Long-term Safety and Tolerability of Repeated Treatments With OnabotulinumtoxinA in Children With Neurogenic Detrusor Overactivity.

PURPOSE: OnabotulinumtoxinA is an approved treatment for neurogenic detrusor overactivity in adults inadequately managed with anticholinergics, and more recently was approved in children on the basis of a phase 3, 48-week, single-treatment study (NCT01852045). Given the paucity of long-term pediatric data, we report on the continued safety in these patients after repeated onabotulinumtoxinA treatment. MATERIALS AND METHODS: This was a multicenter, double-blind, repeat-treatment extension study (NCT01852058) in patients who entered from the preceding single-treatment study. Data were integrated across both studies. All patients (5-17 years) used clean intermittent catheterization and could receive dose escalations based on response to preceding treatment (50 U, 100 U, or 200 U onabotulinumtoxinA [not to exceed 6 U/kg]). RESULTS: Overall, 95, 90, 55, and 11 patients received 1, 2, 3, and 4 treatments with onabotulinumtoxinA, respectively, and median (quartiles) duration of follow-up was 82 (65, 94) weeks. The safety profile was similar across doses and after repeat treatments. The most common treatment-emergent adverse event during cycles 1, 2, and 3 was urinary tract infection (31%, 34%, 22%). Three serious treatment-emergent adverse events related to study treatment (3/95; 3.2%) were reported during the study, which were all cases of urinary tract infection. Annualized urinary tract infection rates post-treatment were similar to pre-screening rates. There were no cases of autonomic dysreflexia, neutralizing antibodies, and treatment-emergent adverse events related to distant spread of toxin. CONCLUSIONS: OnabotulinumtoxinA continued to be well tolerated after repeated treatments in pediatric neurogenic detrusor overactivity patients with similar safety profiles across dose groups. Treatment-emergent adverse events were primarily urological with no new safety concerns.

OnabotulinumtoxinA for the treatment of neurogenic detrusor overactivity in children.

AIMS: This study evaluated whether one (or more) of three doses of onabotulinumtoxinA were safe and effective to treat neurogenic detrusor overactivity (NDO) in children. METHODS: This was a 48-week prospective, multicenter, randomized, double-blind study in children (aged 5-17 years) with NDO and urinary incontinence (UI) receiving one onabotulinumtoxinA treatment (50, 100, or 200 U; not to exceed 6 U/kg). Primary endpoint: change from baseline in daytime UI episodes. Secondary endpoints: change from baseline in urine volume at first morning catheterization, urodynamic measures, and positive response on the treatment benefit scale. Safety was also assessed. RESULTS: There was a similar reduction in urinary incontinence from baseline to Week 6 for all doses (-1.3 episodes/day). Most patients reported positive responses on the treatment benefit scale (75.0%-80.5%). From baseline to Week 6, increases were observed in urine volume at first morning clean intermittent catheterization (50 U, 21.9 ml; 100 U, 34.9 ml; 200 U, 87.5 ml; p = 0.0055, 200 U vs. 50 U) and in maximum cystometric capacity (range 48.6-63.6 ml) and decreases in maximum detrusor pressure during the storage phase (50 U, -12.9; 100 U, -20.1; 200 U, -27.3 cmH2 O; p = 0.0157, 200 U vs. 50 U). The proportion of patients experiencing involuntary detrusor contractions dropped from baseline (50 U, 94.4%; 100 U, 88.1%; 200 U, 92.6%) to Week 6 (50 U, 61.8%; 100 U, 44.7%; 200 U, 46.4%). Safety was similar across doses; urinary tract infection was most frequent. CONCLUSIONS: OnabotulinumtoxinA was well tolerated and effective for the treatment of NDO in children; 200 U showed greater efficacy in reducing bladder pressure and increasing bladder capacity.

Trigger-happy resident memory CD4+ T cells inhabit the human lungs.

Resident memory T cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. Although lung CD8+ TRM have been extensively characterized, the properties of CD4+ TRM remain unclear. Here we determined the transcriptional signature of CD4+ TRM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4+ TRM, whereas expression of tissue egress and lymph node homing molecules were low. CD103+ TRM expressed low levels of T-bet, only a small portion expressed Eomesodermin (Eomes), and although the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103+ TRM showed a Notch signature. CD4+CD103+ TRM constitutively expressed high transcript levels of numerous cytotoxic mediators that was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be because of an accessible interferon-γ (IFNγ) locus and was partially because of rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4+ TRM in the human lung. Understanding the specific properties of CD4+ TRM is required to rationally improve vaccine design.

Male circumcision decreases penile sensitivity as measured in a large cohort.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The sensitivity of the foreskin and its importance in erogenous sensitivity is widely debated and controversial. This is part of the actual public debate on circumcision for non-medical reason. Today some studies on the effect of circumcision on sexual function are available. However they vary widely in outcome. The present study shows in a large cohort of men, based on self-assessment, that the foreskin has erogenous sensitivity. It is shown that the foreskin is more sensitive than the uncircumcised glans mucosa, which means that after circumcision genital sensitivity is lost. In the debate on clitoral surgery the proven loss of sensitivity has been the strongest argument to change medical practice. In the present study there is strong evidence on the erogenous sensitivity of the foreskin. This knowledge hopefully can help doctors and patients in their decision on circumcision for non-medical reason. OBJECTIVES: To test the hypothesis that sensitivity of the foreskin is a substantial part of male penile sensitivity. To determine the effects of male circumcision on penile sensitivity in a large sample. SUBJECTS AND METHODS: The study aimed at a sample size of ≈1000 men. Given the intimate nature of the questions and the intended large sample size, the authors decided to create an online survey. Respondents were recruited by means of leaflets and advertising. RESULTS: The analysis sample consisted of 1059 uncircumcised and 310 circumcised men. For the glans penis, circumcised men reported decreased sexual pleasure and lower orgasm intensity. They also stated more effort was required to achieve orgasm, and a higher percentage of them experienced unusual sensations (burning, prickling, itching, or tingling and numbness of the glans penis). For the penile shaft a higher percentage of circumcised men described discomfort and pain, numbness and unusual sensations. In comparison to men circumcised before puberty, men circumcised during adolescence or later indicated less sexual pleasure at the glans penis, and a higher percentage of them reported discomfort or pain and unusual sensations at the penile shaft. CONCLUSIONS: This study confirms the importance of the foreskin for penile sensitivity, overall sexual satisfaction, and penile functioning. Furthermore, this study shows that a higher percentage of circumcised men experience discomfort or pain and unusual sensations as compared with the uncircumcised population. Before circumcision without medical indication, adult men, and parents considering circumcision of their sons, should be informed of the importance of the foreskin in male sexuality.

Erectile implants in female-to-male transsexuals: our experience in 129 patients.

BACKGROUND: The combination of a neourethra and erection prosthesis in a single neophallus in the female-to-male transsexual remains a challenge. No good data are available on this subject. OBJECTIVE: To report the outcome in 129 female-to-male transsexuals with a neophallus after the implantation of an erectile prosthesis. DESIGN, SETTING, AND PARTICIPANTS: From March 1996 until October 2007, 129 female-to-male transsexuals with a neophallus underwent the implantation of an erectile prosthesis. The mean follow-up was 30.2 mo (range: 0-132 mo). INTERVENTION: A Dynaflex prosthesis was implanted initially in 9 patients, a three-piece hydraulic device (AMS CX or AMS CXM) in 50 patients, and a CX Inhibizone, Ambicor, and Coloplast/Mentor prosthesis in 17, 47, and 6 patients, respectively. MEASUREMENTS: Data on outcome in these patients were retrospectively evaluated. RESULTS AND LIMITATIONS: Of 129 patients, 76 patients (58.9%) still have their original implant in place. Fifty-three patients (41.1%) needed to undergo either removal or revision of the prosthesis due to infection, erosion, dysfunction, or leak. Forty-one patients underwent a replacement of the prosthesis, nine needed a second revision, five needed a third revision, and one patient needed a fourth revision of prosthesis. Malposition of prosthesis was corrected by surgical repositioning so that removal or revision could be avoided. Of 185 prostheses used in 129 patients, 108 (58.4%) still remain in place, with a total infection rate of 11.9%, a total protrusion rate of 8.1%, a total prosthesis leak rate of 9.2%, a total dysfunction rate of 13%, and a total malposition rate of 14.6%. The period of follow-up in the more recent types of prostheses (Ambicor, Coloplast/Mentor) is much shorter; therefore, comparison with earlier types is difficult to make. CONCLUSIONS: Despite high complication rates, implantation of a hydraulic erectile prosthesis remains the best option for achieving the possibility of sexual intercourse in female-to-male transsexuals.

One-stage penectomy and phalloplasty for epithelioid sarcoma of the penis in an adolescent.

Epithelioid sarcoma (ES) of the penis is a rare tumour. We present a case of ES of the penis in a 16-yr-old boy, for which penectomy and immediate reconstruction with a free forearm phalloplasty, including a urethral reconstruction, was performed. Because total penectomy is a dramatic life event for any patient, the option of immediate penile reconstruction is presented. It can help to prevent major psychological problems after this kind of surgery.

Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol.

[reaction: see text] Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O-isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.

Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.

The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase.

Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.

Design of HIV-1 protease inhibitors active on multidrug-resistant virus.

On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.

Increased Ed-B fibronectin plasma levels in spondyloarthropathies: comparison with rheumatoid arthritis patients and a healthy population.

OBJECTIVE: To determine, for the first time, plasma levels of general fibronectin (Fn) and two spliced isoforms, Ed-A and Ed-B, in patients with spondyloarthropathy (SpA) in comparison with rheumatoid arthritis (RA) patients and healthy volunteers (HV). METHODS: Plasmas (EDTA) as well as clinical data, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were collected in two groups of 10 patients fulfilling the European Spondylarthropathy Study Group criteria for SpA or the 1987 American College of Rheumatology criteria for RA. Plasmas of 21 blood donors served as controls. Plasma levels of Fns were determined by using an in-house immunocapture ELISA, using monoclonal antibodies (MAbs) against general Fn and its isoforms. RESULTS: Total Fn plasma levels were significantly higher in the SpA group (mean+/-S.D.=1387+/-569 mg/l) than in the RA group (684+/-196 mg/l; P=0.02) and in HV (303+/-211 mg/l; P<0.0001). Ed-A Fn levels appeared higher in SpA (23+/-10.4 mg/l) and RA (32.5+/-16.5 mg/l) groups than in the HV group (2.8+/-0.9 mg/l; P=0.0003 and P<0.0001, respectively), without a significant difference between SpA and RA groups. Ed-B Fn levels were higher in SpA (6.9+/-2.1 mg/l) than in RA (3.2+/-1.9 mg/l; P=0. 02) and HV (1.1+/-0.8 mg/l; P=0.0003) groups. No significant correlation was observed in SpA patients between each Fn level and clinical activity, ESR or CRP levels. CONCLUSIONS: This study showed an increase in plasma levels of Fn and Ed-B Fn in SpA patients compared with RA patients and HV, which could not be attributed solely to systemic inflammation. It may be hypothesized that Ed-A and Ed-B Fn might reflect local turnover in inflamed tissues, and that Ed-B Fn might be particularly involved in the musculoskeletal inflammatory process of SpA.

Unusual onset of rheumatoid arthritis with diffuse pulmonary nodulosis: a diagnostic problem.

We describe a case of a 50-year-old woman presenting articular manifestations of rheumatoid arthritis associated with severe interstitial lung involvement related to multiple pulmonary nodules. Diagnosis of diffuse pulmonary rheumatoid nodulitis was made only after video assisted thoracoscopic lung biopsies.

Factors linked to disease activity in a French cohort of patients with spondyloarthropathy.

OBJECTIVE: To identify risk factors associated with disease activity, in a group of patients with spondyloarthropathy (SpA) living in France. METHODS: Patients fulfilling the ESSG or Amor criteria for SpA were enrolled in a cross sectional multicenter study. Disease activity was assessed using a French version of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Univariate and multivariate analyses were used to identify a link between BASDAI and disease characteristics, genetic factors, and environmental factors such as infectious events, mental stress, working conditions, and dietary factors. RESULTS: We studied 293 patients. On multivariate analysis, BASDAI appeared to be mainly linked to disease duration (negative correlation), the absence of sacroiliitis, and the "frequency of meals taken out of home" (negative correlation). CONCLUSION: Disease activity in a French population of patients with SpA appeared to be linked mainly to a shorter disease duration and a peripheral pattern of arthritis, as well as to dietary habits. The underlying links between this last environmental factor and disease activity remained hypothetical and could only reflect a nontested social factor.

Two cases of discitis due to Propionibacterium acnes.

We report two cases of discitis due to Propionibacterium acnes and review previously published cases of bone and joint infections in which this organism was recovered as a pure culture. P. acnes is an anaerobic organism usually considered a normal inhabitant of the skin but capable of producing a variety of infections including discitis, osteitis, arthritis, and chest wall osteitis. Most patients were immunocompetent. A few infections occurred spontaneously, whereas others were secondary to a break in the skin or to implantation of foreign material into the body for instance during internal fixation of a fracture or arthroplasty. Cases of P. acnes chest wall infection have been reported in patients with palmoplantar pustulosis or chronic or multifocal osteitis, supporting a role for P. acnes in SAPHO syndrome.

Evaluation of a French version of the Bath Ankylosing Spondylitis Disease Activity Index in patients with spondyloarthropathy.

OBJECTIVE: To develop a French version of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and to determine its metric properties in patients with all forms of spondyloarthropathies (SpA). METHODS: A French version of BASDAI was obtained after a translation and back-translation process. Patients fulfilling the European Spondylarthropathy Study Group or Amor criteria for SpA were included. BASDAI of Day 0, Day 1, and, when treatment was changed, Day 8, and other clinical and biological disease activity variables were recorded, along with assessment of disease activity by the physician or the patient. Scalability, reproducibility, sensitivity to change, internal consistency and redundancy, and construct validity of the index were assessed. RESULTS: We studied 293 patients. Good scalability, reproducibility, construct, and internal validity were observed for BASDAI. Sensitivity to change could not be assessed. CONCLUSION: The French version of BASDAI exhibited good metric properties in patients with all forms of SpA, confirming its utility in further clinical research in SpA. However, sensitivity to changes due to drug therapy remains to be assessed.

Misleading clinical aspects of hydroxyapatite deposits: a series of 15 cases.

OBJECTIVE: To study the characteristics of radiographs in diagnosis of hydroxyapatite deposits in sites other than the shoulders and hips. METHODS: We reviewed the records of patients hospitalized during the last 3 years whose final diagnosis was apatite deposits in sites other than the shoulders and hips. RESULTS: Ten women and 5 men were studied. The initial presentation mimicked septic arthritis or periarticular soft tissue abscess in 12 patients, corresponding to calcifications in the fingers (6), toes (2), wrists (2), elbow (1), and ankle (1). One patient presented with a spontaneous coccygeal pain (precoccygeal deposit), one with a pseudotumoral process of the thigh (paradiaphyseal calcification), and one with acute cervical pain and dysphagia (longus coli muscle calcification). Complete clinical healing was observed after an average of 4.9 days; 11 patients used nonsteroidal antiinflammatory drugs (NSAID), 2 used colchicine, one used oral steroids, and one had brief antibiotic therapy and used NSAID. CONCLUSION: Initial clinical aspects of apatite deposits in sites other than the shoulders and hips can often be misleading, especially by mimicking an infectious process. Careful analysis of immediate radiographic films can help to rapidly ascertain the diagnosis and thus avoid useless investigations or treatment.