Croton stipulaceus Kunth, a native Mexican medicinal plant with antioxidant and anti-inflammatory activities / Croton stipulaceus Kunth, planta medicinal mexicana con actividad antioxidante y antiinflamatoria

Leaves of Croton stipulaceuswere extracted (EHex, ECHCl3and EEtOH extracts) to assesstheir antioxidant potential, anti-inflammatory activity in murine models and acute toxicity. EEtOH showed the highest effect in DPPH (37.80% inhibition), FRAP (1065.00 ± 55.30 µmolFe2+) and total polyphenols (231.24 ± 9.05 meq AG/gM). EHex was the most active, ~ 50% inhibition of TPA-induced ear edema; while EEtOH (dose of 2 mg/ear) showed the highest inhibition in the chronic model (97% inhibition), and inhibited MPO activity (48%). In carrageenan-induced edema, ECHCl3(dose 500 mg/kg) was the most active. None of the extracts showed acute toxicity (LD50) at 2 g/kg (p.o.). This work is the first report that supports the traditional use of C. stipulaceusas an anti-inflammatory.

De las hojas de Croton stipulaceusse obtuvieron diferentes extractos (EHex, ECHCl3y EEtOH) evaluando el potencial antioxidante y la actividad antiinflamatoria en modelos murinos y la toxicidad aguda. El EEtOH mostró mayor efecto en DPPH (37.80% inhibición), FRAP (1065.00 ± 55.30 µmolFe2+) y polifenolestotales (231.24 ± 9.05 meq AG/gM). El EHex fue el más activo, cercano al 50% de inhibición del edema auricular inducido con TPA; mientras que el EEtOH (dosis de 2 mg/oreja) mostró la mayor inhibición en el modelo crónico (97% inhibición), e inhibió la actividad de la MPO (48%). En el edema inducido con carragenina, el ECHCl3(dosis 500 mg/kg) fue el más activo. Ninguno de los extractos mostró una toxicidad aguda (DL50) mayor a 2 g/kg (p.o). Este trabajo es el primer reporte que sustenta el uso tradicional de C. stipulaceuscomo antiinflamatorio.

The challenging management of malignant ureteral obstruction: Analysis of a series of 188 cases.

Background: Malignant ureteral obstruction (MUO) is a common condition that complicates the course of advanced malignancies. The aims of this study are to analyze the causes, management, and survival of patients with obstructive nephropathy due to malignant ureteric obstruction and to determine prognostic factors. Furthermore, we studied the complications and outcomes in patients who underwent urinary diversion. Materials and methods: A retrospective study was conducted on patients with computed tomography-confirmed MUO between January 2016 and November 2020. Demographic, clinical, radiological, laboratory, and management data were collected. Survival curves were estimated using the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards models were used to test the association between parameters and survival. Results: A total of 188 patients were included. The mean age was 69.01 years (SD, 14.95 years), and the majority (54.8%) were male. The most common mechanism leading to MUO was compression by a pelvic mass (36.9%), and the 3 most frequent tumors causing MUO were prostate (17.6%), bladder (16.5%), and rectal cancer (11.7%).Forty-seven patients (25%) underwent urinary diversion: 23 (48.9%) underwent double-J stenting and 21 (44.7%) underwent percutaneous nephrostomy. The most common reason for urinary diversion was acute kidney injury (53.3%). Recovery of renal function was observed in 55.8% of the patients after urinary diversion. The most frequently identified complications after urinary diversion were urinary tract infection (24.4%), hematuria (17.0%), and urinary sepsis (14.9%). The median survival after hydronephrosis diagnosis was 6.43 months (interquartile range, 1.91-14.81 months). In patients who underwent urinary decompression, the median survival after urinary diversion was 8.67 months (interquartile range, 2.99-17.28 months). In the multivariate analysis, a lower grade of hydronephrosis and cancer cachexia negatively impacted survival. Conclusions: Cancer patients with MUO have a poor prognosis; therefore, the risk-benefit ratio of urinary diversion should be carefully considered. Cachexia and hydronephrosis grade can be useful in selecting suitable candidates for urinary diversion.

Sonchus oleraceus L.: ethnomedical, phytochemical and pharmacological aspects.

Sonchus oleraceus L. (Asteraceae) is a cosmopolitan species native to Europe commonly known as lettuce, sowthistle, chicory, or fake dandelion, considered a weed. However, for many years in various cultures around the world, it has been used as food and medicinal plant. The aim of this integrative review is to document the ethnomedical, phytochemical, and pharmacological information of this species. Forty-one papers document the use of S. oleraceus to heal of a wide variety of diseases. However, gastrointestinal problems, diabetes, inflammation, infections, hepatitis, wounds, and to consume it as food are the most common uses. On the other hand, only 11 items highlight that the main groups of secondary metabolites in this species are flavonoids and terpene lactones. Finally, 45 items reveal that antioxidant, antimicrobial, antiproliferative and cytotoxic were the most studied pharmacological activities. In vitro and in vivo studies of extracts and components isolated from different parts of S. oleraceus have provided a concrete overview of the pharmacological properties of this species that supports its ethnomedical uses in cultures from different parts of the world. The reports of this species have focused solely on the study of the complete plant, leaves, and aerial parts, so it is necessary to study other parts of this species to search for bioactive compounds. No clinical studies were found, which creates an opportunity to expand scientific knowledge of this species.

Flaxseed Oil (Linum usitatissimum) Prevents Cognitive and Motor Damage in Rats with Hyperammonemia.

Hyperammonemia is characterized by the excessive accumulation of ammonia in the body as a result of the loss of liver detoxification, leading to the development of hepatic encephalopathy (HE). These metabolic alterations carry cognitive and motor deficits and cause neuronal damage, with no effective treatment at present. In this study, we aimed to evaluate the effect of two subacute oral administrations of flaxseed oil (0.26 and 0.52 mL/kg) on short- and long-term memory, visuospatial memory, locomotor activity, motor coordination, and the neuronal morphology of the prefrontal cortex (PFC) via tests on Wistar rats with hyperammonemia. The goal was to identify its role in the regulation of cerebral edema, without liver damage causing cerebral failure. In contrast with an ammonium-rich diet, flaxseed oil and normal foods did not cause cognitive impairment or motor alterations, as evidenced in the short-term and visuospatial memory tests. Furthermore, the flaxseed oil treatment maintained a regular neuronal morphology of the prefrontal cortex, which represents a neuroprotective effect. We conclude that the oral administration of flaxseed oil prevents cognitive and motor impairments as well as neuronal alterations in rats with hyperammonemia, which supports the potential use of this oil to ameliorate the changes that occur in hepatic encephalopathy.

C-Phycocyanin: A Phycobiliprotein from Spirulina with Metabolic Syndrome and Oxidative Stress Effects.

Spirulina maxima is a cyanobacterium considered a "superfood" due to its metabolites and nutrient content. These include a complex mixture of minerals, vitamins, fatty acids, proteins, and accessory pigments. In recent years, it has positioned itself as a promising source of bioactive molecules for the treatment of several diseases, including metabolic syndrome, coronary diseases, cancer, and the improvement of health modulating oxidative stress. C-Phycocyanin (C-PC) is a photosynthetic pigment from green-blue cyanobacterium and the most abundant phycobiliprotein in the Spirulina genus with various pharmacological properties attributed due to its antioxidant capacity but has no specific cellular target. This has made it a molecule of great interest in biomedical research. This review focuses on the pharmacological effects and the benefits on metabolic syndrome and oxidative stress of C-PC.

Early-Stage Breast Cancer Detection in Breast Milk.

Breast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. SIGNIFICANCE: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image. See related commentary by Cunningham and Turner, p. 2125. This article is featured in Selected Articles from This Issue, p. 2109.

Primary testicular lymphoma: Clinical characteristics and oncological outcomes.

Background: Primary testicular lymphoma (PTL) is a rare testicular malignancy, despite being considered the most common testicular tumor in patients older than 60 years. Primary testicular lymphoma represents only 1%-9% of testicular neoplasms. Few studies have been published regarding its clinical features and management. This study aimed to analyze the clinical characteristics and outcomes of PTL. Materials and methods: Orchiectomy specimens of 15 patients with PTL diagnosed during 2000-2020 at our institution were retrospectively studied. We collected information on demographic data, clinical features, management aspects, and outcomes of PTL treatment. Kaplan-Meier survival curves and Cox regression analyses were used to study survival. Results: The median patient age was 69 years (interquartile range, 61-72 years). The most prevalent clinical presentation was testicular swelling (80%), and only 13.33% of the patients presented with systemic symptoms. Central nervous system involvement was detected in 6 patients (40%). Of the 15 patients, 5 (33.33%) had stage IE and 10 (66.67%) had stage IVE lymphoma. Diffuse large B-cell lymphoma was the most common histological subtype. Twelve patients (80%) received chemotherapy. During follow-up, 4 patients (26.67%) relapsed. The recurrence rate in the contralateral testicle was 13.33%. The median cancer-specific survival was 21.58 months (95% confidence interval, 0-43.95 months). Univariate Cox regression analysis showed that central nervous system involvement and International Prognostic Index score were significantly associated with shorter cancer-specific survival. Conclusions: Primary testicular lymphoma has a high relapse rate and poor prognosis. Management strategies typically include radical orchiectomy and systemic chemotherapy. Central nervous system involvement and International Prognostic Index scores were associated with lymphoma-specific survival.

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials.

BACKGROUND: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. METHODS: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. FINDINGS: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. CONCLUSIONS: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions. FUNDING: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

Schwannoma of the seminal vesicle: Case report and review of the literature.

Seminal vesicles can be affected by tumours originating in other locations. However, primary tumours of the seminal vesicle are extremely rare, with less than 100 cases reported in literature. Seminal vesicle adenocarcinoma is the most common type, but there are also other malign lesions. Diagnosis is challenging due to the lack of early symptoms and well-defined criteria. These tumours are usually asymptomatic and discovered incidentally during imaging tests or pelvic surgery. Definitive diagnosis requires anatomopathological analysis. Case report of 58-years-old man with schwannoma of the seminal vesicle. We describe the main characteristics of these tumours as well as their therapeutic approach.

Noninvasive Ventilation for Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

OBJECTIVES: The worldwide practice and impact of noninvasive ventilation (NIV) in pediatric acute respiratory distress syndrome (PARDS) is unknown. We sought to describe NIV use and associated clinical outcomes in PARDS. DESIGN: Planned ancillary study to the 2016/2017 prospective Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study. SETTING: One hundred five international PICUs. PATIENTS: Patients with newly diagnosed PARDS admitted during 10 study weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children were categorized by their respiratory support at PARDS diagnosis into NIV or invasive mechanical ventilation (IMV) groups. Of 708 subjects with PARDS, 160 patients (23%) received NIV at PARDS diagnosis (NIV group). NIV failure rate (defined as tracheal intubation or death) was 84 of 160 patients (53%). Higher nonrespiratory pediatric logistic organ dysfunction (PELOD-2) score, Pa o2 /F io2 was less than 100 at PARDS diagnosis, immunosuppression, and male sex were independently associated with NIV failure. NIV failure was 100% among patients with nonrespiratory PELOD-2 score greater than 2, Pa o2 /F io2 less than 100, and immunosuppression all present. Among patients with Pa o2 /F io2 greater than 100, children in the NIV group had shorter total duration of NIV and IMV, than the IMV at initial diagnosis group. We failed to identify associations between NIV use and PICU survival in a multivariable Cox regression analysis (hazard ratio 1.04 [95% CI, 0.61-1.80]) or mortality in a propensity score matched analysis ( p = 0.369). CONCLUSIONS: Use of NIV at PARDS diagnosis was associated with shorter exposure to IMV in children with mild to moderate hypoxemia. Even though risk of NIV failure was high in some children, we failed to identify greater hazard of mortality in these patients.

Vascular closure devices in living-donor nephrectomy: a much-needed systematic review and meta-analysis focusing on safety.

OBJECTIVE: To assess the safety of vascular closure devices in living-donor nephrectomy (LDN), as staplers and non-transfixion techniques (polymer locking and metal clips) are the methods employed to secure the renal vessels during laparoscopic and robotic LDN, but the use of clips has come into question since the United States Food and Drug Administration and manufacturers issued a contraindication. METHODS: A systematic review and meta-analysis were conducted to assess the safety of vascular closure devices (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD42022364349). The PubMed, Scopus, the Excerpta Medica dataBASE (EMBASE), and the Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) databases were searched in September 2022. For comparative and non-comparative studies, incidence estimates and odds ratios (ORs), respectively, for the main variables regarding safety of vascular closure devices were pooled by using random effects meta-analyses. Quality assessment of the included comparative studies was conducted using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. RESULTS: Of the 863 articles obtained, data were retrieved from 44 studies, which included 42 902 patients. In non-comparative studies, the pooled estimate rates for device failure, severe haemorrhage rate, conversion to open surgery, and mortality were similar for both clips and staplers. Regarding the meta-analyses for comparative studies (three studies), there were no significant differences between the two groups for the severe haemorrhage rate (OR 0.57, 95% confidence interval [CI] 0.18-1.75; P = 0.33), conversion to open surgery (OR 0.35, 95% CI 0.08-1.54; P = 0.16), or death rate (OR 3.64, 95% CI 0.47-28.45; P = 0.22). Based on weak evidence, device failure was lower in the polymer clip group (OR 0.41, 95% CI 0.23-0.75; P = 0.00). CONCLUSIONS: This study has confirmed that there is no evidence for the superiority of any vascular closure device in terms of safety in LDN. Standardised recommendations for vascular control in this context should be carefully designed and prospectively evaluated.

Dispersal and establishment traits provide a colonization advantage for a polyploid apomictic plant.

PREMISE: Apomictic plants (reproducing asexually through seed) often have larger ranges and occur at higher latitudes than closely related sexuals, a pattern known as geographical parthenogenesis (GP). Explanations for GP include differences in colonizing ability due to reproductive assurance and direct/indirect effects of polyploidy (most apomicts are polyploid) on ecological tolerances. While life history traits associated with dispersal and establishment also contribute to the potential for range expansion, few studies compare these traits in related apomicts and sexuals. METHODS: We investigated differences in early life history traits between diploid-sexual and polyploid-apomictic Townsendia hookeri (Asteraceae), which displays a classic pattern of GP. Using lab and greenhouse experiments, we measured seed dispersal traits, germination success, and seedling size and survival in sexual and apomictic populations from across the range of the species. RESULTS: While theory predicts that trade-offs between dispersal and establishment traits should be common, this was largely not the case in T. hookeri. Apomictic seeds had both lower terminal velocity (staying aloft longer when dropped) and higher germination success than sexual seeds. While there were no differences in seedling size between reproductive types, apomicts did, however, have slightly lower seedling survival than sexuals. CONCLUSIONS: These differences in early life history traits, combined with reproductive assurance conferred by apomixis, suggest that apomicts achieve a greater range through advantages in their ability to both spread and establish.

Analysis of walking speeds and success rates on mid-block crossings using virtual reality simulation.

A focus is set worldwide to study pedestrian behavior in road situations associated with a high frequency of crashes. This paper presents the results from a virtual reality simulation study that recorded pedestrians performing mid-block crossings on a straight segment of an urban street. The experiment was designed with eight scenarios with combinations of one or two lanes, two vehicle speeds, and constant or variable gaps between vehicles. The experiment was conducted with 48 subjects producing 538 crossing observations. The results show that subjects, on average, watched about 5 vehicle gaps in traffic before crossing the street and accepted a gap of 4.5 s between vehicles to cross. A regression model showed that the vehicle speed, the number of lanes, and subjects in the 66-85 years old group had a significant effect on the gap value accepted to cross. An interaction term based on gender and number of lanes also had a significant effect on the accepted gap. The study found average walking speeds between 4.1 and 4.8 ft/s (1.2-1.4 m/s) for different scenarios. A regression model revealed that the gender, the number of lanes, and the gap accepted to cross influenced the walking speed. Significant effects of interactions of the age with gender, number of lanes, and vehicle speed variables were also found that explain the differences in walking speed. The results for the success rate when crossing the street showed the overall worst performance in the scenario with traffic generated with a 25-mph (40 km/h) speed and a constant 3-s gap between vehicles. A Logit model showed that the probability of a pedestrian being hit by a vehicle increased with age, with traffic at the top vehicle speed, and with the constant 3-s vehicle gap. In contrast, the probability decreased with increases in the vehicle gap accepted to cross and the walking speed.

Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-cortico-striatal circuit that are projection-dependent, sex-specific and regulated by mu opioid receptor phosphorylation.

Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) and anterior cingulate cortex (ACC) via activity at µ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in both the DMS and ACC. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses, MThal-ACC synapses, and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation), but decreased subsequent morphine inhibition of transmission at MThal-ACC synapses (morphine tolerance) in a sex-specific manner; these adaptations were present in male but not female mice. Additionally, these adaptations were not observed in knockin mice expressing phosphorylation-deficient MORs, suggesting a role of MOR phosphorylation in mediating both facilitation and tolerance to morphine within this circuit. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex.

High-Flow Oxygen and Other Noninvasive Respiratory Support Therapies in Bronchiolitis: Systematic Review and Network Meta-Analyses.

OBJECTIVES: We present a systematic review on the effectiveness of noninvasive respiratory support techniques in bronchiolitis. DATA SOURCES: Systematic review with pairwise meta-analyses of all studies and network meta-analyses of the clinical trials. STUDY SELECTION: Patients below 24 months old with bronchiolitis who require noninvasive respiratory support were included in randomized controlled trials (RCTs), non-RCT, and cohort studies in which high-flow nasal cannula (HFNC) was compared with conventional low-flow oxygen therapy (LFOT) and/or noninvasive ventilation (NIV). DATA EXTRACTION: Emergency wards and hospitalized patients with bronchiolitis. DATA SYNTHESIS: A total of 3,367 patients were analyzed in 14 RCTs and 8,385 patients in 14 non-RCTs studies. Only in nonexperimental studies, HFNC is associated with a lower risk of invasive mechanical ventilation (MV) than NIV (odds ratio, 0.49; 95% CI, 0.42-0.58), with no differences in experimental studies. There were no differences between HFNC and NIV in other outcomes. HFNC is more effective than LFOT in reducing oxygen days and treatment failure. In the network meta-analyses of clinical trials, NIV was the most effective intervention to avoid invasive MV (surface under the cumulative ranking curve [SUCRA], 57.03%) and to reduce days under oxygen therapy (SUCRA, 79.42%), although crossover effect estimates between interventions showed no significant differences. The included studies show methodological heterogeneity, but it is only statistically significant for the reduction of days of oxygen therapy and length of hospital stay. CONCLUSIONS: Experimental evidence does not suggest that high-flow oxygen therapy has advantages over LFOT as initial treatment nor over NIV as a rescue treatment.

Oncological and Renal Function Outcomes in Patients Who Underwent Simultaneous Radical Cystectomy and Nephroureterectomy for Synchronous or Metachronous Panurothelial Carcinoma.

OBJECTIVE: To assess clinical outcomes of patients who underwent simultaneous radical cystectomy (RC) and radical nephroureterectomy (RNU) for panurothelial carcinoma (PanUC). MATERIALS AND METHODS: A retrospective analysis of 67 patients who underwent simultaneous RC and unilateral RNU for PanUC, from 1996 to 2017. Kaplan-Meier estimates for remnant urothelium recurrence-free survival, metastasis-free survival, overall survival (OS), and cancer-specific survival (CSS) were performed. Cox multivariate models were constructed. RESULTS: The median follow-up was 38 months, 29.8% of patients had a recurrence, 34.3% had metastasis, 67.2% of patients died from any cause, and 37.3% died from urothelial carcinoma. Overall survival and CSS rates at 5 years were 44% and 61%, respectively. In multivariate analysis, progression to muscle-invasive bladder cancer before surgery, presence of muscle-invasive stages at RC and/or RNU, and prostatic urethra involvement were predictors for worse metastasis-free survival and CSS. Forty-one patients (61.2%) had an estimated glomerular filtration rate (eGFR) <60 mL/min before surgery and the number rose to 56 (83.5%) after surgery; 29.8% patients needed renal function replacement therapy after surgery (16 haemodialysis and 4 renal transplant). CONCLUSION: Patients with PanUC who undergo simultaneous surgery have adverse oncological (only 4 out of every 10 remain alive at 5 years) and functional outcomes (1 out of 3 will need renal function replacement therapy after surgery). Up to a third of the patients had a recurrence (urethra or contralateral kidney) within 18 months, justifying close surveillance or considering prophylactic urethrectomy. These data should help in counsel on morbidity and life expectancy.

Nitrergic and Purinergic Nerves in the Small Intestinal Myenteric Plexus and Circular Muscle of Mice and Guinea Pigs.

ATP is an excitatory and inhibitory neurotransmitter, while nitric oxide (NO) is an inhibitory neurotransmitter in the enteric nervous system (ENS). We used a vesicular nucleotide transporter (SLC17A9, VNUT) antibody and a nitric oxide synthase (NOS) antibody to identify purinergic and nitrergic nerves in mouse and guinea ileum. Mouse: VNUT-immunoreactivity (ir) was detected in nerve fibers in myenteric ganglia and circular muscle. VNUT-ir fibers surrounded choline acetyltransferase (ChAT), nitric oxide synthase (nNOS), and calretinin-ir neurons. VNUT-ir nerve cell bodies were not detected. Tyrosine hydroxylase (TH)-ir nerves were detected in myenteric ganglia and the tertiary plexus. Guinea pig: VNUT-ir was detected in neurons and nerves fibers and did not overlap with NOS-ir nerve fibers. VNUT-ir was detected in nerve fibers in ganglia but not nerve cell bodies. VNUT-ir nerve fibers surrounded NOS-ir and NOS- neurons. NOS-ir and VNUT-ir nerve fibers did not overlap in myenteric ganglia or circular muscle. VNUT-ir nerves surrounded some ChAT-ir neurons. VNUT-ir and ChAT-ir were detected in separate nerves in the CM. VNUT-ir nerve fibers surrounded calretinin-ir neurons.Conclusions: VNUT-ir neurons likely mediate purinergic signaling in small intestinal myenteric ganglia and circular muscle. ATP and NO are likely released from different inhibitory motorneurons. VNUT-ir and ChAT-ir interneurons mediate cholinergic and purinergic synaptic transmission in the myenteric plexus.

Novel life cycle stages of Colpodella sp. (Apicomplexa) identified using Sam-Yellowe’s trichrome stains and confocal and electron microscopy / Nuevas etapas del ciclo de vida de Colpodella sp. (Apicomplexa) identificado mediante tinciones tricrómicas de Sam-Yellowe y microscopía confocal y electrónica

Colpodella spp. are free-living flagellates closely related to the apicomplexans. Human infections by Colpodella sp. have been reported. A biflagellated trophozoite and cyst stage comprise the known life cycle stages of Colpodella sp. However, the process of encystation and excystation within the life cycle is unclear. Life cycle stages initiating human infections are unknown. We performed a detailed investigation of the life cycle of Colpodella sp. (ATCC 50594) in culture using Sam-Yellowe’s trichrome stains and differential interference contrast (DIC) for light microscopy and fluorescence microscopy of Congo red-stained cells and investigated ultrastructure using transmission electron microscopy (TEM). We report previously undocumented stages of Colpodella sp. Asymmetric and asynchronous division was detected inside cysts by trichrome staining and by TEM. Odd-numbered juveniles and cysts containing more than four juvenile trophozoites were identified. Live imaging of active cultures captured the excystation and egress of juvenile trophozoites and confirmed the presence of multinucleate cysts. The ultrastructure of the multinucleate cyst is reminiscent of apicomplexan schizonts. Insights gained from the life cycle stages observed in culture allowed the construction of the life cycle of Colpodella sp. Knowledge of the life cycle will aid biochemical and molecular characterization of Colpodella sp. and help identify stages in human infections.(AU)

Medicines in exceptional circumstances for solid tumours: focusing on evidence, effectiveness, and toxicity profiles.

OBJECTIVE: To analyse the applications for drugs in special situations (compassionate use, off-label use and foreign drugs) for solid  tumours, and to assess the level of evidence supporting these applications, as  well as the effectiveness and safety of most frequent drugs. METHOD: We performed a cross-sectional study of all applications for drugs in  special situations during 2018 and 2019 in a representative third-level centre.  We collected data about generic names of drugs, clinical indications, and level  of evidence provided on the application form. Furthermore, tumour response  was assessed according to the Response Evaluation Criteria in Solid Tumours  version 1.1., Progression Free Survival and Overall Survival. Safety was  evaluated with the National Cancer Institute Common Terminology Criteria for  Adverse Events, version 5.0. RESULTS: 2,273 drugs in special situations were approved between January  2018 and December 2019. In 431 cases (19%), they were used to treat solid  tumours. Out of 431, 291 (67.5%) applications were offlabel drugs, 76 (18%)  foreign drugs, and 64 (15%) were compassionate use of drugs. Most of them  were supported by phase 3 (47%) or phase 2 (33%)  clinical trials. The  majority of adverse effects were grade 1 and only in 6/67 cases the treatment  was discontinued due to toxicity. CONCLUSIONS: A significant number of drugs in special situations are prescribed  to Oncology patients. The majority of applications of these drugs was supported by clinical trials. The real-life experience showed an effectiveness and tolerance profile similar to those described in randomised  clinical trials.

OBJETIVO: Analizar las solicitudes de medicamentos en situaciones especiales (uso compasivo, uso fuera de indicación y medicamentos  extranjeros) para tumores sólidos, y evaluar el nivel de evidencia que avala  dichas solicitudes, así como la efectividad y seguridad de los medicamentos  más frecuentes.Método: Estudio transversal que incluyó las solicitudes de medicamentos en  situaciones especiales durante el período 2018-2019 en un centro representativo español de tercer nivel. Se recogieron datos sobre  principios activos, indicaciones clínicas y nivel de evidencia aportado en la  solicitud. Asimismo, la respuesta tumoral fue evaluada mediante criterios  Response Evaluation Criteria in Solid Tumours versión 1.1, supervivencia libre  de progresión y supervivencia global. La seguridad fue evaluada con la versión 5.0 de los criterios de toxicidad Common Terminology Criteria for  Adverse Events del National Cancer Institute de Estados Unidos. RESULTADOS: Un total de 2.273 medicamentos en situaciones especiales fueron aprobados entre enero de 2018 y diciembre de 2019. El 19% (431) se  aprobaron para el tratamiento de tumores sólidos. De estos 431, 291 (67,5%)  solicitudes fueron de medicamentos fuera de indicación, 76 (18%) extranjeros  y 64 (15%) en uso compasivo. La mayoría son avaladas por estudios clínicos  aleatorizados en fase III (47%) o fase II (33%). La mayor parte de los efectos  adversos fueron de grado 1 y solo en 6/67 casos el tratamiento fue  interrumpido por toxicidad. CONCLUSIONES: Un porcentaje importante de medicamentos en usos especiales se prescriben a pacientes oncológicos. La mayoría de las solicitudes fueron  avaladas por algún estudio clínico aleatorizado. La experiencia en vida real  mostró un perfil de efectividad y tolerancia similar al descrito en los estudios  clínicos aleatorizados.