Pharmacotherapy for the treatment of vaginal atrophy

Introduction: Despite its frequency, recognition and therapy of vulvovaginal atrophy (VVA) remain suboptimal. Wet mount microscopy, or vaginal pH as a proxy, allows VVA diagnosis in menopause, but also in young contraception users, after breast cancer, or postpartum. Intravaginal low dose estrogen product is the main therapy. Ultra-low-dose vaginal estriol is safe and sufficient in most cases, even in breast cancer patients, while hyaluronic acid can help women who cannot or do not want to use hormones.

Areas covered: The authors provide an overview of the current pharmaceutical treatment for vulvovaginal atrophy and provide their expert opinions on its future treatment.

Expert opinion: The basis of good treatment is a correct and complete diagnosis, using a microscope to study the maturity index of the vaginal fluid. Minimal dose of estriol intravaginally with or without lactobacilli is elegant, cheap and can safely be used after breast cancer and history of thromboembolic disease. Laser therapy requires validation and safety data, as is can potentially cause vaginal fibrosis and stenosis, and safer and cheaper alternatives are available.     

Phenotype of peripheral blood lymphocytes and serum immunoglobulin concentration in patients with early rheumatoid arthritis

We studied the phenotype of peripheral blood lymphocytes and serum immunoglobulin concentration in patients with early rheumatoid arthritis and rheumatoid arthritis of more than 12 months duration. Subpopulations of CDIgM⁺, CD25⁺, and HLA-DR⁺ lymphocytes and IgA concentration differed in these groups of patients with rheumatoid arthritis. The count of lymphocytes carrying CDIgM⁺ and HLA-DR⁺ receptors correlated with activity of rheumatoid arthritis. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 1, pp. 92–94, January, 2006     

Gender and racial/ethnic differences in addiction severity, HIV risk, and quality of life among adults in opioid detoxification: results from the National Drug Abuse Treatment Clinical Trials Network

PURPOSE: Detoxification often serves as an initial contact for treatment and represents an opportunity for engaging patients in aftercare to prevent relapse. However, there is limited information concerning clinical profiles of individuals seeking detoxification, and the opportunity to engage patients in detoxification for aftercare often is missed. This study examined clinical profiles of a geographically diverse sample of opioid-dependent adults in detoxification to discern the treatment needs of a growing number of women and whites with opioid addiction and to inform interventions aimed at improving use of aftercare or rehabilitation. METHODS: The sample included 343 opioid-dependent patients enrolled in two national multi-site studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-002). Patients were recruited from 12 addiction treatment programs across the nation. Gender and racial/ethnic differences in addiction severity, human immunodeficiency virus (HIV) risk, and quality of life were examined. RESULTS: Women and whites were more likely than men and African Americans to have greater psychiatric and family/social relationship problems and report poorer health-related quality of life and functioning. Whites and Hispanics exhibited higher levels of total HIV risk scores and risky injection drug use scores than African Americans, and Hispanics showed a higher level of unprotected sexual behaviors than whites. African Americans were more likely than whites to use heroin and cocaine and to have more severe alcohol and employment problems. CONCLUSIONS: Women and whites show more psychopathology than men and African Americans. These results highlight the need to monitor an increased trend of opioid addiction among women and whites and to develop effective combined psychosocial and pharmacologic treatments to meet the diverse needs of the expanding opioid-abusing population. Elevated levels of HIV risk behaviors among Hispanics and whites also warrant more research to delineate mechanisms and to reduce their risky behaviors.     

Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues

Mutations in mitochondrial DNA (mtDNA) contribute to multiple diseases. However, how new mtDNA mutations arise and accumulate with age remains understudied because of the high error rates of current sequencing technologies. Duplex sequencing reduces error rates by several orders of magnitude via independently tagging and analyzing each of the two template DNA strands. Here, using duplex sequencing, we obtained high-quality mtDNA sequences for somatic tissues (liver and skeletal muscle) and single oocytes of 30 unrelated rhesus macaques, from 1 to 23 y of age. Sequencing single oocytes minimized effects of natural selection on germline mutations. In total, we identified 17,637 tissue-specific de novo mutations. Their frequency increased ∼3.5-fold in liver and ∼2.8-fold in muscle over the ∼20 y assessed. Mutation frequency in oocytes increased ∼2.5-fold until the age of 9 y, but did not increase after that, suggesting that oocytes of older animals maintain the quality of their mtDNA. We found the light-strand origin of replication (OriL) to be a hotspot for mutation accumulation with aging in liver. Indeed, the 33-nucleotide-long OriL harbored 12 variant hotspots, 10 of which likely disrupt its hairpin structure and affect replication efficiency. Moreover, in somatic tissues, protein-coding variants were subject to positive selection (potentially mitigating toxic effects of mitochondrial activity), the strength of which increased with the number of macaques harboring variants. Our work illuminates the origins and accumulation of somatic and germline mtDNA mutations with aging in primates and has implications for delayed reproduction in modern human societies.

Mitochondria produce energy and are involved in myriad other cellular functions (reviewed in ref. 1). The mammalian mitochondrial DNA (mtDNA) is a small (∼16.6 kb in humans), circular, maternally transmitted molecule, which harbors 37 genes encoding 13 proteins (which form oxidative phosphorylation subunits), 22 transfer RNAs (tRNAs), and 2 ribosomal RNAs (rRNAs; reviewed in ref. 2). mtDNA is present in hundreds to thousands of copies per somatic cell and in >100,000 copies in an oocyte (3).The germline nucleotide substitution rate of mtDNA is an order of magnitude higher than that of nuclear DNA (4, 5). Germline mutations increase in frequency with paternal and maternal age in nuclear DNA of humans (6) and macaques (7); however, whether they accumulate with maternal age in mtDNA of primates has been understudied. Such age-related accumulation was suggested based on the analysis of human pedigrees (4, 8) without the direct examination of germline cells and, thus, might have been influenced by selection. An investigation of mutation accumulation in the oocytes of females of different ages is needed to settle this question unequivocally.The direct examination of mtDNA mutations in oocytes has been challenging due to methodological limitations. Most studies either focused on a limited number of mtDNA sites (e.g., refs. 9, 10) or used sequencing methods with high error rates (e.g., refs. 11, 12). Recently, an age-related increase of mtDNA mutations in mouse oocytes was demonstrated with duplex sequencing (13). However, we still do not know definitively whether the frequency of mtDNA mutations increases with age in primate oocytes. Answering this question is critical due to the association of mtDNA mutations with human genetic diseases (reviewed in ref. 14) and because of frequently delayed reproduction in modern human societies. Examining mutations in human oocytes presents multiple logistical and ethical challenges, requiring one to turn to a primate model.The rhesus macaque is an excellent model organism to study mtDNA mutations in relation to aging due to 1) the high similarity between macaque and human mtDNA, innate defenses against oxidative damage (15), and age-related decline in metabolic rate (16); and 2) the possibility of collecting oocytes from macaques starting at a young age. For humans, oocyte collection is mainly restricted to the reproductive lifespan, when in vitro fertilization procedures are performed.Here, we analyzed mutations in single oocytes and somatic tissues of rhesus macaques over an age span of >20 y, including samples from animals who have not reached sexual maturity (occurring at ∼3 y; ref. 17), as well as from animals up to the age of 23 y, covering the whole reproductive lifespan (macaques reach menopause at the age of ∼25 y; ref. 18). To measure de novo mutations, we used highly accurate duplex sequencing (19), allowing one to distinguish bona fide DNA variants from artifacts (sequencing and PCR errors, or DNA lesions) by barcoding double-stranded sequencing templates and achieving error rates <10⁻⁷. With this method, first, single-strand consensus sequences (SSCSs) are formed for reads originating from each of the two template strands separately. Next, a duplex consensus sequence (DCS) is formed from the two SSCSs. True DNA variants are expected to be present in both SSCSs and, thus, in the DCS. Using this method, we directly measured the frequency of de novo germline and somatic mutations across the whole mtDNA in macaques, demonstrating their accumulation with age. We identified variant hotspots, analyzed the effect of selection, and examined the dependence of allele frequencies of inheritable mtDNA heteroplasmies on age.     

Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia

Background Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy.Methods Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro.Results We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.Conclusion Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.Subject terms: Genetics research, Cancer genomics, Chronic lymphocytic leukaemia, DNA methylation, Epigenomics     

Clinical Features and Comparison of Kingella and Non–Kingella Endocarditis in Children,Israel

Kingella spp. have emerged as an important cause of invasive pediatric diseases. Data on Kingella infective endocarditis (KIE) in children are scarce. We compared the clinical features of pediatric KIE cases with those of Streptococcus species IE (StIE) and Staphylococcus aureus IE (SaIE). A total of 60 patients were included in the study. Throughout the study period, a rise in incidence of KIE was noted. KIE patients were significantly younger than those with StIE and SaIE, were predominately boys, and had higher temperature at admission, history of oral aphthae before IE diagnosis, and higher lymphocyte count (p<0.05). Pediatric KIE exhibits unique features compared with StIE and SaIE. Therefore, in young healthy children <36 months of age, especially boys, with or without a congenital heart defect, with a recent history of oral aphthae, and experiencing signs and symptoms compatible with endocarditis, Kingella should be suspected as the causative pathogen.     

The Ural train-gas pipeline catastrophe: the report of the IDF medical corps assistance

Following the destruction of two trains in the Urals 2000 km east of Moscow, as a consequence of the conflagration caused by an explosion from a leaking natural gas pipeline, 3000 people were injured;* most of them (2200) died* immediately and the others (about 800) were badly burned. At the request of the Soviet Union Government a medical military delegation was sent to give assistance to the injured people. This report describes the treatment given by the delegation to 40 patients with burns of between 40 and 90 per cent TBSA during a period of 10 days. An insight into a Soviet Union Trauma Center is given and the good treatment given by the Soviet colleagues is emphasized.     

Influences of temperature and pH on free T4 and free T3 in charr and trout plasma

The influences of temperature and pH on the percentages of T4 (L-thyroxine) or T3 (3,5,3'-triiodo-L-thyronine) in the free form (%FT4 or %FT3) were determined by equilibrium dialysis on Arctic charr and rainbow trout plasma. %FT4 and %FT3 of plasma from trout or charr acclimated at 12-13 degrees increased with dialysis temperature (5-19 degrees). When charr plasma was dialyzed at fish acclimation temperature (5, 13, 20 degrees), %FT4 and %FT3 also increased with temperature. However, when plasma from charr acclimated at 5, 13, or 20 degrees was dialyzed at 13 degrees, %FT4 and %FT3 showed no dependence on previous thermal acclimation. %FT4 of charr plasma increased with dialysis pH (7.0-7.8); %FT3 was less responsive to pH but was lower at pH 7.0-7.4 than at pH 7.6-8.0. It is concluded that acute in vitro physiologic changes in either temperature or pH alter the proportions of plasma T4 and T3 in the free form; comparable in vivo effects could explain aspects of environmentally modified T4 and T3 metabolism.