Demonstration of a near-IR line-referenced electro-optical laser frequency comb for precision radial velocity measurements in astronomy.

An important technique for discovering and characterizing planets beyond our solar system relies upon measurement of weak Doppler shifts in the spectra of host stars induced by the influence of orbiting planets. A recent advance has been the introduction of optical frequency combs as frequency references. Frequency combs produce a series of equally spaced reference frequencies and they offer extreme accuracy and spectral grasp that can potentially revolutionize exoplanet detection. Here we demonstrate a laser frequency comb using an alternate comb generation method based on electro-optical modulation, with the comb centre wavelength stabilized to a molecular or atomic reference. In contrast to mode-locked combs, the line spacing is readily resolvable using typical astronomical grating spectrographs. Built using commercial off-the-shelf components, the instrument is relatively simple and reliable. Proof of concept experiments operated at near-infrared wavelengths were carried out at the NASA Infrared Telescope Facility and the Keck-II telescope.

Discovery and spectroscopy of the young jovian planet 51 Eri b with the Gemini Planet Imager.

Directly detecting thermal emission from young extrasolar planets allows measurement of their atmospheric compositions and luminosities, which are influenced by their formation mechanisms. Using the Gemini Planet Imager, we discovered a planet orbiting the ~20-million-year-old star 51 Eridani at a projected separation of 13 astronomical units. Near-infrared observations show a spectrum with strong methane and water-vapor absorption. Modeling of the spectra and photometry yields a luminosity (normalized by the luminosity of the Sun) of 1.6 to 4.0 × 10(-6) and an effective temperature of 600 to 750 kelvin. For this age and luminosity, "hot-start" formation models indicate a mass twice that of Jupiter. This planet also has a sufficiently low luminosity to be consistent with the "cold-start" core-accretion process that may have formed Jupiter.

Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis and metastasis.

Expression of the antioxidant enzyme EcSOD in normal human mammary epithelial cells was not recognized until recently. Although expression of EcSOD was not detectable in non-malignant human mammary epithelial cells (HMEC) cultured in conventional two-dimensional (2D) culture conditions, EcSOD protein expression was observed in normal human breast tissues, suggesting that the 2D-cultured condition induces a repressive status of EcSOD gene expression in HMEC. With the use of laminin-enriched extracellular matrix (lrECM), we were able to detect expression of EcSOD when HMEC formed polarized acinar structures in a 3D-culture condition. Repression of the EcSOD-gene expression was again seen when the HMEC acini were sub-cultured as a monolayer, implying that lrECM-induced acinar morphogenesis is essential in EcSOD-gene activation. We have further shown the involvement of DNA methylation in regulating EcSOD expression in HMEC under these cell culture conditions. EcSOD mRNA expression was strongly induced in the 2D-cultured HMEC after treatment with a DNA methyltransferase inhibitor. In addition, epigenetic analyses showed a decrease in the degree of CpG methylation in the EcSOD promoter in the 3D versus 2D-cultured HMEC. More importantly, >80% of clinical mammary adenocarcinoma samples showed significantly decreased EcSOD mRNA and protein expression levels compared with normal mammary tissues and there is an inverse correlation between the expression levels of EcSOD and the clinical stages of breast cancer. Combined bisulfite restriction analysis analysis of some of the tumors also revealed an association of DNA methylation with the loss of EcSOD expression in vivo. Furthermore, overexpression of EcSOD inhibited breast cancer metastasis in both the experimental lung metastasis model and the syngeneic mouse model. This study suggests that epigenetic silencing of EcSOD may contribute to mammary tumorigenesis and that restoring the extracellular superoxide scavenging activity could be an effective strategy for breast cancer treatment.

Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness.

PURPOSE: We determined the efficacy and safety of pelvic floor myofascial physical therapy compared to global therapeutic massage in women with newly symptomatic interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A randomized controlled trial of 10 scheduled treatments of myofascial physical therapy vs global therapeutic massage was performed at 11 clinical centers in North America. We recruited women with interstitial cystitis/painful bladder syndrome with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years' symptom duration. The primary outcome was the proportion of responders defined as moderately improved or markedly improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O'Leary-Sant IC Symptom and Problem Index, and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes cross-sectional descriptive statistics and changes from baseline were calculated. RESULTS: A total of 81 women randomized to the 2 treatment groups had similar symptoms at baseline. The global response assessment response rate was 26% in the global therapeutic massage group and 59% in the myofascial physical therapy group (p=0.0012). Pain, urgency and frequency ratings, and O'Leary-Sant IC Symptom and Problem Index decreased in both groups during followup, and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported. CONCLUSIONS: A significantly higher proportion of women with interstitial cystitis/painful bladder syndrome responded to treatment with myofascial physical therapy than to global therapeutic massage. Myofascial physical therapy may be a beneficial therapy in women with this syndrome.

Sciatic nerve injury induces functional pro-nociceptive chemokine receptors in bladder-associated primary afferent neurons in the rat.

Visceral sensory afferents during disease or following injury often produce vague, diffuse body sensations, and pain referred to somatic targets. Alternatively, injury due to trauma or disease of somatic nerve targets can also lead to referred pain in visceral targets via a somatovisceral reflex. Both phenomenons are thought to be due to convergence of visceral and somatic afferents within the spinal cord. To investigate a potential peripheral influence for referred pain in visceral targets following somatic nerve injury, we examined whether a sciatic nerve injury known to produce hindpaw tactile hyperalgesia alters the frequency of micturition and the sensitivity of bladder-associated sensory neurons to pro-nociceptive chemokines. Adult female Sprague-Dawley rats received injections of cholera toxin B subunit conjugated to 555 into urinary bladder wall to retrogradely label visceral primary afferent neurons. After 7 days, the right sciatic nerve of these animals was subjected to a lysophosphatidylcholine (LPC)-induced focal demyelination injury. Pre- and post-injury tactile sensitivity in the hind paw and micturition frequency were assayed. Animals were allowed to survive for 14-28 days. Lumbosacral and lumbar dorsal root ganglia (DRG) ipsilateral to the nerve injury were acutely dissociated from sham and nerve injured animals. Bladder wall-associated sensory neurons identified via the retrograde marker were assayed for fluxes in intracellular calcium following administration of pro-nociceptive chemokines. The assayed chemokines included monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal cell derived factor-1 alpha (SDF1/CXCL12). LPC nerve injured animals exhibited tactile hyperalgesia and increased micturition frequency for at least 28 days. Focal demyelination of the sciatic nerve also increased the number of injured L4L5 and non-injured L6-S2 bladder-associated sensory neurons that responded to MCP1 and SDF1 when compared with sensory neurons derived from uninjured naïve and sham-injured control animals. Taken together, these data suggest that some visceral hypersensitivity states may have a somatic origin. More importantly, nociceptive somatovisceral sensation may be mediated by upregulation of chemokine signaling in visceral sensory neurons.

Disturbances in the positioning, proliferation and apoptosis of neural progenitors contribute to subcortical band heterotopia formation.

Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6(+) and Tbr2(+) progenitors are mislocalized in tish(+/-) and tish(-/-)- neocortex throughout neurogenesis. In addition, mislocalized tish(-/-) progenitors possess a longer cell cycle than wild type or normally-positioned tish(-/-) progenitors, owing to a lengthened G(2)+M+G(1) time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone (VZ), as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish(-/-) heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish(-/-) neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone (SVZ) progenitors produce neurons that migrate into both the heterotopia and cortical plate (CP). Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

Nocturia, nocturnal incontinence prevalence, and response to anticholinergic and behavioral therapy.

To determine whether participants in the behavior enhances drug reduction of incontinence (BE-DRI) trial experienced reduction in the frequency of nocturia and/or nocturnal leakage during treatment with antimuscarinic phamacotherapy with or without additional behavioral therapy. We analyzed urinary diary data relating to nocturia and nocturnal incontinence before and after 8 weeks of study treatment in the BE-DRI trial, in which patients were randomly assigned to receive drug therapy with tolterodine tartrate extended-release capsules 4 mg alone or in combination with behavioral training. Chi-square tests assessed whether nocturia and nocturnal incontinence prevalence varied by treatment arm and paired t tests assessed the change in mean frequency of nocturia and nocturnal leakage. Among 305 women, 210 (69%) had an average of at least one nocturia episode at baseline. There were small but statistically significant differences (p < 0.001) in mean nocturia frequency and nocturnal incontinence frequency with both treatments after 8 weeks, but no significant difference between study treatment groups. Among these urge incontinent women, tolterodine with or without supervised behavioral therapy had little impact on either nocturic frequency or nocturnal incontinence.

Pelvic support, pelvic symptoms, and patient satisfaction after colpocleisis.

The objective was to study the effect of colpocleisis on pelvic support, symptoms, and quality of life and report-associated morbidity and postoperative satisfaction. Women undergoing colpocleisis for treatment of pelvic organ prolapse (POP) were recruited at six centers. Baseline measures included physical examination, responses to the Pelvic Floor Distress Inventory, and Pelvic Floor Impact Questionnaire. Three and 12 months after surgery we repeated baseline measures. Of 152 patients with mean age 79 (+/-6) years, 132 (87%) completed 1 year follow-up. Three and 12 months after surgery, 90/110 (82%) and 75/103 (73%) patients following up had POP stage < or = 1. All pelvic symptom scores and related bother significantly improved at 3 and 12 months, and 125 (95%) patients said they were either 'very satisfied' or 'satisfied' with the outcome of their surgery. Colpocleisis was effective in resolving prolapse and pelvic symptoms and was associated with high patient satisfaction.

Prolapse severity, symptoms and impact on quality of life among women planning sacrocolpopexy.

OBJECTIVES: To explore the relationship between severity of pelvic organ prolapse (POP), symptoms of pelvic dysfunction and quality of life using validated measures. METHOD: Baseline data from 314 participants in the Colpopexy And Urinary Reduction Efforts (CARE) trial were analyzed. Pelvic symptoms and impact were assessed using the Pelvic Floor Distress Inventory (PFDI) and the Pelvic Floor Impact Questionnaire (PFIQ). PFDI and PFIQ scores were compared by prolapse stage and history of incontinence or POP surgery. Regression analyses were performed to identify other predictors of symptoms and impact. RESULTS: Women were predominantly (90%) Caucasian and had mean age of 61 years. Women with stage II POP, especially those with prior surgery, reported more symptoms and impact than women with more advanced POP. There were no other significant predictors of symptoms or life impact. CONCLUSIONS: Women planning sacrocolpopexy with stage II prolapse and prior pelvic surgery reported more symptoms and quality of life impact than those with more advanced prolapse.

Reference urodynamic values for stress incontinent women.

OBJECTIVE: To determine reference urodynamic values for preoperative urodynamic studies in women undergoing surgery for pure or predominant stress urinary incontinence (SUI). MATERIALS AND METHODS: Six hundred fifty-five women with pure or predominant SUI were enrolled in a multicenter surgical trial and were randomized to undergo a Burch or autologous fascia sling procedure as part of the Urinary Incontinence Treatment Network (UITN) Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr). Preoperative free uroflowmetry, filling cystometry, and pressure flow studies were performed in all women using a standardized research protocol and standardized urodynamic interpretation guidelines. We define the normal range of urodynamic values in this population as the values that encompass 95% of the results. RESULTS: In 655 women undergoing filling cystometry in the standing position, baseline vesical and abdominal pressures were between 12 and 60 cm H(2)O. The upper limit of detrusor pressure increase during bladder filling to maximum cystometric capacity was 16 cm H(2)O. Ten percent of women who qualified for stress incontinence surgery with a positive cough stress test on physical exam did not demonstrate urodynamic stress incontinence (USI) and less than 10% of subjects in this study demonstrated detrusor overactivity. CONCLUSIONS: Results from a large cohort of women with SUI are now available for quantitative plausibility assessments or as reference values when interpreting urodynamic studies.

Urodynamic prolapse reduction alters urethral pressure but not filling or pressure flow parameters.

PURPOSE: To test the hypothesis that advanced stages of pelvic organ prolapse can result in a functional obstruction of the urethra, we studied the effects of manual prolapse reduction on urodynamic and urethral electromyographic parameters in women with stage III and IV pelvic organ prolapse. MATERIALS AND METHODS: Women with advanced pelvic organ prolapse undergoing clinical multichannel urodynamics with concentric needle electromyography of the urethra were invited to participate in this institutional review board approved study. Women underwent filling cystometry and electromyography with prolapse everted and with prolapse reduced. Women were randomized to cystometry order (reduced vs everted). All subjects underwent a third study with prolapse reduction. Maximum urethral closure pressure and quantitative electromyography of the striated urethral sphincter were determined at maximum cystometric capacity. During the pressure flow study voiding parameters, including urethral electromyography quieting, were determined. The nonparametric paired sign test was used to evaluate differences in urodynamic parameters and quantitative electromyography with pelvic organ prolapse reduced and unreduced. Results were considered significant at the 5% level. RESULTS: The 31 participants had mean age of 60 years (range 36 to 78) and 83% were white. There were no clinically significant differences in maximum cystometric capacity, voided volume, maximal flow and detrusor pressure at maximal flow or time to maximal flow between the reduced and everted prolapse states. Prolapse reduction resulted in a clinically and statistically significant decrease in maximum urethral closure pressure (-31%) but it had no impact on quantitative urethral electromyography. CONCLUSIONS: These findings demonstrate that, although prolapse reduction significantly decreases maximum urethral closure pressure, it does not alter intrinsic neuromuscular activity of the striated urethral sphincter. Prolapse reduction does not alter any other filling or pressure flow parameter.

Urinary hesitancy and retention during treatment with sertraline.

We report the cases of two women who began to experience urinary hesitancy and retention after starting treatment with sertraline for depression. Discontinuation of the drug resulted in complete symptom relief. Serotonergic neurons are involved at several levels in control of the lower urinary tract. Retention is apparently an uncommon complication of sertraline. Discontinuation should be considered for patients presenting with voiding difficulties.

Interrater reliability of filling cystometrogram interpretation in a multicenter study.

PURPOSE: As part of a continuous quality control effort to measure the interrater reliability of urodynamic studies performed at multiple centers, we compared agreement levels for urodynamic studies between central and local physician reviewers. We report interrater reliability findings for the filling cystometrogram. MATERIALS AND METHODS: Following a satisfactory interrater reliability study among 4 central physician reviewers in 33 tracings 36 urodynamic study tracings from 9 Urinary Incontinence Treatment Network continence treatment centers and 13 Urinary Incontinence Treatment Network certified urodynamic study testers were randomly selected for review. These tracings were originally interpreted by 11 local physician reviewers using standardized Urinary Incontinence Treatment Network interpretation guidelines. Each of the 4 central physician reviewers reviewed 9 randomly assigned tracings and none reviewed tracings from his or her center. Local and central physician reviewers were instructed to categorize values as invalid if specified technical quality assurance standards were not met or the signal pattern suggested implausible values because of technical deficiencies. An intraclass correlation coefficient was calculated for continuous (numerical) variables and a kappa statistic was calculated for qualitative values with acceptable agreement defined a priori as an intraclass correlation coefficient of greater than 0.6. RESULTS: Filling cystometrogram baseline pressure, Valsalva leak point pressure, and volume and pressure measurements at maximum cystometric capacity had excellent intraclass correlation coefficients of 0.74 to 0.99. There were no significant differences between local and central physician reviewer means, indicating excellent agreement. CONCLUSIONS: With proper quality control measures in place and a set of standardized interpretive guidelines excellent interrater reliability between local and central physician reviewer can be achieved for numerical cystometrogram variables.

What is the pain of interstitial cystitis like?

To describe the characteristics of pain experienced by patients with interstitial cystitis (IC) in terms of pain site, severity, and character, we performed a secondary analysis of data from the IC database (ICDB), which was a prospective, longitudinal, cohort study of IC patients. We analyzed the cross-sectional baseline data from 629 patients who had a completed baseline symptom questionnaire. Patients answered questions about whether they had pain or discomfort associated with urinary symptoms over the past 4 weeks and if so, about the location, characteristics, intensity, and frequency of their pain. Logistic regression examined associations between pain location and the presence of urinary symptoms. Analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC, USA) and considered significant at the 5% level. Five hundred and eighty-nine (94%) patients with a mean age of 45 years (SD 14 years) reported baseline pain or discomfort associated with their urinary symptoms. The most common baseline pain site was lower abdominal (80%), with urethral (74%) and low back pain (65%) also commonly reported. The majority of patients described their pain as intermittent, regardless of the pain site. Most patients reported moderate pain intensity, across all pain sites. There was a statistically significant link between pain in the urethra, lower back, and lower abdomen, and urinary symptoms. Patients with IC report pain at several sites other than the bladder, possibly arising from the previously well-described myofascial abnormalities of pelvic floor and abdominal wall present in patients with IC and other chronic pelvic pain syndromes.

Gender differences in 24-hour urinary diaries of asymptomatic North American adults.

PURPOSE: Two previously published studies from our center have described the urinary habits of asymptomatic men (284) and women (300) as revealed by 24-hour urinary diaries. Those gender specific studies found that urinary diary variables are affected by age and race. By comparing the data from those studies we determined the effect of gender on voiding habits. MATERIALS AND METHODS: In this secondary analysis we matched each female urinary diary to that of a male of similar age and race. Diary variables were compared using paired sign tests with results considered significant at the 5% level. RESULTS: A total of 141 matched pairs were studied. The population age ranged from 18 to 68 years and was racially diverse (56% black, 31% white, 7% Hispanic and 6% Asian). Men had higher total fluid intake and mean voided volume than women (p <0.001 and 0.04, respectively). Women voided more frequently than men (p = 0.006) and had more voids per liter of fluid intake (p <0.001). No gender differences were found for body mass index, nighttime or daytime diuresis rates, total urine volume, maximum voided volume or rates of nocturia. CONCLUSIONS: This analysis suggests that there are significant gender effects on 24-hour diary variables, with females tending to void more often and at lower mean volumes. The results of our study may be useful in the design of research studies or for patient counseling.

New measurements of G using the measurement standards laboratory torsion balance.

This Letter presents the results of a series of measurements of the Newtonian gravitational constant G using the compensated torsion balance developed at the Measurement Standards Laboratory. Since our last published result using the torsion balance in the compensated mode of operation [Meas. Sci. Technol. 10, 439 (1999)]], several improvements have been made to reduce the uncertainty in the final result. The new measurements have used both stainless steel and copper large masses. The values of G for the two sets of masses are in good agreement. After combining all of the measurements we get a value of G=6.673 87(0.000 27) x 10(-11) m3 kg(-1) s(-2). This new value is 5 parts in 10(5) smaller than our previous published values.

Rehabilitation of the short pelvic floor. I: Background and patient evaluation.

Pelvic floor physical therapists have traditionally focused on rehabilitation of the weak pelvic floor of normal length. With the recognition that many urogynecologic symptoms arise from the presence of a short, painful pelvic floor, the role of the physical therapist is expanding. Clinically, the pelvic floor musculature is found to be short, tender, and therefore weak. There are associated trigger points and characteristic extrapelvic connective tissue abnormalities. We report the characteristic patterns of myofascial and connective tissue abnormalities in 49 patients presenting with this syndrome.

Rehabilitation of the short pelvic floor. II: Treatment of the patient with the short pelvic floor.

Several urogynecologic syndromes are associated with the clinical finding of a short, painful, tender and weak pelvic floor and a variety of connective tissue abnormalities. Techniques for rehabilitation include the avoidance of perpetuating factors, rehabilitation of extrapelvic musculoskeletal abnormalities, the use of manual techniques and needling to promote resolution of connective tissue problems, closure of any diastasis recti, and transvaginal/transrectal manual release of muscular trigger points and contractures. Therapy can be facilitated by pudendal or epidural nerve block. Patients contribute to their success through home maintenance programs.

Validation of the clinical bulbocavernosus reflex.

AIMS: To validate the clinically obtained bulbocavernosus reflex (BCR) by comparing it to the results of clitoroanal reflex (CAR) electrodiagnostic testing. MATERIALS AND METHODS: Thirty three women with detrusor overactivity underwent clinical examination and electrodiagnostic testing including evaluation of CAR latency using a Nicolet Viking IIe electrodiagnostic instrument, stimulating the paraclitoral area on each side in turn with paired stimuli while recording anal sphincter compound muscle action potentials bilaterally using surface patch electrodes. The results of clinical and electrodiagnostic testing were compared. RESULTS: The BCR was clinically present on at least one side in 26 (79%) women, and thought to be clinically bilaterally absent in 7 (21%). Electrophysiologic testing revealed CARs to be at least unilaterally present in 30 (91%) patients. When the BCR was clinically present, a CAR was recorded in 92% of patients. Of the seven women with clinically absent BCR, just one had absent CARs. CONCLUSIONS: In this sample of women with detrusor overactivity, the clinical BCR did not have strong correlation with the electrically obtained reflex.