Vaginismus - who takes interest in it?

OBJECTIVE: Vaginismus is caused by involuntary spasm of muscle surrounding the vaginal wall, a condition which makes it impossible to have a comfortable sexual intercourse. Due to its significant psychogenic part this topic is often neglected by specialists, however it is a very sensitive one for women patients. We are bringing a summary of literature dealing with vaginismus, clarifying the possibilities of diagnostics, therapy and we are discussing relation of this dysfuntion to reproduction. DESIGN: Review article. Material a methods: Recent scientific articles indexed in Pubmed, Medline, Web of Science, consultation of Czech specialists and discussion forums of patients have been used. RESULTS: Vaginismus influences the quality of life, in the most serious form in can result in unconsumated marriage, sterility and thus can lead to the separation of a couple. When adeaquately approached the problem can mostly be solved. CONCLUSIONS: There are women for whom vaginismus is a serious problem and who are not able to cope with the situation without specialists help. Deepening the specialists knowledge in this field is essential for successful treatment.

Validation of a free release measurement facility on a decommissioning site.

The paper summarizes measurements and the Monte Carlo simulations performed to adapt the high purity germanium (HPGe) detectors of the system to the particular tasks of the decommissioning site. The work carried out for the installation and adaptation in CIEMAT of the prototype 'SuperMum', developed in the framework of the European MetroDecom II project for segregation and declassification of materials is described. The activities related to the validation of the prototype for the specific needs of a real Waste Management Unit are presented. Monte Carlo models of the SuperMum have been developed at CIEMAT and CMI using different codes and adapted to the geometries used (big-bag containers with the material volume of up to 0.5 m3). Uncertainty budget reporting tailored for the possible deviations between Monte Carlo assumptions and real waste have been analyzed. Data for several filling levels and activity distributions have been measured with reference sources and a good agreement has been obtained with calculated values.

[Office hysteroscopy in the gynaecological ordination]. / Hysteroskopie v ambulantním rezimu v podmínkách gynekologické ordinace.

OBJECTIVE: The office hysteroscopy is technically and legislativelly realized in the gynaecological ordination. SETTING: Gynprenatal s.r.o., Havírov, Workroom of outpatient hysteroscopy. DESIGN: Retrospective analysis. METHODS: From July 2009 to October 2010 we performed 238 diagnostic and operative hysteroscopic office-based procedures. The patients was recomended from 23 outpatient gynecological clinic. CONCLUSIONS: Our present experience confirmed the outpatient hysteroscopy in the gynecological surgery as very efficacious method of assessment. At least 80% hysteroscopic procedures could be transfered to outpatient management.

Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy.

Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.

Determination of emission probabilities of gamma photons in the decay of (56)Co.

The emission probabilities of gamma photons in the decay of (56)Co were determined at Czech Metrology Institute (CMI) by means of an HPGe detector. This detector was calibrated experimentally and by MCNP-computation in the energy range from 40 to 2754keV for a point source geometry and source-to-detector distance of 25cm. Experimental and computed peak and total efficiencies were compared and calibration curves were determined. Full-peak efficiencies were calculated for all (56)Co gamma-ray energies, and were used to calculate the emission probabilities. A set of point sources was prepared from a (56)Co solution. The solution was standardized using the 4pibeta-gamma coincidence method, and an ampoule was sent to international reference system for activity measurement of gamma-ray emitting radionuclides (SIR). Each point source was measured with the HPGe detector at a source-to-detector distance of 25cm. Coincidence emission probabilities of all the gamma photons were calculated and used to determine the summing correction factors.

Postsynthetic modification of a zirconium metal-organic framework at the inorganic secondary building unit with diphenylphosphinic acid for increased photosensitizing properties and stability.

A zirconium metal-organic framework (MOF) PCN-222 was postsynthetically modified with diphenylphosphinic acid, resulting in an increased stability when activated from water and 4 times higher photosensitizing properties for singlet oxygen production. The phosphinic acid did not compromise the crystallinity of the MOF but made strong bonds with the zirconia secondary building units.

New high-throughput measurement systems for radioactive wastes segregation and free release.

This paper addresses the measurement facilities for pre-selection of waste materials prior to measurement for repository acceptance or possible free release (segregation measurement system); and free release (free release measurement system), based on a single standardized concept characterized by unique, patented lead-free shielding. The key objective is to improve the throughput, accuracy, reliability, modularity and mobility of segregation and free-release measurement. This will result in a more reliable decision-making with regard to the safe release and disposal of radioactive wastes into the environment and, resulting in positive economic outcomes. The research was carried out within "Metrology for Decommissioning Nuclear Facilities" (MetroDecom) project.

A new large-volume metal reference standard for radioactive waste management.

A new large-volume metal reference standard has been developed. The intended use is for calibration of free-release radioactivity measurement systems and is made up of cast iron tubes placed inside a box of the size of a Euro-pallet (80 × 120 cm). The tubes contain certified activity concentrations of (60)Co (0.290 ± 0.006 Bq g(-1)) and (110m)Ag (3.05 ± 0.09 Bq g(-1)) (reference date: 30 September 2013). They were produced using centrifugal casting from a smelt into which (60)Co was first added and then one piece of neutron irradiated silver wire was progressively diluted. The iron castings were machined to the desirable dimensions. The final material consists of 12 iron tubes of 20 cm outer diameter, 17.6 cm inner diameter, 40 cm length/height and 245.9 kg total mass. This paper describes the reference standard and the process of determining the reference activity values.

Adsorption and photocatalysis of nanocrystalline TiO2 particles for Reactive Red 195 removal: effect of humic acids, anions and scavengers.

In the present study, the coupling of adsorption capacity and photocatalytic efficiency of two different industrially produced titania catalysts was investigated and compared. The azo dye Reactive Red 195 was selected as a model compound. The tested catalysts, PK-10 and PK-180, exhibited different adsorption capacities due to their significant difference in their specific surface, but both have proven to be effective photocatalysts for photodegradation of the studied dye. PK-10 exhibited strong adsorption of the studied dye due to its high specific surface area, while the second studied catalyst, PK-180, demonstrated negligible adsorption of Reactive Red 195. The effect of the pH, the concentration of the catalyst and the initial concentration of the dye appear to affect the photocatalytic rate. The effect of the presence of humic acids and inorganic ions was also examined, while the contribution of various reactive species was indirectly evaluated through the addition of various scavengers. To evaluate the extent of mineralisation of the studied dye, total organic carbon (TOC) measurements during the experiment were also conducted. Besides total colour removal, evident reduction of TOC was also achieved using both catalysts.

Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax).

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

Gonadal and adrenal effects on hepatic epidermal growth factor receptor expression in a murine model.

We hypothesize that the actions of epidermal growth factor (EGF) may be modulated by changes in cell surface EGF receptor (EGF-R) expression under endocrine influences. Mouse liver cell membrane preparations were used in a RRA. During ontogenesis, both sexes showed a significant increase (P less than 0.005) in hepatic EGF-R numbers at puberty; however, males demonstrated significantly higher levels than females (P less than 0.005). Gonadectomy of adult males and females resulted in a significant (P less than 0.05) decrease and increase, respectively, in hepatic EGF-R expression. Prepubertal gonadectomy in both sexes resulted in EGF-R levels similar to those observed in adult females. Adrenalectomy of adult animals of both sexes had no effect on hepatic EGF-R numbers, but gonadectomy plus adrenalectomy virtually obliterated EGF-R expression. Short term treatment with testosterone of adult females or gonadectomized female and male mice significantly increased EGF-R numbers (P less than 0.05) to adult male levels. 17 beta-Estradiol given short term to adult males or gonadectomized male and female mice did not significantly alter EGF-R levels. EGF-R expression in androgen-insensitive male mice was significantly reduced (P less than 0.005) to female levels. We conclude that 1) hepatic EGF-R numbers increase post-pubertally in both sexes; 2) hepatic EGF-R expression is significantly stimulated by testosterone, and this effect depends on a functional androgen receptor; 3) the ovary has an inhibitory effect on adult hepatic EGF-R numbers; however, this effect does not appear to be mediated by estrogens; and 4) the adrenal gland has a stimulatory effect on adult hepatic EGF-R expression.

Discovery of a well-absorbed, efficacious renin inhibitor, A-74273.

The development of orally active renin inhibitors has been plagued by limited bioavailability in animals and humans. A-74273 is a novel, potent nonpeptide inhibitor of human renin (IC50 = 3.1 nM). This compound was absorbed into the portal and systemic circulations of anesthetized rats, ferrets, monkeys, and dogs after intraduodenal dosing. This favorable pattern also was observed after oral dosing in conscious animals, except in monkeys. Hepatic extraction of A-74273 was more efficient in rats and monkeys than in dogs or ferrets. A-74273 modestly inhibits dog renin, and when given orally as the base (0, 0.3, 1, 3, 10, and 30 mg/kg; n = 8 per dose) to conscious, salt-depleted dogs it induced dose-related reductions in mean arterial pressure and plasma renin activity. Peak falls in mean arterial pressure from normotensive baselines were -14 +/- 1, -26 +/- 3, and -44 +/- 3 mm Hg for the 3, 10, and 30 mg/kg groups, respectively (p < 0.05). Baseline plasma renin activity values (10.9 +/- 1.1-12.7 +/- 1.1 ng angiotensin I/ml/hr) were maximally inhibited, ranging from 43 +/- 8% at 0.3 mg/kg to 98 +/- 1% at 30 mg/kg. Bioavailability in this model was estimated to be 54 +/- 13% when plasma drug levels were determined by a renin inhibitory activity assay, but bioavailability was lower when compared with high-performance liquid chromatographic analysis of A-74273. This discrepancy was accounted for by the identification of structurally similar metabolites that are as active as the parent drug against human renin but much less potent against dog renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.

Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC(50) 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC(50) 3000 nM) and squalene synthase (SSase) (IC(50)>10000 nM). A-176120 inhibited ras processing in H-ras-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED(50) 1.6 and 0.5 microM, respectively). The anti-angiogenic potential of A-176120 was demonstrated by a decrease in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the secretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespan of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-176120 also had an additive effect in combination with cyclophosphamide in nude mice inoculated with K-ras NIH3T3 transformed cells. Overall, our results demonstrate that A-176120 is a potent FPP mimetic with both antitumour and anti-angiogenic properties.

Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3- [[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517).

Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

Rapid colchicine competition-binding scintillation proximity assay using biotin-labeled tubulin.

We have developed a rapid [3H]colchicine competition-binding scintillation proximity assay (SPA) to evaluate antimitotic compounds that bind to the colchicine-binding site on tubulin. The premise of our assay is that compounds will compete with radiolabeled colchicine for the tubulin-binding domain. Biotin-labeled tubulin is incubated first with unlabeled compound and radiolabeled ligand. Streptavidin-labeled SPA beads are added, and the radiolabel associated with tubulin is directly counted with no separation steps. Under our experimental conditions, the dissociation constant of binding (Kd) for colchicine to tubulin was determined to be 1.4 microM, which was consistent with previously reported values. Assay validation was performed by competitively inhibiting [3H]colchicine binding to tubulin with known microtubule inhibitors and comparing their inhibition constants (Ki). Our SPA bead method is a powerful tool since it overcomes the disadvantage of traditional filtration techniques, as there are no separation steps. It is extremely easy to set up, multiple samples can be assayed and supply and labor costs are reduced because of the minimal volume and test reagents used.

Effects of renin inhibitor A-72517 on hemodynamics and cardiac function in sodium-depleted dogs.

A-72517 is a potent inhibitor of human renin (IC50 = 1.0 nmol/L, pH 7.4 in plasma) and, aside from displaying modest activity against canine plasma renin (IC50 = 110 nmol/L), has been shown to be orally active in the dog and other animals. Renin inhibitors, in general, are presumed to exert their hypotensive effect through a reduction in total peripheral resistance. To elucidate the hemodynamic mechanism of action of this new dipeptidic renin inhibitor, the cardiac and systemic hemodynamic effects of A-72517 were studied in sodium-depleted, pentobarbital-anesthetized dogs. Each dog received either vehicle (n = 8) or a single dose (n = 8/dose) of A-72517 administered intravenously as a priming bolus followed by a 30 min constant infusion; infusion doses were 0.01, 0.05, and 0.1 mg/kg/min. A-72517 elicited significant (P < .05) dose-related reductions in mean arterial pressure (MAP) and systemic vascular resistance (SVR) compared to baseline values and the vehicle-treated group, and the recoveries of MAP and SVR were also dose-related. Plasma renin activity, measured by radioimmunoassay, was nearly completely suppressed during drug infusion at all doses. The hypotensive responses did not alter cardiac output nor did they induce reflex tachycardia at any dose. Left ventricular dP/dtmax did not change during infusion of A-72517, but, when corrected for changes in afterload, showed dose-related increases with drug treatment. Moreover, left ventricular end-diastolic pressure and pulmonary arterial wedge pressure were significantly reduced at the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

One-year followup of patients with osteoarthritis of the knee who participated in a program of supervised fitness walking and supportive patient education.

OBJECTIVE: To determine whether gains in functioning observed immediately following participation in an 8-week program of supervised fitness walking for patients with knee osteoarthritis were sustained at 1-year followup. METHODS: Twenty-nine (61.1%) of 47 original intervention program patients and 23 (51.1%) of 45 original control patients were interviewed by telephone at 1-year followup. Patients completed the Arthritis Impact Measurement Scales physical activity, arthritis impact, pain, medication use, and general health perceptions subscales, as well as a separate visual analog pain scale and measures of perceived self-efficacy to cope with arthritis pain and other symptoms. RESULTS: Adherence to walking was low, and there were no statistically significant differences between intervention and control patients at one year. CONCLUSIONS: The failure of intervention patients to maintain regular walking resulted in loss of functional benefits that were observed at 8 weeks in the original study. Long-term adherence to walking is critical to maintenance of initial gains in functional outcomes.

[Can hysteroscopy reliably detect malignancy? Analysis of 1200 hysteroscopy findings]. / Muze hysteroskopující spolehlive odhadnout malignitu? (analýza 1200 hysteroskopických nálezu).

OBJECTIVE: The aim of this study was retrospective analysis of how accurate was per-operational visual evaluation of malign process in an uterus cavity during hysteroscopy. And to evaluate whether increasing experience of hysteroscopiers leads to significant accuracy considering the neoplasm of an uterus cavity. SETTING: Department of Gynaecology and Obstetrics, Havírov. METHOD: In Havírov Hospital, 1,200 hysteroscopies altogether were performed in the period from December 1995 to March 1999. In this group, there were 26 cases of histologically verified endometrial cancer. The authors retrospectively attempted to evaluate how accurately the suspected disorder was already stated during the per-operational hysteroscopy. The advantage of comparing the sub-group was taken in the first 690 hysteroscopies, of which the complex analysis was published in Cs. Gynekologie 5/98, and in the sub-group of 510 hysteroscopies performed in the following period, to state whether experience can more precisely define the per-operational malignity recognition. The statistical analysis was performed by means of the Fischer exact test of numerical charts. Among other things, the MEDLINE database was used during discussion. RESULTS: The endometrial cancer was encountered 26 times altogether, it means in 2.2% cases of hysteroscopies. Carcinoma in situ occurred three times, the stage IA three times, IB 17 times, IC three times. A hysteroscopier described the negative finding incorrectly 13 times altogether, it means 50% of all cases. The sensitivity and the specificity of hysteroscopy for endometrial cancer prediction was 50% and 99.5% (P < 0.01). The comparison of the first sub-group results (16 cases of endometrial cancer, sensitivity 75%, specificity 99.7%, (P < 0.01) and the second sub-group (10 cases of endometrial cancer, sensitivity 10%, specificity 99.2%, P = 0.09%) indicates that even increasing experience of a hysteroscopier does not more precisely define per-operation malign consideration. CONCLUSION: The authors have come to the conclusion that the pre-operation consideration of intrauteral pathology during hysteroscopy does not allow to assess precisely whether there is a neoprocess of an uterus cavity, or not. Even growing experience does not define with more precision verification of malign disorders especially at early stages of this illness. Hysteroscopy always has to be supplemented with endometrium biopsy.