Gender and cystectomy for bladder cancer: A high-volume tertiary urologic care center experience.

BACKGROUND: Differences have often been reported in the outcomes of bladder cancer (BC) patients according to gender. OBJECTIVE: This study aims to provide data on patients undergoing radical cystectomy (RC) in a high-volume tertiary urologic center and to assess whether gender discrepancies do exist in terms of surgical options and clinical outcomes. MATERIALS AND METHODS: Consecutive BC patients treated between 2016 and 2020 at a single center (Careggi University Hospital, Florence, Italy) were included in the study. The impact of gender on disease stage at diagnosis, overall survival (OS), and type of surgery was analyzed. RESULTS: The study series comprised 447 patients (85 females and 362 males). At a median follow-up of 28.3 months (IQR: 33.5), OS was 52.6% and cancer-specific survival was 67.6%. Significant differences in OS emerged for age, acute myocardial infarction (AMI), Charlson Comorbidity Index (CCI), pT, and pN. OS rates were higher in patients undergoing robot-assisted surgery and in those receiving open orthotopic neobladder (ONB) (p = 0.0001). No statistically significant differences were found between male and female patients regarding surgical offer in any age group, surgical time, early postoperative complications, pathologic stage, and OS. CONCLUSIONS: After adjustment for pathologic tumor stage and treatment modalities, female and male patients showed similar oncologic outcomes. Further studies should be undertaken to evaluate functional results in women subjected to RC.

Effect of propolis on Th2 and Th17 cells: interplay with EtxB- and LPS-treated dendritic cells.

Dendritic cells (DCs) are antigen-presenting cells that drive the differentiation of T CD4+ cells into different profiles according to the nature of the antigen or immunomodulator. Propolis is a resinous product made by bees that has numerous pharmacological properties, including an immunomodulatory action. To assess whether propolis can modulate the activation of CD4+ T cells by stimulating DCs with heat-labile enterotoxin B subunit (EtxB) or lipopolysaccharide (LPS), we aimed to elucidate the mechanisms affected by propolis in the differential activation of T lymphocytes. Cell viability, lymphocyte proliferation, gene expression (GATA-3 and RORc), and cytokine production (interleukin (IL)-4 and IL-17A) were analyzed. Propolis, EtxB, and LPS induced a higher lymphoproliferation compared with the control. Propolis induced GATA-3 expression and, in combination with EtxB, maintained the baseline levels. Propolis alone or in combination with LPS inhibited RORc expression. EtxB alone and in combination with propolis increased IL-4 production. Propolis in combination with LPS prevented LPS-induced IL-17A production. These results opened perspectives for the study of biological events that may be favored by propolis by promoting Th2 activation or helping in the treatment of inflammatory conditions mediated by Th17 cells.

Modulating Expression of Endogenous Interleukin 1 Beta in the Acute Phase of the Pilocarpine Model of Epilepsy May Change Animal Survival.

The pilocarpine-induced (PILO) model has helped elucidate the electrophysiological and molecular aspects related to mesial temporal lobe epilepsy. It has been suggested that the extensive cell death and edema observed in the brains of these animals could be induced by increased inflammatory responses, such as the rapid release of the inflammatory cytokine interleukin 1 beta (Il1b). In this study, we investigate the role of endogenous Il1b in the acute phase of the PILO model. Our aim is twofold. First, we want to determine whether it is feasible to silence Il1b in the central nervous system using a non-invasive procedure. Second, we aim to investigate the effect of silencing endogenous Il1b and its antagonist, Il1rn.We used RNA interference applied non-invasively to knockdown Il1b and its endogenous antagonist Il1rn. We found that knocking down Il1b prior to pilocarpine injection increased the mortality rate of treated animals. Furthermore, we observed that, when exposing the animals to more Il1b by silencing its endogenous antagonist Il1rn, there was a better response to status epilepticus with decreased animal mortality in the acute phase of the PILO model. Thus, we show the feasibility of using a novel, less invasive approach to study genes involved in the inflammatory response in the central nervous system. Furthermore, our results provide suggestive evidence that modulating endogenous Il1b improves animal survival in the acute phase of the PILO model and may have effects that extend into the chronic phase.

Effect of propolis on Th2 and Th17 cells: interplay with EtxB- and LPS-treated dendritic cells

Dendritic cells (DCs) are antigen-presenting cells that drive the differentiation of T CD4+ cells into different profiles according to the nature of the antigen or immunomodulator. Propolis is a resinous product made by bees that has numerous pharmacological properties, including an immunomodulatory action. To assess whether propolis can modulate the activation of CD4+ T cells by stimulating DCs with heat-labile enterotoxin B subunit (EtxB) or lipopolysaccharide (LPS), we aimed to elucidate the mechanisms affected by propolis in the differential activation of T lymphocytes. Cell viability, lymphocyte proliferation, gene expression (GATA-3 and RORc), and cytokine production (interleukin (IL)-4 and IL-17A) were analyzed. Propolis, EtxB, and LPS induced a higher lymphoproliferation compared with the control. Propolis induced GATA-3 expression and, in combination with EtxB, maintained the baseline levels. Propolis alone or in combination with LPS inhibited RORc expression. EtxB alone and in combination with propolis increased IL-4 production. Propolis in combination with LPS prevented LPS-induced IL-17A production. These results opened perspectives for the study of biological events that may be favored by propolis by promoting Th2 activation or helping in the treatment of inflammatory conditions mediated by Th17 cells.

False recalls, but not false recognitions, at the DRM paradigm are increased in subjects reporting insomnia symptoms: An online study.

BACKGROUND: In insomnia, poor sleep is accompanied by several cognitive impairments affecting prefrontal functioning that could affect source-monitoring processes and contribute to false memories production. By using a modified version of the Deese-Roediger-McDermott paradigm (DRM), we previously found that individuals suffering from insomnia produced more false memories than good sleepers adopting a free-recall task, especially for sleep-related stimuli. However, whether poor sleep affects false memory production in a task-dependent manner (i.e., free recall or recognition) remains unclear. METHODS: Through an online research method, we adopted the classical DRM paradigm to investigate the production of false recalls and false recognitions in 32 subjects referring insomnia symptoms (IN group) and 37 good sleepers (GS group), addressing also executive functioning and source monitoring ability in both groups. RESULTS: Compared to the GS group, the IN group produced more false memories (p = .002) and intrusions (p = .004) at the free recall task and showed a lower working memory index (p = .008). No between-groups differences emerged at the recognition task. Correlational analysis revealed significant associations between DRM performance, executive functioning and source monitoring (SM) variables. Moreover, false recalls were predicted by being in the presence of insomnia symptoms (p = .012) and intrusions by the number of correct responses to the Stroop task (p = .051) and SM task (p = .015), as well as by the presence of insomnia symptoms (p = .003). CONCLUSIONS: Our data show that the presence of insomnia symptoms can influence false memories production. Furthermore, the evidence that free recall is more affected than recognition suggests that poor sleep mainly affects performance at more cognitively demanding tasks. Finally, correlational and regression analyses support the hypothesis of a link between false memories production and both the presence of insomnia symptoms and executive functioning impairments.

Sleep and psychological characteristics in habitual self-awakeners and forced awakeners.

Previous studies described the modifications of physiological and behavioural variables associated with self-awakening, while only few studies assessed subjective sleep quality and psychological characteristics in habitual self-awakeners. Here we investigated self-reported sleep habits and features, as well as psychological variables of habitual self-awakeners and forced-awakeners, with special regard to subjective sleep quality, personality characteristics, anxiety and depression symptoms. In our sample, the prevalence of habitual self-awakeners was 15.1%. Compared to forced-awakeners, habitual self-awakeners showed more regular sleep/wake schedules and were more frequently morning types. Moreover, habitual self-awakeners referred to be more satisfied about their sleep, to wake up more easily in the morning, to need less time to get out of bed and to feel more refreshed upon awakening than forced-awakeners. We also observed an association between the habit of self-awakening and the "ability" to set the awakening to an unusual time. Concerning psychological features, habitual self-awakeners showed higher scores in Conscientiousness and Openness and lower scores in Extraversion compared to forced-awakeners, whereas no differences between groups emerged for anxiety and depression levels. In conclusion, our findings point to an association between the habit of self-awakening and good subjective sleep quality. In this perspective, future research should objectively test in detail the effects of the self-awakening habit on sleep structure and organization, taking into account also microstructural sleep features.

Cerebral small vessel disease burden and longitudinal cognitive decline from age 73 to 82: the Lothian Birth Cohort 1936.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD's association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised ß: -0.201; 95% CI: [-0.36, -0.04]; pFDR = 0.022) and processing speed (-0.222; [-0.40, -0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD's association with greater decline in general cognitive ability remained significant, prior to FDR correction (-0.222; [-0.39, -0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

Potential Hazards Associated with Raw Donkey Milk Consumption: A Review.

Donkey milk can be used as a substitute for infants and children who suffer from cow milk proteins intolerance and multiple food hypersensitivity. Up to date, this is one of the main reasons why donkey milk has become a substantial area for reasearch, with an increase over the the last fifteen years. In donkey milk chain, risk analysis should be the object of particular attention because children are the main consumers of this food. In fact, this process is one of the main tool to achieve a high level of protection of human health and life; thus, the most important safety hazards should be monitored in order to attain this goal. This review focuses on the main hazards possibly present in raw donkey milk, including bacteria, fungal toxins, parasites, and chemical pollutants. Literature data have been considered, including some information that is not provided in the international literature. In the authors' opinion, the current scientific knowledge should be improved, with the aim of allowing a suitable risk assessment along the whole donkey milk chain. However, in the meantime, the competent authorithies must carry out more stringent official controls, with particular attention given to the level of primary production. The issue of a traceability system in donkey milk chain should be considered of paramount importance.

Transport and fate of 137Cs in the Mediterranean and Black Seas system during 1945-2020 period: A modelling study.

The compartment model POSEIDON-R with an embedded dynamic food web model was used to assess 137Cs distributions in the Mediterranean and Black Seas during 1945-2020 due to the weapon testing and accident at the Chernobyl nuclear power plant. Three maximums of contamination of surface waters can be identified from 1950 in the Mediterranean Sea system. Two of them (in 1959 and 1963) were caused by atmospheric deposition due to the nuclear weapon testing. Third maximum in 1986 was related with the Chernobyl accident. Maximum of inventory of 137Cs in the Mediterranean Sea (11461 TBq) was achieved in 1968, whereas secondary maximum caused by Chernobyl accident in 1986 was almost the same (11460 TBq). The corresponding maximum in the Black Sea (3703 TBq) was reached in 1986. It is approximately two times larger than nuclear weapon tests maximum. The results of simulations conducted with generic parameters agreed well with measurements of 137Cs concentrations in the water, bottom sediments, and in marine organisms. The inventory in the Mediterranean Sea is most sensitive to the global deposition, whereas water exchange with Atlantic Ocean and the Black Sea plays minor role. The cumulative individual dose for the period 1945-2020 from consumption of marine products contaminated by 137Cs was in the range 41-130 µSv in the Mediterranean Sea and 213-274 µSv in the Black Sea. The dose increased up to 40% due to Chernobyl accident in the Mediterranean countries and 66-103% in the Black Sea countries comparatively with dose from the global deposition. A useful application of the modelling for monitoring purposes was selection of representative regions in the Mediterranean Sea (5 regions) and in the Black Sea (4 regions) using "etalon" method for classification.

Optimal number and sizes of the doses in fractionated radiotherapy according to the LQ model.

We address a non-linear programming problem to find the optimal scheme of dose fractionation in cancer radiotherapy. Using the LQ model to represent the response to radiation of tumour and normal tissues, we formulate a constrained non-linear optimization problem in terms of the variables number and sizes of the dose fractions. Quadratic constraints are imposed to guarantee that the damages to the early and late responding normal tissues do not exceed assigned tolerable levels. Linear constraints are set to limit the size of the daily doses. The optimal solutions are found in two steps: i) analytical determination of the optimal sizes of the fractional doses for a fixed, but arbitrary number of fractions n; ii) numerical simulation of a sequence of the previous optima for n increasing, and for specific tumour classes. We prove the existence of a finite upper bound for the optimal number of fractions. So, the optimum with respect to n is found by means of a finite number of comparisons amongst the optimal values of the objective function at the first step. In the numerical simulations, the radiosensitivity and repopulation parameters of the normal tissue are fixed, while we investigate the behaviour of the optimal solution for wide variations of the tumour parameters, relating our optima to real clinical protocols. We recognize that the optimality of hypo or equi-fractionated treatment schemes depends on the value of the tumour radiosensitivity ratio compared to the normal tissue radiosensitivity. Fast growing, radioresistant tumours may require particularly short optimal treatments.

Four days of simulated shift work reduces insulin sensitivity in humans.

AIM: The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule. METHODS: Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively. RESULTS: Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L-1 ; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2). CONCLUSION: Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose.

Mutations in PGM1 (phosphoglucomutase 1) cause Glycogen Storage Disease type XIV, which is also a congenital disorder of protein N-glycosylation. It presents throughout life as myopathy with additional systemic symptoms. We report the effect of oral galactose treatment during five months in a patient with biochemically and genetically confirmed PGM1 deficiency. The 12-minute-walking distance increased by 225 m (65%) and transferrin glycosylation was restored to near-normal levels. The exercise assessments showed a severe exercise intolerance due to a block in skeletal muscle glycogenolytic capacity and that galactose treatment tended to normalize skeletal muscle substrate use from fat to carbohydrates during exercise.

Tooth agenesis and orofacial clefting: genetic brothers in arms?

Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFß3, TGFßR1, TGFßR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.

Optimal weekly scheduling in fractionated radiotherapy: effect of an upper bound on the dose fraction size.

This work concerns the optimization of the dose fractionation for cancer radiotherapy schedules of the kind one fraction/day, five fractions/week, assuming a fixed overall treatment time. Constraints are set to limit the radiation damages to surrounding normal tissues, as well as the daily fraction size. The response to radiation of tumour and normal tissues is represented by the classical LQ model, including the exponential repopulation term. We provide a framework to analytically determine the optimal weekly scheme of radiation doses as a function of the tumour type, the fraction upper bound and the normal tissue parameters. For a comparison with the literature, we present some numerical examples of optimal treatment schedules for specific tumour types.

Cost-effectiveness of kidney transplantation from DCD in Italy.

INTRODUCTION: Kidney transplantation represents the best therapeutic option for patients with end-stage renal disease (ESRD), providing the best outcomes for survival, quality of life, and cost-effectiveness. To increase kidney donations, in 2007, the Italian IRCCS Policlinico San Matteo Foundation in Pavia designed and conducted Programma Alba, a protocol for organ donation after cardiac death (DCD). This study evaluated the costs and health outcomes of DCD transplantation and in all types of transplants compared with current clinical practice. PATIENTS AND METHODS: A Markov-based model was used to assess costs and health outcomes for new ESRD patients for 2008 to 2013. A health care founder perspective was used. Data sources were the Italian National Institute of Statistics and the Lombardy Registry of Dialysis and Transplantation. A microcosting analysis was performed to calculate costs related to clinical pathways for DCD. We assessed costs, survival, quality-adjusted survival, and cost-effectiveness. FINDINGS: Changing the actual practice pattern for new patients with ESRD and increasing the availability of kidneys from DCD to 10 extra transplants per year will induce an incremental cost per quality-adjusted life-year of €4255. Increases in transplantation to reach an extra 10% by transplant type would result in reduced costs and increased patient survival and quality of life compared with the current scenario. INTERPRETATION: Our data show that increasing DCD transplants would result in a cost-effective policy to expand the kidney donor pool compared with current ESRD treatment patterns. Italian policies should make an effort to increase transplant rates to optimize cost-effectiveness in ESRD service supply.

Application of the Pearl model to analyze fecal coliform data from conditionally approved shellfish harvest areas in seven Texas bays.

The U.S. National Shellfish Sanitation Program (NSSP) 14/43 standard states that conditionally approved shellfish growing areas must be closed for harvest when the geometric mean of fecal coliform concentration exceeds the NSSP limit of 14 most probable number (MPN)/100 mL, or the estimated 90th percentile of fecal coliform concentrations exceeds 43 MPN/100 mL for a five-tube test. The authors hypothesized that the NSSP 14/43 standard is not sufficient to protect the public from risks from consumption of biologically contaminated shellfish and the standard should be modified to 8/26 MPN/100 mL. To verify this hypothesis, the authors analyzed fecal coliform data from conditionally approved shellfish harvest areas of seven Texas bays using the Pearl sanitation model. Results showed that the shellfish closure rules mandated by the Texas Department of State Health Services actually enforced the "Pearl" limits of 8/26 MPN/100 mL, and not the NSSP limit of 14/43 MPN/100 mL.

Post-traumatic headaches: a clinical overview.

Headache attributed to head and/or neck trauma or injury, the so-called post-traumatic headache (PTH), is the most common secondary headache disorder and one of the most controversial clinical entities in the headache field, due to its unclear pathophysiological mechanisms and the unsolved role of associated psychological and medico-legal aspects. PTH, as a significant cause of morbidity after traumatic brain injury, may occur as an isolated symptom or as one of a constellation of symptoms known as post-concussive syndrome. However, in many cases, PTH might also represent an accentuation of non-disabling, remote or infrequent pre-existing primary headaches rather than a new onset headache strictly related to the trauma. Recently, the International Classification of Headache Disorders attempted to classify PTH; however, many unsolved issues are still to be clarified. In this brief review, we will focus on PTH clinical aspects and diagnostic criteria.

Post-traumatic headaches: an epidemiological overview.

Post-traumatic headache (PTH) is the most common secondary headache disorder, corresponding to approximately 4 % of all symptomatic headaches. PTH, a cardinal feature of the post-concussive syndrome, usually shows a phenotype similar to migraine or tension-type headache. However, rare cases of PTH similar to trigeminal autonomic cephalalgias have been described. Many studies have investigated PTH prevalence and potential risk factors for its development and maintenance. In general population, the majority of PTH patients is female and has been involved in vehicle-related accidents. Generally, headache gradually disappears over few weeks or months; however, PTH could become persistent and very disabling in a minority of patients. This brief review will focus on PTH epidemiological aspects.

The role of BOLD-fMRI in elucidating migraine pathophysiology.

Migraine is a neurologic disorder characterized by disabling attacks of throbbing headache with specific features and associated symptoms. Despite the recent discoveries in basic neurosciences, migraine pathophysiology is not completely understood. Nevertheless, in the last decades, advances in functional magnetic resonance imaging (fMRI) have significantly provided new insights into migraine mechanisms. Blood oxygen level dependent (BOLD) fMRI technique is the most commonly used method to explore brain function and connectivity due to high temporal and spatial resolution. The purpose of this review is to present a synthesis of recent BOLD-fMRI studies which have allowed us to elucidate the complex process involved in migraine pathophysiology.

Effect of dietary vitamin E on cortisol and glucose responses to handling stress in juvenile beluga Huso huso.

An 8-week feeding experiment was conducted to investigate the effect of dietary vitamin E on the physiological response to handling stress in juvenile beluga Huso huso. Fish were fed six experimental diets supplemented with 0, 25, 50,100, 200, or 400 mg Dl-all-rac-alpha-tocopherol acetate/kg diet. At the end of the experiment, the fish in each tank were subjected to acute handling and air exposure stress. Cortisol and glucose were measured as the primary hormonal and secondary metabolic responses to the stressors, both before and 3 h after application of the stressors. The growth parameters and feed utilization rates were significantly lower in fish fed the diet not supplemented with vitamin E than in fish fed diets supplemented with vitamin E. Cortisol concentration was not affected by dietary treatment but glucose concentration was. Fish fed vitamin E at 0, 25, 100, and 400 mg/kg diet had higher concentrations of glucose than those fed vitamin E at 50 and 200 mg/kg. However, fish fed diets with 50 and 200 mg/kg exhibited higher growth rates. These results indicate that dietary vitamin E has some effect on plasma glucose but no effect on plasma cortisol. In general, when the stressors were applied to belugas, the glucose and cortisol responses were relatively low. This may be due to higher resistance and lower physiological responses to these types of stressors by this species or by chondrosteans in general.