Docking and three-dimensional quantitative structure-activity relationship (3D QSAR) analyses of nonsteroidal progesterone receptor ligands

We report a docking and comparative molecular similarity indices analysis (CoMSIA) study of progesterone receptor (PR) ligands with an emphasis on nonsteroids including tanaproget. The ligand alignment generation, a critical part of model building, comprised two stages. First, thorough conformational sampling of docking poses within the PR binding pocket was made with the program GOLD. Second, a strategy to select representative poses for CoMSIA was developed utilizing the FlexX scoring function. After manual replacement of five poses where this approach had problems, a significant correlation (r(2) = 0.878) between the experimental affinities and electrostatic, hydrophobic, and hydrogen bond donor properties of the aligned ligands was found. Extensive model validation was made using random-group cross-validations, external test set predictions (r(pred)(2) = 0.833), and consistency check between the CoMSIA model and the PR binding site structure. Robustness, predictive ability, and automated alignment generation make the model a potential tool for virtual screening.     

The relationship between uterine volume, plasma progesterone and intrauterine pressure. A preliminary report

8 nulliparous women, all approximately 15 weeks pregnant, were administered 350 ml Macrodex intraamniotically during a period of 15-30 minutes to increase uterine volume. 4 of the patients aborted following a decrease in plasma progesterone and an increase in resting pressure, active pressure, and oxytocin response. In 2 patients, plasma progesterone increased while resting pressure, active pressure, and oxytocin response did not increase, and pregnancy continued undisturbed. It is concluded that increasing uterine volume may induce a compensatory synthesis of progesterone in the palcenta provided that: 1) the osmotic action of the injected hypertonic solution does not suppress placental function to a degree equal to that of the stimulatory effect of increasing volume; 2) the osmotic increase in volume is slow enough to permit the time-dependent increase in progesteronegenesis; and 3) the increase in intrauterine pressure and clinical progress in abortion does not suppress placental endocrine function. Further experiments are necessary to verify this interpretation.     

Hysterography in evaluating the uterine cavity in patients with endometrial carcinoma

In 49 patients with endometrial carcinoma hysterographic study was performed. This finding was correlated with fractional curettage, hysteroscopy and surgery. The best correlation was noted between hysterography and hysteroscopy. The flow into the tubes or abdominal cavity using low pressure was found in 20% of the cases. In our opinion hysterography is a useful aid when examining the uterine cavity and cervical canal, and, thus, important when planning treatment and determining clinical stage.     

No correlation between patient outcome and abnormal lumbar MRI findings 21 years after posterior or posterolateral fusion for isthmic spondylolisthesis in children and adolescents

Between 1977 and 1987, posterior (n=29) or posterolateral (n=73) fusion was performed for mild to moderate (slip <50%) isthmic spondylolisthesis on 102 patients (46 females, 56 males). The patients average age at the time of operation was 15.9 (range, 8.1–19.8) years. Clinical (physical examination and Oswestry disability index (ODI)) and radiological (MRI and plain radiographs) examinations were performed on these patients after an average follow-up time of 21.0 (range, 26.2–15.1) years. In the radiographs, the mean slip preoperatively was 27% (range, 5–50%) and at the last follow-up visit 26% (range, 5–78%). Inside the fusion, there were a total of 148 intervertebral discs, 121 (82%) of them had decreased signal intensity in T2-weighted MR images and 113 (76%) were narrowed. Above the fusion level, 27 (27%) discs were speckled and 27 (27%) were black; 21 (21%) intervertebral disc spaces were narrowed. Two levels above the fusion level the numbers were 8 (8%), 16 (16%) and 16 (16%), respectively. Six (6%) patients had a prolapse. Degenerative facet joint hypertrophy above fusion was seen at 80 (79%) of the levels studied. When compared to healthy subjects higher frequency of disc and facet joint degeneration was found. In MR images, none of the patients had lumbar spinal stenosis inside or above the fusion. Narrowing of one or both of the neural foramina at the level of the L5–S1 interververtebral disc was noted in 32 (31%) patients. Seventeen (17%) of the patients had, usually mild, muscular atrophy of the psoas and 33 (32%) of the paraspinal muscles. There was no difference in frequency of abnormal MRI findings between patients (n=93) with ODI 20 or less compared with patients (n=9) with ODI more than 20. In situ fusion due to isthmic spondylolsthesis at adolescence is associated with moderate degenerative changes in the lumbar spine during a 20-year follow-up. Changes were most commonly found at the level of the spondylolisthesis and above fusion level. Neural foramina stenosis seems to be associated with spondylolisthesis and its severity to severity of the slip. Muscle atrophy tended to be mild. However, there was no correlation between patient outcome (ODI) and abnormal lumbar MRI findings.     

Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCgamma pathway, reduced anxiety, and facilitated learning

We have investigated the biochemical, physiological, and behavioral properties of transgenic mice overexpressing the full-length neurotrophin receptor trkB (trkB.TK+). The highest trkB.TK+ mRNA overexpression was achieved in the cerebral cortex and hippocampal subfields, both areas also showing strongly increased trkB.TK+ receptor protein expression and phosphorylation. Furthermore, as a result of trkB.TK+ overexpression, partial activation of trkB downstream signaling was observed. Phosphorylation of phospholipaseCgamma-1 was increased but unexpectedly, the expression and phosphorylation levels of signaling molecules Shc and mitogen-activated protein kinase (MAPK) were unaltered. Behavioral studies revealed improved learning and memory in the water maze, contextual fear conditioning, and conditioned taste aversion tests, and reduced anxiety in the elevated plus maze (EPM) and light-dark exploration tests in trkB.TK+ transgenic mice. Electrophysiological studies revealed a reduced long-term potentiation (LTP) at the Schaffer collateral-CA1 synapse in trkB.TK+ mice. Altogether, overexpression of the trkB.TK+ receptor postnatally leads to selective activation of trkB signaling pathways and enhanced learning and memory.     

Trends and educational disparities in functional capacity among people aged 65-84 years

BACKGROUND: This study examined 10 year trends in functional capacity by gender, age, and education among elderly Finns aged 65-84 years, focusing on difficulties in basic activities of daily living (BADL). Educational disparities and their trends in the prevalence of these difficulties were also assessed. METHODS: Data were derived from nationally representative monitoring surveys conducted biennially from 1993 to 2003 by the National Public Health Institute (KTL). A total of 5740 men and 5746 women were included in the study (response rate 80%). Activities of daily living (ADL) measures were used to assess levels of functional capacity. Education was divided into two groups: low (0-8 years) and high (9+ years). Age-adjusted trends and logistic regression analyses were computed. RESULTS: A clear downward trend in BADL difficulties was observed in all age groups in both genders. 80-84 year olds had clearly poorer functional ability than 65-69 year olds, even when adjusted for chronic diseases. Despite the overall improvement in functional capacity in both educational groups, low educational status persistently predicted poorer functional capacity. When chronic diseases and survey period were controlled for, the educational disparities attenuated slightly but remained significant. CONCLUSIONS: The number of Finnish elderly with BADL difficulties has declined markedly over the past 10 years. However, persistent educational disparities continue to present a challenge to public health initiatives for reducing inequalities in health.     

Intravascular adenovirus-mediated lipoprotein-associated phospholipase A2 gene transfer reduces neointima formation in balloon-denuded rabbit aorta

Postangioplasty restenosis is a multifactorial process and involves mechanisms such as inflammation and stimulation of the expression of growth factors. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) can modify inflammatory responses by hydrolyzing phospholipids with shortened and/or oxidized sn-2 residues. In this study, we tested a hypothesis that adenovirus-mediated Lp-PLA(2) gene transfer can reduce restenosis in rabbits. Aortas of cholesterol-fed NZW rabbits were balloon-denuded and intra-arterial gene transfer was performed using Dispatch catheter with Lp-PLA(2) or LacZ adenoviruses (1.15 x 10(10)pfu). Intima/media ratio (I/M), histology and cell proliferation were analyzed. Two weeks after the gene transfer I/M in the LacZ-transduced control group was 0.45+/-0.05 but Lp-PLA(2) gene transfer reduced I/M to 0.25+/-0.03. At four weeks time point I/M in the Lp-PLA(2) group (0.34+/-0.05) was also lower than in the LacZ group (0.53+/-0.06). Plasma Lp-PLA(2) activity was increased in the Lp-PLA(2) group (48.2+/-4.2) as compared to the LacZ group (33.6+/-3.51) at two weeks time point. Transgene expression was detected in the arterial wall two and four weeks after the procedure. Apoptosis was higher in the control vessels than in the Lp-PLA(2) group at two weeks time point. In conclusion, local adenovirus-mediated Lp-PLA(2) gene transfer resulted in a significant reduction in neointima formation in balloon-denuded rabbit aorta and may be useful for the prevention of restenosis after arterial manipulations.     

Surgically Treated Unsuspected N2-Positive NSCLC: Role of Extent and Location of Lymph Node Metastasis

Background

The role of surgery in the treatment of non–small-cell lung cancer that has spread to ipsilateral mediastinal or hilar lymph nodes (LNs) is controversial. We examined whether the location of LNs positive for non–small-cell lung cancer in mediastinum or hilum influences the survival of these patients.