Patient perspectives on Peyronie's disease: results of poststudy interviews from a phase 2 trial of collagenase clostridium histolyticum.

Intralesional injection of collagenase clostridium histolyticum (CCH) improves Peyronie's disease (PD) symptoms; however, patient perspectives regarding PD and CCH treatment have not been fully elucidated. This cross-sectional qualitative study included heterosexual men with PD who received ≥1 injection of study medication and had ≥1 posttreatment Peyronie's Disease Questionnaire (PDQ) assessment during a prior phase 2b clinical trial. These patients were "responders" if they reported (as part of the Global Assessment of the PDQ) that overall symptoms and effects of PD had at least "improved in a small but important way" after CCH therapy. Among 45 patients interviewed, penile bending or curvature was the most common and bothersome PD symptom reported (by 97.8% and 48.9% of patients, respectively). Patients indicated that multiple alterations were necessary in their sex lives because of penile symptoms and specified that these changes impacted their emotional health and partner relationship. Treatment with CCH improved PD symptoms (44.4%), frequency of or ability to have vaginal intercourse (22.2%) and partner relationship (22.2%), particularly among responders. Given that physical, psychologic and sexual function are impacted by PD, clinical trials that evaluate treatments for PD should include patient-reported outcome measures (e.g., the PDQ) to assess overall well-being after treatment.

The POTENT II randomised trial: efficacy and safety of an orodispersible vardenafil formulation for the treatment of erectile dysfunction.

AIMS: The aim of this study was to investigate the efficacy and safety of 10 mg vardenafil orodispersible tablet (ODT) vs. placebo in a general population of men with erectile dysfunction (ED). METHODS: This was a double-blind, multicentre, randomised, parallel-group, placebo-controlled study conducted at 35 centres in Australia, Canada, Mexico and the United States. Subjects aged > or =18 years, with ED for at least 6 months, were randomised to receive 12 weeks of on-demand treatment with either 10 mg vardenafil ODT or placebo. Each treatment group was stratified such that approximately half of the subjects were aged > or = 65 years. Primary efficacy variables were the erectile function domain of the International Index of Erectile Function (IIEF-EF) and Sexual Encounter Profile questions 2 (SEP2) and 3 (SEP3). Secondary variables included SEP diary questions 1, 4, 5 and 6, the patient version of the Treatment Satisfaction Scale (TSS) and the Global Assessment Question (GAQ). RESULTS: Of the 473 men enrolled in the study (51.4% aged > or =65 years), 331 were included in the intent-to-treat population (vardenafil ODT, n = 169; placebo, n = 162). Vardenafil ODT therapy was statistically significantly superior to placebo for all primary (i.e. IIEF-EF, SEP2, SEP3) and secondary efficacy variables (p < 0.0001). Treatment-emergent adverse events were mostly mild to moderate in severity, and comparable in both incidence and type with those of the film-coated tablet formulation. CONCLUSIONS: Treatment with 10 mg vardenafil ODT, taken on demand, significantly improved erectile function and was effective and well tolerated in a broad population of men with ED.

Efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist: an investigation of warning time in patients with OAB.

This double-blind, randomised placebo-controlled, multicentre study evaluated the efficacy, tolerability and safety of 12 weeks' treatment with controlled release darifenacin 15 mg once daily (qd), in 445 patients with overactive bladder (OAB). The primary endpoint was warning time (time from first sensation of urgency to voiding), and secondary endpoints included urge incontinence episodes and volume voided. Darifenacin treatment resulted in numerical increases in warning time, but these were not significant compared with placebo -- highlighting difficulties in assessing this parameter. Significant improvements were seen with darifenacin vs. placebo in urge incontinence episodes/week, volume voided and quality of life (QoL). Darifenacin was associated with increases in urgency-free time (UFT; time between any void to the next urgency event) vs. placebo. Treatment was well tolerated; the most commonly reported adverse events were the typical antimuscarinic effects of dry mouth and constipation, both infrequently leading to discontinuation. This study demonstrated the difficulty in measuring warning time, due in part to its subjective nature; the authors believe further investigation is warranted to allow urgency to be better defined. Further investigation of UFT is required to determine its role in evaluating urgency. The study confirmed that darifenacin 15 mg qd is an effective and well-tolerated treatment for OAB, which improves QoL.

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.

PURPOSE: We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS: In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS: No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS: Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.

Management of febrile infants and children by pediatric emergency medicine and emergency medicine: comparison with practice guidelines.

OBJECTIVES: Management of febrile infants and children remains controversial despite the 1993 publication in Pediatrics and Annals of Emergency Medicine of practice guidelines. Our aim was to determine the management of febrile infants and children by pediatric emergency medicine (PEM) fellowship directors and emergency medicine (EM) residency directors and compare their approach with the published practice guidelines. METHODS: Four case scenarios were sent to 64 PEM directors and 100 EM directors in the United States and Canada, describing four febrile, nontoxic infants and children aged 25 days (case 1), 7 weeks (case 2), 5 months (case 3), and 22 months (case 4). Respondents were asked to select which laboratory tests and radiographs they would obtain and to decide on treatment and disposition for each hypothetical case. RESULTS: Ninety-two percent (53/64) of PEM directors and 64% (64/100) of EM directors responded (overall response rate 74%). Compliance with the guidelines (PEM/EM) was 54%/16% for case 1, 31%/6% for case 2, 35%/19% for case 3, and 20%/11% for case 4. Only 11% of PEM and 2% of EM directors followed the guidelines for all four cases. Overall, directors performed fewer laboratory tests, ordered more chest radiographs and treated fewer patients with antibiotics than the expert panel suggested. EM directors ordered more chest radiographs (cases 1-4) and admitted more patients (case 2) than PEM directors. CONCLUSIONS: There is poor compliance with published practice guidelines in the management of febrile infants and children among PEM and EM directors.

Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group.

OBJECTIVES: To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. METHODS: Three thousand forty men with benign prostatic hyperplasia enrolled in the PLESS trial were randomly assigned to finasteride 5 mg or placebo for 4 years. Symptoms and flow rate were assessed every 4 months, and data were analyzed by dividing the patients into three groups by baseline PSA tertiles (0 to 1.3, 1.4 to 3.2, and 3.3 ng/mL or greater) and baseline prostate volume tertiles (14 to 41, 42 to 57, and 58 to 1 50 mL). RESULTS: After the initial placebo effect, a slow deterioration in symptoms over time was observed in the placebo-treated men with a baseline PSA 1.4 ng/mL or greater. However, placebo-treated men in the lowest PSA tertile (less than 1.4 ng/mL) had sustained symptomatic improvement that was not seen in placebo-treated men in the higher tertiles (P<0.001). In all finasteride-treated groups, there was initial improvement followed by maintenance or continued symptom improvement over time (approximately 3 to 3.5 points by the end of 4 years). The differences in symptom score improvement between placebo and finasteride were marginal for men with baseline PSA levels less than 1.4 ng/mL (P = 0.128) but were highly significant for men with PSA levels 1.4 ng/mL or greater (P<0.001). Urinary flow rate results were similar to those observed for symptoms. Analysis of symptom and flow rate data by prostate volume tertiles in a 10% subset of men yielded similar results, namely a deterioration of symptoms and flow rate in the two higher tertiles treated with placebo (greater than 41 mL) and a sustained improvement in all three groups of finasteride-treated patients. CONCLUSIONS: Baseline PSA and prostate volume are good predictors of long-term symptomatic and flow rate changes. Baseline PSA levels of 1.4 ng/mL or greater and enlarged prostate glands predict the best long-term response to finasteride compared with placebo.

Acute pediatric digoxin ingestion.

Although most acute pediatric ingestions of digoxin or other related cardiac glycosides result in minimal or no symptoms, occasionally a child is symptomatic. Gastrointestinal complaints or first-degree AV block are the most common presenting symptoms. Children can generally be given a single dose of activated charcoal, observed, and discharged without any subsequent problems. However, some patients will be toxic and require monitoring, medication, and possibly digoxin-specific antibody fragments. The most important role of the clinician is to recognize the clinical manifestations and institute the appropriate therapy. As in the case presented, the history of an ingestion may not always be obtained initially. Thus, the physician should maintain a high index of suspicion for acute digoxin ingestion and order the appropriate confirmatory tests (eg, a digoxin level, a potassium level, and a 12-lead ECG) when necessary.

Group psychoeducation of relatives of schizophrenic patients: two-year experiences.

In order to assess the feasibility and acceptability of group psychosocial education for the relatives of schizophrenics in the community, a 2-year project was carried out in two cities: Jinan and Shanghai, China. The completed sample included 682 cases in the experimental group and 366 cases in the control group. The experimental group received group psychotherapy including 14 lectures and five group discussions with conventional services, and the control group had conventional services only. The annual relapse rate in the experimental group was much lower than that in the control group (17.6 and 23.2%, P < 0.01) and the rate of regular work in the experimental group was higher than that in the control group (37.5 and 30.0%, P < 0.05). At the end of the second year, the relatives in the experimental group had less care burden, better mental and physical health status and more knowledge of caring for schizophrenics than those in the control group. This approach was well accepted by both mental health workers and relatives of schizophrenics and the rate of drop-out was 18.4% only during the 2-year period.

Folding and stability of trp aporepressor from Escherichia coli.

Equilibrium and kinetic studies of the urea-induced unfolding of trp aporepressor from Escherichia coli were performed to probe the folding mechanism of this intertwined, dimeric protein. The equilibrium unfolding transitions at pH 7.6 and 25 degrees C monitored by difference absorbance, fluorescence, and circular dichroism spectroscopy are coincident within experimental error. All three transitions are well described by a two-state model involving the native dimer and the unfolded monomer; the free energy of folding in the absence of denaturant and under standard-state conditions is estimated to be 23.3 +/- 0.9 kcal/mol of dimer. The midpoint of the equilibrium unfolding transition increases with increasing protein concentration in the manner expected from the law of mass action for the two-state model. We find no evidence for stable folding intermediates. Kinetic studies reveal that unfolding is governed by a single first-order reaction whose relaxation time decreases exponentially with increasing urea concentration and also decreases with increasing protein concentration in the transition zone. Refolding involves at least three phases that depend on both the protein concentration and the final urea concentration in a complex manner. The relaxation time of the slowest of these refolding phases is identical with that for the single phase in unfolding in the transition zone, consistent with the results expected for a reaction that is kinetically reversible. The two faster refolding phases are presumed to arise from slow isomerization reactions in the unfolded form and reflect parallel folding channels.

Long-range electrostatic interactions can influence the folding, stability, and cooperativity of dihydrofolate reductase.

To test the possibility that long-range interactions might influence the folding and stability of dihydrofolate reductase, a series of single and double mutations at positions 28 and 139 were constructed and their urea-induced unfolding reactions studied by absorbance and circular dichroism spectroscopy. The alpha carbons of the two side chains are separated by 15 A in the native conformation. The replacement of Leu 28 by Arg and of Glu 139 by Gln resulted in additive effects on both kinetic and equilibrium properties of the reversible unfolding transition; no evidence for interaction was obtained. In contrast, the Arg 28/Lys 139 double replacement changed the equilibrium folding model from two state to multistate and showed evidence for interaction in one of the two kinetic phases detected in both unfolding and refolding reactions. The results can be explained in terms of a long-range, repulsive electrostatic interaction between the cationic side chains at these two positions.

Effect of single amino acid replacements on the folding and stability of dihydrofolate reductase from Escherichia coli.

The role of the secondary structure in the folding mechanism of dihydrofolate reductase from Escherichia coli was probed by studying the effects of amino acid replacements in two alpha helices and two strands of the central beta sheet on the folding and stability. The effects on stability could be qualitatively understood in terms of the X-ray structure for the wild-type protein by invoking electrostatic, hydrophobic, or hydrogen-bonding interactions. Kinetic studies focused on the two slow reactions that are thought to reflect the unfolding/refolding of two stable native conformers to/from their respective folding intermediates [Touchette, N. A., Perry, K. M., & Matthews, C. R. (1986) Biochemistry 25, 5445-5452]. Replacements at three different positions in helix alpha B selectively alter the relaxation time for unfolding while a single replacement in helix alpha C selectively alters the relaxation time for refolding. This behavior is characteristic of mutations that change the stability of the protein but do not affect the rate-limiting step. In striking contrast, replacements in strands beta F and beta G can affect both unfolding and refolding relaxation times. This behavior shows that these mutations alter the rate-limiting step in these native-to-intermediate folding reactions. It is proposed that the intermediates have an incorrectly formed beta sheet whose maturation to the structure found in the native conformation is one of the slow steps in folding.

Recent developments in the care, treatment, and rehabilitation of the chronic mentally ill in Greece.

The chronic mentally ill in Greece are primarily cared for in large public mental hospitals or by their families because of the absence of community-based alternatives and the centralization of existing services in Athens and Thessaloniki. However, in the last decade new legislation to improve the lives of the chronically ill has been passed, additional day care facilities have been opened, and the development of decentralized mental health services has been scheduled by the National Health System. A case report illustrates the care provided at Greece's first community mental health center, established in 1979 in Athens.

Diagnosis of acute testicular torsion using radionuclide scanning.

We analyzed retrospectively 99mtechnetium scrotal scan findings in 37 patients with acute scrotal pain. Correlation between scan interpretation, and either surgical findings and/or final clinical diagnosis revealed an accuracy of 89 per cent. Only 1 false negative and 3 false positive results were recorded. Scan data revealed a positive predictive value of 75 per cent, negative predictive value of 96 per cent, sensitivity of 90 per cent and specificity of 89 per cent. An inter-institutional observer study also was conducted to assess reliability of the scan, resulting in an 88 per cent agreement. The testicular scan has been found to be an accurate and reliable method to distinguish between epididymo-orchitis and testicular torsion.