Bladder pain syndrome and sexual function: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS)/interstitial cystitis can adversely affect physical, mental, and sexual health. The aim of the systematic review is to compare sexual function between patients with BPS and healthy controls and to examine whether or not treatment of BPS improves sexual function. METHODS: A literature search was conducted on Embase, Medline, and other databases. Studies comparing sexual function in BPS patients with healthy controls and before/after treatment were included. Where appropriate, data were pooled in a meta-analysis, using a random effects model and the standardised mean difference (SMD) was used for comparison. RESULTS: Out of 384 studies initially identified, 26 studies met the inclusion criteria for the systematic review and 11 for the meta-analysis. Six studies compared sexual function in BPS cases with healthy controls. All studies found that the Female Sexual Function Index (FSFI) was worse in BPS cases than in controls. Pooled data from 5 studies showed that the SMD was -1.02 (CI -1.64, -0.4) in total FSFI scores between the cases and controls, p=0.001. Further analysis showed better sexual function in all FSFI subdomains in healthy controls. Five studies compared sexual function in BPS patients before treatment with after treatment. Pooled data from 3 studies showed an overall improvement in total FSFI score after intravesical treatment: SMD=0.69 (CI 0.23, 1.14), p=0.003. Further analysis showed improvement in all subdomains. CONCLUSION: Our review suggests that sexual function might be worse in BPS patients than in the general population, but it seems to improve with intravesical BPS treatment.

Intramuscular Tranexamic Acid Administration on the Battlefield.

Background: Tranexamic acid (TXA) is routinely administered intravenously (IV) and intraosseously (IO) in response to exsanguination. Case: This report describes a patient who sustained multiple high-powered rifle gunshot wounds that received battlefield-environment intramuscular (IM) administration of TXA due to inability to obtain IV / IO access. This case represents the unlikely positive outcome in the setting of multiple remarkable obstacles, which may have been ameliorated by novel administration of TXA. Conclusion: Cases of IM TXA administration as a primary intervention are not well represented in the current body of medical literature. This case report highlights a clinical scenario where IM TXA was utilized as part of first-line treatment that led to a positive clinical outcome. Although IM TXA is not yet endorsed by current trauma guidelines, this case suggests that IM route administration of TXA should be further investigated. If indeed IM administration of TXA proves just as efficacious as alternative routes, this would hold considerable advantageous implications for austere situations were sterility and IV / IO placement are impractical. This would also represent another avenue by which to decrease the time-to-TXA for patients, allowing sooner correction of hemorrhage and trauma-associated coagulopathy.

Intervention to maximise the probability of epidemic fade-out.

The emergence of a new strain of a disease, or the introduction of an existing strain to a naive population, can give rise to an epidemic. We consider how to maximise the probability of epidemic fade-out - that is, disease elimination in the trough between the first and second waves of infection - in the Markovian SIR-with-demography epidemic model. We assume we have an intervention at our disposal that results in a lowering of the transmission rate parameter, ß, and that an epidemic has commenced. We determine the optimal stage during the epidemic in which to implement this intervention. This may be determined using Markov decision theory, but this is not always practical, in particular if the population size is large. Hence, we also derive a formula that gives an almost optimal solution, based upon the approximate deterministic behaviour of the model. This formula is explicit, simple, and, perhaps surprisingly, independent of ß and the effectiveness of the intervention. We demonstrate that this policy can give a substantial increase in the probability of epidemic fade-out, and we also show that it is relatively robust to a less than ideal implementation.

The probability of epidemic fade-out is non-monotonic in transmission rate for the Markovian SIR model with demography.

Epidemic fade-out refers to infection elimination in the trough between the first and second waves of an outbreak. The number of infectious individuals drops to a relatively low level between these waves of infection, and if elimination does not occur at this stage, then the disease is likely to become endemic. For this reason, it appears to be an ideal target for control efforts. Despite this obvious public health importance, the probability of epidemic fade-out is not well understood. Here we present new algorithms for approximating the probability of epidemic fade-out for the Markovian SIR model with demography. These algorithms are more accurate than previously published formulae, and one of them scales well to large population sizes. This method allows us to investigate the probability of epidemic fade-out as a function of the effective transmission rate, recovery rate, population turnover rate, and population size. We identify an interesting feature: the probability of epidemic fade-out is very often greatest when the basic reproduction number, R0, is approximately 2 (restricting consideration to cases where a major outbreak is possible, i.e., R0>1). The public health implication is that there may be instances where a non-lethal infection should be allowed to spread, or antiviral usage should be moderated, to maximise the chance of the infection being eliminated before it becomes endemic.

Parents as the start of the solution: a social marketing approach to understanding triggers and barriers to entering a childhood weight management service.

BACKGROUND: Childhood obesity is a sensitive subject and barriers exist with respect to accessing weight management programmes. Social marketing insight gathering provides an opportunity to understand behaviours and address these challenges. This project gained insight into the views of parents/carers on triggers and barriers to entering a childhood weight management service. METHODS: Participants were identified from the public using marketing recruitment. Four focus groups were conducted with parents of school aged children (n = 27) by an experienced interviewer. Twenty two mothers, three fathers and two grandmothers participated, with half describing their child as overweight. Groups discussed health behaviours; attitudes to health messages and weight issues; and motivations, benefits and barriers with respect to accessing weight management services. Discussions were taped and transcribed. Themes were identified using framework analysis of content matrix data analysis. RESULTS: Participants were aware of healthy lifestyle messages, although the ability to implement these was variable. Triggers to seeking help included bullying, health concerns and inability to participate in school activities. Barriers included feeling a lack of control, desire to avoid conflict and no proven case that weight was a problem. Parents wished to be given information regarding their child's weight by a trusted person. The Internet and word of mouth were identified as methods of recruitment into a weight management service, with a focus on fitness, fun and friendliness and being free-of-charge. CONCLUSIONS: Insight gathering can be used to establish parental/carer opinion regarding engaging in childhood weight management services. A fun, friendly programme that is free of charge appealed to parents. Local community involvement around normalising child weight issues may boost referrals into child healthy weight interventions.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites.

OBJECTIVE: Inhaled nitric oxide (iNO) is a potential new therapy for prevention of bronchopulmonary dysplasia and brain injury in premature infants. This study examined dose-related effects of iNO on NO metabolites as evidence of NO delivery. STUDY DESIGN: A subset of 102 premature infants in the NO CLD trial, receiving 24 days of iNO (20 p.p.m. decreasing to 2 p.p.m.) or placebo, were analyzed. Tracheal aspirate (TA) and plasma samples collected at enrollment and at intervals during study gas were analyzed for NO metabolites. RESULT: iNO treatment increased NO metabolites in TA at 20 and 10 p.p.m. (1.7- to 2.3-fold vs control) and in plasma at 20, 10, and 5 p.p.m. (1.6- to 2.3-fold). In post hoc analysis, treated infants with lower metabolite levels at entry had an improved clinical outcome. CONCLUSION: iNO causes dose-related increases in NO metabolites in the circulation as well as lung fluid, as evidenced by TA analysis, showing NO delivery to these compartments.

Determination of microsome and hepatocyte scaling factors for in vitro/in vivo extrapolation in the rat and dog.

1. In vivo clearance predictions from in vitro assays require scaling factors to relate the concentrations of hepatocytes or microsomal protein to the intact liver. 2. The aims were to measure the variability in scaling factors for Wistar rat and beagle dog for which the literature is particularly scarce and determine any sex differences. 3. Scaling factors were determined by comparing the cytochrome P450 (P450) content in hepatocytes or microsomes against the P450 content of fresh liver homogenate. The use of fresh homogenate is recommended as freezing can increase contamination and affect the P450 assay. 4. Mean(geo) hepatic microsomal concentrations in Wistar rats were 61 mg g(-1) liver (95% confidence interval (CI); 47-75 mg g(-1) liver) and in beagle dogs 55 mg g(-1) liver (95% CI = 48-62 mg g(-1) liver). Mean(geo) hepatocellularity was 163 x 10(6) cells g(-1) liver for Wistar rats (95% CI = 127-199 x 10(6) cells g(-1) liver) and 169 x 10(6) cells g(-1) liver (95% CI = 131-207 x 10(6) cells g(-1) liver) for beagle dogs. The data generated in this study indicate a consistency in scaling factors between rat and dog. No sex differences were observed.

Treatment with zoledronic acid ameliorates negative geometric changes in the proximal femur following acute spinal cord injury.

Acute spinal cord injury is associated with rapid bone loss and an increased risk of fracture. In this double-blind, randomized, placebo-controlled trial, 17 patients were followed for 1 year after administration of either 4 or 5 mg of zoledronic acid or placebo. Bone mineral density (BMD) and structural analyses of the proximal femur were performed using the hip structural analysis program at entry, 6 months, and 12 months. The 17 subjects completed 12 months of observation, nine receiving placebo and eight zoledronic acid. The placebo group showed a decrease in BMD, cross-sectional area, and section modulus and an increase in buckling ratio at each proximal femur site at 6 and 12 months. Six months after zoledronic acid, BMD, cross-sectional area, and section modulus increased at the femoral neck and intertrochanteric regions and buckling ratio decreased consistent with improved bone stability. However, at 12 months, the femoral narrow-neck values declined to baseline. In contrast to placebo, the intertrochanteric region and femur shaft were maintained at or near baseline through 12 months in the zoledronic acid-treated group. Urine N-telopeptide excretion was increased at baseline and declined in both the placebo and treatment groups during the 12 months of observation. We conclude that a single administration of zoledronic acid will ameliorate bone loss and maintain parameters of bone strength at the three proximal femur sites for 6 months and at the femur intertrochanteric and shaft sites for 12 months.

Maintenance of differentiated function of the surfactant system in human fetal lung type II epithelial cells cultured on plastic.

We report a simplified culture system for human fetal lung type II cells that maintains surfactant expression. Type II cells isolated from explant cultures of hormone-treated lungs (18-22 wk gestation) by collagenase + trypsin digestion were cultured on plastic for 4 days in serum-free medium containing dexamethasone (Dex, 10 nM) + 8-bromo-cAMP (0.1 mM + isobutylmethylxanthine (0.1 mM) or were untreated (control). Surfactant protein (SP) mRNAs decreased markedly in control cells between days 1 and 4 of culture, but mRNA levels were high in treated cells on day) 4 (SP-A, SP-B, SP-C, SP-D; 600%, 100%, 85%, 130% of day 0 content, respectively). Dex or cAMP alone increased SP-B, SP-C, and SP-D mRNAs and together had additive effects. The greatest increase in SP-A mRNA occurred with cAMP alone. Treated cells processed pro-SP-B and pro-SP-C proteins to mature forms and had a higher rate of phosphatidylcholine (PC) synthesis (2-fold) and higher saturation of PC (approximately 34% versus 27%) than controls. Only treated cells maintained secretagogue-responsive phospholipid synthesis. By electron microscopy, the treated cells retained lamellar bodies and extensive microvilli. We conclude that Dex and cAMP additively stimulate expression of surfactant components in isolated fetal type II cells, providing a simplified culture system for investigation of surfactant-related, and perhaps other, type II cell functions.

Respiratory distress after intratracheal bleomycin: selective deficiency of surfactant proteins B and C.

Intratracheal bleomycin in rats is associated with respiratory distress of uncertain etiology. We investigated the expression of surfactant components in this model of lung injury. Maximum respiratory distress, determined by respiratory rate, occurred at 7 days, and surfactant dysfunction was confirmed by increased surface tension of the large-aggregate fraction of bronchoalveolar lavage (BAL). In injured animals, phospholipid content and composition were similar to those of controls, mature surfactant protein (SP) B was decreased 90%, and SP-A and SP-D contents were increased. In lung tissue, SP-B and SP-C mRNAs were decreased by 2 days and maximally at 4--7 days and recovered between 14 and 21 days after injury. Immunostaining of SP-B and proSP-C was decreased in type II epithelial cells but strong in macrophages. By electron microscopy, injured lungs had type II cells lacking lamellar bodies and macrophages with phagocytosed lamellar bodies. Surface activity of BAL phospholipids of injured animals was restored by addition of exogenous SP-B. We conclude that respiratory distress after bleomycin in rats results from surfactant dysfunction in part secondary to selective downregulation of SP-B and SP-C.

Association of plasma cortisol and chronic lung disease in preterm infants.

BACKGROUND: It has been suggested that preterm infants may have developmental immaturity of the hypothalamic-pituitary-adrenal axis, and that decreased cortisol response to stress increases risk of chronic lung disease (CLD) secondary to inflammatory lung injury. METHODS: To investigate the relationship between endogenous corticosteroid and CLD, we measured plasma cortisol during the first 28 days of life in a subset of neonates in the North American Thyrotropin-Releasing Hormone (TRH) Collaborative Trial. Analyses were performed on 314 infants, 24 to 32 weeks' gestation, whose mothers received 1 or 2 courses of antenatal corticosteroids plus TRH or placebo. RESULTS: Mean cortisol was 3.1 microg/dL (range: 0.1-17.9) at birth, reached maximal levels at 24 hours (19.4 microg/dL, range: 0.8-124.6), and decreased to 5.9 microg/dL (range: 0.2-24.7) at 14 to 28 days of age; levels during the first week were not associated with gestational age. The Clinical Risk Index for Babies (CRIB), a neonatal assessment tool that is correlated with risk of mortality, was positively associated with cortisol level on days 1 and 3 through 7. TRH versus placebo treatment did not influence cortisol levels at any time point. To examine the relationship between cortisol and adverse outcome of death or CLD at 36 weeks' postmenstrual age (CLD36), logistic regression models adjusting for known contributing clinical factors (gestational age and CRIB score) were fit. There was a statistically borderline negative association between median cortisol level at 3 to 7 days and CLD36. After adjusting for gestational age and CRIB score, the predicted probability of CLD36 was only minimally influenced by the cortisol concentration. CONCLUSION: In preterm infants, basal plasma cortisol concentration during the first week is a weak predictor for CLD36. Possible benefits as well as risks of supplemental, low-dose cortisol treatment of high-risk preterm infants remain to be determined.

Transforming growth factor-beta(1) regulation of surfactant protein B gene expression is mediated by protein kinase-dependent intracellular translocation of thyroid transcription factor-1 and hepatocyte nuclear factor 3.

The transforming growth factor-beta (TGF beta) polypeptides control a variety of cellular processes including organogenesis and cellular proliferation and differentiation. In the developing lung, TGF beta(1) treatment inhibits airway branching and expression of the genes for surfactant proteins (SP). Many effects of TGF beta are mediated at the level of gene transcription but there is limited information regarding signaling pathways and target transcription factors. In this study with human pulmonary adenocarcinoma H441 cells, we investigated TGF beta(1) effects on SP-B, a protein which is essential for normal function of pulmonary surfactant. TGF beta(1) (10 ng/ml) reduced SP-B mRNA content in a time-dependent fashion, and transient transfection studies localized responsiveness to the region of the SP-B promoter (-112/-72 bp) containing binding sites for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor 3 (HNF3), transcription factors that are important enhancers of SP gene expression. Using electrophoretic mobility shift assay and immunofluorescence, we demonstrated rapid accumulation of these transcription factors in the cytoplasm and subsequent loss from the nucleus on TGF beta(1) treatment of both adenocarcinoma cells and cultured human fetal lung. TGF beta(1) treatment caused intracellular translocation of protein kinase C and effects of TGF beta(1) were mostly abrogated in the presence of the protein kinase inhibitor calphostin C. We conclude that TGF beta(1), acting via protein phosphorylation, blocks nuclear translocation of TTF-1 and HNF3 which results in down-regulation of the SP-B gene and presumably other pulmonary genes which are transactivated by these factors.

Prediction of in vivo tissue distribution from in vitro data 1. Experiments with markers of aqueous spaces.

PURPOSE: The aim of this study was to evaluate the ability of an in vitro method of tissue distribution to accurately predict total water and extracellular aqueous spaces using marker compounds urea and inulin. METHODS: Slices (50-200 mg) of all the major tissues in the rat were incubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and 3H-inulin for 2 h at 37 degrees C. Tissue weight was noted before and after incubation and the tissue-to-buffer ratios determined. RESULTS: 14C-Urea Kp estimates were generally greater than total tissue water due to tissue swelling, which varied widely among the tissues, up to 41% in muscle. In most cases, Kp values were much closer to in vivo values after correcting for the 14C-urea in the imbibed media (Kpcorr). The method was able to distinguish between 14C-urea and 3H-inulin Kp values and indicated that inulin occupied a smaller space than urea, which for the majority of tissues corresponded to the extracellular space. CONCLUSIONS: The Kp(corr) values for 14C-urea and Kp for 3H-inulin were consistent with total tissue water and extracellular space for the majority of tissues studied, indicating their suitability as marker compounds for checking the viability of this in vitro method for estimating tissue distribution.

Errors in the measurement of endometrial depth using transvaginal sonography in postmenopausal women on tamoxifen: random error is reduced using saline instillation sonography.

OBJECTIVE: The endometrium in women on tamoxifen is often made irregular by small cysts. The aim of this study was to assess the accuracy and precision of the measurement of endometrial depth by transvaginal sonography. METHODS: The endometrial depth from endometrial biopsies obtained with the resectoscope in 15 women receiving tamoxifen was compared to the endometrial depth measured by TVS. The inter-observer variability was measured in 58 women. RESULTS: In those biopsies of sufficient quality to allow a measurement, the corresponding depth measurement obtained by ultrasound was up to 3 mm greater than the histological measurement. The interobserver variability for the measurement of endometrial depth using TVS was assessed in 58 postmenopausal women on tamoxifen. The interobserver variability deteriorated as the mean endometrial depth increased, probably because the increase in depth resulted from greater morphological changes within the endometrium such as cyst formation which resulted in an irregular endometrial/myometrial boundary. This may, however, be improved by performing saline instillation sonography. In a prospective study of 10 postmenopausal women, the interobserver variability was significantly greater during tamoxifen treatment compared to pretreatment. CONCLUSIONS: On the basis of the above, if uterine surveillance using TVS were to be offered to postmenopausal women on tamoxifen, then the procedure should be augmented by saline instillation sonography if the endometrial depth is > 4 mm, as this will improve the measurement precision and also identify intrauterine pathology.

Pulmonary surfactant metabolism in infants lacking surfactant protein B.

Infants with inherited deficiency of pulmonary surfactant protein (SP) B develop respiratory failure at birth and die without lung transplantation. We examined aspects of surfactant metabolism in lung tissue and lavage fluid acquired at transplantation or postmortem from ten infants born at term with inherited deficiency of SP-B; comparison groups were infants with other forms of chronic lung disease (CLD) and normal infants. In pulse/chase labeling studies with cultured deficient tissue, no immunoprecipitable SP-B was observed and an approximately 6-kD form of SP-C accumulated that was only transiently present in CLD tissue. SP-B messenger RNA (mRNA) was approximately 8% of normal in deficient specimens, and some intact message was observed after, but not before, explant culture. Transcription rates for SP-B, assessed by nuclear run-on assay using probes for sequences both 5' and 3' of the common nonsense mutation (121ins2), were comparable in all lungs examined. The minimal surface tension achieved with lavage surfactant was similarly elevated in both deficient and CLD infants (26-31 mN/m) compared with normal infants (6 mN/m). Both SP-B-deficient and CLD infants had markedly decreased phosphatidylglycerol content of lavage and tissue compared with normal lung, whereas synthetic rates for phospholipids, including phosphatidylglycerol, were normal. We conclude that the mutated SP-B gene is transcribed normally but produces an unstable mRNA and that absence of SP-B protein blocks processing of SP-C. Chronic infant lung disease, of various etiologies, reduces surfactant function and apparently alters phosphatidylglycerol degradation.

Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs.

Glucocorticoid treatment increases content of surfactant protein (SP) A and SP-B in lung tissue and lavage fluid of preterm lambs. To investigate this process, we determined the ontogeny and glucocorticoid induction of SP mRNAs. In separate treatment protocols, each with its own controls, sheep were injected with betamethasone 15 h, 48 h, or weekly for 1-4 doses before preterm delivery. Using ovine SP cDNAs, we found an increase equal to or more than threefold in basal levels of all three SP mRNAs between 125 days and term. After betamethasone treatment, SP-B and SP-C mRNA levels increased by 15 h and all SP mRNAs were elevated after 24 h (>/=2-fold); mRNA levels in fetuses delivered 1-3 wk after betamethasone were not different from control. We conclude that in vivo betamethasone rapidly induces a coordinated increase in SP mRNAs, which is fully reversible within 7 days despite repetitive doses of betamethasone. Similar increases in mRNA and protein contents for SP-A and SP-B suggest that glucocorticoid regulation of these SPs in vivo is primarily pretranslational.