Can the outcome of pelvic-floor rehabilitation in patients with fecal incontinence be predicted?

Purpose: Pelvic-floor rehabilitation does not provide the same degree of relief in all fecal incontinent patients. We aimed at studying prospectively the ability of tests to predict the outcome of pelvic-floor rehabilitation in patients with fecal incontinence. Materials and methods: Two hundred fifty consecutive patients (228 women) underwent medical history and a standardized series of tests, including physical examination, anal manometry, pudendal nerve latency testing, anal sensitivity testing, rectal capacity measurement, defecography, endoanal sonography, and endoanal magnetic resonance imaging. Subsequently, patients were referred for pelvic-floor rehabilitation. Outcome of pelvic-floor rehabilitation was quantified by the Vaizey incontinence score. Linear regression analyses were used to identify candidate predictors and to construct a multivariable prediction model for the posttreatment Vaizey score. Results: After pelvic-floor rehabilitation, the mean baseline Vaizey score (18, SD±3) was reduced with 3.2 points (p<0.001). In addition to the baseline Vaizey score, three elements from medical history were significantly associated with the posttreatment Vaizey score (presence of passive incontinence, thin stool consistency, primary repair of a rupture after vaginal delivery at childbed) (R2, 0.18). Th

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron

We have measured the number of like-sign (LS) and opposite-sign (OS) lepton pairs arising from double semileptonic decays of $b$ and $\bar{b}$-hadrons, pair-produced at the Fermilab Tevatron collider. The data samples were collected with the Collider Detector at Fermilab (CDF) during the 1992-1995 collider run by triggering on the existence of $\mu \mu$ and $e \mu$ candidates in an event. The observed ratio of LS to OS dileptons leads to a measurement of the average time-integrated mixing probability of all produced $b$-flavored hadrons which decay weakly, $\bar{\chi} = 0.152 \pm 0.007$ (stat.) $\pm 0.011$ (syst.), that is significantly larger than the world average $\bar{\chi} = 0.118 \pm 0.005$.Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Site-specific analysis of gene expression in early osteoarthritis using the Pond-Nuki model in dogs

BACKGROUND: Osteoarthritis (OA) is a progressive and debilitating disease that often develops from a focal lesion and may take years to clinically manifest to a complete loss of joint structure and function. Currently, there is not a cure for OA, but early diagnosis and initiation of treatment may dramatically improve the prognosis and quality of life for affected individuals. This study was designed to determine the feasibility of analyzing changes in gene expression of articular cartilage using the Pond-Nuki model two weeks after ACL-transection in dogs, and to characterize the changes observed at this time point. METHODS: The ACL of four dogs was completely transected arthroscopically, and the contralateral limb was used as the non-operated control. After two weeks the dogs were euthanatized and tissues harvested from the tibial plateau and femoral condyles of both limbs. Two dogs were used for histologic analysis and Mankin scoring. From the other two dogs the surface of the femoral condyle and tibial plateau were divided into four regions each, and tissues were harvested from each region for biochemical (GAG and HP) and gene expression analysis. Significant changes in gene expression were determined using REST-XL, and Mann-Whitney rank sum test was used to analyze biochemical data. Significance was set at (p < 0.05). RESULTS: Significant differences were not observed between ACL-X and control limbs for Mankin scores or GAG and HP tissue content. Further, damage to the tissue was not observed grossly by India ink staining. However, significant changes in gene expression were observed between ACL-X and control tissues from each region analyzed, and indicate that a unique regional gene expression profile for impending ACL-X induced joint pathology may be identified in future studies. CONCLUSION: The data obtained from this study lend credence to the research approach and model for the characterization of OA, and the identification and validation of future diagnostic modalities. Further, the changes observed in this study may reflect the earliest changes in AC reported during the development of OA, and may signify pathologic changes within a stage of disease that is potentially reversible

Menstrual function among women exposed to polybrominated biphenyls: A follow-up prevalence study

BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997–1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20–35 days (age range: 24–56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976–1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds

Methamphetamine Preconditioning Alters Midbrain Transcriptional Responses to Methamphetamine-Induced Injury in the Rat Striatum

Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse

Type 1 Fimbriae, a Colonization Factor of Uropathogenic Escherichia coli, Are Controlled by the Metabolic Sensor CRP-cAMP

Type 1 fimbriae are a crucial factor for the virulence of uropathogenic Escherichia coli during the first steps of infection by mediating adhesion to epithelial cells. They are also required for the consequent colonization of the tissues and for invasion of the uroepithelium. Here, we studied the role of the specialized signal transduction system CRP-cAMP in the regulation of type 1 fimbriation. Although initially discovered by regulating carbohydrate metabolism, the CRP-cAMP complex controls a major regulatory network in Gram-negative bacteria, including a broad subset of genes spread into different functional categories of the cell. Our results indicate that CRP-cAMP plays a dual role in type 1 fimbriation, affecting both the phase variation process and fimA promoter activity, with an overall repressive outcome on fimbriation. The dissection of the regulatory pathway let us conclude that CRP-cAMP negatively affects FimB-mediated recombination by an indirect mechanism that requires DNA gyrase activity. Moreover, the underlying studies revealed that CRP-cAMP controls the expression of another global regulator in Gram-negative bacteria, the leucine-responsive protein Lrp. CRP-cAMP-mediated repression is limiting the switch from the non-fimbriated to the fimbriated state. Consistently, a drop in the intracellular concentration of cAMP due to altered physiological conditions (e.g. growth in presence of glucose) increases the percentage of fimbriated cells in the bacterial population. We also provide evidence that the repression of type 1 fimbriae by CRP-cAMP occurs during fast growth conditions (logarithmic phase) and is alleviated during slow growth (stationary phase), which is consistent with an involvement of type 1 fimbriae in the adaptation to stress conditions by promoting biofilm growth or entry into host cells. Our work suggests that the metabolic sensor CRP-cAMP plays a role in coupling the expression of type 1 fimbriae to environmental conditions, thereby also affecting subsequent attachment and colonization of host tissues

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Rationale Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many \u201coff target\u201d effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence