Vesico-urethral anastomotic stenosis following radical prostatectomy: a multi-institutional outcome analysis with a focus on endoscopic approach, surgical sequence, and the impact of radiation therapy.

OBJECTIVES: To investigate the predictors of recurrence and of de novo incontinence in patients treated by transurethral incision or resection for vesico-urethral anastomotic stenosis (VUAS) after radical prostatectomy. MATERIAL AND METHODS: All patients undergoing endoscopic treatment for VUAS between March 2009 and October 2016 were identified in our multi-institutional database. Digital chart reviews were performed and patients contacted for follow-up. Recurrence was defined as any need for further instrumentation or surgery, and de-novo-incontinence as patient-reported outcome. RESULTS: Of 103 patients undergoing endoscopic VUAS treatment, 67 (65%) underwent transurethral resection (TR) and 36 (35%) transurethral incision (TI). TI was performed more frequently as primary treatment compared to TR (58% vs. 37%; p = 0.041). Primary and repeated treatment was performed in 46 (45%) and 57 patients (55%), respectively. Overall, 38 patients (37%) had a history of radiation therapy. There was no difference in time to recurrence for primary vs repeat VUAS treatment, previous vs no radiation, TR compared to TI (all p > 0.08). Regarding treatment success, no difference was found for primary vs. repeat VUAS treatment (50% vs. 37%), previous radiation vs. no radiation (42% vs. 43%), and TR vs. TI (37% vs. 53%; all p ≥ 0.1). Postoperative de novo incontinence was more common after TI vs. TR (31% vs. 12%; p = 0.032), no difference was observed for previous radiation therapy vs. no radiation therapy (18% vs. 18%; p > 0.9) or primary vs. repeat VUAS treatment (22% vs. 16%; p = 0.5). CONCLUSION: VUAS recurrence after endoscopic treatment is not predictable. Endoscopic treatment with TI showed a higher risk for de novo incontinence than TR, and previous irradiation and the number of treatments do not influence incontinence.

The T-plasty as therapy for recurrent bladder neck stenosis: success rate, functional outcome, and patient satisfaction.

PURPOSE: To determine success rate (SR), functional outcome, and patient satisfaction of a modified YV-plasty for reconstruction of the bladder neck in case of recurrent bladder neck stenosis (BNS) after transurethral surgery of the prostate: the T-plasty. PATIENTS AND METHODS: We identified all patients who underwent T-plasty at our center between December 2008 and July 2016. Patients' charts were reviewed. Patients were queried by telephone and by mail at time of follow-up (FU). Primary endpoint was SR. Secondary endpoints were complications, continence, satisfaction, and changes in quality of life measured by validated questionnaires. RESULTS: Thirty patients underwent the T-plasty. Median age at surgery was 69 (IQR 62-73) years. Most patients had BNS due to TUR-P [n = 25 (83.3%)]. No severe blood loss or severe complications occurred perioperatively. Median FU was 45 (IQR 18-64) months. Three patients were lost to FU. Success rate was 100%. Compared to pre-OP Q max, mean Q max post-OP improved significantly [pre-OP 6.79 (SD ± 4.76) ml/s vs post-OP was 24.42 (SD ± 12.61) ml/s; (t(5) = 4.12, p = 0.009)]. Mean post-void residual urine decreased significantly [pre-OP 140.77 (SD ± 105.41) ml vs post-OP 14.5 (SD ± 22.42) ml; (t(9) = -3.86, p = 0.004)]. One patient developed a de-novo-incontinence post-OP. Mean ICIQ-SF Score was 1.2 (SD ± 2.27). 88.5% of patients were pleased or delighted by surgery. 75% of patients claimed their quality of life has been (strongly) improved. CONCLUSIONS: The T-plasty is a valuable option as treatment of recurrent BNS. SR, rates of continence, and high patient satisfaction are very encouraging.

Management of Anterior Urethral Strictures in Adults: A Survey of Contemporary Practice in Germany.

INTRODUCTION: Treatment methods of anterior urethral strictures in adults have undergone considerable changes in the recent past. Our goal was to determine national practice patterns among German urologists and to compare results with the results of prior international surveys. METHODS: We conducted a survey on the management of urethral strictures among German urologists. RESULTS: Eight hundred forty-five urologists, representing about 14.6% of German urologists, answered the survey. Most common procedures were direct vision internal urethrotomy (DVIU; 87.2%), blind internal urethrotomy (57.5%), dilatation (56.3%), ventral buccal mucosa graft urethroplasty (31.6%) and excision and primary anastomosis (28.9%). In case of a 3.5-cm bulbar stricture and in the case of a 1-cm bulbar stricture after 2 failed DVIUs, a consecutive urethroplasty was significantly more often favoured compared to transurethral treatment options (44.9 vs. 21.3% and 59.4 vs. 8.3%, both p < 0.001). CONCLUSION: Open urethral reconstruction reveals to be a more common method in practice nowadays. Adherence to recommended treatment algorithms improved in comparison to prior surveys.

The T-plasty: a modified YV-plasty for highly recurrent bladder neck contracture after transurethral surgery for benign hyperplasia of the prostate: clinical outcome and patient satisfaction.

OBJECTIVE: To describe a modified surgical technique for treatment of highly recurrent bladder neck contracture (BNC) after transurethral surgery for benign hyperplasia and to evaluate success rate and patient satisfaction of this novel technique. METHODS: Ten patients with highly recurrent BNC and multiple prior attempts of endoscopic treatment underwent the T-plasty. Perioperative complications were recorded and classified according to the Clavien classification. Patient reported functional outcomes were retrospectively analysed using a standardized questionnaire assessing recurrence of stenosis, incontinence, satisfaction and changes in quality of life (QoL). The questionnaires included validated IPSS and SF-8-health survey items. RESULTS: Mean age at the time of surgery was 69.2 years (range 61-79), and the mean follow-up was 26 months (range 3-46). No complications grade 3 or higher according to the Clavien classification occurred. Success rate was 100 %. No de novo stress incontinence occurred. Urinary stream was described as very strong to moderate by 80 % of the patients, mean post-operative IPSS-score was 11.3 (range 4-29), and mean post-operative IPSS-QoL was 2.4 (range 1-5). Patients satisfaction was very high or high in 90 %, and QoL improved in 90 %. The SF-8-health survey showed values comparable to the reference population. CONCLUSION: The T-plasty represents a safe and valuable option in treating highly recurrent BNC after surgery for benign hyperplasia. It offers multiple advantages compared to other techniques such as a single-staged approach and the opportunity for reconstruction of a reliable wide bladder neck by usage of two well-vascularized flaps. Success rate, low rate of complications and preservation of continence are highly encouraging.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Panurethral and complex urethral strictures. Reconstruction in several steps: current techniques and indications.

Patients with panurethral and complex urethral strictures after failed urethral reconstruction due to strictures and hypospadias repair is a rare but challenging condition. Contemporary surgical techniques include one and two staged urethroplasties using different graft substitutes (i.e., buccal mucosa) or full thickness skin grafts (i.e., from the inner thigh(, thereby providing satisfactory results with reducing the re-stricture rate in these patients. However, all current techniques do so at the expense of higher revision rates and thus requiring multiple procedures. Studies investigating the outcomes of reconstruction in panurethral and complex urethral strictures often have heterogeneous patient cohorts including children and adults, different underlying causes, and different techniques, thus allowing only limited interpretation of the published data. In the field of urethral reconstruction, where personal experience and expertise presents an accepted necessity, however, leading to rather small single center studies,only well-designed randomized clinical trials can truly answer the question of which technique will be advantageous in these patients.

Natalizumab may improve cognition and mood in multiple sclerosis.

Immunomodulating therapies may prevent relapses in multiple sclerosis and stabilize neurological status. However, little is known about the influence particularly of newer drugs on cognitive functions. We conducted an open-label prospective study to demonstrate whether natalizumab is apt to improve cognitive functions and mood in 29 patients tested psychometrically while under treatment for 6 months. We found improvements in some measures of attention, memory, mood, and well-being, but no deterioration, although patients suffered from their diseases for more than 10 years and had an EDSS score of 3.5. It is concluded that natalizumab is able to stabilize or improve cognition and mood even in longer-lasting multiple sclerosis.

Estimating the average distribution of Antarctic krill Euphausia superba at the northern Antarctic Peninsula during austral summer and winter.

This study was performed to aid the management of the fishery for Antarctic krill Euphausia superba. Krill are an important component of the Antarctic marine ecosystem, providing a key food source for many marine predators. Additionally, krill are the target of the largest commercial fishery in the Southern Ocean, for which annual catches have been increasing and concentrating in recent years. The krill fishery is managed by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), which has endorsed a new management framework that requires information about the spatial distribution and biomass of krill. Here, we use krill density estimates from acoustic surveys and a GAMM framework to model habitat properties associated with high krill biomass during summer and winter in the northern Antarctic Peninsula region, an area important to the commercial fishery. Our models show elevated krill density associated with the shelf break, increased sea surface temperature, moderate chlorophyll-a concentration and increased salinity. During winter, our models show associations with shallow waters (< 1500 m) with low sea-ice concentration, medium sea-level anomaly and medium current speed. Our models predict temporal averages of the distribution and density of krill, which can be used to aid CCAMLR's revised ecosystem approach to fisheries management. Our models have the potential to help in the spatial and temporal design of future acoustic surveys that would preclude the need for modelled extrapolations. We highlight that the ecosystem approach to fisheries management of krill critically depends upon such field observations at relevant spatial and temporal scales. Supplementary Information: The online version contains supplementary material available at 10.1007/s00300-022-03039-y.

Specificity of the helper T cell for the cytolytic T lymphocyte response to influenza viruses.

We have described a model system in which helper T cells are required to mount a primary antiviral cytolytic T lymphocyte response. The radioresistant helper cell can be found in the spleens of mice that have been immunized subcutaneously with influenza viruses 6-8 d previously. These helper cells appear to be type specific but cross-reactive among the subtypes of influenza A viruses. The phenotypes of the interacting cell populations were determined.

Dissection of serological and cytolytic T lymphocyte epitopes on murine major histocompatibility antigens by a recombinant H-2 gene separating the first two external domains.

A novel H-2 gene in which the first external (N) domain of the H-2Ld antigen was replaced with that of the H-2Dd antigen was constructed and introduced into L cells. A transformant expressing the products of the hybrid gene was studied for binding to monoclonal antibodies specific for H-2Ld and H-2Dd antigens. It was found that serological determinants are distributed both in the N (Dd) and Cl (Ld) domains. Determinants recognized by allospecific cytotoxic T lymphocytes (CTLs) and virus-specific CTLs also mapped to the N and Cl domains. Determinants recognized by vesicular stomatitis virus (VSV)-specific effect cells, however, were not present on the recombinant molecule. These results show that a recombinant gene of two H-2 antigens in which the first external domain has been reshuffled can express a functional H-2 antigen that can then be used to map serological and CTL determinants to specific domains.

Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon.

We have used monoclonal antibody binding, measured by radioimmunoassay, fluorescence flow cytometry, and ultrastructural immunocytochemistry, to measure expression of Ia antigens on cultured human umbilical vein endothelial (HUVE) cells. Under standard culture conditions, HUVE cells do not express Ia antigens. However, treatment of primary HUVE cultures with phytohemagglutinin induces the expression of Ia antigens. Every endothelial cell in the culture becomes Ia-positive and endothelial cells appear to synthesize Ia. HLA-A,B is concomitantly increased. The expression of Ia appears to be mediated by T cells because (a) pretreatment of primary HUVE cultures with OKT3 plus complement blocks the action of the lectins but not of medium conditioned by lectin-activated peripheral blood mononuclear cells; (b) co-culture of endothelial cells with allogeneic T cells, in the absence of lectin, also induces endothelial Ia; and (c) human immune (gamma) interferon, produced by Chinese hamster ovary cells transfected with the human gamma interferon gene, directly induces endothelial Ia. During co-culture with lymphocytes, about one-third of the endothelial cells are Ia-positive after 24 h and all of the endothelial cells are Ia-positive by 72 h. Proliferation of allogeneic T cells starts by 96 h and peaks at 144 h. Thus, endothelial Ia appears sufficiently early to be a determinant for the proliferation of allogeneic T cells. Inducible expression of Ia by endothelium may be important both for allograft rejection and for recruitment of circulating T cells into the site of an immune response.

Evidence for genetic restriction in the suppression of erythropoiesis by a unique subset of T lymphocytes in man.

The suppression of erythropoiesis by lymphocytes from patients with a T cell lymphoproliferative syndrome and pure erythrocyte aplasia has been previously demonstrated. To study the nature of the suppressor cell and possible genetic restriction of this suppression, we investigated a patient with severe anemia, splenomegaly, lymphocytosis, and erythroid aplasia. A 3-mo course of low-dose daily oral cyclophosphamide achieved a complete remission for over 12 mo. The surface phenotype of his lymphocytes was analyzed by means of antibodies to lineage, differentiation, and activation-specific surface antigens. The cells expressed mature T cell antigens T3, T8, and T11, while lacking T1. Immature T cell, B cell, and the monocyte-specific antigen Mo2 were absent, while Mo1, a monocyte-associated antigen not normally expressed on T cells, was present. T10 and Ia expressed as activation antigens were also present. The cells, cryopreserved at diagnosis, were thawed and co-cultured in plasma clot with patient remission marrow samples at T cell/bone marrow ratios of 1:1 and 2:1. There was nearly 90% suppression of erythroid colony-forming unit expression and 60% suppression of erythroid burst-forming unit expression at 2:1 T cell to bone marrow ratios and somewhat less suppression at 1:1. Granulocyte/macrophage progenitor expression was unaffected. Erythroid progenitor differentiation in the marrows of two HLA identical siblings was similarly suppressed. The cells were co-cultured with the marrows of nine nonrelated donors to investigate the potential genetic restriction of this suppression. Colony suppression equal to that observed in the marrow of the patient and his siblings was found in studies of two partially HLA identical individuals. No suppression was detected in marrow co-cultures of two entirely HLA dissimilar individuals. These results show that suppression of erythropoiesis by a unique subset of T8, Mo1, Ia-positive lymphocytes isolated from a patient with lymphocytosis and erythrocyte aplasia is genetically restricted.

Human dermal fibroblasts present tetanus toxoid antigen to antigen-specific T cell clones.

Cultured human dermal fibroblasts treated with immune interferon express HLA-DR antigens. We report here that DR-positive fibroblasts present tetanus toxoid (TT) to autologous TT-specific monoclonal helper T cells vigorously depleted of monocytes by passage over Sephadex G10 columns followed by treatment with the monoclonal antibodies (mAb) OKM1 and Leu M1 plus complement. The extent of T cell proliferation in response to TT presented by DR-positive fibroblasts was similar to that elicited using monocytes as antigen-presenting cells. The proliferative response was TT dependent, antigen specific, depended upon DR expression by fibroblasts, appeared MHC restricted, and was completely blocked by mouse mAb to HLA-DR but not by mAb to HLA-A,B, or DQ. DR-positive fibroblasts pulsed with TT were similarly effective in antigen presentation. In summary, immune interferon-stimulated human dermal fibroblasts can substitute for classical antigen-presenting cells in antigen-specific proliferative responses. Since fibroblasts are a ubiquitous cell type in the body, they may play a significant role in the immunobiology of the host.

H-2Ld antigen encoded by a recombinant retrovirus genome is expressed on the surface of infected cells.

A recombinant murine retrovirus was constructed which contains, within its genome, a truncated version of the gene encoding the murine H-2Ld major histocompatibility antigen. The H-2Ld gene, which was inserted 3' of the env splice acceptor site in the recombinant retrovirus MSV-neo, lacked the 5' promoter and TATA sequences and the 3' transcription termination and polyadenylate addition sites of the normal H-2Ld gene. Transfection of the MSV-neo/H-2Ld plasmid (pLTV-11) into Y-2 cells resulted in the production of the transmissible recombinant retrovirus LTV-11. Cells infected with LTV-11 virus were resistant to the eucaryotic antibiotic G418 and expressed H-2Ld on the cell surface. These infected cells contained a viral RNA species which possessed both the H-2Ld and the neomycin resistance gene sequences but did not contain significant levels of the smaller H-2Ld-specific mRNA. The H-2Ld antigen expressed on the surface of infected cells functioned as a target for cytolytic T cells specific for the H-2Ld antigen.

Biochemical and functional analyses of a secreted H-2Ld molecule.

A truncated H-2Ld gene was constructed by deleting the transmembrane and cytoplasmic exons. The truncated H-2Ld gene was introduced into mouse L cells using the thymidine kinase gene as a selectable marker. Transformants were isolated and screened for the presence of truncated H-2Ld antigen. The truncated H-2Ld gene product was present in both the cytoplasm and culture medium, but not on the cell surface. The truncated H-2Ld antigen was stable in culture medium for at least 9 h and was secreted into the medium at a rate similar to the kinetics with which complete H-2 antigens reach the cell surface. Transformants expressing the truncated H-2Ld molecule were not recognized by cytotoxic T lymphocytes specific for the H-2Ld antigen.

IL-12 and viral infections.

Interleukin-12 activates natural killer cells and promotes the differentiation of Th1 CD4+ cells; it is a critical factor in viral immunity. IL-12 is secreted by antigen presenting cells including dendritic cells, macrophages and astrocytes, both in tissues and in secondary lymphoid organs. Experimental studies have shown that administration of the cytokine rapidly activates both innate and specific immune responses; this results in enhanced host cellular responses and generally, promotes clearance of virus and host recovery from infection. The observations of many laboratories, studying viral immunity to both RNA and DNA based pathogens, are summarized.

Direct Vision Internal Urethrotomy for Short Anterior Urethral Strictures and Beyond: Success Rates, Predictors of Treatment Failure, and Recurrence Management.

OBJECTIVE: To determine success rates, predictors of recurrence, and recurrence management of patients treated for short anterior urethral strictures by direct vision internal urethrotomy (DVIU). MATERIALS AND METHODS: We identified 128 patients who underwent DVIU of the anterior urethra between December 2009 and March 2016. Follow-up was conducted by telephone interviews. Success rates were assessed by Kaplan-Meier estimators. Predictors of stricture recurrence and different further therapy strategies were identified by uni- and multivariable Cox regression analyses. RESULTS: The mean age was 63.8 years (standard deviation: 16.3) and the overall success rate was 51.6% (N = 66) at a median follow-up of 16 months (interquartile range: 6-43). Median time to stricture recurrence was six months (interquartile range: 2-12). In uni- and multivariable analyses, only repeat DVIU (hazard ratio [HR] = 1.87, 95% confidence interval (CI) = 1.13-3.11, P= .015; and HR=1.78, 95% CI = 1.05-3.03, P = .032, respectively) was a risk factor for recurrence. Of 62 patients with recurrence, 35.5% underwent urethroplasty, 29% underwent further endoscopic treatment, and 33.9% did not undergo further interventional therapy. Age (HR = 1.05, 95% CI = 1.01-1.09, P = .019) and diabetes (HR = 2.90, 95% CI = 1.02-8.26, P = .047) were predictors of no further interventional therapy. CONCLUSION: DVIU seems justifiable in short urethral strictures as a primary treatment. Prior DVIU was a risk factor for recurrence. In case of recurrence, about one-third of the patients did not undergo any further therapy. Higher age and diabetes predicted the denial of any further treatment.

Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort.

OBJECTIVES: The purpose of this study was to assess the relative proportions of normal versus impaired left ventricular (LV) systolic function among persons with congestive heart failure (CHF) in the community and to compare their long-term mortality during follow-up. BACKGROUND: Several hospital-based investigations have reported that a high proportion of subjects with CHF have normal LV systolic function. The prevalence and prognosis of CHF with normal LV systolic function in the community are not known. METHODS: We evaluated the echocardiograms of 73 Framingham Heart Study subjects with CHF (33 women, 40 men, mean age 73 years) and 146 age- and gender-matched control subjects (nested case-control study). Impaired LV systolic function was defined as an LV ejection fraction (LVEF) <0.50. RESULTS: Thirty-seven CHF cases (51%) had a normal LVEF; 36 (49%) had a reduced LVEF. Women predominated in the former group (65%), whereas men constituted 75% of the latter group. During a median follow-up of 6.2 years, CHF cases with normal LVEF experienced an annual mortality of 8.7% versus 3.0% for matched control subjects (adjusted hazards ratio = 4.06, 95% confidence interval 1.61 to 10.26). Congestive heart failure cases with reduced LVEF had an annual mortality of 18.9% versus 4.1% for matched control subjects (adjusted hazards ratio = 4.31, 95% confidence interval 1.98 to 9.36). CONCLUSIONS: Normal LV systolic function is often found in persons with CHF in the community and is more common in women than in men. Although CHF cases with normal LVEF have a lower mortality risk than cases with reduced LVEF, they have a fourfold mortality risk compared with control subjects who are free of CHF.

Innate immune responses in viral encephalitis.

The innate immune system is multifaceted, comprised of preformed factors, cells, and many proteins and lipid mediators produced by those cells. In the CNS these are critical in initiation and amplification of the inflammatory response and in the subsequent elicitation of the specific T cell response to viral encephalitis. Cells that are resident in brain parenchyma and peripheral cells that are recruited both play key roles in the hosts's responses. Unlike the peripheral compartments, in the CNS, non-cytolytic means of eliminating viral infections have been critical, since, in contrast to columnar epithelial cells, neurons are non-renewing. When the innate immune responses are inefficient or absent in viral encephalitis, pathology is more likely. Much more work remains to elucidate all of the critical cells and their mediators, as well as to develop new therapies for infections of the CNS.

The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood.

BACKGROUND AND PURPOSE: Stimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function. EXPERIMENTAL APPROACH: The effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice. KEY RESULTS: Riociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100 nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100 µM riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood. CONCLUSIONS AND IMPLICATIONS: Riociguat inhibits platelet activation in whole blood only at concentrations above 50 µM, while the plasma concentrations in riociguat-treated patients are 150 to 500 nM. This finding indicates that riociguat treatment does not affect platelet function in patients. Nevertheless, the possibility that riociguat acts synergistically with iloprost to inhibit platelet activation should be considered.