Prostatic Fossa Pseudoaneurysm After Robot-Assisted Radical Prostatectomy (RARP): A Case Report.

BACKGROUND RARP is an established procedure in treatment of localized prostate cancer. Hemorrhagic complications in the postoperative period are rare, but sometimes life-threatening. Adequate monitoring and prompt intervention in these unusual scenarios rely on clinical judgement and blood and imaging studies. Prostatic fossa pseudoaneurysm formation after RARP is very rare and its etiology is not well known; it may be related to small vessel trauma. It becomes apparent with the development of hematuria 1-6 weeks after surgery. CASE REPORT A 58-year-old man underwent RARP with extended lymph node dissection for intermediate-risk prostate cancer, with bilateral preservation of neurovascular bundles and puboprostatic ligaments. He was discharged on day 2 without complications. In the following 4 weeks he came to the Emergency Department 3 times with hematuria and acute urinary retention. Four weeks after surgery, a pelvic CT angiogram showed a 20-mm pseudoaneurysm in the prostatic fossa, which was embolized by percutaneous angiography, with resolution of symptoms. He was discharged soon thereafter. CONCLUSIONS This case study describes a patient with prostatic fossa pseudoaneurysm after RARP. It was diagnosed 1 month after surgery and effectively managed by percutaneous embolization. Despite being a very rare condition, it must be kept in mind, especially when postoperative hematuria develops 1-6 weeks after surgery. Use of a management algorithm including serial blood tests, CT angiogram, and percutaneous angiography can lead to early detection and avoid life-threatening hemorrhage and overall postoperative morbidity.

Eighteen years of experience in laparoscopic implantation of artificial urinary sphincter in women with intrinsic sphincter deficiency.

INTRODUCTION AND OBJECTIVES: Artificial urinary sphincter (AUS) is a treatment option for women with stress urinary incontinence (SUI) after failure of previous surgery or as a primary procedure in severe intrinsic sphincter deficiency (ISD). The aim of the study was to assess the long-term efficacy and risk factors for surgical revision and definitive explantation of AUS laparoscopic implantation in female patients. METHODS: A retrospective review of all women submitted to AUS implantation between April 2005 and March 2023 was conducted. The AUS was implanted via transperitoneal laparoscopic approach, by two experienced surgeons. The primary endpoint was postoperative continence. Continence was defined as no leakage and no pad usage or leakage and/or pad usage with no impact on social life and failure as leakage and/or pad usage impacting social life. As secondary outcomes, clinical predictive factors for AUS revision and definitive explantation were evaluated. RESULTS: In the last 18 years, females with a mean age of 68±12 years-old were submitted to laparoscopic implantation of AUS. Early overall complication rate was 16%, but only one case was Clavien-Dindo ≥3. After a median follow-up of 67 months, 22.2% of the patients needed a device revision, the majority due to mechanical device dysfunction. AUS definitive explantation was performed in 16%, mainly due to urethral/vaginal erosion (9.9%) and infection (6.2%). Patients with age ≥70 years and follow-up ≥10 years significantly predisposed for device revision. At the time of the last follow-up, 72% of the patients were keeping the urinary continency. CONCLUSIONS: Laparoscopic AUS implantation in females is an effective treatment for SUI due to ISD. Meanwhile, adequate patient selection, multidisciplinary evaluation and careful expectation management are essential to achieving good results, concerning their significant complication rate.

Complications after surgical correction of penile fractures-Is there a clinical impact?

BACKGROUND: Surgical exploration and closure of the tunica albuginea is the recommended treatment for penile fractures. The recovery of sexual function is the main result that surgeons and patients pursue. OBJECTIVE: We sought to evaluate the sexual health effects of a surgically corrected penile fracture. Secondarily, we sought to identify risk factors that may influence long-term sexual function and their effects on genital body image satisfaction. METHODS: A retrospective analysis of patients who underwent surgical correction of penile fractures between 2007 and 2022 in a tertiary center was performed. Lesion characteristics, weeks until the resumption of sexual activity, and post-operative sexual function were recorded. The presence of glans hypoesthesia, penile deformation, penile nodule palpation, and self-satisfaction with body image were assessed. RESULTS: Sixty-nine patients with a mean age of 42.30 ± 12.98 years and a median follow-up of 70 (20-134) months were identified. Sexual intercourse was recorded as a percentage. Penile deformation was the most common complication, appearing in 14.5% of patients, erectile dysfunction in 5.8%, penile nodules in 4.3%, and glans hypoesthesia in 2.9%. The median post-operative International Index of Erectile Function-5 was 24 (21.5-24). Self-satisfaction with body image had a median of 9 and was negatively associated with bilateral lesions and penile deformation. DISCUSSION AND CONCLUSION: Distal fractures could be linked to erectile dysfunction and glans hypoesthesia. Surgical correction of penile fractures shows positive functional and self-reported outcomes, and the potential andrological complications rarely necessitate specific treatment.

Development and Study of a New Silane Based Polyurethane Hybrid Flexible Adhesive-Part 1: Mechanical Characterization.

The need for more sustainable adhesive formulations has led to the use of silane-based adhesives in different industrial sectors, such as the automotive industry. In this work, the mechanical properties of a dual cure two-component prototype adhesive which combined silylated polyurethane resin (SPUR) with standard epoxy resin was characterized under quasi-static conditions. The characterization process consisted of tensile bulk testing, to determine the Young's modulus, the tensile strength and the tensile strain to failure. The shear stiffness and shear strength were measured by performing a thick adherend shear test. The in-plane strain field was obtained using a digital image correlation method. Double-cantilever beam and mixed-mode tests were performed to assess the fracture toughness under pure modes. The prototype adhesive showed promising but lower properties compared to commercial solutions. Furthermore, the adhesive was modified via the addition of three different resin modifier additives and characterized via measuring the shear and tensile properties, but no enhancements were found. Finally, the adhesive was formulated with three different SPUR viscosities. The critical energy release rate analysis showed an optimum value for the medium viscosity SPUR adhesive.

The Development and Study of a New Silylated Polyurethane-Based Flexible Adhesive-Part 2: Joint Testing and Numerical Modelling.

The need for more sustainable adhesive formulations has presented the possibility of using silane-based adhesives in the automotive industry. In this work, a dual-cure two-component silylated polyurethane resin (SPUR) adhesive was tested in single-lap joints, to assess in-joint behaviour at room temperature under quasi-static conditions for aluminium substrates. The effect of two different overlap lengths, 25 and 50 mm, was also considered. A numerical model was built using cohesive zone modelling in finite element software, to reproduce the mechanical behaviour of the joint. The model was fed with data experimentally withdrawn from the first part of this paper. A triangular-shaped cohesive zone model (CZM) law was chosen as the adhesive behaviour was highly elastic and lacked yielding phenomena. The experimental results served as the base for the numerical validation, allowing accurate CZM parameters to be successfully determined.

Release of HIV-1 particles from macrophages is promoted by an anchored cytoskeleton and driven by mechanical constraints.

A feature of HIV-1 replication in macrophages is that viral assembly occurs at the limiting membrane of a compartment often named the virus-containing compartment (VCC). Assembled virions accumulate in the lumen of the VCC, from where they can be released into the extracellular medium via mechanisms that remain poorly described. Here, we show that the actin cytoskeleton contributes to this process by performing experiments combining pharmacological and mechanical perturbations with imaging and biochemical analysis. We found that jasplakinolide inhibited HIV-1 release from macrophages and led to scattering of the compartment. Concomitantly, both the integrin CD18 (ß2-integrin) and the phosphorylated form of PYK2 (also known as PTK2B) were displaced away from the VCC. Inhibition of PYK2 activity promoted retention of viral particles in VCCs that lost their connections to the surface. Finally, in infected macrophages undergoing frustrated phagocytosis, VCCs rapidly trafficked to the basal membrane and released their viral content, in a manner dependent on their association with the actin cytoskeleton. These results highlight that the trafficking of VCCs and virus release are intimately linked to a reorganization of the macrophage actin cytoskeleton that can be modulated by external physical cues.

Undergraduate teaching of urology: Quo vadis?

BACKGROUND: The undergraduate teaching of urology is not uniform in the various European medical schools and even absent in some of them, despite the widespread adoption of the Bologna process, which advocates a standardization and harmonization of medical education. Our aim was to evaluate the perception of junior doctors about the undergraduate teaching of Urology and the exposure to the specialty of Urology in undergraduate education in Portuguese medical schools. METHODS: A questionnaire was emailed to all physicians who first enrolled in the Board of Portuguese Doctors in 2017 and 2018. The questionnaire consisted of several questions about specialty exposure, pathology, and basic urological procedures. A database for statistical analysis was created. RESULTS: One hundred and eighty-six answers were considered valid. Although almost all participant physicians attribute considerable importance to Urology specialty, most find their exposure to urological pathology and basic urological procedures to be inappropriate in medical school. Urinary lithiasis and lower urinary tract symptoms are the subjects on which doctors feel most prepared after graduating. Interestingly, 63.4% of doctors consider that the education they had in college was preponderant in choosing their specialty. CONCLUSIONS: The teaching of Urology in Portuguese Medical Schools is considered by junior doctors as inadequate, not reflecting the importance of this specialty in the clinical practice. These results are like those found in other countries. A reflection and consequent change of the teaching paradigm is necessary, namely at the practical teaching level.

Prognostic Factors in Penile Cancer: Should We Avoid Inguinal Lymph Node Staging?

INTRODUCTION: Penile cancer (PC) is a rare neoplasm, mostly in developed countries. Herewith, we evaluate the main prognostic factors of patients with PC undergoing surgery. METHODS: This is a retrospective analysis of prognostic factors of overall survival in 65 patients with PC treated at a tertiary referral center over the last 15 years (2004-2018). RESULTS: Almost half (48%) of the patients were diagnosed at an advanced local stage pT3/4. Thirty-eight (58%) patients underwent inguinal lymphadenectomy, and 25 (66%) were negative for lymph node (LN) invasion. Overall survival was 80% at a median follow-up of 31 months. In the multivariate analysis, the main factors of poor prognosis were nodal staging (pN) (p = 0.008) and perineural invasion (p = 0.023). The presence of LN metastasis and perineural invasion in the primary tumor increased the risk of death by 29 (hazard ratio 29.0, 95% confidence interval 2.4-354.2) and 13 (hazard ratio 12.7, 95% confidence interval 1.4-112.0) times, respectively. DISCUSSION/CONCLUSION: Late diagnosis of PC has a negative impact on overall survival, as nodal invasion correlates with survival. Despite the high number of negative inguinal lymphadenectomy, we continue to advocate aggressive surgical treatment of this disease due to the poor prognosis associated with LN metastasis.

HIV-2-Infected Macrophages Produce and Accumulate Poorly Infectious Viral Particles.

A significant proportion of HIV-2-infected patients exhibit natural virological control that is generally absent from HIV-1-infected patients. Along with CD4+ T cells, HIV-1 targets macrophages which may contribute to viral spreading and the latent reservoir. We have studied the relationship between macrophages and HIV-2, focusing on post-entry steps. HIV-2-infected monocyte-derived macrophages (MDMs) produced substantial amounts of viral particles that were largely harbored intracellularly. New viruses assembled at the limiting membrane of internal compartments similar to virus-containing compartments (VCCs) described for HIV-1. VCCs from MDMs infected with either virus shared protein composition and morphology. Strikingly, HIV-2 Gag was mostly absent from the cytosol and almost exclusively localized to the VCCs, whereas HIV-1 Gag was distributed in both locations. Ultrastructural analyses of HIV-2-infected MDMs revealed the presence of numerous VCCs containing both immature and mature particles in the lumen. HIV-2 particles produced de novo by MDMs were poorly infectious in reporter cells and in transmission to activated T cells through a process that appeared independent of BST2 restriction. Rather than being involved in viral spreading, HIV-2-infected macrophages may represent a cell-associated source of viral antigens that can participate in the immune control of HIV-2 infection.

Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells.

Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell-mediated immunity. Interestingly, IL-12 and anti-IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1ß and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.

Non-human primates and Leishmania immunity.

In the context of infectious diseases, non-human primates (NHP) provide the best animal models of human diseases due to the close phylogenetic relationship and the similar physiology and anatomical systems. Herein, we summarized the contribution of NHP models for understanding the immunity to leishmaniases, which are a group of diseases caused by infection with protozoan parasites of the genus Leishmania and classified as one of the neglected tropical diseases.

Transcriptional Analysis of Human Skin Lesions Identifies Tryptophan-2,3-Deoxygenase as a Restriction Factor for Cutaneous Leishmania.

Disease manifestation after infection with cutaneous Leishmania species is the result of a complex interplay of diverse factors, including the immune status of the host, the infecting parasite species, or the parasite load at the lesion site. Understanding how these factors impact on the pathology of cutaneous leishmaniasis (CL) may provide new targets to manage the infection and improve clinical outcome. We quantified the relative expression of 170 genes involved in a diverse range of biological processes, in the skin biopsies from patients afflicted with CL caused by infection with either L. major or L. tropica. As compared to healthy skin, CL lesions bear elevated levels of transcripts involved in the immune response, and conversely, present a significant downregulation in the expression of genes involved in epidermal integrity and arginine or fatty acid metabolism. The expression of transcripts encoding for cytotoxic mediators and chemokines in lesions was inversely correlated with the expression of genes involved in epidermal integrity, suggesting that cytotoxicity is a major mediator of CL pathology. When comparing the transcriptional profiles of lesions caused by either L. major or L. tropica, we found them to be very similar, the later presenting an aggravated inflammatory/cytotoxic profile. Finally, we identified genes positively correlated with the parasite load in lesions. Among others, these included Th2 or regulatory cytokines, such as IL4 or IL10. Remarkably, a single gene among our dataset, encoding for tryptophan-2,3-deoxygenase (TDO), presented a negative correlation with the parasite load, suggesting that its expression may restrict parasite numbers in lesions. In agreement, treatment of macrophages infected with L. major in vitro with a TDO inhibitor led to an increase in parasite transcripts. Our work provides new insights into the factors that impact CL pathology and identifies TDO as a restriction factor for cutaneous Leishmania.

Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27.

Mesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.

The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques.

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.

Treatment adoption and relative effectiveness of aromatase inhibitors compared to tamoxifen in early breast cancer: A multi-institutional observational study.

BACKGROUND: Since 2005, aromatase inhibitors (AIs) have been the adjuvant treatment of choice for postmenopausal women with early breast cancer (BC). In this study we characterize the adoption of AIs in Portugal, variables associated with treatment administration, and compare its effectiveness (either in monotherapy or sequential therapy) to tamoxifen monotherapy (TAM). PATIENTS AND METHODS: This was a retrospective cohort study that included postmenopausal women with stage I-III hormone receptor (HR) positive BC diagnosed from 2006 to 2008 and treated with adjuvant endocrine therapy in four participating institutions. RESULTS: Of the 1283 eligible patients, 527 (41%) received an AI (16% as monotherapy, 25% as sequential therapy) and 756 (59%) TAM. Patients treated with AI had less differentiated tumors, with higher TNM stage, and were more frequently HER2-positive. Use of AI also differed by center (use range from 33% to 75%, p < 0.001). With a median follow-up of 6.3 years and controlling for clinicopathological and treatment characteristics, treatment with AI had a better overall survival (OS) when compared with TAM (adjusted-HR 0.55, 95% CI 0.37-0.81). CONCLUSION: AIs were successfully introduced as adjuvant treatment for HR-positive BC in Portuguese hospitals. Its use was influenced by tumor and patient characteristics, but also center of care. In this large cohort, AI use was associated with an OS benefit.

Myeloid Cell Interaction with HIV: A Complex Relationship.

Cells of the myeloid lineage, particularly macrophages, serve as primary hosts for HIV in vivo, along with CD4 T lymphocytes. Macrophages are present in virtually every tissue of the organism, including locations with negligible T cell colonization, such as the brain, where HIV-mediated inflammation may lead to pathological sequelae. Moreover, infected macrophages are present in multiple other tissues. Recent evidence obtained in humanized mice and macaque models highlighted the capacity of macrophages to sustain HIV replication in vivo in the absence of T cells. Combined with the known resistance of the macrophage to the cytopathic effects of HIV infection, such data bring a renewed interest in this cell type both as a vehicle for viral spread as well as a viral reservoir. While our understanding of key processes of HIV infection of macrophages is far from complete, recent years have nevertheless brought important insight into the uniqueness of the macrophage infection. Productive infection of macrophages by HIV can occur by different routes including from phagocytosis of infected T cells. In macrophages, HIV assembles and buds into a peculiar plasma membrane-connected compartment that preexists to the infection. While the function of such compartment remains elusive, it supposedly allows for the persistence of infectious viral particles over extended periods of time and may play a role on viral transmission. As cells of the innate immune system, macrophages have the capacity to detect and respond to viral components. Recent data suggest that such sensing may occur at multiple steps of the viral cycle and impact subsequent viral spread. We aim to provide an overview of the HIV-macrophage interaction along the multiple stages of the viral life cycle, extending when pertinent such observations to additional myeloid cell types such as dendritic cells or blood monocytes.

Moroccan strains of Leishmania major and Leishmania tropica differentially impact on nitric oxide production by macrophages.

BACKGROUND: Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease caused by protozoa of the genus Leishmania. In Morocco, CL is a public health problem mainly caused by Leishmania major and Leishmania tropica, which are responsible for zoonotic and anthroponotic CL, respectively. Macrophages are the primary cells infected by Leishmania parasites and their capacity to produce nitric oxide (NO) is of critical importance for parasite elimination. To our knowledge, the role of NO on autochthonous infections has never been investigated before. In this study, we evaluated in vitro the capacity of autochthonous primary dermotropic strains of L. major and L. tropica to modulate NO production by J774-macrophages and determine the sensitivity of both species to exogenous NO. METHODS: The infectivity of the J774 cell line was analyzed by optical microscopy. NO production by macrophages was measured by the Griess method. The sensitivity to NO by the two strains was assessed by the MTT assay using NO donors. RESULTS: Our results show that the percentage of infected macrophages and the average number of parasites per macrophage were similar for L. major and L. tropica strains. While L. tropica significantly inhibited NO production induced by LPS and IFN-γ stimulation in J774 macrophages, L. major did not affect it. However, soluble Leishmania antigens (SLAs) from both autochthonous primary strains significantly inhibited the production of NO by J774-macrophages in a dose-dependent manner. Finally, our results demonstrated that promastigotes and amastigotes from both strains are sensitive to SNAP NO donor in a dose-dependent manner, although L. tropica demonstrated an increased sensitivity. CONCLUSIONS: Our results suggest a differential ability of L. major and L. tropica strains to modulate the capacity of macrophages to produce NO. The increased ability of L. tropica to inhibit NO production by macrophages might come as a necessity due to its higher sensitivity to NO donor. Our results provide one explanation for the tendency of L. tropica to cause chronic lesions and may contribute to the different physiopathology of CL in Morocco.

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages.

Along with CD4+ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection.