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Small bowel transplantation is a recent innovation and thus a relatively new area of nursing practice. There is a lack of literature on the nursing care of children whose only hope of long-term survival is small bowel transplantation. The aim of this article is to raise awareness about intestinal transplantation in children using a case study to highlight the main nursing implications including: multidisciplinary team working, monitoring fluid balance, caring for immunosuppressed patients, monitoring for acute rejection and discharge preparation of the child and family. [ABSTRACT FROM AUTHOR]

Study objective The purpose of this study is to investigate the analgesic efficacy of ultrasound-guided fascial plane blocks (FPBs) versus local infiltration in patients undergoing laparoscopic non-donor nephrectomy. This study specifically compares the efficacy of FPBs with liposomal bupivacaine (LB) versus FPBs with dexamethasone sodium phosphate (DXP) and methylprednisolone acetate (MPA) versus surgical site local anesthetic infiltration without FPBs.  Design This is a retrospective cohort study conducted over a five-year period (January 2018-December 2022). Setting The study was conducted in a tertiary care, academic, multi-hospital healthcare system.  Participants Patients who underwent elective radical or partial laparoscopic non-donor nephrectomy were included in the study. Intervention Patients either received preoperative FPBs without intraoperative surgical site local anesthetic infiltration or received surgical site local anesthetic infiltration without FPBs (n = 141) at participating hospitals. Measurements The primary endpoint of this study was postoperative opioid use, measured as oral milligram morphine equivalents (MME). Secondary endpoints included postoperative pain scores, length of hospital stays, and significant adverse events within 30 days. The impact of medications utilized in FPBs was determined by univariate and multivariable analyses with covariates balancing propensity score weighting. Main results Patients undergoing non-donor laparoscopic radical or partial nephrectomy who received FPBs with bupivacaine or ropivacaine plus glucocorticoids DXP and MPA were more likely to be opioid-free 24-48 hours postoperatively compared to those who received FPBs with LB or surgical site local anesthetic infiltration without FPBs (40.5% vs. 30% vs. 13.9%, respectively; p = 0.017). Patients who received FPBs with glucocorticoids also reported the lowest pain scores at rest and with activity 0-12 hours postoperatively as compared to patients who received LB or local infiltration (p = 0.006 and p = 0.014, respectively). Additionally, patients who received FPBs with glucocorticoids received over 30% fewer opioids during the first 48 hours postoperatively compared to patients who received surgical site local anesthetic infiltration alone (30 MME vs. 44 MME, respectively). However, there was no significant difference in total opioid use during the first 48 hours postoperatively between patients who received FPBs with bupivacaine plus glucocorticoids and those who received FPBs with bupivacaine plus LB (mean ratio: 0.91, (95% CI: 0.05 ~ 15.97); p = 0.948). There was also no difference in the length of hospital stays or rate of adverse events between the groups. Conclusion Perioperative FPBs for non-donor laparoscopic nephrectomy using glucocorticoids as an adjuvant to long-acting local anesthetics may decrease postoperative opioid use and reduce pain scores as compared to FPBs with LB or surgical site local anesthetic infiltration. Bupivacaine or ropivacaine combined with DXP and MPA is a safe and effective alternative to LB for FPBs in laparoscopic nephrectomy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Yale School of Medicine Institutional Review Board (IRB) issued approval (2000029282). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sobhani et al.)

Purpose: Pancreatic cancer currently holds the position of third deadliest cancer in the United States and the 5-year survival rate is among the lowest for major cancers at just 12%. Thus, continued research efforts to better understand the clinical and molecular underpinnings of pancreatic cancer are critical to developing both early detection methodologies as well as improved therapeutic options. This study introduces Pancreatic Cancer Action Network's (PanCAN's) SPARK, a cloud-based data and analytics platform that integrates patient health data from the PanCAN's research initiatives and aims to accelerate pancreatic cancer research by making real-world patient health data and analysis tools easier to access and use., Materials and Methods: The SPARK platform integrates clinical, molecular, multiomic, imaging, and patient-reported data generated from PanCAN's research initiatives. The platform is built on a cloud-based infrastructure powered by Velsera. Cohort exploration and browser capabilities are built using Velsera ARIA, a specialized product for leveraging clinicogenomic data to build cohorts, query variant information, and drive downstream association analyses. Data science and analytic capabilities are also built into the platform allowing researchers to perform simple to complex analysis., Results: Version 1 of the SPARK platform was released to pilot users, who represented diverse end users, including molecular biologists, clinicians, and bioinformaticians. Included in the pilot release of SPARK are deidentified clinical (including treatment and outcomes data), molecular, multiomic, and whole-slide pathology images for over 600 patients enrolled in PanCAN's Know Your Tumor molecular profiling service., Conclusion: The pilot release of the SPARK platform introduces qualified researchers to PanCAN real-world patient health data and analytical resources in a centralized location.

Background: Image-guided approaches improve the diagnostic yield of prostate biopsy and frequently modify estimates of clinical risk. To better understand the impact of magnetic resonance imaging-ultrasound fusion targeted biopsy (MRF-TB) on risk assessment, we compared the distribution of National Comprehensive Cancer Network (NCCN) risk groupings, as calculated from MRF-TB vs systematic biopsy alone., Methods: We performed a retrospective analysis of 713 patients who underwent MRF-TB from January 2017 to July 2021. The primary study objective was to compare the distribution of National Comprehensive Cancer Network risk groupings obtained using MRF-TB (systematic + targeted) vs systematic biopsy., Results: Systematic biopsy alone classified 10% of samples as very low risk and 18.7% of samples as low risk, while MRF-TB classified 10.5% of samples as very low risk and 16.1% of samples as low risk. Among patients with benign findings, low-risk disease, and favorable/intermediate-risk disease on systematic biopsy alone, 4.6% of biopsies were reclassified as high risk or very high risk on MRF-TB. Of 207 patients choosing active surveillance, 64 (31%), 91 (44%), 42 (20.2%), and 10 (4.8%) patients were classified as having very low-risk, low-risk, and favorable/intermediate-risk and unfavorable/intermediate-risk criteria, respectively. When using systematic biopsy alone, 204 patients (28.7%) were classified as having either very low-risk and low-risk disease per NCCN guidelines, while 190 men (26.6%) received this classification when using MRF-TB., Conclusion: The addition of MRF-TB to systematic biopsy may change eligibility for active surveillance in only a small proportion of patients with prostate cancer. Our findings support the need for routine use of quantitative risk assessment over risk groupings to promote more nuanced decision making for localized cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Cystoscopy and cauterization performed in the operating room is expensive and exposes patients to anesthesia risks. Patient tolerability during office cystoscopy and cauterization is critical to the office management of bladder cancer (BC) and other urologic diseases. We evaluated the risk factors for pain of flexible cystoscopy in the office-setting with emphasis on a sub-group of BC patients who underwent cauterization., Materials and Methods: Retrospective analyses of 110 anonymous patient surveys completed after cystoscopy and/or cauterization. Survey information included age, gender, indication for cystoscopy, number of prior cystoscopies, number of prior office-based cauterizations, anxiety prior/during cystoscopy, and pain during cystoscopy and/or cauterization. Univariate/multivariate and linear-regression analyses were performed to evaluate the association of pain with clinical parameters., Results: Average pain during cystoscopy (1.75 ± 1.331) was not significantly different when cauterization was also performed (2.37 ± 2.214) (p < 0.001) (p = 0.2840). Patients in the lower age group (<66 years) indicated higher anxiety levels (p = 0.0005), more pain at cystoscopy (P = 0.004) and cauterization (p < 0.001). Although the patients' overall anxiety level was low (1-3/10), it was associated with some pain during cystoscopy (p = 0.0005) and cauterization (p < 0.000). In multivariate analysis, anxiety was the only independent predictor of pain during cystoscopy (p = 0.03, OR: 6.52,95% CI: 1.2-35.6) and cauterization (p = 0.0012, OR: 3.4, 95%CI: 1.6-7.0). In BC patients, pain scores during cystoscopy and cauterization were not significantly different (p = 0.4772) but associated with anxiety., Conclusion: Office-based cystoscopy and cauterization are tolerable with minimal pain. Higher pain levels during cystoscopy were associated with procedure anxiety, and pain during cauterization was associated with procedure anxiety and younger age. Younger and more anxious patients may need more counseling before cystoscopy., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To evaluate perioperative outcomes related to sexual and urinary function in patients who underwent a holmium laser enucleation of the prostate (HoLEP) with selective laser enucleation of the median lobe., Materials and Methods: We retrospectively reviewed the first 450 HoLEP cases by a single surgeon from April 2019 to March 2022. Fifty-five patients with intravesical-prostatic protrusion or high bladder neck without obstructing lateral lobes underwent selective enucleation of the median lobe of the prostate. Patients were asked to comment on whether they had retrograde ejaculation during their follow-up appointment. Urinary function was assessed using the American Urological Association Symptom Score and subjective evaluation of urinary incontinence., Results: Median age of the cohort was 65 years (range: 44-91). Compared to preoperative, there was significant improvement in mean postoperative American Urological Association Symptom Score (22.5 vs 6.9, P < .001), mean postoperative quality of life scores (4 vs 1.2, P < .001), and mean postoperative post void residual volumes (244.1 vs 69.3 cc, P < .001). No patients reported stress urinary incontinence. Of the 55 patients who underwent selective enucleation of the median lobe, 40 were sexually active. Of those men, 35 reported normal ejaculation, 3 had retrograde ejaculation that was unchanged from pre-op, and 2 had new ejaculatory dysfunction., Conclusion: In this case series of selective laser enucleation of the median lobe, urinary function significantly improved in short-term follow-up with preservation of ejaculation in approximately 90% of men., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Patients with low-grade (LG), grade 1-2, Ta bladder cancer (BC) will frequently have a "recurrence". However, they rarely progress in stage. Although current guidelines mention surveillance and office management for these new or recurrent tumors, transurethral resection (TURBT) is the most common treatment. The purpose of this study is to determine if surveillance and/or office cautery is safe., Materials and Methods: This study was conducted as a retrospective case series analysis of 45 patients who had recurrent LG Ta appearing bladder cancer (BC) and were managed primarily with surveillance and/or office cautery. Patients with carcinoma in-situ were excluded. The primary outcome was stage progression., Results: Median follow up was 62 months. 41 (91%) patients did not progress in stage. Three patients recurred with HG T1 BC; one is receiving systemic immunotherapy. One patient developed HG T2 BC and was treated with a bladder preservation protocol. 40 (89%) patients underwent office cauterization. Eleven received BCG and 26 received post-cautery intravesical chemotherapy. Five (11%) patients developed HG BC during follow up. No patients died. None of the 17 (38%) Hispanic patients had progression., Conclusions: Active surveillance and/or office cautery for patients with small recurrent LG Ta bladder tumors is safe, reduces cost and improves quality of life by avoiding TURBTs., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To compare operative efficiency of Holmium laser enucleation of the prostate (HoLEP) using both the standard multi-incisional approach and en-bloc enucleation with early apical release during the initial learning curve., Materials and Methods: We retrospectively reviewed the initial 95 consecutive men who underwent HoLEP between April 2019 and September 2020 by a single surgeon. We compared patient demographics, and pre-, intra-, and post-operative metrics between both groups. Differences between groups were evaluated with Mann-Whitney U and Kruskal-Wallis tests., Results: Forty-nine patients underwent the standard HoLEP approach, and 46 patients underwent the en-bloc approach. Compared to a standard HoLEP, the en-bloc approach was associated with decreased operative time (131.11 minutes vs 153.59 minutes, P = .007) with similar weights of tissue removed. Operative efficiency, as measured by grams of prostate tissue removed per minute, was greater for the en-bloc approach (0.49 g/min vs 0.36 g/min, P = .005). There was no difference in length of stay (0.91 days vs 0.96 days, P = .383), laser efficiency (4.41 kJ/g vs 4.83 kJ/g, P = .200), or number of post-operative complications (10 vs 6, P = .236) between the groups., Conclusion: Utilization of the en-bloc technique during the initial learning curve allows for a faster, more efficient operation without any difference in functional outcomes or major complications compared to a standard HoLEP., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The authors aimed to chronicle the evolution of the medical community's study of physician and surgeon pregnancy by investigating thematic trends in the literature in the context of pertinent sociopolitical events., Method: A scoping review was conducted in Cochrane Library, Google Scholar, Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science Core Collection from inception through August 11, 2020, using vocabulary and terms for physicians (including surgeons), pregnancy, and family leave. Study populations were categorized by all physician specialties or exclusively surgical specialties as well as by all career levels or exclusively trainees. Subthemes and themes were based on a priori assumptions of physician pregnancy and extrapolated from previously published reviews, respectively. Thematic trends were analyzed by plotting the total number of publications and the frequency of themes and subthemes by publication year., Results: After title and abstract and full-text reviews, 407 manuscripts met inclusion criteria. Publications on physician pregnancy first emerged in the 1960s and surged from 1988 to 1996 and again from 2010 to 2019. The first known manuscript exclusively on surgeon pregnancy was published in 1991; subsequent publication frequency trends for surgeon pregnancy generally paralleled those for all physician pregnancy publications albeit in reduced quantities. Four major themes were found: impact of pregnancy on the physician and her colleagues, pregnant physician work productivity, physician maternity leave policies, and physician maternal-fetal health outcomes., Conclusions: As the number of women physicians increased and the sociopolitical environment progressed, the thematic focus of the literature on physician pregnancy evolved. Multi-institutional prospective observational studies are needed to develop definitive evidence-based recommendations that will positively impact physician pregnancy., (Copyright © 2022 by the Association of American Medical Colleges.)

Background: The personal health and professional impact of physician pregnancy requires further study. We performed a comprehensive scoping review of physician pregnancy to synthesize and assess the evidence to aid decision-making for relevant stakeholders., Methods: A search of 7 databases resulted in 3733 citations. 407 manuscripts were included and scored for evidence level. Data were extracted into themes using template analysis., Results: Physician pregnancy impacted colleagues through perceived increased workload and resulted in persistent stigmatization and discrimination despite work productivity and academic metrics being independent of pregnancy events. Maternity leave policies were inconsistent and largely unsatisfactory. Women physicians incurred occupational hazard risk and had high rates of childbearing delay, abortion, and fertility treatment; obstetric and fetal complication rates compared to controls are conflicting., Conclusions: Comprehensive literature review found that physician pregnancy impacts colleagues, elicits negative perceptions of productivity, and is inadequately addressed by current parental leave policies. Data are poor and insufficient to definitively determine the impact of physician pregnancy on maternal and fetal health. Prospective risk-matched observational studies of physician pregnancy should be pursued., (Published by Elsevier Inc.)

Objectives : To assess the incidence of postoperative arterial malformation (AM) and urine leak/urinoma (UL) after robotic partial nephrectomy (RPN) in a contemporary series and to evaluate risk factors for these complications. Materials and Methods: All RPNs were queried from Institutional Review Board-approved retrospective and prospective nephrectomy databases. Demographics, perioperative variables, and postoperative complications were collected. Differences between cohorts were analyzed using univariate analysis. Postoperative complications were graded using the Clavien-Dindo system. UL was defined in the context of signs and symptoms of a collection with supporting evidence of urine collection through drainage or aspiration. AM was identified based on postoperative imaging indicative of arteriovenous fistula or pseudoaneurysm and/or requirement for selective embolization. Predictors of AM and UL were assessed by univariate analysis. Results: A total of 395 RPNs were performed by four urologists between January 2014 and October 2018. Tumor complexity, defined by nephrometry score, was significantly greater in the prospective cohort ( p  = 0.01). Overall incidence of postoperative complications was 5.6% with cohort-specific incidences of 5.3% and 5.8%. The retrospective cohort had a greater percentage of complications classified as ≥IIIa: 8/13 (61.5%) vs 2/8 (25%). Overall incidence of AM was 2.3% with cohort-specific incidence of 3.1% (7/225) vs 1.1% (2/170). Overall incidence of UL was 0.25% with cohort-specific incidence of 0.55% (1/225) and 0.0% (0/170). The difference in incidence of both complications between cohorts was significant ( p  < 0.05). No significant predictors for AM were identified. Conclusions : The incidence of postoperative complications after RPN remains low (5.3% vs 5.8%, overall: 5.6%). UL and AM are becoming rarer with experience, despite increasing surgical complexity (0.55% vs 0%, 3.1% vs 1.1%).

Objective: To determine whether the presence of an ultrasound hypoechoic region at the site of a region of interest (ROI) on magnetic resonance imaging (MRI) results in improved prostate cancer (PCa) detection and predicts clinically significant PCa on MRI-ultrasonography fusion-targeted prostate biopsy (MRF-TB)., Materials and Methods: Between July 2011 and June 2017, 1058 men who underwent MRF-TB, with or without systematic biopsy, by a single surgeon were prospectively entered into an institutional review board-approved database. Each MRI ROI was identified and scored for suspicion by a single radiologist, and was prospectively evaluated for presence of a hypoechoic region at the site by the surgeon and graded as 0, 1 or 2, representing none, a poorly demarcated ROI-HyR, or a well demarcated ROI-HyR, respectively. The interaction of MRI suspicion score (mSS) and ultrasonography grade (USG), and the prediction of cancer detection rate by USG, were evaluated through univariate and multivariate analysis., Results: For 672 men, the overall and Gleason score (GS) ≥7 cancer detection rates were 61.2% and 39.6%, respectively. The cancer detection rates for USGs 0, 1 and 2 were 46.2%, 58.6% and 76.0% (P < 0.001) for any cancer, and 18.7%, 35.2% and 61.1% (P < 0.001) for GS ≥7 cancer, respectively. For MRF-TB only, the GS ≥7 cancer detection rates for USG 0, 1 and 2 were 12.8%, 25.7% and 52.0%, respectively (P < 0.001). On univariate analysis, in men with mSS 2-4, USG was predictive of GS ≥7 cancer detection rate. Multivariable regression analysis showed that USG, prostate-specific antigen density and mSS were predictive of GS ≥7 PCa on MRF-TB., Conclusions: Ultrasonography findings at the site of an MRI ROI independently predict the likelihood of GS ≥7 PCa, as men with a well-demarcated ROI-HyR at the time of MRF-TB have a higher risk than men without., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Introduction: Penectomy for PC is useful in staging, disease prognosis, and treatment. Limited studies have evaluated its surgical complications. We sought to assess these complications and determine predictive models to create a novel risk score for penectomy complications., Patients and Methods: A retrospective review of patients undergoing PC surgical management from the 2005-2016 American College of Surgeons National Surgical Quality Improvement Program was performed. Data were queried for partial and total penectomy among those with PC. To develop predictive models of complications, we fit LASSO logistic, random forest, and stepwise logistic models to training data using cross-validation, demographic, comorbidity, laboratory, and wound characteristics as candidate predictors. Each model was evaluated on the test data using receiver operating characteristic curves. A novel risk score was created by rounding coefficients from the LASSO logistic model., Results: A total of 304 cases met the inclusion criteria. Overall incidence of penectomy complications was 19.7%, where urinary tract infection (3.0%), superficial surgical site infection (3.0%), and bleeding requiring transfusion (3.9%) were most common. LASSO logistic, random forest, and stepwise logistic models for predicting complications had area under the curve (AUC) [95% confidence interval] values of 0.66 [0.52-0.81], 0.73 [0.63-0.83], and 0.59 [0.45-0.74], respectively. Eleven variables were included in the risk score. The LASSO model-derived risk score had moderately good performance (area under the curve [95% confidence interval] 0.74 [0.66-0.82]). Using a cutoff point of 6, the score attains sensitivity 0.58, specificity 0.74, and kappa 0.26., Conclusion: PC management through penectomy is associated with appreciable complications rates. Predictive models of penectomy complications performed moderately well. Our novel prognostic risk score may allow for improved preoperative counseling and risk stratification of men undergoing surgical management of PC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Bone marrow biopsies are essential for evaluating patients with suspected or confirmed hematopoietic disorders or malignancies, but little is known about how biopsy needle type affects biopsy length and/or quality. We sought to compare bone marrow biopsy quality in specimens obtained with two different needles., Methods: A retrospective analysis was performed on bone marrow specimens obtained with manual single-bevel (n = 114) or triple-bevel (n = 166) needles. The lengths of evaluable marrow, core quality, and aspirate quality were assessed by blinded hematopathologists., Results: The triple-bevel needle produced 1.33-mm shorter lengths of evaluable marrow than the single-bevel needle and was five times less likely to produce a specimen rated as "adequate" and 4.2 times more likely to produce crush artifact. The triple-bevel needle was also 2.4 times more likely to produce hemodilute aspirates., Conclusions: Bone marrow biopsy needle type affects the length of evaluable marrow and quality of core and aspirate specimens.

Background: The American Society of Anesthesiologists physical status classification system, modified Charlson Comorbidity Index (mCCI), and modified Frailty Index have been associated with complications after urologic surgery. No study has compared the predictive performance of these indexes for postoperative complications after radical cystectomy (RC) for bladder cancer., Materials and Methods: Data from 1516 patients undergoing elective RC for bladder cancer were extracted from the 2005 to 2011 American College of Surgeons National Surgical Quality Improvement Program for a retrospective review. The perioperative outcome variables assessed were occurrence of minor adverse events, severe adverse events, infectious adverse events, any adverse event, extended length of hospital stay, discharge to a higher level of care, and mortality. Patient comorbidity indexes and demographic data were assessed for their discriminative ability in predicting perioperative adverse outcomes using an area under the curve (AUC) analysis from the receiver operating characteristic curves., Results: The most predictive comorbidity index for any adverse event was the mCCI (AUC, 0.511). The demographic factors were the body mass index (BMI; AUC, 0.519) and sex (AUC, 0.519). However, the overall performance for all predictive indexes was poor for any adverse event (AUC < 0.52). Combining the most predictive demographic factor (BMI) and comorbidity index (mCCI) resulted in incremental improvements in discriminative ability compared with that for the individual outcome variables., Conclusion: For RC, easily obtained patient mCCI, BMI, and sex have overall similar discriminative abilities for perioperative adverse outcomes compared with the tabulated indexes, which are more difficult to implement in clinical practice. However, both the demographic factors and the comorbidity indexes had poor discriminative ability for adverse events., (Copyright © 2018 Elsevier Inc. All rights reserved.)

It is critically important to the evolving goals of prostate biopsy to find clinically significant cancer with lethal potential and avoid detection of indolent disease. Better tests and markers are required for improved detection of clinically significant prostate cancer and avoidance of biopsies in men with indolent disease. Currently, there are myriad alternative prostate cancer risk-assessment tests available derived from serum and urine that are designed to improve the specificity for detection of "significant" prostate cancer. Herein we discuss these tests and their clinical implications.

Methyl bromide chemical burns are rare. Only two cases have been reported to date. The presentation of methyl bromide chemical burns is unusual. Patients with an acute exposure should be observed closely as the initial presentation can appear deceptively benign. The latency period lasts several hours prior to the development of chemical burn wounds. In this article, we review the literature on methyl bromide chemical burns and present our experience managing a patient with an extensive methyl bromide burn., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cellax is a PEGylated carboxymethylcellulose conjugate of docetaxel (DTX) which condenses into a 120-nm nanoparticle, and was compared against the approved clinical taxane nanoformulation (Abraxane®) in mouse models. Cellax increased the systemic exposure of taxanes by 37× compared to Abraxane, and improved the delivery specificity: Cellax uptake was selective to the tumor, liver and spleen, with a 203× increase in tumor accumulation compared to Abraxane. The concentration of released DTX in Cellax treated tumors was well above the IC50 for at least 10 d, while paclitaxel released from Abraxane was undetectable after 24h. In s.c. PC3 (prostate) and B16F10 (melanoma) models, Cellax exhibited enhanced efficacy and was better tolerated compared to Abraxane. In an orthotopic 4T1 breast tumor model, Cellax reduced the incidence of lung metastasis to 40% with no metastasic incidence in other tissues. Mice treated with Abraxane displayed increased lung metastasic incidence (>85%) with metastases detected in the bone, liver, spleen and kidney. These results confirm that Cellax is a more effective drug delivery strategy compared to the approved taxane nanomedicine., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In vitro permeability assays are a valuable tool for scientists during lead compound optimization. As a majority of discovery projects are focused on the development of orally bioavailable drugs, correlation of in vitro permeability data to in vivo absorption results is critical for understanding the structural-physicochemical relationship (SPR) of drugs exhibiting low levels of absorption. For more than a decade, the Caco-2 screening assay has remained a popular, in vitro system to test compounds for both intestinal permeability and efflux liability. Despite advances in artificial membrane technology and in silico modeling systems, drug compounds still benefit from testing in cell-based epithelial monolayer assays for lead optimization. This chapter provides technical information for performing and optimizing the Caco-2 assay. In addition, techniques are discussed for dealing with some of the most pressing issues surrounding in vitro permeability assays (i.e., low aqueous solubility of test compounds and low postassay recovery). Insights are offered to help researchers avoid common pitfalls in the interpretation of in vitro permeability data, which can often lead to the perception of misleading results for correlation to in vivo data.

In vitro permeability assays remain a valuable tool of screening scientists for lead compound optimization. As a majority of discovery projects are focused on the development of orally bioavailable drugs, the need for predictability and correlation of in vitro permeability data to in vivo absorption results has never been greater. For more than a decade, the Caco-2 screening assay has remained a popular, in vitro system to test compounds for intestinal permeability and efflux liability. Despite advances in artificial membrane technology and in silico modeling systems, drug compounds still benefit from testing in cell-based epithelial monolayer assays for lead optimization and SAR. This review discusses the strengths and limitations of the Caco-2 permeability assay, and puts into context the power of combining multiple assays and approaches to improve predictability and rank-ordering for lead compound optimization. Technical information for dealing with some of the most pressing issues with in vitro permeability assays (i.e. low aqueous solubility and low post-assay recovery) is also discussed. Insights are offered to help researchers avoid common pitfalls in the interpretation of in vitro permeability data, which can often lead to the perception of misleading results for correlation to in vivo data. In addition, the advantages of addressing the issue of efflux liability early in the drug development process is discussed, detailing the usefulness of Caco-2 cells for this type of screening paradigm.

This study compared the effects of occupational therapy, using a sensory integration (SI) approach and a control intervention of tabletop activities, on the frequency of self-stimulating behaviors in seven children 8-19 years of age with pervasive developmental delay and mental retardation. Daily 15-min videotape segments of the subjects were recorded before, immediately after, and 1 hour after either SI or control interventions performed during alternating weeks for 4 weeks. Each 15-min video segment was evaluated by investigators to determine the frequency of self-stimulating behaviors. The results indicate that self-stimulating behaviors were significantly reduced by 11% one hour after SI intervention in comparison with the tabletop activity intervention (p = 0.02). There was no change immediately following SI or tabletop interventions. Daily ratings of self-stimulating behavior frequency by classroom teachers using a 5-point scale correlated significantly with the frequency counts taken by the investigators (r = 0.32, p < 0.001). These results suggest that the sensory integration approach is effective in reducing self-stimulating behaviors, which interfere with the ability to participate in more functional activities.

The Bcl-x(gamma) cytosolic protein is essential for costimulatory activity after CD3/CD28 coligation. Here we delineate the Bcl-x(gamma)/Bcl-x genomic organization and the molecular mechanism that allows expression. We show that exon 4 of the Bcl-x gene encodes the unique C-terminal end of the Bcl-x(gamma) molecule while exons 5, 6, 7 and 8 are differentially transcribed to yield three alternative Bcl-x(gamma) 3' untranslated regions (UTR). CD28-dependent signals may increase levels of Bcl-x(gamma) protein through induction of an alternatively-spliced Bcl-x(gamma) 3' UTR that contains stem loop structures that stabilize Bcl-x(gamma) RNA. The ability receptor-induced signals to regulate the splicing pattern of the complex Bcl-x gene may allow T-cells to respond appropriately to antigenic stimuli.

The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xgamma is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xgamma-deficient (Bcl-xgamma-/-) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE). In contrast, enforced expression of Bcl-xgamma largely replaces the requirement for B7-dependent ligation of CD28. These findings identify the Bcl-xgamma cytosolic protein as an essential downstream link in the CD28-dependent signaling pathway that underlies T cell costimulation.

Stable BHK cell lines inducibly expressing wild-type or dominant negative mutant forms of the rab7 GTPase were isolated and used to analyze the role of a rab7-regulated pathway in lysosome biogenesis. Expression of mutant rab7N125I protein induced a dramatic redistribution of cation-independent mannose 6-phosphate receptor (CI-MPR) from its normal perinuclear localization to large peripheral endosomes. Under these circumstances approximately 50% of the total receptor and several lysosomal hydrolases cofractionated with light membranes containing early endosome and Golgi markers. Late endosomes and lysosomes were contained exclusively in well-separated, denser gradient fractions. Newly synthesized CI-MPR and cathepsin D were shown to traverse through an early endocytic compartment, and functional rab7 was crucial for delivery to later compartments. This observation was evidenced by the fact that 2 h after synthesis, both markers were more prevalent in fractions containing light membranes. In addition, both were sensitive to HRP-DAB- mediated cross-linking of early endosomal proteins, and the late endosomal processing of cathepsin D was impaired. Using similar criteria, the lysosomal membrane glycoprotein 120 was not found accumulated in an early endocytic compartment. The data are indicative of a post-Golgi divergence in the routes followed by different lysosome-directed molecules.

Cytokines have been implicated as pivotal mediators of the wound-healing process. An understanding of the production and interaction of cytokines may lead to a better appreciation of the complex mechanisms of flap ischemia. The potential would then exist for novel diagnostic and therapeutic approaches to prevent and reverse damage to the endangered flap. The goal of this study was to determine the expression of parenchymal cytokines at various time points during flap ischemia. Punch biopsies were obtained from McFarlane dorsal flaps in the Sprague-Dawley murine model. We examined cytokine mRNA profiles for interleukin 1 alpha (IL-1 alpha), IL-2, IL-6, basic fibroblast growth factor (b-FGF), gamma-interferon (gamma IFN), transforming growth factor beta (TGF-beta), and platelet-derived growth factor A chain (PDGF-alpha) using in situ hybridization. Samples were taken from 0 to 48 hours postoperatively, with n = 3 for each time point. Eight hours postoperatively there was an abrupt peak of parenchymal cytokine expression at the bases of the flaps. Clinically at this time the flaps appeared completely viable without evidence of ischemic change. Leukocyte cytokine production peaked at 16 hours, when distal flap ischemia was evident clinically. These findings demonstrate an early peak of cytokine expression prior to clinical evidence of ischemia.