Deceleration and Trapping of SrF Molecules.

We report on the electrostatic trapping of neutral SrF molecules. The molecules are captured from a cryogenic buffer-gas beam source into the moving traps of a 4.5-m-long traveling-wave Stark decelerator. The SrF molecules in X^{2}Σ^{+}(v=0,N=1) state are brought to rest as the velocity of the moving traps is gradually reduced from 190 m/s to zero. The molecules are held for up to 50 ms in multiple electric traps of the decelerator. The trapped packets have a volume (FWHM) of 1 mm^{3} and a velocity spread of 5(1) m/s, which corresponds to a temperature of 60(20) mK. Our result demonstrates a factor 3 increase in the molecular mass that has been Stark decelerated and trapped. Heavy molecules (mass>100 amu) offer a highly increased sensitivity to probe physics beyond the standard model. This work significantly extends the species of neutral molecules of which slow beams can be created for collision studies, precision measurement, and trapping experiments.

A supersonic laser ablation beam source with narrow velocity spreads.

A supersonic beam source for SrF and BaF molecules is constructed by combining the expansion of carrier gas (a mixture of 2% SF6 and 98% argon) from an Even-Lavie valve with laser ablation of a barium/strontium metal target at a repetition rate of 10 Hz. Molecular beams with a narrow translational velocity spread are produced at relative values of Δv/v = 0.053(11) and 0.054(9) for SrF and BaF, respectively. The relative velocity spread of the beams produced in our source is lower in comparison with the results from other metal fluoride beams produced in supersonic laser ablation sources. The rotational temperature of BaF is measured to be 3.5 K. The source produces 6 × 108 and 107 molecules per steradian per pulse in the X2Σ+ (ν = 0, N = 1) state of BaF and SrF molecules, respectively, a state amenable to Stark deceleration and laser cooling.

Preoperative urodynamic and symptom evaluation of patients undergoing transurethral prostatectomy: analysis of variables relevant for outcome.

OBJECTIVE: To assess the value of preoperative symptom score assessment and pressure-flow measurement in men undergoing transurethral prostatectomy (TURP). PATIENTS AND METHODS: In a prospective study, 95 men (mean age 74.3 years) scheduled for TURP because of their lower urinary tract symptoms, flow rates and urinary residual volumes were assessed using the self-administered International Prostate Symptom Score (IPSS) and urodynamic pressure-flow studies. At 3 months after TURP the patients were reassessed with a flow rate measurement and the IPSS. The baseline IPSS and urodynamic values were analysed with respect to the endpoints of the study, flow rate and IPSS after TURP, and the improvements thereof, respectively. RESULTS: There were significant improvements in mean IPSS (- 10.87 points) and peak flow rate (+ 7.06 mL/s) 3 months after TURP. Classifying the patients into subgroups with distinctly different initial values for IPSS, flow rate, residual urine volume and degree of obstruction (as expressed by Abrams-Griffiths number) showed that the flow rate and degree of obstruction influenced the improvement in flow rate but not in symptoms after TURP. Symptom improvement was only related to the initial level of symptoms. In a multivariate analysis, only age was an independent predictor of the outcome variables of flow rate and symptoms. CONCLUSIONS: Clinical decision-making remains a valid instrument for selecting patients for TURP. Both the IPSS and pressure-flow assessment are useful to exclude patients who are unlikely to benefit from TURP. Age is an important predictor of the improvement in symptoms and flow rates after TURP for the lower urinary tract symptom complex associated with benign prostatic enlargement.

Intracrystalline proteins and the hidden ultrastructure of calcium oxalate urinary crystals: implications for kidney stone formation.

The external appearance of urinary calcium oxalate (CaOx) crystals suggests that they are solid, homogeneous structures, despite their known association with proteins. Our aim was to determine whether proteins comprising the organic matrix of CaOx crystals are superficial or intracrystalline in order to clarify the role of urinary proteins in the formation of kidney stones. CaOx crystals were precipitated from centrifuged and filtered, or ultrafiltered, healthy human urine. They were then treated with dilute NaOH to remove bound proteins, partially demineralized with EDTA, or fractured and subjected to limited proteolysis before examination by low-resolution scanning electron microscopy or field emission scanning electron microscopy. Crystals precipitated from centrifuged and filtered urine had a complex interior network of protein distributed throughout the mineral phase, which appeared to comprise closely packed subcrystalline particles stacked in an orderly array among an amorphous organic matrix. This ultrastructure was not evident in crystals deposited in the absence of macromolecules, which were completely solid. This is the first direct evidence that crystals generated from cell-free systems contain significant amounts of protein distributed throughout a complex internal cribriform ultrastructure. Combined with mineral erosion in the acidic lysosomal environment, proteins inside CaOx crystals would render them susceptible to attack by urinary and intracellular renal proteases and facilitate their further dissolution or disruption into small particles and ions for removal by exocytosis. The findings also have broader ramifications for industry and the materials sciences, as well as the development and resorption of crystals in biomineralization systems throughout nature.

Collocation of androgen receptor gene mutations in prostate cancer.

Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain, to the NH(2)-terminal transactivation domain, and to the hinge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regions of the receptor contribute to altered androgen signaling and provide a potential mechanism to explain the reemergence of tumor growth during the course of hormone ablation therapies.

Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function.

The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues (668)QPIF(671) at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues (668)QPIF(671) form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.

Metastatic malignant melanoma presenting as bilateral incidentalomas.

Incidentally discovered adrenal masses often pose a diagnostic challenge in the asymptomatic patient. The majority represent functional adrenal adenomas but primary or secondary malignancy must be considered. Bilateral incidentalomas are rare, and a case of asymptomatic bilateral adrenal melanoma metastases is presented. The diagnostic and treatment strategies relevant to this clinical problem are presented and discussed.

The hole truth: intracrystalline proteins and calcium oxalate kidney stones.

The ultimate aim of our research is to understand the role of macromolecules in the formation of human kidney stones, particularly their interactions with calcium oxalate (CaOx) crystals. The invariable association of stones with proteins raises the possibility that proteins play a role in their formation, similar to the role of proteins in healthy biomineralization. Do these proteins induce mineralization? Are they merely a response to the disease process? Or are they protective molecules that were overwhelmed by mineral supersaturation? A protein of particular interest is fragment 1 (F1) of prothrombin. We have shown that mRNA for prothrombin is present in the kidney. Because the F1 fragment of prothrombin present in urine is slightly different from that found in the blood, we refer to this protein as "urinary prothrombin fragment 1" (UPTF1). Available evidence suggests that the kidney manufactures the protein for protection against stone disease and that the protein has a directive role in stone formation. We now have evidence that proteins are interred within CaOx crystals precipitated from human urine, where it is distributed in continuous channels. These proteins could facilitate crystal deconstruction and removal after attachment to the renal epithelium and endocytosis. We suspect that the formation of CaOx crystals in the urine is a normal process designed to permit harmless disposal of an excess of calcium, oxalate, or both. The incorporation of proteins provides a second line of defense against stone formation by enabling the destruction and removal of retained crystals. Understanding the basic molecular strategies by which plants produce protein-containing CaOx crystals may provide insight into human CaOx stone formation.

Erectile dysfunction in the community: a prevalence study.

OBJECTIVE: To investigate the prevalence of erectile dysfunction (ED) in the South Australian community, and the influence of demographic and other risk factors. DESIGN: Survey by mailed questionnaire (based on the University of California, Los Angeles prostate cancer index) of a subset (men who agreed to participate) of a probability sample of the South Australian community who completed a multiuser interview survey. PARTICIPANTS AND SETTING: Men over the age of 40 in South Australia. MAIN OUTCOME MEASURES: Sexual desire, orgasm, ability to have an erection, adequacy (firmness) of erections for intercourse, frequency of erections when wanted, frequency of intercourse, nocturnal or morning erections, and history of prostate surgery; total sexual function score based on these. RESULTS: 612 men (86.7%) agreed to answer the sexual function survey; 427 (69.8%) returned questionnaires. ED was strongly correlated with age in all seven domains of sexual function. Erections inadequate for intercourse affected 3% of 40-49-year-olds, increasing to 64% of 70-79-year-olds. The frequency of intercourse considered normal for age by men 50-69 years was 1-6 times weekly; the disparity between this and reported frequency increased in men over 60 years, as did the difference between sexual desire and potency. A history of vigorous exercise was protective across all ages. High triglyceride levels, blood pressure medication and non-cancer surgery for prostate disease were independent predictors of poor sexual function at older ages. High cholesterol level was an independent predictor of impotence. CONCLUSIONS: We found similar or higher levels of ED than in comparable overseas studies. Disparity between potency and desire was greatest, and hence the age group in whom demand for treatment may be highest, in those 60 years and older. Cardiovascular risk factors were predictors of ED in these older men, suggesting that prevention may benefit sexual function. Non-cancer prostate surgery may be a greater contributor to ED than previously realised.

Bladder mucosal cell abnormalities and symptomatic outcome after transurethral resection of the prostate.

OBJECTIVES: To identify predictors of poor symptomatic improvement after transurethral resection of the prostate (TURP), we investigated mucosal cell abnormalities in men about to undergo this procedure, and any association between these abnormalities and pre- and postoperative urinary tract symptoms. METHODS: Bladder lavages were obtained from patients undergoing TURP for outflow obstruction during 1995 to 1996 at the Repatriation General Hospital. Pressure flow studies were obtained preoperatively, and International Prostate Symptom Scores and flow rates were obtained preoperatively and 3 months and 2 years postoperatively. Cells from bladder washings were examined flow-cytometrically for Tn antigen expression and DNA cell cycle parameters. RESULTS: Of 192 patients recruited, 145 met the inclusion criteria. The frequency of Tn antigen expression, aneuploidy, and tetraploid aneuploidy in bladder mucosal cell washings in this group was comparable to a previous study. Weak, statistically significant associations were found between S-phase fraction and the initial International Prostate Symptom Score irrespective of whether total S-phase fraction cell numbers or categories were used. The trend of each of these associations was consistent (ie, patients with higher S-phase fraction values had more severe symptoms, poorer quality of life, and lower flow rates). The association was maintained at 3 months postoperatively but not at 2 years. Potential confounding factors did not explain the association. CONCLUSIONS: Bladder mucosal cell abnormalities can be found in men selected to undergo TURP to relieve obstruction and are associated with poor short-term symptomatic outcome. Further studies are needed to confirm these findings, in particular any association between higher mucosal cell proliferation rates and the presence of lower urinary tract symptoms.

The follow-up of patients with unfavourable early results of transurethral prostatectomy.

OBJECTIVE: To determine the natural course of patients with subjectively disappointing early results after transurethral prostatectomy (TURP), who experience prolonged discomfort and an initial deterioration in symptoms. PATIENTS AND METHODS: A consecutive series of 127 patients undergoing urodynamic studies and TURP were assessed 3 months after surgery using symptom scores and measurements of urinary flow rate; 107 patients reported improved symptom and quality-of-life scores, but 20 did not improve, with no change or a deterioration. These 20 patients were followed for several months using symptom scores, and measurements of flow rates and residual urine volumes. Baseline variables, including preoperative urodynamic studies, were compared between those who improved and those who did not. RESULTS: Over a mean (range) follow-up of 10.6 (6-15) months, all those initially not improving showed spontaneous improvement in all three variables with no further treatment and eventually achieved the same significant degree of improvement as those who improved soon after TURP. Preoperatively, those initially not improving had mean lower symptom scores, more bladder irritability and less obstruction than did those who improved. CONCLUSION: A significant proportion (approximately 15%) of patients with obstructive symptoms will experience considerable symptomatic discomfort for a prolonged period after an uncomplicated TURP and will not gain the full symptomatic benefit from the procedure until 6-9 months afterward.

Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer.

The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.

Self-reported prevalence of prostate-specific antigen testing in South Australia: a community study.

OBJECTIVE: To determine the prevalence and other characteristics of self-reported blood testing (prostate-specific antigen [PSA]) for prostate cancer in the community. DESIGN: Interview-based prevalence study. PARTICIPANTS AND SETTING: 695 men aged 40 years and over in the Spring 1996 South Australian Health Omnibus survey of a probability sample of 3011 households, weighted to reflect the age and sex distribution of the South Australian population. OUTCOME MEASURES: Number of men who had a PSA test in the preceding 12 months; number of first tests; the person initiating and performing the test; knowledge of the next step if test result abnormal; number of men visiting doctor for lower urinary tract symptoms in the preceding 12 months. RESULTS: 20.3% of participants reported having a PSA test in the preceding 12 months; 62.1% were first tests. Prevalence of testing was highest in the age group 70-79 years (35.8%). Most tests were initiated by the general practitioner (41.2%) and by patients (35.7%). Of those tested, 45.3% had inadequate knowledge of the next step. Visiting a doctor for urinary symptoms was significantly associated with PSA testing (P < 0.001): 47.7% of men who visited a doctor for urinary symptoms had been tested compared with only 17.4% of those who did not visit the doctor for this problem. Only age and visiting a doctor for urinary symptoms were significant independent predictors of having a PSA test. CONCLUSIONS: Investigation of lower urinary tract symptoms contributed substantially to PSA testing, and those tested did not adequately understand the consequences. Our findings suggest a need for a better framework for PSA testing in general practice, including all important elements of decision-making, such as evidence and patient preference, as well as the means to ensure adequate patient counselling before testing.

Immunolocalization of apolipoprotein D, androgen receptor and prostate specific antigen in early stage prostate cancers.

PURPOSE: To determine the cellular distribution and levels of immunohistochemical staining for apolipoprotein D (Apo-D), prostate specific antigen (PSA) and androgen receptor (AR) in early stage prostate cancers. MATERIALS AND METHODS: Cellular distribution of Apo-D, PSA and AR in 30 stage A/B prostate cancers and in non-malignant glandular tissue contained in the same sections was detected immunohistochemically, and staining was evaluated by computerized video image analysis. RESULTS: Staining for Apo-D (percentage positive cellular area) was significantly increased in tumor cells of early stage prostate cancers compared with non-malignant glandular tissue. PSA and AR were present at high levels in both early stage prostate tumors and non-malignant prostate. CONCLUSIONS: Malignant transformation in the prostate is associated with increased cellular levels of Apo-D.

Older men's concerns about their urological health: a qualitative study.

While there has been widespread recent interest in men's health issues, and prostate cancer in particular, there have been few studies to determine which issues are important from the viewpoint of men themselves. This study was undertaken to identify genitourinary issues of concern to older men. A series of 19 focus groups involved 137 men and 14 women from a broad demographic background. Men expressed consistent concern about urinary symptoms, prostate cancer and sexual function. They revealed misunderstanding and a desire for more information about all issues. Urinary symptoms had a high impact on quality of life that could be made worse by environmental constraints such as working conditions and availability of toilets. Prostate cancer was a concern in all groups, even those at low risk, and men believed that screening for prostate cancer should be offered. Men believed sexuality was not recognised as an issue of concern to older people. Potential barriers to health action included stoicism, not talking about health issues and poor relationships with doctors. The study suggests a substantial need for community and professional education and for health promotion focused on preventable morbidity.

Prostate cancer testing in SA men: influence of sociodemographic factors, health beliefs and LUTS.

This study investigates the prevalence and determinants of prostate cancer screening in the South Australian community. An interview-based survey of a probability sample of the SA population (N = 3,016) in 1995 addressed previous PSA testing, beliefs about vulnerability to prostate cancer and efficacy of screening, presence of uncomplicated lower urinary tract symptoms (LUTS) and sociodemographic variables. Of 736 men, 40 years and over with no history of prostate cancer, 24.7% (182/736) reported ever having had a test and 53.9% (397) reported an intention to test; 74% (547) agreed that prostate cancer could be cured if detected early, while only 14.9% (109) believed they were unlikely to suffer from prostate cancer. In a logistic regression model, visit to a doctor for (but not presence of) LUTS was a strong, independent predictor of participation in PSA testing (OR 9.0, 95% CI 5.0, 16.0). Beliefs, occupation and education were not. In a similar model examining intention to test, belief in vulnerability to prostate cancer was the strongest predictor (OR 3.32, 95% CI 1.9, 5.9), followed by doctor visit for urinary symptoms. These data are consistent with widespread PSA testing and with seeking treatment for LUTS being a major determinant of previous testing. NHMRC Clinical Guidelines for LUTS recommend against PSA testing for investigation of uncomplicated LUTS. Implementation of those guidelines may therefore have a significant effect on PSA testing rates. Belief in personal vulnerability to prostate cancer remains a significant component of reported future testing, suggesting a focus for community education.

Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer.

Patients with clinically localized prostate cancer who might be cured by aggressive management are not easily identified using current clinical information. Additional, more accurate, biomarkers of tumor behavior need to be identified to improve clinical outcome. Our previous studies indicated that the concentration of the glycosaminoglycan chondroitin sulfate in prostatic stroma might be a useful biomarker of disease progression in early-stage prostate cancer. In this study, two chondroitin sulfate proteoglycans, versican and decorin, were investigated. Versican and decorin were immunolocalized to the periacinar and peritumoral fibromuscular stroma in sections of nonmalignant and malignant human prostate tissues. Video image measurements indicated that the concentrations of both proteoglycans were increased in the prostatic tissue of men with early-stage prostate cancer compared with tissue from men without cancer (P = 0.0006). Cox's univariate analysis indicated that increases in versican concentration but not in that of decorin were associated with increased risk of prostate-specific antigen (PSA) progression. Versican concentration was compared with other clinical or biological features of prognosis in two-variable regression analyses. Versican and serum PSA concentrations were independent predictors of PSA progression. Versican was a stronger prognostic factor than tumor grade, and it could predict outcome for patients with moderately differentiated tumors. Patients with low versican concentration had significantly better progression-free survival than patients with high levels of versican (Kaplan-Meier plot, 89% versus 27% PSA progression-free at 5 years, respectively; P = 0.0001). We conclude that the measurement of prostatic concentrations of versican, a molecule with reported anticellular adhesive properties, may be a useful marker of disease progression in patients with early-stage prostate cancer and that further study of versican in other patient cohorts is warranted.

An evidence-based approach to hypercalciuria: is it really necessary for the study of the role of calcium in urolithiasis?

An abnormally raised 24-h urinary excretion of calcium has long been regarded as a common feature of calcium stone disease. However, hypercalciuria can be defined only by reference to a range of values measured in a representative population of individuals who have never suffered from stone disease. To date, there have been significant flaws in all published studies reporting normal ranges for daily urinary calcium excretion. There is no doubt that additional, carefully performed and documented investigations need to be undertaken to establish what is truly abnormal for a given population; the persistent use of arbitrarily defined limits may be hindering rather than helping to unravel the role of calcium in the pathogenesis of calcium stones.

Prospective study of biofeedback for treatment of constipation.

PURPOSE: This study was designed to evaluate prospectively the results of pelvic floor physiotherapy with the aid of biofeedback in a heterogeneous group of patients with intractable constipation. METHODS: Biofeedback was used to treat 19 patients (age range, 16-78 (median, 63) years) with intractable constipation. Assessment, using visual linear analog scales of symptoms, was performed prospectively by an independent researcher. Biofeedback was performed by a physiotherapist, and patients were required to attend six sessions on an outpatient basis. The cause of constipation was heterogeneous, with no specific disorder being implicated on testing with anal manometry, defecating proctography, and colonic transit time. RESULTS: At six weeks, there was a median 27 percent (range, -8-93 percent) improvement in symptom scores. At six months, there was a median 23 percent (range, -54-64 percent) improvement in symptom scores. These were statistically significant compared with the scores at outset, six weeks (P = 0.0006), and six months (P = 0.012). However, only two (12.5 percent) patients at the six-month follow-up had an improvement of greater than 50 percent in their symptoms. CONCLUSION: Biofeedback is not recommended in the management of constipation.