Individual receptor profiling as a novel tool to support diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC)

Purpose

Dysregulation of neurotransmitter receptors may contribute to bladder overactivity (OAB) symptoms. To address the question whether specific receptor expression patterns are associated with bladder pain syndrome/interstitial cystitis (BPS/IC), we examined the expression of muscarinic, purinergic and histamine receptors in the detrusor.

Methods

Detrusor receptor expression was investigated in bladder biopsies of female BPS/IC patients (n?=?44; age 60.64?±?13.78, mean?±?SD) and carcinoma patients (n?=?11; age 58.91?±?12.72) undergoing cystectomy. Protein expression of muscarinic (M2, M3), purinergic (P2X1–3) and histamine receptors (H1, H2) was analysed by confocal immunofluorescence, and gene expression was quantified by real-time polymerase chain reaction (qPCR).

Results

M2, P2X1, P2X2 and H1 receptor immunoreactivity (-IR) was significantly enhanced in BPS/IC compared to the control group, while there was no difference for M3-, P2X3- and H2-IR. We calculated a score, which separated BPS/IC from control patients with an AUC of 89.46%, showing 84.09% sensitivity and 90.91% specificity. Patients had a 9.25 times enhanced calculated risk for BPS/IC. In addition, two patient subgroups (M2?>?M3 and M3?>?M2) were observed, which differed in associated purinergic and histamine receptor expression.

Conclusions

M2, P2X1, P2X2 and H1 were significantly upregulated in BPS/IC patients, and H2 was occasionally highly overexpressed. There was no significant correlation between receptor protein and gene expression, implying posttranslational mechanisms being responsible for the altered receptor expressions. On the basis of individual receptor profiles, upregulated receptors could be targeted by monotherapy or combination therapy with already approved receptor inhibitors, thereby promoting tailored therapy for patients suffering from BPS/IC-like symptoms.     

Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone

A multicenter, open-label, randomized efficacy and safety study was performed with combined human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) (Puregon(R)) treatment to induce spermatogenesis in hypogonadotropic hypogonadal male patients. Patients were pretreated for 16 weeks with hCG to normalize testosterone levels. A total of 30 of 49 (61%) subjects had normalized testosterone levels but were still azoospermic after the hCG-alone phase. These patients were randomized into 2 treatment schemes with recFSH (2 x 225 IU recFSH per week [group A] or 3 x 150 IU recFSH per week [group B]), in combination with hCG for a period of 48 weeks. Total testosterone increased during the hCG-alone period from 1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL for groups A and B, respectively. Combined gonadotropin treatment was effective in inducing spermatogenesis (sperm count >/=1 x 10(6)/mL) in 14 of 30 subjects (47%) and this was achieved after a median duration of treatment of approximately 5.5 months. Treatment time necessary for first sperm cells to appear in the ejaculate was related to the initial testicular volume. Subjects with a history of maldescended testes (11 of 30 subjects, 37%) showed a lower mean response to treatment as indicated by the relatively lower number of subjects reaching levels of at least 1 x 10(6) sperm cells per milliliter. Combined testicular volume increased during combined gonadotropin treatment from 11.4 to 24.0 mL. Although subjects with a history of maldescended testes had a lower starting testicular volume, subjects with and without a history of maldescended testes showed approximately the same relative increase in testicular volume. Total testosterone levels showed only a minor further increase during the combined gonadotropin treatment period. In conclusion, a weekly dose of 450 IU (3 x 150 IU or 2 x 225 IU) recFSH, in addition to hCG, was able to induce spermatogenesis in many hypogonadotropic azoospermic men who failed to respond to treatment with hCG alone.     

Evaluation of 4-mm to 7-mm versus 6-mm prosthetic brachial-antecubital forearm loop access for hemodialysis: results of a randomized multicenter clinical trial

OBJECTIVE: Prosthetic arteriovenous fistulas for hemodialysis vascular access have a high incidence rate of thrombotic occlusions that result in graft failure. This randomized multicenter study was performed to assess the patency rates and the effect of 4-mm to 7-mm grafts on the development of stenoses. METHODS: A total of 109 patients who needed vascular access for hemodialysis were randomized to receive either 6-mm (n = 57) or 4-mm to 7-mm prosthetic brachial-antecubital forearm loop accesses (polytetrafluoroethylene). Duplex scanning, with measurement of blood flow and peak systolic velocity and detection of stenoses (>50%), was performed at 1, 6, and 12 months after surgery. Clinical data were obtained in a prospective manner and primary, assisted primary, and secondary patency rates were calculated with the Kaplan-Meier life-table analysis. Statistical analysis was performed with the independent samples t test and chi(2) test. RESULTS: At 1 year, patency rates were similar for both 4-mm to 7-mm and 6-mm prostheses (primary, 46% versus 43%; assisted primary, 62% versus 58%; secondary, 87% versus 91%). The incidence rate of thrombotic occlusion was comparable for both groups (0.74/patient-year versus 0.88/patient-year; P >.05). Mean graft flow at 1, 6, and 12 months was 1416 versus 1415 mL/min, 1345 versus 1319 mL/min, and 1595 versus 1265 mL/min (P >.05) for 4-mm to 7-mm and 6-mm grafts, respectively. Also, no differences in peak systolic velocities in any part of the grafts were observed. The percentage of stenoses detected was equal in both groups at 1 year after surgery (27% versus 20%; P >.05). CONCLUSION: A 4-mm to 7-mm tapered prosthetic brachial-antecubital forearm loop access did not reduce the incidence rates of stenoses and thrombotic occlusions compared with a 6-mm prosthetic conduit. Moreover, no differences in patency rates were observed. Therefore, we believe that the 4-mm to 7-mm graft should not be used routinely for hemodialysis vascular access.     

Evaluation of new prosthetic meshes for ventral hernia repair

Background In hernia repair, particularly laparoscopic hernia repair, direct contact between mesh and abdominal organs cannot always be avoided. Several mesh materials and composite meshes have been developed to decrease subsequent adhesion formation. Recently, new meshes have been introduced. In an experimental rat study, their value was established and compared with that of meshes already available on the market. Methods In 200 rats, eight different meshes were placed intraperitoneally and in direct contact with abdominal viscera. The following meshes were tested: polypropylene (Prolene), e-PTFE (Dualmesh), polypropylene– polyglecaprone composite (Ultrapro), titanium–polypropylene composite (Timesh), polypropylene with carboxymethylcellulose–sodium hyaluronate coating (Sepramesh), polyester with collagen-polyethylene glycol–glycerol coating (Parietex Composite), polypropylene–polydioxanone composite with oxidized cellulose coating (Proceed), and bovine pericardium (Tutomesh). At 7 and then at 30 days postoperatively, adhesion formation, mesh incorporation, tensile strength, shrinkage, and infection were scored by two independent observers. Results Parietex Composite, Sepramesh, and Tutomesh resulted in decreased surface coverage with adhesions, whereas Prolene, Dualmesh, Ultrapro, Timesh, and Proceed resulted in increased adhesion coverage. Parietex Composite, Prolene, Ultrapro, and Sepramesh resulted in the most mesh incorporation. Dualmesh and Tutomesh resulted in significantly increased shrinkage. There were no differences in mesh infection. Parietex Composite and Dualmesh resulted in a moderate inflammatory reaction, as compared with the mild reaction the other meshes exhibited. Conclusion Parietex Composite and Sepramesh combine minimal adhesion formation with maximum mesh incorporation and tensile strength. The authors recommend the use of these meshes for hernia repair in which direct contact with the abdominal viscera cannot be avoided.     

Saphenous vein spiral graft: successful emergency repair of a mycotic aneurysm with aortoduodenal fistula.

Mycotic aneurysms leading to aortoduodenal fistula (ADF) are associated with high morbidity and mortality. We report a patient with a mycotic aneurysm and ADF who required emergency laparotomy. After excision of the aneurysm, vascular reconstruction was performed using an autologous graft. The left long saphenous vein was harvested and constructed into a spiral graft. The graft was inserted using a standard inlay technique. After 12 months the patient is in good health. No inflammation or dilation of the saphenous vein spiral graft has been noted. We suggest that in the emergency treatment of mycotic abdominal aneurysm, aortic reconstruction with saphenous vein spiral graft is a valuable option.     

Epithelial–mesenchymal transformation markers E-cadherin and survivin predict progression of stage pTa urothelial bladder carcinoma

Purpose

To determine whether the immunohistochemical markers survivin and E-cadherin can predict progress at initially diagnosed Ta bladder cancer.

Methods

We retrospectively searched for every initially diagnosed pTa urothelial bladder carcinoma having been treated at our single-center hospital in Germany from January 1992 up to December 2004. Follow-up was recorded up to June 2010, with recurrence or progress being the endpoints. Immunohistochemical staining and analysis of survivin and E-cadherin of the TURB specimens were performed. Outcome dependency of progression and no progression with immunohistochemical staining was analyzed using uni- and multivariate regression analysis, Kaplan–Meier analysis and uni- and multivariate Cox regression analysis.

Results

Overall, 233 patients were included. Forty-two percent of those were tumor free in their follow-up TURBs, 46 % had at least one pTa recurrence and 12 % even showed progress to at least pT1 bladder cancer. Aberrant staining of E-cadherin was found within 71 % of patients with progression in contrast to only 40 % in cases without progression (p = 0.004). Of all progressed patients, 92 % showed overexpression of survivin in their initial pTa specimen compared to 61 % without progression (p = 0.001). Kaplan–Meier analysis revealed aberrant E-cadherin staining to be associated with worse progression-free survival (PFS) (p = 0.005) as well as overexpression of survivin (p = 0.003). In multivariate Cox regression analysis, strong E-cadherin staining was an independent prognosticator for better PFS (p = 0.033) and multifocality (p = 0.046) and tumor size over 3 cm (p = 0.042) were prognosticators for worse PFS.

Conclusion

Adding the immunohistochemical markers survivin and E-cadherin could help to identify patients at risk of developing a progressive disease in initial stage pTa bladder cancer.

     

Adolescent idiopathic scoliosis - to operate or not? A debate article

Adolescent idiopathic scoliosis (AIS) represents a rare condition with a potentially detrimental impact on young patients. Despite vast clinical research and published treatment guidelines and algorithms, the optimal therapeutic choice for these patients remains highly controversial. While advocates of early surgery emphasize the benefits of surgical deformity correction with regard to physical and psychological outcome, the opponents base their arguments on the high risk of complications and a lack of documented subjective long-term outcome. In the present paper, the authors were invited to debate the opposite positions of "pro" versus "contra" surgical treatment of AIS, based on the currently available evidence and published guidelines.     

Does photodynamic transurethral resection of bladder tumour improve the outcome of initial T1 high‐grade bladder cancer? A long‐term follow‐up of a randomized study

OBJECTIVE

To evaluate, in a long‐term follow‐up of T1 high‐grade bladder cancer treated in a prospective, randomized trial, whether fluorescence diagnosis (FD) increases recurrence‐free survival (RFS) or reduces progression to muscle‐invasive stages.

PATIENTS AND METHODS

In all, 191 patients with suspected superficial bladder cancer were treated with transurethral resection under white light (WL) or with FD; 46 presented with initial T1 high‐grade BC (WL, 25; FD, 21). There were no differences in multifocality of tumours, concomitant carcinoma in situ or tumour size in either group.

RESULTS

Patients were followed for a median of 7.3 (WL) and 7.5 (FD) years to evaluate RFS. In the WL group there were 11, and in the FD group three, recurrent tumours of the same stage and grade. The RFS at 4 and 8 years was 69% and 52% in the WL, and 91% and 80% in FD group, respectively. With FD, the RFS was significantly longer according to Kaplan‐Meier analysis (P = 0.025). In the WL group, three (12%), and in the FD group four (19%) patients progressed to muscle‐invasive stages (≥ T2).

CONCLUSION

In initial T1 high‐grade bladder cancer, FD is significantly better than conventional WL transurethral resection for RFS. However, the progression rate to muscle‐invasive disease was not reduced by FD. Thus the clinical course (progression) of T1 high‐grade bladder cancer remains unaffected by FD.     

Etanercept therapy for late-onset idiopathic pneumonia syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication of allogeneic hematopoietic stem cell transplantation (AHSCT), which usually develops within the first 100 days after transplantation. Donor T-cell-derived tumor necrosis factor-alpha (TNF-alpha) may play a crucial role in the pathogenesis of IPS, and inhibition of TNF-alpha has been used as a therapeutic option. We report two patients who had late-onset IPS about day 150 after nonmyeloablative AHSCT (NMA-AHSCT). They responded well to etanercept in combination with standard immunosuppressive drugs. Both patients had relapses and responded to retreatment with etanercept-based therapy. One patient was alive at 30 months after the initial diagnosis on long-term maintenance therapy with etanercept. The second patient was lost to follow-up at our institution but died 13 months after the onset of IPS. Our two cases showed that IPS could develop late after NMA-AHSCT and inhibition of TNF-alpha activity can be therapeutically effective.