Water-fat Dixon sequences in the evaluation of breast implants: proposal of a time effective rapid approach in the clinical practice.

AIM: To evaluate the diagnostic accuracy achieved from a fat-water Dixon sequence alone compared to a combination of a silicone-specific magnetic resonance imaging (MRI) sequence and a water-specific MRI sequence in the assessment of breast implants. MATERIALS AND METHODS: In this institutional review board (IRB)-approved study the integrity of breast implants was assessed retrospectively in 27 patients undergoing breast MRI at 3 T. A qualitative evaluation of (set 1) a silicon-selective water-saturated short tau inversion recovery (STIR) sequence in combination with a water-only Dixon dataset (total acquisition time 7 minutes 17 seconds), and of (set 2) fat-only and water-only Dixon datasets (4 minutes 8 seconds) was performed by two readers independently evaluating the following features: margin definition of the implant, water suppression homogeneity, image quality, presence of artefacts and their effects on the imaging interpretation, and diagnostic confidence. Diagnostic accuracy in implant rupture detection was determined and either surgical confirmation or diagnosis from the radiological report was used as a standard of reference. RESULTS: In both sequences, margin definition of the implant wall, water suppression homogeneity, and overall image quality were rated good-excellent in most of cases. Water suppression homogeneity was moderate-poor in a greater number of cases in set 1. Movement artefacts were more frequent in set 1 whereas five cases (18.5%) exhibited swap artefacts between silicone and water in set 2. Diagnostic confidence was rated high-very high with both sequences in most of cases. Diagnostic accuracy was 100% for both readers using set 1 and 96.2% and 100% using set 2. CONCLUSION: A single Dixon sequence allows an accurate diagnostic evaluation of breast implants and concomitant shortening of the overall acquisition time.

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.

Whole-Body Diffusion Imaging Applying Simultaneous Multi-Slice Excitation.

PURPOSE: The purpose of this study was to examine the feasibility of a fast protocol for whole-body diffusion-weighted imaging (WB-DWI) using a slice-accelerated echo-planar sequence, which, when using comparable image acquisition parameters, noticeably reduces measurement time compared to a conventional WB-DWI protocol. MATERIALS AND METHODS: A single-shot echo-planar imaging sequence capable of simultaneous slice excitation and acquisition was optimized for WB-DWI on a 3 T MR scanner, with a comparable conventional WB-DWI protocol serving as the reference standard. Eight healthy individuals and one oncologic patient underwent WB-DWI. Quantitative analysis was carried out by measuring the apparent diffusion coefficient (ADC) and its coefficient of variation (CV) in different organs. Image quality was assessed qualitatively by two independent radiologists using a 4-point Likert scale. RESULTS: Using our proposed protocol, the scan time of the WB-DWI measurement was reduced by up to 25.9 %. Both protocols, the slice-accelerated protocol and the conventional protocol, showed comparable image quality without statistically significant differences in the reader scores. Similarly, no significant differences of the ADC values of parenchymal organs were found, whereas ADC values of brain tissue were slightly higher in the slice-accelerated protocol. CONCLUSION: It was demonstrated that slice-accelerated DWI can be applied to WB-DWI protocols with the potential to greatly reduce the required measurement time, thereby substantially increasing clinical applicability. KEY POINTS: •Whole-body diffusion-weighted imaging (WB-DWI) using simultaneous multi-slice and blipped-CAIPIRINHA reduces the measurement time strongly without having a significant impact on image quality. •The reduction in measurement time might strongly contribute to the clinical applicability of WB-DWI. •However, further refinement of the slice-accelerated EPI sequence, and the WB-DWI protocol applying this sequence type seems necessary; and the value of such WB-DWI protocols for assessment of systemic oncological diseases needs to be investigated in further clinical studies.

Age- and Level-Dependence of Fatty Infiltration in Lumbar Paravertebral Muscles of Healthy Volunteers.

BACKGROUND AND PURPOSE: Normative age-related decline in paravertebral muscle quality is important for reference to disease and risk identification in patients. We aimed to establish age- and vertebral level-dependence of paravertebral (multifidus and erector spinae) muscle volume and fat content in healthy adult volunteers. MATERIALS AND METHODS: In this prospective study multifidus and erector spinae fat signal fraction and volume at lumbar levels L1-L5 were measured in 80 healthy volunteers (10 women and men per decade, 20-62 years of age) by 2-point Dixon 3T MR imaging. ANOVA with post hoc Bonferroni correction compared fat signal fraction and volume among subgroups. Pearson and Spearman analysis were used for correlations (P < .05). RESULTS: Fat signal fraction was higher in women (17.8% ± 10.7%) than men (14.7% ± 7.8%; P < .001) and increased with age. Multifidus and erector spinae volume was lower in women (565.4 ± 83.8 cm(3)) than in men (811.6 ± 98.9 cm(3); P < .001) and was age-independent. No differences in fat signal fraction were shown between the right and left paravertebral muscles or among the L1, L2, and L3 lumbar levels. The fat signal fraction was highest at L5 (women, 31.9% ± 9.3%; men, 25.7% ± 8.0%; P < .001). The fat signal fraction at L4 correlated best with total lumbar fat signal fraction (women, r = 0.95; men, r = 0.92, P < .001). Total fat signal fraction was higher in the multifidus compared with erector spinae muscles at L1-L4 for both sexes (P < .001). CONCLUSIONS: Lumbar paravertebral muscle fat content increases with aging, independent of volume, in healthy volunteers 20-62 years of age. Women, low lumbar levels, and the multifidus muscle are most affected. Further study examining younger and older subjects and the functional impact of fatty infiltrated paravertebral muscles are warranted.

Inhalation of [123I]alpha1-protease inhibitor: toward a new therapeutic concept of alpha1-protease inhibitor deficiency?

UNLABELLED: The alpha1-protease inhibitor (alpha1-Pi) is separated from human serum and is therefore extremely expensive. Because only 2%-3% concentrates in the lung after intravenous administration, inhalational therapy for alpha1-Pi deficiency would seem likely to be better. The aims of this study were therefore to determine the pattern of deposition of inhaled alpha1-Pi labeled with 123I and measure the amount deposited in the lungs. METHODS: Eighteen patients with congenital severe alpha1-Pi deficiency were enrolled in the study. The low-specific-activity 123I-labeled alpha1-Pi aerosol (median particle size +/- SD, 3.9 +/- 2.5 microm) was generated by an air pressure-driven nebulizer. The patients inhaled for an average of 23.6 +/- 8.9 min. Static scintigrams in two projections were acquired immediately after (T1) and 1 (T2), 4 (T3), and 24 h (T4) after inhalation. The patients were divided into the following three groups according to their forced expiratory volume in 1 s (FEV1): group I, < or =40% of predicted normal (n = 8); group II, 40% < FEV1 < or = 60% of predicted normal (n = 4); group III, >60% of predicted normal (n = 6). RESULTS: The absolute percentage uptake values of alpha1-Pi in group I were 12.4 for T1, 7.3 for T2, 4.6 for T3, and 1.2 for T4; in group II the values were 13.0, 9.6, 6.2, and 2.0, respectively; and in group III, 14.6, 11.4, 6.5, and 3.6, respectively. Differences between the groups were generally statistically significant. Between T1 and T2, the probability value was <0.05 for group I versus group II, <0.006 for group I versus group III, and <0.39 for group II versus group III. Between T1 and T3, the probability value was <0.29 for group I versus group II, <0.22 for group I versus group III, and <0.94 for group II versus group III. Retention (between T1 and T4) was also dependent on the grade of the disease: P < 0.2 for group I versus group II, P < 0.001 for group I versus group III, and P < 0.02 for group II versus group III. Grading of the uptake pattern by three independent experienced investigators (87% agreement) revealed a peripheral deposition that was group dependent. We found that greater peripheral deposition corresponded with lower lung functional impairment: P < 0.5 for group I versus group II, P < 0.01 for group I versus group III, and P < 0.08 for group II versus group III. Degradation also corresponded with functional impairment: P < 0.05 for group I versus group II, P < 0.006 for group I versus group III, and P < 0.3 for group II versus group III. CONCLUSION: The results of this study show that sufficient amounts of alpha1-Pi can be deposited in the periphery of the lung by inhalation at least in patients with low-grade disease. Inhalation of alpha1-Pi may thus represent a new and more convenient route of drug administration.

The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial.

Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5, 10 and 20 mg of vardenafil. Primary endpoints were Q3 (vaginal penetration) and Q4 (maintenance of erection) of the International Index of Erectile Function (IIEF). In the intent-to-treat population (n=580), the changes from baseline for 5, 10 and 20 mg vardenafil (1.2, 1.3 and 1.5, respectively) were all improved (P<0.001) over placebo (0.2) for Q3 and were similarly improved for Q4 (1.4, 1.5 and 1.7) compared to placebo (0.5) (P<0.001). All vardenafil doses improved all IIEF domains compared to placebo (P<0.001). The percentage of successful intercourses was between 71 and 75% for the three vardenafil doses. For the 20 mg dose, 80% of the patients experienced improved erections (GAQ) compared to 30% for placebo. Most frequent treatment-emergent adverse events were headache (7-15%), flushing (10-11%) and up to 7% for dyspepsia or rhinitis. Vardenafil treatment resulted in a high efficacy and low adverse-event profile in a population with mixed ED etiologies.

Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast.

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.

Three explorative studies on the efficacy of the antihistamine mebhydroline (Omeril).

The efficacy of a multiple oral dose treatment with mebhydroline (Omeril coated tablets, 100 mg t.i.d.) was examined in 3 studies which were performed in a randomized, double-blind and placebo-controlled 2-way cross-over design. A second target was to investigate the suitability of different pharmacodynamic models for testing the efficacy of antihistamines. Study A involved a nasal provocation with a specific allergen in 11 symptom-free patients suffering from seasonal allergic rhinitis. In study B, a nasal provocation with histamine was investigated in 11 healthy volunteers. Study C involved a cutaneous provocation with a specific allergen in 12 symptom-free patients suffering from seasonal allergic rhinitis/atopy. The mebhydroline treatment's superiority over placebo was shown statistically at the 95% confidence level for the symptoms itchy nose in study A and for nasal congestion in study B. In study C, allergen-induced weals (planimetric measurement) and itching (visual analog scale) were significantly changed by mebhydroline. A qualitative evaluation revealed a reaction intensity that differed between the 2 treatments to a clinically relevant degree, however, without reaching significance. On the basis of the data it is expected that the clinical efficacy of mebhydroline may be further substantiated in confirmatory clinical trials which should include placebo and positive controls. The test methods used differed in their suitability for measuring the pharmacodynamic effects of antihistamines. Overall, the most clear-cut results were seen in hay fever patients using a specific allergen for provocation. The planimetric assessment of weal response should be preferred as a cutaneous model. Both AR and AARM have their clinical relevance. Based on highly significant results of a subgroup analysis there are indications in favor to AR, but momentary there is no definite conclusion in favor of or against either of the 2 methods.

[Significance of phosphodiesterase isoenzymes in the control of human detrusor smooth muscle function. An immunohistochemical and functional study]. / Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur. Eine immunhistochemische und funktionelle In-vitro-Studie.

OBJECTIVES: The use of inhibitors of phosphodiesterase (PDE) isoenzymes 1 and 5 to treat overactive bladder has been suggested. To further evaluate the significance of PDE isoenzymes in detrusor smooth muscle relaxation, we investigated the effects of selective PDE inhibitors on the tension induced by carbachol of isolated human detrusor tissue. Using immunohistochemical methods, the expression of PDE1, PDE4, and PDE5 in human detrusor was also investigated. MATERIAL AND METHODS: The expression of PDE1, PDE4, and PDE5 was evaluated by means of conventional immunohistochemistry (IHC). Using the organ bath technique, the effects of the PDE inhibitors vinpocetine, rolipram, sildenafil, tadalafil, and vardenafil on the tension induced by the muscarinic agonist carbachol (1 microM) were investigated. RESULTS: The tension induced by carbachol was dose-dependently reversed by the PDE inhibitors; the maximum reversal of tension ranged from 7% (tadalafil) to 34% (vardenafil). IHC revealed that the expression of PDE isoenzymes was limited to the smooth musculature of the detrusor. While there was prominent expression of PDE4 and PDE5, immunoreactions indicating the presence of PDE1 were less abundant. CONCLUSION: Despite the fact that inhibitors of PDE1, PDE4, and PDE5 exerted only a weak relaxant response on detrusor strips precontracted by carbachol, our findings indicate that both the cAMP and cGMP pathways might be involved in the relaxation mechanism of human detrusor smooth muscle.

Long-term multicentric study with azelastine in patients with intrinsic asthma.

Efficacy and tolerance of azelastine (A 5610; CAS 58581-89-8), a new antiallergic compound with a unique structure, were investigated over up to one year of treatment in 225 male and female out-patients (age mean +/- s = 48 +/- 13 years) suffering from chronified intrinsic asthma. The trial was conducted by 24 German and Austrian consulting physicians of pneumology. Plasma levels indicated sufficient compliance in almost 90% of the patients. Tablets containing 4.4 mg azelastine HCl were administered b.i.d. in addition to the pre-existing antiasthmatic medication. Only other antiallergic agents were excluded. Adverse events, vital parameters and laboratory tests on safety were tightly assessed. Eighteen patients dropped out because of adverse events, 78 reported adverse experiences under therapy, normally mild and "vegetative" symptoms. No indicative findings regarding blood pressure, heart rate and laboratory tests were seen. The most frequent observations were taste disorders, asthenia and weight gain. No serious side effects at all were reported. The results on efficacy obtained from this non-controlled study may be predicative due to a baseline validation by an initial single blind placebo controlled run-in phase. Statistically significant improvements were seen for FEV1 and for the physicians' and the patients' rating on efficacy. To a lesser extent peak flow and airway resistance were improved, too. Thus, azelastine was safely tolerated over one year and might be effective in intrinsic asthma.

Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction.

This randomised, double-blind study assessed the long-term efficacy and tolerability of vardenafil 10 and 20 mg in men with erectile dysfunction (ED). A total of 566 men who completed an initial 12-month treatment period entered a 12-month extension. In these men, both doses of vardenafil produced improvement in scores for the 'erectile function' Domain of the International Index of Erectile Function, evident from week 4 and maintained through 2 years. Sexual Encounter Profile diary responses indicated that following treatment, penetration was achieved on 92-94% of attempts and erections that lasted long enough for successful intercourse were achieved on 87-89% of attempts. In response to the General Assessment Question, 90-92% of patients reported improved erections with vardenafil. Most treatment-emergent events were mild and transient with no cardiovascular safety concerns. These results support the long-term efficacy, reliability and tolerability of vardenafil 10 and 20 mg in men with ED.

The intrapulmonary half-life and safety of aerosolized alpha1-protease inhibitor in normal volunteers.

Aerosol delivery of alpha1-protease-inhibitor (alpha1-PI) has the potential for reducing the amount of alpha1-PI needed to treat persons who are severely alpha1-PI-deficient, thereby decreasing the high cost of treatment and making alpha1-PI available to treat many alpha1-PI-deficient persons who do not now have access to that product. Aerosolized alpha1-PI may also be useful in cystic fibrosis. The goal of our study was to evaluate the duration of action of aerosolized alpha1-PI and possible side effects in normal volunteers. Twenty-nine volunteers underwent bronchoalveolar lavage (BAL) and 3 to 7 d later inhaled 200 mg of alpha1-PI. Subjects were subsequently assigned to one of five groups; a second BAL was performed 0.5, 6, 12, 24, or 36 h after the aerosol, respectively. The BAL fluid samples were analyzed for alpha1-PI concentrations, anti-neutrophil elastase (NE) activity, cell count and differential, alpha1-PI-NE complex level, and uptake of alpha1-PI by alveolar macrophages. Overall we observed no substantial side effects. The one-time alpha1-PI aerosol induced a significant increase of alpha1-PI concentrations as well as anti-NE activity. Even in the BAL fluid samples obtained 36 h after aerosol administration alpha1-PI concentrations and anti-NE activity were about double baseline values. The half-time in the lungs for alpha1-PI concentrations and anti-NE activity were about double baseline values. The half-time in the lungs for alpha1-PI was 69.2 h and for anti-NE activity was 53.2 h, respectively. We conclude from our data in normal volunteers that inhalation of aerosolized alpha1-PI may be a safe, effective, and conveniently administered therapy for persons with severe alpha1-PI deficiency; this mode of administration warrants further study.

Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific.

Viable mice nullizygous in genes encoding the 300 kDa and the 46 kDa mannose 6-phosphate receptors (MPR 300 and MPR 46) and the insulin like growth factor II (IGF II) were generated to study the trafficking of lysosomal enzymes in the absence of MPRs. The mice have an I-cell disease-like phenotype, with increase of lysosomal enzymes in serum and normal activities in tissues. Surprisingly, the ability of MPR-deficient cells to transport newly synthesized lysosomal enzymes to lysosomes and the underlying mechanisms were found to depend on the cell type. MPR-deficient thymocytes target newly synthesized cathepsin D to lysosomes via an intracellular route. In contrast, hepatocytes and fibroblasts secrete newly synthesized cathepsin D. In fibroblasts recapture of secreted lysosomal enzymes, including that of cathepsin D, is limited and results in lysosomal storage, both in vivo and in vitro, whereas recapture by hepatocytes is remarkably effective in vivo and can result in lysosomal enzyme levels even above normal.

I-cell disease-like phenotype in mice deficient in mannose 6-phosphate receptors.

Mannose 6-phosphate receptor deficient mice were generated by crossing mice carrying null alleles for Igf2 and the 300 kDa and 46 kDa mannose 6-phosphate receptors, Mpr300 and Mpr46. Pre- and perinatal lethality of mice nullizygous for Igf2, Mpr300 and Mpr46 was increased. Triple deficient mice surviving the first postnatal day had normal viability and developed a phenotype resembling human I-cell disease. The triple deficient mice were characterized by dwarfism, facial dysplasia, waddling gait, dysostosis multiplex, elevated lysosomal enzymes in serum and histological signs of lysosomal storage predominantly in fibroblasts, but also in parenchymal cells of brain and liver. A paternally inherited Mpr300 wild type allele that is normally inactive in mice due to imprinting was reactivated in some tissues of mice lacking IGF II and MPR 46 and carrying a maternal Mpr300 null allele. Inspite of the partial reactivation the phenotype of these mice was similar to that of triple deficient mice.