Knowledge, practices and barriers to access sexual health of women in the menopausal stages: a cross-sectional study with Brazilian gynecologists.

BACKGROUND: Sexual health access and care for women in the menopausal stages face significant barriers, presenting deficits in relation to diagnosis and treatment. Although epidemiological data indicate high prevalence of problems related to sexual health in this population, traditionally, the theme is not discussed in health care settings. This study aimed to analyze knowledge, practices and barriers to access sexual health of women in the menopausal stages in the context of women's health care in Brazil. METHODS: With a cross-sectional design, a questionnaire was distributed electronically, encompassing variables related to knowledge; practices; and barriers to access sexual health of women in the menopausal stages. The data obtained were subjected to analysis using both descriptive and inferential statistics. Specifically, we employed multivariate analysis, employing multiple linear regression models, to discern potential factors associated with outcomes concerning the level of knowledge and the frequency of addressing the topic in professional practice. RESULTS: The sample included 70 physicians with specialization in obstetrician/gynecologists who work in health care with women in the menopausal transition or postmenopausal women. A high level of self-reported knowledge about sexual health was identified. Regarding the practices, most of them reported directly proposing the subject and not using instruments. Although they reported frequently addressing the topic in general, topics related to vaginal lubrication, dyspareunia, and sexual dysfunction have been more present in the clinic compared to sexual orientation and women's relationship with themselves. The main barriers were time limitation and patient discomfort with the topic. The multivariate models indicated that female gynecologists and professionals with higher levels of knowledge on the subject had a higher frequency of addressing sexual health in clinical practice with women in menopausal stages. CONCLUSIONS: Sexual health access and care for brazilian women in the menopausal stages presents discrepancies in the frequency of approach between the various topics, in addition to the predictive character of technical knowledge in the practices of professionals. To ensure universal access to sexual health services for this population, an active approach through specific instruments is important, as well as the reinforcement of strategies to improve the level of knowledge of professionals.

Radiation therapy facility risk analysis in Brazil with SEVRRA software.

Risk assessment deals with processes, accident-initiating events, barriers and risk ratings to unveil the fragility and weakness of some processes; within this study, specifically related to radiation therapy facilities. Barriers are technical or organizational safety measures put in place to avoid, prevent, detect, control, reduce or mitigate the consequences of an accident once an initiating event has occurred. In this work, radiological risk analysis was performed for a set of 20 Brazilian radiotherapy facilities making use of the freeware sevrra risk-management software. The objective of this study was to define parameters that could be useful in creating an overall risk profile. This profile would be helpful for establishing priorities for decision making and support a risk-informed regulatory process. The most relevant missing barriers in facilities were identified according to three parameters: the 'importance index', 'impacted facilities index' and the 'barrier-effectiveness index'. Barriers such as 'in vivo dosimetry in the first treatment session', 'weekly in vivo dosimetry to detect errors in the dose delivering process', 'annual external audit for the control of reference dose rate' and 'independent verification of calibration by various medical physicists with a different dosimetry equipment' were found to be the most effective in reducing the risk level of the facilities. The present investigation reinforces the need to strengthen the mechanisms that guarantee the effectiveness of such barriers in radiation therapy procedures.

Urine concentrations of xanthine, hypoxanthine and uric acid in UK Cavalier King Charles spaniels.

OBJECTIVES: Xanthine urolithiasis and asymptomatic xanthinuria have been diagnosed in Cavalier King Charles spaniel dogs suggesting that primary xanthinuria may be a breed-related disorder, although its prevalence remains unclear. The hypothesis of this study was that asymptomatic xanthinuria is common in Cavalier King Charles spaniel dogs. METHODS: Free catch urine samples were collected from 35 client-owned Cavalier King Charles spaniel dogs and from 24 dogs of other breeds. The purine metabolites were measured by high-performance liquid chromatography. The urine ratios of xanthine/creatinine and hypoxanthine/creatinine were calculated and compared between the two groups of dogs. RESULTS: The urine concentrations of purine metabolites were not significantly different between the two groups and were very low in both. The urine concentrations of xanthine in all 35 Cavalier King Charles spaniel were markedly lower than in the previously reported case of xanthine urolithiasis in a UK Cavalier King Charles spaniel dog. CLINICAL SIGNIFICANCE: Asymptomatic xanthinuria was not detected in this UK Cavalier King Charles spaniel population. This data may be used as a reference for urinary purine metabolite concentrations in the dog.

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

Mechanism of allopurinol induced TPMT inhibition.

Up to 1/5 of patients with wildtype thiopurine-S-methyltransferase (TPMT) activity prescribed azathioprine (AZA) or mercaptopurine (MP) demonstrate a skewed drug metabolism in which MP is preferentially methylated to yield methylmercaptopurine (MeMP). This is known as thiopurine hypermethylation and is associated with drug toxicity and treatment non-response. Co-prescription of allopurinol with low dose AZA/MP (25-33%) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites; however, the biochemical mechanism remains unclear. Using intact and lysate red cell models we propose a novel pathway of allopurinol mediated TPMT inhibition, through the production of thioxanthine (TX, 2-hydroxymercaptopurine). In red blood cells pre-incubated with 250 µM MP for 2h prior to the addition of 250 µM TX or an equivalent volume of Earle's balanced salt solution, there was a significant reduction in the concentration of MeMP detected at 4h and 6h in cells exposed to TX (4 h, 1.68, p=0.0005, t-test). TX acts as a direct TPMT inhibitor with an apparent Ki of 0.329 mM. In addition we have confirmed that the mechanism is relevant to in vivo metabolism by demonstrating raised urinary TX levels in patients receiving combination therapy. We conclude that the formation of TX in patients receiving combination therapy with AZA/MP and allopurinol, likely explains the significant reduction of methylated metabolites due to direct TPMT inhibition.

Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency.

Adenosine deaminase deficiency is a disorder of purine metabolism manifesting severe combined immunodeficiency (ADA-SCID) and systemic abnormalities. Increased levels of the substrate deoxyadenosine triphosphate (dATP) lead to immunodeficiency and are associated in a murine model with pulmonary insufficiency. We compared a cohort of patients with ADA-SCID and X-linked SCID and found that despite similar radiological and respiratory findings, positive microbiology is significantly less frequent in ADA-SCID patients (p < 0.0005), suggesting a metabolic pathogenesis for the lung disease. Clinicians should be aware of this possibility and correct metabolic abnormalities either through enzyme replacement or haematopoietic stem cell transplant, in addition to treating infectious complications.

HPRT deficiency: identification of twenty-four novel variants including an unusual deep intronic mutation.

Hypoxanthine phosphoribosyltranferase (HPRT) deficiency is an X-linked disorder of purine salvage that ranges phenotypically from hyperuricaemia to Lesch-Nyhan Syndrome. Molecular testing is necessary to identify female carriers within families as a prelude to prenatal diagnosis. During the period 1999-2010 the Purine Research Laboratory studied 106 patients from 68 different families. Genomic sequencing revealed mutations in 88% of these families, 24 of which were novel. In eight patients, exon sequencing was not informative. Copy-DNA analysis in one patient revealed an insertion derived from a deep intronic sequence with a genomic mutation flanking this region, resulting in the creation of a false exon. Carrier testing was performed in 21 mothers of affected patients, out of these, 81% (17) were found to be carriers of the disease-associated mutation. Our results confirm the extraordinary variety and complexity of mutations in HPRT deficiency. A combination of genomic and cDNA sequencing may be necessary to define mutations.

Environmental stress alters genetic regulation of novelty seeking in vervet monkeys.

Considerable attention has been paid to identifying genetic influences and gene-environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences in response to a stressful life event for a behavioural trait with relevance for psychopathology. Genetic and environmental influences on free-choice novelty seeking behaviour were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of novelty seeking scores, and genetic correlations within and between environments were conducted using variance components analysis. The results showed that novelty seeking was markedly inhibited in the higher stress environment, with effects persisting across a 2-year period for adults but not for juveniles. There were significant genetic contributions to novelty seeking scores in each year (h(2) = 0.35-0.43), with high genetic correlations within each environment (rhoG > 0.80) and a lower genetic correlation (rhoG = 0.35, non-significant) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h(2) = 0.48). These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene-environment interactions in a behavioural trait with relevance for mental health.

Fetal and maternal factors associated with infant mortality in vervet monkeys.

BACKGROUND: Causes of infant death remain unknown in significant proportions of human and non-human primate pregnancies. METHODS: A closed breeding colony with high rates of infant mortality had pregnancies assessed (n=153) by fetal measurements and maternal characteristics. Infant outcome was classified as neonatal death (stillborn or died <48 hours from birth), postnatal death (died 2-30 days) or surviving (alive after 30 days). RESULTS: Fetal size did not predict outcome. Poor maternal glycemic control and low social ranking increased odds for adverse outcome (OR=3.72, P=0.01 and 2.27, P=0.04, respectively). Male sex was over-represented in stillbirths (P=0.04), and many were macrosomic, but size did not associate with maternal glycemic control measured as glycated hemoglobin A1c. Postnatally dead infants were smaller (P<0.01), which associated with behavioral factors and glycemic control. CONCLUSIONS: Fetal growth estimates predicted gestational age but not fetal outcome. Maternal social status and metabolic health, particularly glycemic control, increased risks of adverse pregnancy outcome.

Clinicopathologic characterization of naturally occurring diabetes mellitus in vervet monkeys.

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys (Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitochondrial inheritance pattern, which supports a monogenic form of DM. The authors thus hypothesize that a naturally occurring monogenic form of diabetes may occur in vervet monkeys, making them a potential animal model for future studies.

An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency.

Molybdenum cofactor deficiency (MOCOD) is a rare inherited metabolic disorder resulting in the combined deficiency of aldehyde oxidase (AO, EC 1.2.3.1), xanthine dehydrogenase (XDH, EC 1.1.1.204), and sulfite oxidase (SUOX, EC 1.8.3.1). The majority of patients typically present soon after birth with intractable seizures, developmental delay and lens dislocation and do not survive early childhood. Milder cases have been reported. We report an unusual mutation in the MOCS1 gene associated with a relatively mild clinical phenotype, in a patient who presented with normal uric acid (UA) levels in plasma. We also report a new MOCS1 mRNA splice variant in the 5' region of the gene. MOCS1 genomic DNA and cDNA from peripheral blood leukocytes were sequenced. MOCS1 mRNA splice variants were amplified with fluorescently labelled primers and quantitated. A novel homozygous mutation MOCS1c.1165+6T > C in intron 9 resulting in miss-splicing of exon 9 was found. Multiple alternatively spliced MOCS1 transcripts have been previously reported. A new MOCS1 transcript in the 5' - exon 1 region was identified in both patient and controls. This new transcript derived from the Larin variant and lacked exon 1 d.

Depression, diabetes and metabolic-nutritional factors in elderly Hispanics.

OBJECTIVE: To examine the relationship of depression to metabolic and nutritional risk factors in older Hispanics. DESIGN: Crossectional study. SETTING: Subjects were part of a community-based, cognitive evaluation project that examined 301 subjects in the Eastern San Fernando Valley of Southern California. PARTICIPANTS: Two elderly Hispanic groups: 53 clinically depressed, with memory complaints but not demented subjects, and 33 generally healthy, cognitively asymptomatic subjects. MEASUREMENTS: The results of functional and nutritional questionnaires, a medical and neurological examination, 12-hour fasting clinical laboratory tests, MRI or CT scans, and neuropsychological testing. RESULTS: Both groups were nearly identical along socio-demographic variables. However, the depressed group differed significantly from the general healthy group not only in percent of diabetics (38% vs.18%), but in the amount of poorly controlled diabetes, and the depressed group consumed about half the amount of fish that the generally healthy group did. CONCLUSIONS: This study suggests that factors such as poorly controlled diabetes combined with low consumption of foods high in omega-3 fatty acid content such as sea fish may be associated with an increased risk of developing depression in late life. These factors may be socio-economically and culturally influenced and are therefore amenable to modification.

Influence of xanthine oxidase on thiopurine metabolism in Crohn's disease.

BACKGROUND: The thiopurines, azathioprine (AZA) and mercaptopurine are extensively used in Crohn's discase (CD). Thiopurine bioactivation can be diverted by either thiopurine methyltransferase (TPMT), or by xanthine oxidase/dehydrogenase (XOD) which forms 6-thiouric acid (6TU). AIM: To investigate whether chronic inflammation could influence small intestinal XOD activity using urinary excretion of 6TU as a surrogate marker of XOD activity. METHODS: 6-Thiouric acid excretion was compared between 32 CD patients and nine dermatology patients (control group), on AZA. Six CD patients were interesting: five with low TPMT activity (one deficient, four intermediate), and one receiving AZA/allopurinol co-therapy. RESULTS: There was no statistical difference in 6TU excretion between the CD and control group. CD location, severity or surgery did not affect excretion. The TPMT-deficient patient excreted 89% of daily AZA dose as 6TU, but excretion by TPMT carriers was essentially normal. Concurrent 5-aminosalicylic acid therapy increased 6TU excretion significantly (median 32.9%), consistent with inhibiting TPMT. 6TU was undetectable in the patient on AZA/allopurinol co-therapy. CONCLUSIONS: The results refuted our hypothesis, but fitted a model where most of an oral thiopurine dose effectively escapes first-pass metabolism by gut XOD, but is heavily catabolized by TPMT. Bioavailability of thiopurines may be competitively inhibited by dietary purines.

Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey.

To elucidate the organization of the serotoninergic innervation within the orbitofrontal cortex (OFC), serotonin transporter (SERT) density was quantified by autoradiography using [(3)H]cyanoimipramine binding. In six adult vervet monkeys, 15 architectonic areas were delineated according to cytoarchitectonic (Nissl), myeloarchitectonic (Gallyas) and chemoarchitectonic (acetylcholinesterase) criteria to assess SERT distribution at two levels of organization: cortical area and cortical type. For cortical type, the 15 areas were evenly divided into three different categories primarily based upon the degree of granularization of layer IV: agranular, dysgranular, and granular. Within agranular and dysgranular, but not granular cortical types, SERT density was area-specific and progressively decreased in a medial to lateral gradient. Across cortical types, SERT density decreased in a caudal to rostral gradient: agranular>dysgranular>granular. A similar caudal to rostral gradient was seen when serotonin content was measured (using high performance liquid chromatography) in areas representative of each cortical type. Collectively, these results suggest that the serotoninergic innervation is organized according to both cortical type and area, and is thus structured to differentially modulate information processing within the OFC.

Human islets derived from donors after cardiac death are fully biofunctional.

Islets from brain-dead donors (BDDs) are being used in the treatment of Type 1 diabetes. However, both donor numbers and islet survival are limited. We explored the clinical potential for islets from non-heart-beating donors (NHBDs), who have lower circulating cytokines, by comparing islets from 10 NHBDs against 12 identically-isolated islets from BDDs over the same time period. The quantity and quality of islets from NHBDs was good. NHBD yielded approximately 12.6% more islets than those of BDDs (505,000 +/- 84,230 vs. 400,970 +/- 172,430 islet equivalent number [IEQ]/pancreas, p = 0.01) with comparable viability. ATP and GTP contents were lower (6.026 +/- 3.076 vs. 18.105 +/- 7.8 nM/mg protein, p = 0.01 and 1.52 +/- 0.87 vs. 3.378 +/- 0.83 nM/mg protein, p = 0.04) and correlated negatively to warm ischemia time (R(2)= 0.8022 and R(2)= 0.7996, respectively). Islets from NHBDs took longer to control hyperglycemia in diabetic mice, but were equally able to sustain euglycemia. With a warm ischemia time (WIT) of

Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an inborn error of purine metabolism responsible for Lesch-Nyhan Disease (LND) and its partial phenotypes, HPRT-related hyperuricemia with neurologic dysfunction (HRND) and hyperuricemia alone. We report here the recognition of six Argentine patients, two with LND and four with HRND. All patients presented elevated excretion of uric acid, hypoxanthine, and xanthine and decreased HPRT enzyme activities <1 nmol/h/mg Hb. The molecular analysis demonstrated in the two LND patients a novel inherited transition mutation, c.203T >C (L68P), in one subject and a germline transition mutation, c.209G >A (G70E), in the other. In the HRND patients a novel transversion mutation, c.584 A >C (Y195S), was found in three related patients and an inherited transition mutation, c.143G >A (R48H), in the fourth subject.

Lactate threshold does not influence metabolic responses during exercise in cyclists.

The purpose of this study was to compare plasma markers of metabolic stress and other physiological parameters during prolonged endurance exercise of different intensity in trained subjects possessing a "high" or "low" lactate threshold (LT) expressed as a percentage (%) of peak power output (PPO). Fifteen trained male cyclists completed an incremental exercise test for determination of PPO and the LT (% PPO). Each subject then completed a 90-min and 20-min exercise trial at an intensity representing 75 and 85 % of PPO, respectively. Blood lactate (La), as well as plasma hypoxanthine (Hx) and uric acid (UA) were measured during each exercise trial. The responses in two groups, one (n = 8) with a LT approximately 65 % PPO (LT (low)), the other group (n = 7) with a LT approximately 75 % (LT (high)) (p < 0.01), were then compared. With the exception of UA, La and Hx increased significantly (p < 0.01) throughout each exercise trial compared to rest. However, there were no significant differences in each trial between the two groups of cyclists. There were also no significant differences in the other physiological parameters in each exercise trial between the subjects in LT (low) and LT (high). This study demonstrates that in trained cyclists homogeneous in terms of PPO, plasma markers of metabolic demand during prolonged exercise are not influenced by the LT when measured in an incremental exercise test.

The novel nucleotide 4KNTP, in high concentrations in erythrocytes of renal failure children: a comparison with accumulation of other putative precursors in the plasma.

We have measured the concentrations of metabolites related to the turnover of NAD, which accumulate in the blood of children with renal failure. One is a novel nucleotide, identified as the N1-riboside triphosphate of 4-pyridone-3-carboxamide (4PYTP), also described as 4KNTP, which accumulates in the erythrocytes in parallel with renal failure.