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.

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.

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.

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.

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.

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.

Nuclear import of LASP-1 is regulated by phosphorylation and dynamic protein-protein interactions.

LASP-1 is a multidomain protein predominantly localized at focal contacts, where it regulates cytoskeleton dynamics and cell migration. However, in different tumor entities, a nuclear LASP-1 accumulation is observed, thought to have an important role in cancer progression. Until now, the molecular mechanisms that control LASP-1 nuclear import were not elucidated. Here, we identified a novel LASP-1-binding partner, zona occludens protein 2 (ZO-2), and established its role in the signal transduction pathway of LASP-1 nucleo-cytoplasmatic shuttling. Phosphorylation of LASP-1 by PKA at serine 146 induces translocation of the LASP-1/ZO-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of ZO-2 and the SH3 domain in LASP-1. In situ proximity ligation assay confirmed the direct binding between LASP-1 and ZO-2 and visualized the shuttling. Nuclear export is mediated by Crm-1 and a newly identified nuclear export signal in LASP-1. Finally, dephosphorylation of LASP-1 by phosphatase PP2B is suggested to relocalize the protein back to focal contacts. In summary, we define a new pathway for LASP-1 in tumor progression.

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.

STAT3 and SMAD1 signaling in Medaka embryonic stem-like cells and blastula embryos.

The activation and transcriptional activity of signal transducer and activator of transcription 3 (STAT3) is essential for maintaining mouse embryonic stem (ES) cell cultures in an undifferentiated state. However, reports from human and monkey ES-cell culture suggest that STAT3 is dispensable for pluripotency in these systems. At the same time, BMP signaling via smad1 was shown to be able to counteract STAT3 signaling in murine ES-cell cultures, while it influences differentiation in multifaceted ways in other cellular contexts. Hence, the question arises whether the signaling situation found in mice or primates and human ES-cells represent the rule or the exception. With this study, we want to contribute an answer to this question from an evolutionary perspective. Therefore, we analyzed the expression and activation status of the Medaka (Oryzias latipes) STAT3 and SMAD1 in Medaka ES-cell-like cultures and their in vivo counterpart, the Medaka blastula embryo. While SMAD signaling is active in the culture system as well as in blastula embryos, our results indicate that STAT3 is inactive and can thus not be involved in pluripotency control of blastula cells or their derived pluripotent in vitro counterparts. These results suggest that the signaling pathways active in the mouse ES-cell culture system represent the exception, while inactivity of STAT3 is apparently the rule in vertebrate ES-cell cultures.

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.

Leukotrienes play protective roles early during experimental VSV encephalitis.

Leukotrienes (LT) are potent lipid mediators of inflammation. 5-Lipoxygenase (5-LO) is the key enzyme in the conversion of arachidonic acid to LT. There are four LT: LTB(4), LTC(4), LTD(4) and LTE(4). LT have been extensively studied in airway inflammation but little is known about their roles in viral infection in the CNS. LTB(4) is a chemoattractant for neutrophils. In this work, we studied the roles of LT in acute vesicular stomatitis virus (VSV) encephalitis. Two methods were used to disrupt 5-LO activity: mice were treated with Zileuton, an enzyme antagonist, or 5-LO genetic knockout mice were used. We found that inhibition or deletion of 5-LO resulted in: (a) impaired process of neutrophil infiltration into the CNS early during viral infection; (b) fewer neurons expressed nitric oxide synthase-1 (NOS-1); (c) higher viral titers 1 day after viral infection; and (d) increased disruption of blood brain barrier (BBB). Our studies suggest that LT are important innate immune players during VSV pathogenesis and are beneficial to the host in early control of viral replication in the CNS.

The role of interleukin-18 in vesicular stomatitis virus infection of the CNS.

Intranasal application of vesicular stomatitis virus (VSV) results in the initial infection of the olfactory receptor neurons and a rapid progression of the virus through the mouse central nervous system (CNS). Interleukin-18 (IL-18) is an 18.3-kd cytokine that induces interferon gamma (IFN-gamma) production in mice. IL-18 is synthesized as an inactive precursor that is cleaved and activated by caspase-1/interleukin-1beta converting enzyme (ICE). IL-18 shares several biological properties with IL-12, including the ability to induce IFN-gamma production in T lymphocytes and natural killer (NK) cells. In the CNS, microglia and astrocytes produce IL-18 and IL-12. We have previously shown that IL-12 promotes recovery from VSV encephalitis. This led us to examine the potential role of IL-18 in the pathogenesis of VSV encephalitis. We show that both IL-18 and caspase-1 mRNA are consistently present in the CNS of mice. The addition of exogenous IL-18 to cell cultures does not affect the production of VSV, and addition of exogenous IL-18 at the time of infection does not alter the morbidity or mortality of BALB/c mice. In vitro studies with neutralizing monoclonal antibody to IL-18 had no effect. From these results we conclude that in this system and under the experimental conditions used, unlike IL-12 and IFN-gamma, IL-18 does not play a significant role in the host response to VSV infection.

Conformational toxicity and sporadic conformational diseases.

Spontaneous, so-called 'conformational' diseases, specially of the neurodegenerative type like Alzheimer's, are linked to certain protein types which have the normal amino-acid sequence but are misfolded and accumulate due to resistance to proteolysis. In the case of prion diseases, the 'protein only' hypothesis assumes that the misconformation of a native protein could be initiated upon interaction with a sister-protein already in the misfolded state. There is an alternative to this sister protein contamination scheme, which assumes that the misconformation is acquired upon protein synthesis, that is de novo. Misfoldling and resistance to proteolysis could result from defects responsible for shortage or inactivity of the cellular factors in charge of protein folding and degradation. The defects could have a genetic origin (the gene of the faulty factor involved could have been mutated, or control and regulation of its expression could have been altered, etc.). Alternatively, the cell's actual biosynthetic and/or proteolytic resources could have become overloaded and unavailable, due to unscheduled mass-production of proteins resulting from unscheduled cell growth or proliferation, cell stress, etc. Xenobiotics, active for instance as endocrine proliferators, stressors, or inducing copious, unscheduled gene expression, etc. could give rise to shortage of cellular factors necessary for the production of native proteins and for proteolysis. Alternatively, xenobiotics could alter expression or activity of some of these factors. In both cases, the xenobiotic could be a 'conformational toxicant' by inducing misfolding of selected proteins. The xenobiotic could trigger some conformational disease if it targets a specific protein and tissue.