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ABSTRACTIntroductionThe demand for effective and safe treatments of genitourinary syndrome (GSM) in post-menopausal women (PMW) is growing. Published data on the efficacy and safety of ospemifene (OSP) prompt an updated literature review to enlighten possible improvements in the GSM treatment.Area coveredWe searched articles published in English from 2010 to 2023 through Medline (PubMed) and Embase databases with Boolean terms: OSP, PMW, GSM, endometrium, breast cancer, cardiometabolic syndrome, bone metabolism, adherence to treatment, and patient satisfaction. We selected randomized controlled trials (RCTs) and observational and cross-sectional studies and completed the search manually.Expert opinionOf the 157 retrieved records, 25 primary studies met the inclusion criteria (15 regarding efficacy and safety, two for additional effects, and four for adherence and satisfaction with the OSP treatment). Seven RCTs involved nearly 5,000 patients, 10 out of 18 prospective observational studies 563, and six retrospective analyses 356,439. Evidence of OSP treatment in PMW with GSM relies on RCTs and remarkable real-world data. The 25 primary studies showcased the high clinical response to symptoms, the favorable safety profile of OSP with very few adverse events, a neutral impact on the endometrium, breast, bone, and thrombosis, and the possible improvement of cardiovascular risk factors.

Paraneoplastic syndromes include a variety of cutaneous presentations that have an associated internal malignancy. Some syndromes have a strong correlation to specific internal malignancies, whereas others are associated with a multitude of tumors. There are many cutaneous manifestations that suggest hematologic disorders, which will be reviewed in detail. Cutaneous metastases are commonly from breast and lung cancers and can present as nodules, vascular lesions, eczematous dermatitis, or inflammatory lesions. The most common histologic presentation of cutaneous metastasis is that of a dermal-based or subcutaneous-based nodule with sparing of the epidermis. Determination of origin of tumor requires immunohistochemistry and clinical correlation.

Objective Recurrent bacterial vaginosis (RBV) after antibiotic treatment has relapse rates of 35% within 3 months and 60% within 12 months. A medical device containing polycarbophil, lauryl glucoside, and glycerides (PLGG) inhibits bacterial growth and has mucoadhesive properties. This study examined the efficacy of the device in women with RBV.Methods This post-market clinical follow-up study comprised two phases. The first phase was an interventional, open-label, non-controlled, multicenter study enrolling 56 women. The second phase was an observational 10-month follow-up without treatment.Results After three cycles of PLGG treatment, recurrence was identified in 8 of 54 evaluable patients (14.81%). A positive effect on lactobacilli in the vaginal secretions was observed in 26 of 39 patients (66.67%). Among 35 patients observed after stopping PLGG treatment, one case of RBV (2.86%) was observed after 4 months, and an additional six cases (17.14%) were observed after 10 ± 2 months. Therefore, no recurrence was evidenced in 12 subjects (34.28%) at the end of the study.Conclusion The use of PLGG vaginal ovules in the treatment of BV reduces the rate of recurrence and apparently produces a positive effect on the vaginal microbiota.

Background: Most women experience a urinary tract infection (UTI) at least once in their lifetime. The present study determined the efficacy and safety of a combination of Lactobacillus paracasei LC11, cranberry and D-mannose (Lactoflorene Cist®) in the prophylaxis of recurrent uncomplicated UTIs in premenopausal women.Methods: This single-centre study enrolled premenopausal women aged 18–50 years with an acute UTI and a history of recurrent uncomplicated UTIs. Patients were first treated with fosfomycin (3 g once a day for 2 days) to eliminate any underlying infection, followed by treatment with Lactoflorene Cist®once a day for 10 days/month for 90 days (Group 1), Lactoflorene Cist®once daily for 90 days (Group 2) or no treatment (Group 3; control). The main study endpoint was the rate of UTI recurrence during the study period. Any adverse events with treatment were also recorded.Results: A total of 55 women (mean age 39.3 years; range: 20–46) were enrolled in the study. A significantly higher proportion of patients in the control group experienced UTIs during the study period compared with the two treatment groups (52.9% vs 16.0% in Group 1 and 15.5% in group 2; p< 0.01). Similarly, a higher proportion of patients in Group 1 (65.8%) and Group 2 (68.7%) remained UTI-free during the study versus the control group. No adverse events were reported in the treated patients.Conclusion: Prophylactic treatment with Lactoflorene Cist®was effective and safe in the management of recurrent uncomplicated UTIs in premenopausal women.

In this study, Parry et al. report PRIM1, encoding the catalytic subunit of DNA primase, as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals and phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component.

The observation that BRCA1-and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP–ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination1. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein–DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins1–4. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor1. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair5. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2Bin metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically. Mutations in all three genes encoding ribonuclease H2 sensitize cells to poly(ADP–ribose) polymerase inhibitors by compromising ribonucleotide excision repair.

DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP–AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS).

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.

Power system stability is the ability of an electric power system unit, for giving operating conditions beginning to recover operating state of equilibrium after being subjected to a physical interference. Power system stability has been recognized as an important problem for safe operation of system unit. Stability of power system is similar to the stability of any dynamic system, and has basic mathematical. Concepts from the mathematics and theoretical stability control are first revised to provide background information related to stability of dynamic system generally and establish a connection theoretical. This paper presents to improve of dynamic power system stability using frequency response as tuning of system stabilizer. It is started by electrical power systems mathematic modeling in state variable equation then set the expertise function of frequency response as tuning of system stabilizer. The plant controlled by function of frequency response is tuned to left half plane (LHP) as system stabilizer which their input from the rotor speed. When the system occur fault, the rotor speed should be synchronized, for this case one electrical controller is needed to make sure the system is stable.

To assess the effectiveness of the association of 2 specific strains, Lactobacillus fermentumLF10 (DSM 19187) and Lactobacillus acidophilusLA02 (DSM 21717), specifically formulated in slow-release effervescent tablets, in patients with recurrent vulvovaginal candidiasis.

The resolution of DNA interstrand crosslinks (ICLs) requires a complex interplay between several processes of DNA metabolism, including the Fanconi anemia (FA) pathway and homologous recombination (HR). FANCD2 monoubiquitination and CtIP-dependent DNA-end resection represent key events in FA and HR activation, respectively, but very little is known about their functional relationship. Here, we show that CtIP physically interacts with both FANCD2 and ubiquitin and that monoubiquitinated FANCD2 tethers CtIP to damaged chromatin, which helps channel DNA double-strand breaks generated during ICL processing into the HR pathway. Consequently, CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, which leads to increased levels of nonhomologous end-joining activity and ICL hypersensitivity. Interestingly, we also observe that CtIP depletion aggravates the genomic instability in FANCD2-deficient cells. Thus, our data indicate that FANCD2 primes CtIP-dependent resection during HR after ICL induction but that CtIP helps prevent illegitimate recombination in FA cells.

A search for proteins which interact with the eRF1 termination translation factor encoded by SUP45gene in yeast Saccharomyces cerevisiaewas carried out by screening yeast genes located on a multicopy plasmid. This approach allowed finding the ECM23gene whose increased expression led to lower viability of the sup45nonsense mutants. Overexpression ECM23gene led also to an antisuppressor effect, although the amount of the eRF1protein was not changed. Possible mechanisms of how ECM23can affect the viability of the sup45nonsense mutants are discussed.

Temperature-dependent transient processes initiated by a direct photogeneration of singlet oxygen in suspensions of human erythrocytes and solutions of serum albumin are studied. The processes appear as anomalous jumps in the temperature dependences of the deformability coefficient of erythrocytes and the refractive index of the extracellular medium and protein solution. In the temperature regions of anomalous jumps, cells and proteins transfer to a metastable state of a lower activity, but they can be isothermally photoreactivated. Simultaneously, a reversible rearrangement of the aqueous phase occurs near the cell and protein surfaces, accompanied by the formation of an extended corona (hydrogel). The transient processes are interpreted as phase transitions in the membrane of erythrocytes and conformation transitions in proteins. The interaction between erythrocytes and albumin via hydrogel is discovered (hydro-conformational interaction). A qualitative physical model of the early stages of the light-oxygen effect is proposed, in which collective magnetic interactions between the electron spins of oxygen molecules and the nuclear magnetic moments of protons in H2O molecules play a dominant role.

The effect of Maillard reaction products (MRPs) on the kinetics of lipid oxidation in intermediate‐moisture model systems containing pregelatinised starch, glucose, lysine and soybean oil has been studied. The samples, either containing all components or excluding one or more of them, were heated at 100 °C for different times. Lipid oxidation and browning indices were measured and the results confirmed the ability of MRPs to retard peroxide formation. Under the conditions adopted, the rate of the Maillard reaction was increased by the presence of the oil and its oxidation products. The antioxidant action of MRPs was also evaluated using a peroxide‐scavenging test based on crocin bleaching. The results demonstrated that antioxidant activity developed with increased browning of the samples. © 2000 Society of Chemical Industry

The effect of Maillard reaction products (MRPs) on the kinetics of lipid oxidation in intermediate-moisture model systems containing pregelatinised starch, glucose, lysine and soybean oil has been studied. The samples, either containing all components or excluding one or more of them, were heated at 100 °C for different times. Lipid oxidation and browning indices were measured and the results confirmed the ability of MRPs to retard peroxide formation. Under the conditions adopted, the rate of the Maillard reaction was increased by the presence of the oil and its oxidation products. The antioxidant action of MRPs was also evaluated using a peroxide-scavenging test based on crocin bleaching. The results demonstrated that antioxidant activity developed with increased browning of the samples. © 2000 Society of Chemical Industry

A number of cell culture studies have been reported on the influence of shear stress on vascular endothelial cells. Although through such studies much has been learned about the effect of an endothelial cell’s hydrodynamic environment on its structure and function, the reports indicate significant differences in methodology. Using cell shape as an indicator of differences that might result from differing methodologies, an investigation of the influence of selected variables has been carried out. The results presented indicate that not only are such variables as the level of shear stress and the duration of exposure important, but also substrate, media composition, characteristics of the cell itself, and the nature of the flow, e.g. whether it is steady state or pulsatile.

1.Thea-phenylethylamide of 3-methoxy-4-acetoxyphenylalanine of predominantly SS configuration is obtained in the reaction of the azlactone of 3-methoxy-4-acetoxy-N-acetaminocinnamic acid with S(-)-a-phenylethylamine and hydrogen in the presence of a palladium catalyst in aprotic solvents.2.The optimal conditions were found for preparing the pure SS diastereomer which yields, upon hydrolysis, optically pure S(-)-3,4-dihydroxyphenylalanine.3.The methyl esters of N-acetyl-3-methoxy-4-acetoxy- and N-acetyl-3-methoxy-4-hydroxyphenylalanine, predominantly of the R configuration, are obtained in the reduction of the azlactone of 3-methoxy-4-acetoxy- a-acetaminocinnamic acid in methanol in the presence of S(-)-a-phenylethylamine and a palladium catalyst, which indicates the dissymmetrical nature of the catalyst.4.The reductive aminolysis proceeds mainly by the synchronous reaction of the azlactone with the amine and hydrogen on the catalyst surface.

1.The rate constants of the mutarotation ofß-D-arabinose in 50% aqueous ethanol in the presence of the investigated catalysts obey the Bronsted function withß = 0.84±0.01 at 20°.2.The thermodynamic parameters of the activation of the mutarotation ofß-D-arabinose under the action of the investigated catalysts are related by an isokinetic function (ß = 250 ± 2K).

In enantioselective hydrogenation of ethyl acetoacetate on a Raney nickel catalyst modified with (+)-tartaric acid, we found an inhibiting effect of the reaction products, namely, racemic ethylß-hydroxybutyrate and (-)-ethylß-hydroxybutyrate, and also of acetic acid, pyridine, and thiophene, and we determined their relative adsorption coefficients.

Abstract: An original nephelometric method allows one to measure initial platelet aggregation after a long-term storage of platelet concentrate. This attests to a high level of platelet activity despite the fact that final platelet aggregation cannot be detected by usual turbidimetric method. N-chloroalanine more slowly inhibits initial platelet aggregation in comparison with sodium hypochlorite, which implies different mechanisms of their membrane-modifying effects.

An attempt is made to correlate absolute and relative geochronologies by using age determinations. of glauconite which is syngenetic with the enclosing sediments. The data thus obtained for the Mesozoic-Cenozoic and lower Paleozoic - upper Proterozoic are considered most reliable and suggest great possibilities for the Ar-method. For the first time age values are obtained which range from 500 to 1, 300 million years for the oldest sedimentary formations within the Russian platform, Urals and East Siberia. — Auth. English summ.

Objective: Vulvovaginal health is important to women's overall health, fertility, sexuality, self-perception, self-confidence and intimacy. It is important to identify the existing perceptions and levels of knowledge about intimate care practices from women in different countries, and with different cultures, religions, and perspectives to help women overcome barriers to optimal intimate care.

Vulvar dermatoses are characterized by dehydration leading to symptoms as itching and burning. Topical corticosteroids and lanolin cream are the standard therapy. A new non-irritant cleanser based on soft natural surfactants (Saugella idraSerum, a product by Rottapharm|Madaus) (SiS) exhibited interesting clinical properties. Purpose of the study was to compare the activity of SiS in vulvar dermatoses versus a common reference cleanser (Aveeno intimo) (Ref).

Comparison of antiaggregation capacity of N-chloramine acids with different position of the chloramine group in the molecule showed that in the most efficient compounds the distance between the chloramine and carboxyl groups was 3–5 carbon atoms. This feature of antiaggregation activity was not related to the difference in oxidation capacity of N-chloramine acids. It was hypothesized that the revealed structural dependence of antiaggregation activity of N-chloramine acids is determined by the structure of platelet membrane, in particular, the presence of a negatively charged group near the site of interaction between N-chloramine acids and platelet membrane.

Intravenous injection of chloramine derivatives of amino acids and taurine reduced the mortality rate in mice with thrombosis induced by intravenous injection of ADP or collagen-epinephrine mixture. Intravenous injection of N,N-dichlorotaurine caused 50% inhibition of platelet aggregation induced by ADP and measured in the platelet-enriched plasma in vitro. The antithrombotic effect of chloramine derivatives of amino acids and taurine is related to their ability to suppress functional activity of platelets.

Conclusions Ionization constants were obtained of 14 amino alcohols and one tertiary amine in 50% ethanol in the range of 10–25° and thermodynamic characteristics of the ionization process of the investigated ammonium ions were calculated.

In liquid-phase hydrogenation of ethyl acetoacetate on bimetallic Ni-Pd catalysts supported on Al2O3, the reaction rate increases sharply and passes through a maximum with an increase in the concentration of Pd. The change in the rate of hydrogenation with a change in the composition of the catalysts is not due to a change in the dispersion of the metallic phase in them or enrichment of their surface with one of the metals.

The direction of the reaction of alkyl furfuryl ethers and sulfides with n-butyllithium is in agreement with the results of basic H-D exchange in the same compounds: In the case of the ethers H-D exchange and metallation take place primarily in the free a position of the furan ring, whereas in the case of the sulfides these reactions take place primarily at the methylene group of the side chain located between the sulfur atom and the furan ring.

Abstract: The proteins fibrinogen and serum albumin and the amino acid alanine modified by sodium hypochlorite are shown to inhibit thrombin-induced aggregation of isolated platelets. The hypochlorite sodium-treated proteins and amino acids acquire the capacity to counter platelet aggregation as a result of the formation of chloramine derivatives. The aggregating capacity of hypochlorite sodium-inactivated platelets can be restored by native plasma and fibrinogen.

1.We have prepared a skeletal Cu-Pd catalyst modified with tartaric acid, on which there is 100% selectivity in the hydrogenation of ethyl a-acetylamino-ß-ketobutyrate with a yield of N-acetyl-allo-threonine ethyl ester of about 90%.2.It is shown that the nature of the metal phase of the catalysts has an effect on their activity, selectivity, and diastereoselectivity in this process.

The presence of a modifier and nature of the catalyst affect the steric selectivity of the hydrogenation of ethyl a-acetylamino-ß-ketobutyrate. The hydrogenation of this ester in ethanol at 75°C and 10.0 MPa on Raney nickel modified by 5% aqueous RR-(+)-tartaric acid at pH 5.0 and 50°C gave the ethyl ester of N-acetyl-allo-threonine in 82% yield.

The properties of immersed bimetallic Cu−Pd and Ni−Pd catalysts have been examined. They depend on both the nature of support and the method for introducing metal components onto support.

The intensity of infection of the mussel Mytilus galloprovincialis Lamarck in the Black Sea by the turbellarian Urastoma cyprinae (Graff), which lives on its gills, was found to be higher in larger hosts, reaching a maximum in mussels of 50–70 mm length. Greater numbers occured in mussels inhabiting a silty bottom than in cultivated mussels suspended above the bottom. Over the period 1982–1987, U. cyprinae was most numerous in winter and especially so in years that were colder. The spionid polychaete Polydora ciliata (Johnston) also infects M. galloprovincialis, burrowing into the shell. Young spionids of up to 1 mm length occured in mussels with a shell length of 35 mm. Numbers of this commensal reached a maximum in mussels of intermediate size.

The thermodynamic ionizaton constants of 12 amino alcohols and 4 tertiary amines were determined in 50% aqueous ethanol medium at 20°. The relation between the basicity and the structure of the investigated compounds was discussed.

1.A decrease in the sterospecificity of the asymmetrical addition of methylmagnesium iodide to (-)-menthyl phenylglyoxylate on increasing the pressure to 5000 kg/cm2 was found.2.The hypothesis, according to which the additional accelerating effect of pressure in sterically hindered reactions is due to a decrease in the free volume, was confirmed; the latter is due to the restriction of the conformational mobility of the interacting groups of atoms during the formation of the transition state.3.The previously formulated rule which determines the effect of pressure on the stereospecificity of asymmetrical synthesis was confirmed.

No relevant conflicts of interest to declare.

The therapeutic exploitation of molecular defects within the DNA damage response (DDR) in tumour cells has become an important treatment paradigm. ‘Synthetic lethality’ relies on pharmacological inhibition of pathways upon which DDR-deficient tumour cells have become dependent for their survival. This induces an intolerable level of unrepaired DNA damage in the tumour cells resulting in cell death, whilst sparing DDR-proficient normal cells