An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A broad-spectrum anti-vomiting effect of neurokinin1 receptor antagonists (NK1 RA), shown in pre-clinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for anti-emetics. The stimulus-independent effects of NK1 RAs against vomiting are explicable by actions within the central pattern generator (ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The central pattern generator and NTS neurones are multifunctional so the notable lack of obvious effects of NK1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1 RAs to inhibit nausea emphasizes: (i) our inadequate understanding of the mechanisms of nausea; and (ii) that classification of a drug as an anti-emetic may give a false impression of efficacy against nausea vs. vomiting. We discuss the potential mechanisms for the differential efficacy of NK1 RA and the implications for future development of drugs that can effectively treat nausea, an area of unmet clinical need.

Anti-emetic effects of thalidomide: Evidence, mechanism of action, and future directions.

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (KCa1.1) channels and GABAA/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting.

Single Incision Robotic Cystectomy and Hybrid Orthotopic Neobladder Reconstruction: A Step by Step Description.

OBJECTIVE: To describe a new technique for single incision robotic cystectomy and Studer-type ileal neobladder using the single-port (SP) da Vinci SP robotic platform. METHODS: In April 2021, a 71 year-old patient underwent a single incision robotic cystectomy and orthotopic Studer-type ileal neobladder using the single-port da Vinci SP robotic platform for cT2, cN0 urothelial carcinoma of the bladder. He was not a candidate for neoadjuvant cisplatin-based combination chemotherapy and declined participation in a clinical trial. RESULTS: Total operative time was 554 minutes and estimated blood loss was 250 cc. He was discharged on postoperative day six without developing any Clavien complications. He underwent adjuvant chemotherapy for node-positive disease and follow-up through June 2021 was notable for the absence of any significant complications or readmissions. We provide a comprehensive discussion of the required instrumentation, a description of the technique with illustrations, and discuss the advantages and disadvantages of this technology as it pertains to cystectomy and urinary diversion. CONCLUSION: We make no claim regarding the superiority of this technique over others, only that it is technically feasible and that the approach holds promise.

Can Cephalopods Vomit? Hypothesis Based on a Review of Circumstantial Evidence and Preliminary Experimental Observations.

In representative species of all vertebrate classes, the oral ejection of upper digestive tract contents by vomiting or regurgitation is used to void food contaminated with toxins or containing indigestible material not voidable in the feces. Vomiting or regurgitation has been reported in a number of invertebrate marine species (Exaiptasia diaphana, Cancer productus, and Pleurobranchaea californica), prompting consideration of whether cephalopods have this capability. This "hypothesis and theory" paper reviews four lines of supporting evidence: (1) the mollusk P. californica sharing some digestive tract morphological and innervation similarities with Octopus vulgaris is able to vomit or regurgitate with the mechanisms well characterized, providing an example of motor program switching; (2) a rationale for vomiting or regurgitation in cephalopods based upon the potential requirement to void indigestible material, which may cause damage and ejection of toxin contaminated food; (3) anecdotal reports (including from the literature) of vomiting- or regurgitation-like behavior in several species of cephalopod (Sepia officinalis, Sepioteuthis sepioidea, O. vulgaris, and Enteroctopus dofleini); and (4) anatomical and physiological studies indicating that ejection of gastric/crop contents via the buccal cavity is a theoretical possibility by retroperistalsis in the upper digestive tract (esophagus, crop, and stomach). We have not identified any publications refuting our hypothesis, so a balanced review is not possible. Overall, the evidence presented is circumstantial, so experiments adapting current methodology (e.g., research community survey, in vitro studies of motility, and analysis of indigestible gut contents and feces) are described to obtain additional evidence to either support or refute our hypothesis. We recognize the possibility that further research may not support the hypothesis; therefore, we consider how cephalopods may protect themselves against ingestion of toxic food by external chemodetection prior to ingestion and digestive gland detoxification post-ingestion. Reviewing the evidence for the hypothesis has identified a number of gaps in knowledge of the anatomy (e.g., the presence of sphincters) and physiology (e.g., the fate of indigestible food residues, pH of digestive secretions, sensory innervation, and digestive gland detoxification mechanisms) of the digestive tract as well as a paucity of recent studies on the role of epithelial chemoreceptors in prey identification and food intake.

Testing the Analytical Rumination Hypothesis: Exploring the Longitudinal Effects of Problem Solving Analysis on Depression.

Depression is a mental health condition for which individuals commonly seek treatment. However, depressive episodes often resolve on their own, even without treatment. One evolutionary perspective, the analytical rumination hypothesis (ARH), suggests that depression occurs in response to complex problems. According to this perspective, depressive symptoms promote analytical rumination, i.e., distraction-resistant thoughts about the causes of problems [causal analysis (CA)] and how they can be solved [problem-solving analysis (PSA)]. By helping individuals solve complex problems, analytical rumination may contribute to remission from depression. The aim of this study was to investigate (1) whether clinically-depressed individuals have more complex problems and engage in more CA and PSA than non-depressed and (2) the effects of CA and PSA on decreases in problem complexity, depressive symptoms, and remission from the depression. Samples of 85 patients were treated for depression with antidepressants and psychotherapy, and 49 healthy subjects were assessed three times over a 4-month period (at Weeks 1, 5, and 16). At each assessment, they completed measures of depression, analytical rumination, and problem complexity. Depressed individuals reported having more complex problems and engaging in more CA than non-depressed participants. The two groups engaged in a similar degree of PSA. Findings from a multiple regression suggested that more PSA at Week 1 was related to a decrease in depressive symptoms at Week 5, even after controlling for baseline depression, problem number, and complexity. PSA at Week 1 did not predict the remission after hospitalization or at follow-up; however, having less complex problems at the baseline made it more likely that a patient would later remit. Engaging in more CA or PSA at Week 1 did not affect perceived problem complexity at Week 5 or at follow-up. However, these findings were not statistically significant when influential observations (or outliers) were included in the analysis. Our findings suggest that PSA may contribute to a decrease in symptoms of depression over time. However, alleviations in problem complexity and remission might only be achieved if problems are initially less complex. Future directions involve exploring how PSA might contribute to decreases in depressive symptoms and other mechanisms underlying remission from depression.

The effect of urinary diversion on long-term kidney function after cystectomy.

OBJECTIVES: Cystectomy with urinary diversion is associated with decreased long-term kidney function due to several factors. One factor that has been debated is the type of urinary diversion used: ileal conduit (IC) vs. neobladder (NB). We tested the hypothesis that long-term kidney function will not vary by type of urinary diversion. METHODS AND MATERIALS: We retrospectively identified all patients who underwent cystectomy with urinary diversion at our institution from January 1, 2007, to January 1, 2018. Data were collected on patient demographics, comorbid conditions, perioperative radiotherapy, and complications. Creatinine values were measured at several time points up to 120 months after surgery. Glomerular filtration rate (GFR) (ml/min per 1.73 m2) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. A linear mixed model with inverse probability of treatment weighting (IPTW) was used to compare GFR between the IC and NB cohorts over time. Multiple sensitivity analyses were performed based on 2 different calculations of GFR (Chronic Kidney Disease Epidemiology Collaboration equation vs. Modification of Diet in Renal Disease), with and without excluding patients with preoperative GFR less than 40 ml/min per 1.73 m2. RESULTS: Among 563 patients who underwent cystectomy with urinary diversion, a NB was used for 72 (12.8%) individuals. Patients who had a NB were significantly younger, had a lower American Society of Anesthesiologists score, greater baseline GFR, better Eastern Cooperative Oncology Group performance status, lower median Charlson comorbidity index, and were less likely to have received preoperative abdominal radiation (all P < 0.05). Both NB and IC patients had decreased kidney function over time, with mean GFR losses at 5 years of 17% and 14% of baseline values, respectively. The IPTW-adjusted linear mixed model revealed that IC patients had slightly more deterioration in kidney function over time, but this was not statistically significant (estimate, 0.12; P = 0.06). The sensitivity analyses yielded a similar trend, in that GFR decrease appeared to be greater in the IC cohort. This trend was statistically significant when using Modification of Diet in Renal Disease (P = 0.04). CONCLUSIONS: Among highly selected patients with an NB, deterioration of kidney function may potentially be lower over time than among IC patients. However, the statistical significance varied between analyses and we cautiously attribute these observed differences to patient selection.

Stainless steel crowns as a restoration for permanent posterior teeth in people with special needs: A retrospective study.

BACKGROUND: Limited information exists regarding the use of stainless steel crowns (SSCs) in permanent teeth. The objective of this retrospective cohort study was to present the long-term clinical outcomes of the SSC compared with those of amalgam and composite resin restorations and the SSC radiographic outcomes in a special-needs population. METHODS: This study included 271 patients with at least 1 SSC restoration from the Mount Sinai Hospital Dentistry Clinic for Persons with Special Needs in Toronto, Ontario, Canada. A total of 2,621 posterior permanent tooth restorations were documented: 766 SSCs, 1,651 amalgam restorations, and 204 composite resin restorations. Clinical analysis included patient demographics, treatment parameters, and outcome assessments for each restoration recorded. Radiographic analysis of SSC restorations included 127 bite-wing radiographs and 118 periapical radiographs, measurement of interproximal bone loss, and assessment of periapical status using the Periapical Index Scale. RESULTS: The 10-year survival rates for new SSC and amalgam restorations were 79.2% and 63.5%, respectively. The 91 SSC failures included 2 recementations, 33 replacements, and 56 extractions. Primary diagnoses at the time of failure included chronic periodontal disease (25) and loose or lost SSCs (24). Of the 528 failed conventional restorations that were replaced, 60% were replaced with SSCs. The mean alveolar bone loss from mesial and distal sites was 1.36 millimeters and 1.40 mm, respectively. Therefore, 93% of the sites recorded were less than 2 mm and classified as healthy. All pre-SCC and post-SSC periapical radiographs had healthy Periapical Index Scale scores (1 or 2) recorded over an average duration of 8.4 years (1-29.1 years). CONCLUSIONS: SSCs are a durable treatment option for the restoration of the posterior permanent dentition. PRACTICAL IMPLICATIONS: Posterior permanent teeth restored with stainless steel crowns can be expected to last for 10 years and represent a viable treatment choice for severely carious or fractured posterior permanent teeth.

Feasibility of holmium laser enucleation of the prostate as a 1-day surgery.

PURPOSE: To assess the safety and feasibility of HoLEP as a day-case procedure. METHODS: We reviewed all consecutive patients who underwent HoLEP at our institution between February 2017 and March 2018. During this time, we began a prospective trial aimed at same-day discharge of specific patients. Baseline and demographic variables, and past medical, past urological, intra-operative and post-operative variables in addition to disposition and readmission data were collected. Bivariate analysis was conducted to compare patients based on the day of discharge and readmission. A multivariable model using multiple-regression analysis was used to assess predictors for early discharge or readmission. RESULTS: There were 179 total HoLEP procedures that were performed during the study period. Forty-seven patients were suitable candidates for same-day discharge. Among this group, 28 (59.5%) patients were successfully discharged home on the same day. Nineteen patients (40.4%) could not be discharged. The most common cause of not to discharge patients was the degree of hematuria without continuous bladder irrigation. Pre-operative prostate volume was different between the two groups (88.4 ± 30.7 cc for discharged patients vs 69.0 ± 30.7 cc for admitted patients, p = 0.033). No other pre-operative differences were identified. There were five readmissions (17.8%) following same-day discharge. Readmitted patients had higher rates of history of urinary tract infection (80% vs 26.2%, p = 0.0304). On multivariable analysis, no statistically significant predictors were identified for early discharge or readmission. CONCLUSIONS: Same-day discharge following HoLEP is safe and feasible in well-selected patients.

Prostate cancer and the role of biomarkers.

PURPOSE: To review available prostate cancer biomarkers and their performance in a clinical order, from prostate cancer detection, to treatment of localized and advanced disease. METHODS: We used an electronic literature search of the PubMed database using the key words "prostate biomarkers," "genomic markers," and "prostate cancer screening," as well as specific biomarkers, until March 2019. RESULTS: Prostate-specific antigen (PSA) lacks sensitivity for prostate cancer detection, and PSA derivatives have slightly improved its specificity, but have not resolved the limitations of PSA screening. Prostate cancer biomarkers have emerged as an ancillary tool to guide the clinical decision-making in different clinical scenarios. Urine-based tests can identify patients who may benefit from a prostate biopsy, and issue-based markers are helpful in guiding the decision regarding a second biopsy, stratifying patient with newly diagnosed prostate cancer to active surveillance or treatment, and identifying patients who may benefit from adjuvant treatment after surgery. CONCLUSIONS: New biomarkers have improved risk stratification in diagnosing and treating prostate cancer. Many of these markers are still considered experimental, and their efficacy and cost utility have not been determined.

MRI - ultrasound fusion guided biopsy of the prostate: lesion volume as a predictor of cancer in patients with repeat biopsies.

INTRODUCTION: The objective was to analyze the diagnostic value of multiparametric magnetic resonance imaging (MRI) prostate lesion volume (PLV) and its correlation with the subsequent MRI-ultrasound (MRI-US) fusion biopsy results. MATERIALS AND METHODS: Between March 2014 and July 2016, 150 men underwent MRI-US fusion biopsies at our institution. All suspicious prostate lesions were graded according to the Prostate Imaging Reporting and Data System (PIRADS) and their volumes were measured. These lesions were subsequently biopsied. All data were prospectively collected and retrospectively analyzed. The PLV of all suspicious lesions was correlated with the presence of cancer on the final MRI-US fusion biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: There were 206 suspicious lesions identified in 150 men. The overall cancer detection rate was 102/206 (49.5%). The mean PLV for benign lesions was 0.63 ± 0.94 cm3 versus 1.44 ± 1.76 cm3 for cancerous lesions (P < 0.01). There was a statistically significant difference between the PLV of PIRADS 5 lesions when compared to PIRADS 4, 3, and 2 lesions (P < 0.0001, < 0.0001, and 0.006, respectively). The area under the curve for volume in predicting prostate cancer (PCa) was 0.66. The optimal volume for predicting PCa was 0.26 cm3 with a sensitivity, specificity, PPV, and NPV of 80.7%, 42.7%, 41.2%, and 74.6%, respectively. CONCLUSION: PLV may serve as a useful measure to triage patients prior to MRI-US fusion biopsy and help better understand the limits of this technology for individual patients.

Clonal analyses of refractory testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) are unique amongst solid tumors in terms of the high cure rates using chemotherapy for metastatic disease. Nevertheless, TGCTs still kill approximately 400 men per year, at a median age of 30 years, in the United States. This young age of mortality dramatically amplifies the impact of these deaths for the patients and their often young families. Furthermore the high cure rate makes it difficult to conduct further clinical trials of non curable disease. TGCTs are characterized by a marked aneuploidy and the presence of gain of chromosomal region 12p. Genomic testing may offer the ability to identify potentially lethal TGCTs at the time of initial diagnosis. However sequencing based studies have shown a paucity of somatic mutations in TGCT genomes including those that drive refractory disease. Furthermore these studies may be limited by genetic heterogeneity in primary tumors and the evolution of sub populations during disease progression. Herein we applied a systematic approach combining DNA content flow cytometry, whole genome copy number and whole exome sequence analyses to interrogate tumor heterogeneity in primary and metastatic refractory TGCTs. We identified both known and novel somatic copy number aberrations (12p, MDM2, and RHBDD1) and mutations (XRCC2, PIK3CA, RITA1) including candidate markers for platinum resistance that were present in a primary tumor of mixed histology and that remained after tandem autologous stem cell transplant.

Robotic vs. open cystectomy: How length-of-stay differences relate conditionally to age.

OBJECTIVES: The length-of-stay (LOS) benefit of minimally invasive cystectomy varies in the published literature, potentially because of subgroup effects. Here, we investigated the effect of minimally invasive cystectomy on LOS among different age groups. METHODS AND MATERIALS: Adult patients who underwent cystectomy (open or minimally invasive) from January 1, 2012, to December 31, 2016, were identified from the National Surgical Quality Improvement Program database. Multivariable linear regression was used to evaluate the adjusted association between the surgical approach and LOS after stratifying patients by age (40-64, 65-79, and ≥80 years). A sensitivity analysis was performed after multiple imputation by using age as a continuous variable with a third-order polynomial term. RESULTS: Of the 5,561 patients identified, 640 underwent minimally invasive cystectomy and 4,921 had open cystectomy. The unadjusted analysis showed that minimally invasive cystectomy was associated with a shorter mean LOS compared with the open approach (8.0 vs. 9.7 days; P < 0.001). The predicted difference in LOS between the 2 approaches was 0.72 days (95% confidence interval (CI), -0.28 to 1.72; P = 0.16) for patients aged 40 to 64 years, 1.48 days (95% CI, 0.73-2.23; P < 0.001) for 65 to 79 years, and 2.56 days (95% CI, 0.84-4.29; P = 0.01) for ≥80 years favoring the minimally invasive approach. The sensitivity analysis did not materially change the results. CONCLUSIONS: Older patients may derive more LOS benefit from minimally invasive approaches than younger patients. Given the greater expense associated with the minimally invasive approach, an age-adapted strategy to using this technology may be reasonable.

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

Lack of value of juvenile animal toxicity studies for supporting the safety of pediatric oncology phase I trials.

Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals. The present paper examines pediatric-specific clinical findings to focus on dose setting in pediatric oncology patients and safety monitoring in terms of the potential value of JAS. Our assessment demonstrates that pediatric starting doses were safe for all 29 therapeutics examined in that no life-threatening toxicities occurred in the first cohort, and overall the ratio of the pediatric maximum tolerated dose (MTD) to the recommended adult dose was close to 1. In addition, the 4 serious adverse events (SAEs) that weren't detectable with standard monitoring plans for pediatric oncology trials would not have been detectable in a standard JAS. This review demonstrates that safe starting doses in pediatric oncology patients for these therapeutics could have been solely based on adult doses without any knowledge of findings in JAS.

Macrophage Transactivation for Chemokine Production Identified as a Negative Regulator of Granulomatous Inflammation Using Agent-Based Modeling.

Cellular activation in trans by interferons, cytokines, and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and/or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling, and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation.

Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum.

Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum We show that curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds.

The Digestive Tract of Cephalopods: a Neglected Topic of Relevance to Animal Welfare in the Laboratory and Aquaculture.

Maintenance of health and welfare of a cephalopod is essential whether it is in a research, aquaculture or public display. The inclusion of cephalopods in the European Union legislation (Directive 2010/63/EU) regulating the use of animals for scientific purposes has prompted detailed consideration and review of all aspects of the care and welfare of cephalopods in the laboratory but the information generated will be of utility in other settings. We overview a wide range of topics of relevance to cephalopod digestive tract physiology and their relationship to the health and welfare of these animals. Major topics reviewed include: (i) Feeding cephalopods in captivity which deals with live food and prepared diets, feeding frequency (ad libitum vs. intermittent) and the amount of food provided; (ii) The particular challenges in feeding hatchlings and paralarvae, as feeding and survival of paralarvae remain major bottlenecks for aquaculture e.g., Octopus vulgaris; (iii) Digestive tract parasites and ingested toxins are discussed not only from the perspective of the impact on digestive function and welfare but also as potential confounding factors in research studies; (iv) Food deprivation is sometimes necessary (e.g., prior to anesthesia and surgery, to investigate metabolic control) but what is the impact on a cephalopod, how can it be assessed and how does the duration relate to regulatory threshold and severity assessment? Reduced food intake is also reviewed in the context of setting humane end-points in experimental procedures; (v) A range of experimental procedures are reviewed for their potential impact on digestive tract function and welfare including anesthesia and surgery, pain and stress, drug administration and induced developmental abnormalities. The review concludes by making some specific recommendations regarding reporting of feeding data and identifies a number of areas for further investigation. The answer to many of the questions raised here will rely on studies of the physiology of the digestive tract.

The Digestive Tract of Cephalopods: Toward Non-invasive In vivo Monitoring of Its Physiology.

Ensuring the health and welfare of animals in research is paramount, and the normal functioning of the digestive tract is essential for both. Here we critically assess non- or minimally-invasive techniques which may be used to assess a cephalopod's digestive tract functionality to inform health monitoring. We focus on: (i) predatory response as an indication of appetitive drive; (ii) body weight assessment and interpretation of deviations (e.g., digestive gland weight loss is disproportionate to body weight loss in starvation); (iii) oro-anal transit time requiring novel, standardized techniques to facilitate comparative studies of species and diets; (iv) defecation frequency and analysis of fecal color (diet dependent) and composition (parasites, biomarkers, and cytology); (v) digestive tract endoscopy, but passage of the esophagus through the brain is a technical challenge; (vi) high resolution ultrasound that offers the possibility of imaging the morphology of the digestive tract (e.g., food distribution, indigestible residues, obstruction) and recording contractile activity; (vii) needle biopsy (with ultrasound guidance) as a technique for investigating digestive gland biochemistry and pathology without the death of the animal. These techniques will inform the development of physiologically based assessments of health and the impact of experimental procedures. Although intended for use in the laboratory they are equally applicable to cephalopods in public display and aquaculture.

Natural Orifice Transluminal Endoscopic Partial Prostatectomy: A Real-time Image-guided Focal Extirpative Feasibility Study.

OBJECTIVE: To assess the feasibility of focal endoscopic excision of prostate cancer (PCa) under guidance of real-time magnetic resonance imaging (MRI) or magnetic ultrasound fusion (MUF). MATERIALS AND METHODS: Using a cadaveric model, multifocal PCa was simulated using 2 MRI-compatible fiducial markers. These were inserted transrectally and used to generate regions of interests (ROIs) on a 1.5-T surface-coil MRI. The first marker was placed in the right mid-peripheral zone (ROI 1), and the second marker was placed in the left seminal vesicle as a referent lesion for subsequent imaging. MRI of the specimen was then obtained. The radiologist created ROIs using fusion biopsy system at each marker. Two additional incidental ROIs were identified in the left transitional zone (ROI 2-suspicious for benign prostatic hyperplasia nodule) and in the right anterior peripheral zone (ROI 3-suspicious for PCa). Holmium laser enucleation of the transitional zone of the prostate was performed to gain access to the peripheral zone lesions. MUF was used during endoscopic laser excision to convey targeting accuracy. The cadaver was then reimaged to determine the adequacy of resection and examined for histopathologic correlation. RESULTS: Real-time MUF imaging identified the target lesions consistently at the locations designated as ROIs. Complete endoscopic resection of ROIs was possible. Repeated MUF imaging and the postprocedure MRI confirmed the completeness of resection. Pathologic examination demonstrated complete excision, intact neurovascular bundles, and posterior prostatic capsule. CONCLUSION: This approach may represent a new minimally invasive frontier for focal surgical resection of PCa, making histopathologic margin status determination possible.