel HLA-A*03 allele, HLA-A*03:71, was identified by PCR sequence-based typing.

A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis.

This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., "epigenetic" silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life.

Superparamagnetic gadonanotubes are high-performance MRI contrast agents.

We report the nanoscale loading and confinement of aquated Gd3+n-ion clusters within ultra-short single-walled carbon nanotubes (US-tubes); these Gd3+n@US-tube species are linear superparamagnetic molecular magnets with Magnetic Resonance Imaging (MRI) efficacies 40 to 90 times larger than any Gd3+-based contrast agent (CA) in current clinical use.

A gene coding for a novel protein specific to the olfactory rosettes of Atlantic salmon.

We have isolated a 1.6 kb clone from a cDNA library made from the olfactory rosettes of the Atlantic salmon (Salmo salar). The clone contains a 1200 bp, open reading frame (named OSC) which codes for a protein with 400 amino-acid residues (Oscp). The mRNA corresponding to OSC is strongly expressed in the olfactory rosettes and weakly expressed in gills but is expressed in only these two tissues. This suggests that Oscp may have a specific and important role in olfaction. The sequence of Oscp suggests that it is not globular. Predictions show only a small fraction of alpha-helix. Oscp is hydrophilic but with the number of positively charged residues equal to the number of negatively charged residues. No closely similar protein can be found on the basis of homology searches or hydrophobicity comparisons. However, a 44 residue segment (G300 through K343) is significantly homologous to a segment of alpha-lactalbumin (G51 through K94). The similarities include the 19 residues of the "alpha- lactalbumin-lysozyme C signature," the ten residues of the Ca(2+) binding elbow and the four cysteine residues which provide two key disulfide links in alpha-lactalbumin and lysozyme C. Two more Cys residues are also very similarly placed. We conclude that the gene OSC codes for a unique protein which most likely contains a specific site for binding Ca(2+) and plays a unique role in the signal pathway of olfaction in salmon.

The crystal structure of nucleoplasmin-core: implications for histone binding and nucleosome assembly.

The efficient assembly of histone complexes and nucleosomes requires the participation of molecular chaperones. Currently, there is a paucity of data on their mechanism of action. We now present the structure of an N-terminal domain of nucleoplasmin (Np-core) at 2.3 A resolution. The Np-core monomer is an eight-stranded beta barrel that fits snugly within a stable pentamer. In the crystal, two pentamers associate to form a decamer. We show that both Np and Np-core are competent to assemble large complexes that contain the four core histones. Further experiments and modeling suggest that these complexes each contain five histone octamers which dock to a central Np decamer. This work has important ramifications for models of histone storage, sperm chromatin decondensation, and nucleosome assembly.

Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults.

Following myeloablative therapy, it is unknown to what extent age-dependent thymic involution limits the generation of new T cells with a diverse repertoire. Normal T-cell receptor gene rearrangement in T-cell progenitors results in the generation of T-cell receptor rearrangement excision circles (TRECs). In this study, a quantitative assay for TRECs was used to measure T-cell neogenesis in adult patients with leukemia who received myeloablative therapy followed by transplantation of allogeneic hematopoietic stem cells. Although phenotypically mature T cells had recovered by 1 to 2 months after bone marrow transplantation (BMT), TREC levels remained low for 3 months after BMT. T-cell neogenesis became evident by 6 months, and normal levels of adult thymic function were restored at 6 to 12 months after BMT. Subsequent leukemia relapse in some patients was associated with reduced TREC levels, but infusion of mature donor CD4(+) T cells resulted in rapid restoration of thymic function. These studies demonstrate that T-cell neogenesis contributes to immune reconstitution in adult patients and suggest that thymic function can be manipulated in vivo. (Blood. 2001;98:1116-1121)

Core decompression with bone grafting for osteonecrosis of the femoral head.

Although core decompression is one of the more popular procedures for treating avascular necrosis, considerable controversy exists concerning its safety and effectiveness. The current authors review the results of a prospective study of 406 hips in 285 patients treated by one surgeon with core decompression and bone grafting. Patients were followed up for 2 to 14 years. The outcome was determined by the change in the Harris hip score, quantitative radiographic measurements, and need for total hip replacement. These hips were compared with 55 hips in 39 patients treated non-operatively and with historic controls. Five complications occurred after 406 procedures including two fractures that resulted from falls during the first postoperative month. Of the 312 hips in 208 patients with a minimum 2-year followup, 36% of hips (113 hips in 90 patients) required hip replacement at a mean of 29 months: 18 of 65 hips (28%) with Stage I disease; 45 of 133 hips (34%) with Stage II disease; three of 13 hips (23%) with Stage III disease; and 45 of 92 hips (49%) with Stage IV disease. Before femoral head collapse (Stages I and II combined) hip replacement was performed in 10 of 77 hips (14%) with small lesions (A), 33 of 68 hips (48%) with intermediate lesions (B), and 20 of 48 hips (42%) with large lesions (C). Results as determined by changes in Harris hip scores and radiographic progression were similar. Patients who underwent core decompression and bone grafting have a very low complication rate. In patients treated before femoral head collapse, the outcome is significantly better than in patients who received symptomatic treatment. The results are correlated with the stage and the size of the necrotic lesion.

Persistence of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte clones in a subject with rapid disease progression.

We longitudinally measured T-cell receptor transcript frequencies of human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) in an individual with rapidly progressive disease and high levels of viremia. CTL clones elicited during acute HIV-1 infection were present at the time of death, despite absent functional CTL responses, arguing against clonal deletion as a mechanism for the decline of CTL responses observed during HIV-1 infection.

Improved branching ratio measurement for the decay K(0)(L) --> &mgr;(+)&mgr;(-)

We report results from Experiment 871, performed at the BNL AGS, of a measurement of the branching ratio K(0)(L)-->&mgr;(+)&mgr;(-) with respect to the CP-violating mode K(0)(L)-->pi(+)pi(-). This experiment detected over 6200 candidate &mgr;(+)&mgr;(-) events, a factor of 6 more than that seen in all previous measurements combined. The resulting branching ratio gamma(K(0)(L)-->&mgr;(+)&mgr;(-))/gamma(K(0)(L)-->pi(+)pi(-)) = (3. 474+/-0.057)x10(-6) leads to a branching fraction B(K(0)(L)-->&mgr;(+)&mgr;(-)) = (7.18+/-0.17)x10(-9), which is consistent with the current world average, and reduces the uncertainty in this decay mode by a factor of 3.