Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium. Effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity

We measured the concentration of progesterone and estradiol and calculated the progesterone:estradiol ratio in nonpregnant and pregnant human myometrium. Progesterone, estradiol and the progesterone:estradiol ratio were higher in pregnant than in nonpregnant myometrium. There was no difference in the concentration in the presence of labor. The progesterone:estradiol ratio showed a similar pattern. We also investigated the effect of the ovarian steroids on the activity of cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE). Progesterone in pharmacologic doses inhibited the activity of the high-affinity enzyme as much as 72% and the low-affinity form as much as 34%. High-affinity phosphodiesterase from nonpregnant myometrium was the least sensitive to inhibition, and the enzyme from pregnant myometrium obtained from laboring women was the most sensitive. Low-affinity phosphodiesterase from nonpregnant myometrium was less sensitive to inhibition than enzyme from pregnant women with or without labor. The degree of inhibition of the low-affinity enzyme in the two pregnant groups was not different. The type of inhibition was competitive in both the high- and low-affinity forms. Estradiol at similar concentrations did not have any effect on the activity of the enzyme. Progesterone in part may exert its effect on the human myometrium by its effect on cyclic adenosine monophosphate-PDE activity and the metabolism of cAMP.     

Towards knowledge-based gene expression data mining

The field of gene expression data analysis has grown in the past few years from being purely data-centric to integrative, aiming at complementing microarray analysis with data and knowledge from diverse available sources. In this review, we report on the plethora of gene expression data mining techniques and focus on their evolution toward knowledge-based data analysis approaches. In particular, we discuss recent developments in gene expression-based analysis methods used in association and classification studies, phenotyping and reverse engineering of gene networks.     

FreeViz--an intelligent multivariate visualization approach to explorative analysis of biomedical data

Visualization can largely improve biomedical data analysis. It plays a crucial role in explorative data analysis and may support various data mining tasks. The paper presents FreeViz, an optimization method that finds linear projection and associated scatterplot that best separates instances of different class. In a single graph, the resulting FreeViz visualization can provide a global view of the classification problem being studied, reveal interesting relations between classes and features, uncover feature interactions, and provide information about intra-class similarities. The paper gives mathematical foundations of FreeViz, and presents its utility on various biomedical data sets.     

Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis

Objective. To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months. Methods. Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6–12 weeks from prior second-line therapy was required. Results. Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg dosage groups compared to placebo. Twenty-one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the 10-mg and 25-mg dosage groups. The incidence of infections was similar between the treatment and placebo groupsno opportunistic infections were seen. Transient elevations in liver function studies were noted in a small number of patients. Conclusion. Leflunomide is effective in daily doses of 10 mg and 25-mg in patients with active RA. Improved efficacy at the 25-mg dose was associated with a higher incidence of AEs. Randomized, placebocontrolled trials using daily doses of 10 mg and 20 mg are under way in the US and Europe to confirm these positive results.     

Prolactin and Autoimmunity

Evidence points to an association of prolactin to autoimmune diseases. We examined the correlation between hyperprolactinemia and disease manifestations and activity in a large patient cohort. Age- and sex-adjusted prolactin concentration was assessed in 256 serum samples from lupus patients utilizing the LIASON prolactin automated immunoassay method (DiaSorin S.p.A, Saluggia, Italy). Disease activity was defined as present if European Consensus Lupus Activity Measurement (ECLAM)?>?2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)?>?4. Lupus manifestations were grouped by organ involvement, laboratory data, and prescribed medications. Hyperprolactinemia was presented in 46/256 (18%) of the cohort. Hyperprolactinemic patients had significantly more serositis (40% vs. 32.4%, p?=?0.03) specifically, pleuritis (33% vs. 17%, p?=?0.02), pericarditis (30% vs. 12%, p?=?0.002), and peritonitis (15% vs. 0.8%, p?=?0.003). Hyperprolactinemic subjects exhibited significantly more anemia (42% vs. 26%, p?=?0.02) and marginally more proteinuria (65.5% vs. 46%, p?=?0.06). Elevated levels of prolactin were not significantly associated with other clinical manifestations, serology, or therapy. Disease activity scores were not associated with hyperprolactinemia. Hyperprolactinemia in lupus patients is associated with all types of serositis and anemia but not with other clinical, serological therapeutic measures or with disease activity. These results suggest that dopamine agonists may be an optional therapy for lupus patients with hyperprolactinemia.     

Inspiratory- and finger-flexion-related cortical potentials in patients with amyotrophic lateral sclerosis--an exploratory study

Objective

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons. Each voluntary movement, including inspiration, is preceded by movement-related cortical potential (MRCP) that can be recorded from the scalp. MRCPs of ALS patients with severe upper motor neuron involvement are smaller. Our aim was to explore whether the inspiratory-(sniffing)-related cortical potentials (SRCPs) and index-finger-flexion MRCPs (FFRCPs) can be used as markers of cortical involvement in ALS.

Methods

Thirteen ALS patients and 15 healthy volunteers were assessed for their hand dexterity and strength, respiratory function, speech capacity, spasticity, electromyographic parameters and functional rating scales. EEG was recorded during self-paced sniffing and the right index finger flexion. The MRCP amplitudes were assessed at the relevant electrode positions.

Results

No statistically significant difference was found between the MRCP amplitudes of the ALS patients and the control subjects. However, patients with more severely affected upper limb functions generated smaller FFRCPs and those with more affected respiratory functions generated smaller SRCPs. Excessively high FFRCPs were associated with better while excessively low FFRCPs with worse scores on some of the clinical measures of the upper limb function.

Conclusion

Our preliminary results demonstrate that it is feasible to record SRCP in ALS patients, which combined with FFRCP, may be useful to determine the spectrum of motor control changes in this population.     

Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression

Background and purpose

In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signalling, homologous recombination (HR) and non-homologous end-joining (NHEJ) repair proteins. We investigated panobinostat (PAN) as a potential radiosensitiser in bladder cancer cells.

Materials and methods

Clonogenic assays were performed in RT112 bladder cancer cells, and RT112 cells stably knocked down for RAD51 or Ku80 by shRNAi. Resolution of γH2AX foci was determined by immunofluorescence confocal microscopy, cell cycle progression by FACS analysis and protein expression by western blotting.

Results

PAN had a greater radiosensitising effect in Ku80KD than RT112 or RAD51KD cells; enhancement ratios 1.35 for Ku80KD at 10 nM (IC₂₀ for Ku80KD) and 1.31 for RT112 and RAD51KD at 25 nM (IC₄₀ for both). PAN downregulated MRE11, NBS1 and RAD51, but not Ku70 and Ku80, increased γH2AX foci formation in a dose-dependent manner and delayed γH2AX foci repair after ionising radiation.

Conclusions

PAN acts as a radiosensitiser in bladder cancer cell lines, and appears to target HR rather than NHEJ. As muscle-invasive bladder tumours have reduced Ku-DNA binding, PAN could be particularly useful as a radiosensitiser in bladder cancer.     

Virtual histology-intravascular ultrasound assessment of lesion coverage after angiographically-guided stent implantation in patients with ST Elevation myocardial infarction undergoing primary percutaneous coronary intervention

An occlusion or severe stenosis (angiographic culprit lesion) of the infarct-related artery is frequently located at the site of the maximum thrombus burden, whereas the origin of the plaque rupture (the true culprit) can be situated proximal or distal to it. The aim of this study was to examine stent coverage of true culprit lesions in 20 patients who underwent primary percutaneous coronary intervention and had Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow restored in the infarct-related artery by angiographically guided direct stenting. Images of lesions were obtained using virtual histology-intravascular ultrasound before and after intervention (blinded to the operator). Plaque rupture sites were identified by intravascular ultrasound in 12 lesions (60%), 11 proximal and 1 distal to the minimum luminal area (MLA). Maximum necrotic core sites were found proximal to the MLA in 16 lesions, at the MLA in 3 lesions, and distal to the MLA in 1 lesion. Plaque rupture sites were fully covered by stents in 11 lesions. Virtual histology-intravascular ultrasound-derived thin-cap fibroatheroma longitudinal geographic misses were found in 10 lesions, 7 in the proximal reference segment and in 3 patients in the proximal and distal reference segments. In conclusion, in about 50% of patients who undergo primary percutaneous coronary intervention for ST-segment elevation myocardial infarction with optimal angiographic results, the stent does not fully cover the maximum necrotic core site related to the culprit lesion.     

Phantom haptic device upgrade for use in fMRI

This paper presents an upgrade of a Phantom Premium 1.5 haptic device for use within a functional magnetic resonance imaging (fMRI) environment. A special mechanical extension that allows the haptic device to operate at a safe distance from the high-density magnetic field of an fMRI scanner has been developed. Extended haptic system was subjected to a series of tests to confirm electromagnetic compatibility with the fMRI scanner, for which key results are presented. With this fMRI compatible haptic platform a human brain activation during controlled upper limb movements can be studied. A simple virtual environment reaching task was programmed to study brain motor control functions. At the end preliminary results of an ongoing neurophysiological study are presented.