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The purpose of this study was to investigate the potential for a CYP3A4-mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15-mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (C(max) = 50.8 vs 46.2 ng/mL; AUC(0-last) = 215 vs 216 ng.h/mL; AUC(0-last) ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates. [ABSTRACT FROM AUTHOR]

Rationale and Objective: This study aimed to develop a cosmesis scale to evaluate the cosmetic appearance of hemodialysis (HD) arteriovenous (AV) accesses from the perspective of the patient and clinician, which could be incorporated into clinical trials., Study Design: Using a modified Delphi process, two AV access cosmesis scale (AVACS) components were developed in a four-round Delphi panel consisting of two surveys and two consensus meetings with two rounds of patient consultation., Setting and Participants: The Delphi panel consisted of 15 voting members including five interventional or general nephrologists, five vascular surgeons, three interventional radiologists, and two vascular access nurse coordinators. Four patients experienced with vascular access were involved in patient question development., Analytical Approach: For a component to be included in the AVACS, it had to meet the prespecified panel consensus agreement of ⩾70%., Results: The clinician component of the AVACS includes nine questions on the following AV access features: scarring, skin discoloration, aneurysm/pseudoaneurysms and megafistula appearance. The patient component includes six questions about future vascular access decisions, interference with work or leisure activities, clothing choices, self-consciousness or attractiveness, emotional impact, and overall appearance., Limitations: Delphi panel methods are subjective by design, but with expert clinical opinion are used to develop classification systems and outcome measures. The developed scale requires further validation testing but is available for clinical trial use., Conclusions: While safety and efficacy are the primary concerns when evaluating AV access for HD, cosmesis is an important component of the ESKD patient experience. The AVACS has been designed to assess this important domain; it can be used to facilitate patient care and education about vascular access choice and maintenance. AVACS can also be used to inform future research on developing new techniques for AV access creation and maintenance, particularly as relates to AV access cosmesis., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that they have no conflicts of interest regarding patents or royalties, stock/stock options, or first-degree relatives with any of these relationships related to this work. No reimbursement was received for the development of the manuscript.DR, VN, MM, CR, ED, CG, TV, SH, PB, LD and patients CS, DDR, FM, and MB (see acknowledgements) received remuneration from Becton Dickinson (BD) for their participation in the Delphi process.GW, AH, and NF are employees of CRG-EVERSANA Canada Inc., which was contracted by BD to facilitate the Delphi panel process and analyze the results.EK and DC are employees of the American Association of Kidney Patients (AAKP) which was contracted by BD to advise on patient input and recruited the Patient Ambassadors.DR is a consultant for BD and Gore Medical. VN is a consultant for the NACCME – Moderator for AV Access Webcast, supported by an educational grant from Medtronic. SH is a consultant/speaker for BD, Merit Medical, Medtronic, and Gore Medical. ED is a consultant for WL Gore, Angiodynamics, and 3M/KCI. ED is a scientific advisor for Boston Scientific. TY is a consultant for BD, WL Gore and Merit Medical and a scientific advisory board member of BD and Medtronic. CK is a consultant for BD and ACI/Humacyte and advisory board member for Boston Scientific. CL is a consultant for BD, Gore, and Medtronic.Other ConflictsED, KW, and TY are authors and ED is an editor for UpToDate.

Cancer is the second most common cause of death in children aged 1-14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease., (© 2024. The Author(s).)

The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) pandemic has challenged medical systems and clinicians globally to unforeseen levels. Rapid spread of COVID-19 has forced clinicians to care for patients with a highly contagious disease without evidence-based guidelines. Using a virtual modified nominal group technique, the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from 6 countries, generated consensus guidelines on airway management in pediatric anesthesia based on expert opinion and early data about the disease. PeDI-C identified overarching goals during care, including minimizing aerosolized respiratory secretions, minimizing the number of clinicians in contact with a patient, and recognizing that undiagnosed asymptomatic patients may shed the virus and infect health care workers. Recommendations include administering anxiolytic medications, intravenous anesthetic inductions, tracheal intubation using video laryngoscopes and cuffed tracheal tubes, use of in-line suction catheters, and modifying workflow to recover patients from anesthesia in the operating room. Importantly, PeDI-C recommends that anesthesiologists consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19. Airway procedures should be done in negative pressure rooms when available. Adequate time should be allowed for operating room cleaning and air filtration between surgical cases. Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic. Until further information is available, PeDI-C advises that clinicians consider these guidelines to enhance the safety of health care workers during airway management when performing aerosol-generating medical procedures. These guidelines have been endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society.

Introduction: Renal vein thrombosis post kidney transplant is a rare but graft threatening event. RVT is reported in 0.3-4.2% of kidney transplants. When occurring early post transplant, prior to development of collateral venous outflow, may be catastrophic with loss of the allograft or even death. Anatomic abnormalities or technical problems during surgery are common causes. Early diagnosis and urgent treatment are necessary but often unsuccessful., Presentation of Case: We report a patient with residual function in a failing allograft who developed RVT in a living donor preemptive kidney transplant., Discussion: We review the literature regarding renal vein thrombosis following kidney transplant., Conclusion: Prompt diagnosis and immediate surgicathrombectomy after ex-planting allograft with subsequent re-implanting the allograft was successful., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 54-year-old woman with a symptomatic giant hepatic hemangioma underwent an extended left hepatic trisegmentectomy complicated by 250-350 mL/d postoperative bilious drainage. After 5 months of therapy, drainage was unabated, and the patient was no longer a surgical candidate. Sinography revealed three distinct isolated bile duct leaks involving segments 6, 7, and 8. Endobiliary segmentectomy was achieved by obliterating the isolated systems with ethylene-vinyl alcohol copolymer (Onyx; ev3, Plymouth, Minnesota) during three fluoroscopic procedures. Bilious leaks were successfully eliminated, and compensatory hypertrophy of noninvolved liver occurred. At 2 years from the last embolization procedure, the patient remained asymptomatic with no bilious leak., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

After creation of an arteriovenous fistula or placement of an arteriovenous graft, several weeks are required for maturation prior to first cannulation. Patients need an alternative way to receive hemodialysis during this time, frequently a catheter. After multiple failed access attempts, patients can run out of options and become catheter dependent. At our institution, we place HeRO grafts in eligible patients who have otherwise been told they would be catheter dependent for life. By combining the HeRO graft system with a Flixene graft, patients are able to remove catheters sooner or avoid placement as they can undergo cannulation for hemodialysis the next day. Utilizing this novel technique, twenty-one patients over a two-year period with various forms of central venous stenosis, catheter dependence, or failing existing arteriovenous access have been successfully converted to stable long term noncatheter based upper extremity access.

The histologic features seen in the prostate following cryotherapy can be highly variable. However, most previous studies were performed on specimens following salvage cryotherapy, which introduces additional confounding variables of the histologic changes after the other primary treatment modalities. We examined prostate needle core biopsies from a cohort of patients following cryotherapy as monotherapy for prostatic adenocarcinoma, to evaluate the true spectrum of morphologic changes in the prostate. Cases that had prior radiation therapy or androgen-deprivation therapy were excluded from the study. Thirty cases were identified. The average patient age was 69 years (range, 51-81 years), and the average time interval between cryotherapy and repeat biopsy was 19.2 months (range, 2-60 months). The original Gleason scores were as follows: 3 + 3 = 6 in 14 (46%) of 30 cases, 3 + 4 = 7 in 8 (27%) of 30 cases, 4 + 3 = 7 in 2 (7%) of 30 cases, 4 + 4 = 8 in 3 (10%) of 30 cases, 4 + 5 = 9 in 2 (7%) of 30 cases, and 5 + 4 = 9 in 1 (3%) of 30 cases. Postcryotherapy, 11 of 30 cases (37%) had recurrent/residual prostatic adenocarcinoma, which showed no therapy-related changes, similar to the residual benign glands. Gleason scores were higher in 5 (46%) of 11 cases, same in 4 (36%) of 11 cases, and lower in 2 (18%) of 11 cases. Multiple additional histologic findings were documented. Unlike other nonsurgical therapeutic modalities, cases with recurrent/residual prostatic adenocarcinoma and benign glands showed therapy-related changes predominantly involving the stroma. It is therefore conceivable that benign or malignant prostatic glands are either completely destroyed during cryotherapy or left unaltered if not in the direct field of cryoablation., (Published by Elsevier Inc.)

Cyclooxygenases (COX) are prostanoid synthesizing enzymes constitutively expressed in the brain that contribute to excitotoxic neuronal cell death. While the neurotoxic role of COX-2 is well established and has been linked to prostaglandin E(2) synthesis, the role of COX-1 is not clearly understood. In a model of N-Methyl-D-aspartic acid (NMDA) induced excitotoxicity in the mouse cerebral cortex we found a distinctive temporal profile of COX-1 and COX-2 activation where COX-1, located in microglia, is responsible for the early phase of prostaglandin E(2) synthesis (10 minutes after NMDA), while both COX-1 and COX-2 contribute to the second phase (3-24 hours after NMDA). Microglial COX-1 is strongly activated by ATP but not excitatory neurotransmitters or the Toll-like receptor 4 ligand bacterial lipopolysaccharide. ATP induced microglial COX-1 dependent prostaglandin E(2) synthesis is dependent on P2X7 receptors, extracellular Ca(2+) and cytoplasmic phospholipase A2. NMDA receptor activation induces ATP release from cultured neurons leading to microglial P2X7 receptor activation and COX-1 dependent prostaglandin E(2) synthesis in mixed microglial-neuronal cultures. Pharmacological inhibition of COX-1 has no effect on the cortical lesion produced by NMDA, but counteracts the neuroprotection exerted by inhibition of COX-2 or observed in mice lacking the prostaglandin E(2) receptor type 1. Similarly, the neuroprotection exerted by the prostaglandin E(2) receptor type 2 agonist butaprost is not observed after COX-1 inhibition. P2X7 receptors contribute to NMDA induced prostaglandin E(2) production in vivo and blockage of P2X7 receptors reverses the neuroprotection offered by COX-2 inhibition. These findings suggest that purinergic signaling in microglia triggered by neuronal ATP modulates excitotoxic cortical lesion by regulating COX-1 dependent prostanoid production and unveil a previously unrecognized protective role of microglial COX-1 in excitotoxic brain injury.

As a result of genomics initiatives worldwide, it has become increasingly easy to obtain cDNA clones representing the 3' ends of many human genes. This unit describes methods that allow these clones to be used as hybridization detectors in a highly parallel assay of gene expression. Protocols are provided for preparing cDNA microarrays, extracting RNA from cells of interest and preparing fluorescently labeled cDNA representations of the message pools, and hybridizing the labeled cDNAs to the microarrays.

Radiolabeling of monoclonal antibodies (mAbs) is often one of the principal methods for the in vitro and in vivo assessment of these reagents, whether this is determining the affinity of a new reagent, preparing for preclinical testing, or clinically for diagnostic or therapeutic use.

Unlabelled: The development of stable chelating agents for metal isotopes (e.g., 90Y) such as CITC-DTPA, a benzyl-analog of DTPA, allowed us to evaluate the efficacy of 90Y-labeled HMFG1 MAb administered intraperitoneally in patients with ovarian cancer. Our previous studies of 90Y-HMFG1 antibody, however, showed that all patients developed anti-chelate antibody responses (to the macrocycle benzyl-DOTA), resulting in clinical side effects in a significant percentage of this group., Methods: We evaluated the immunogenicity of CITC-DTPA (administered to 12 patients as 90Y-HMFG1-CITC-DTPA after coupling it to HSA using solid-phase ELISA., Results: Eleven of 12 evaluable patients developed anti-CITC-DTPA antibodies. Five patients (approximately 40%) developed hypersensitivity syndrome, most likely due to a type III immune reaction (serum sickness). Most patients had a low titer of pre-existing anti-chelate response which correlated positively with post-therapy response levels (p = 0.001). IgM anti-CITC-DTPA antibodies developed 2 wk while IgG antibodies developed 3 wk after treatment. Western blot analysis of post-therapy sera revealed a reaction with HSA-CITC-DTPA (60 kDa band) and no reaction with HSA or HSA-DTPA, whereas pre-therapy sera of the same patients were negative to all antigens., Conclusion: CITC-DTPA is immunogenic in patients after intraperitoneal administration of 90Y-CITC-DTPA labeled MAbs. Self-limiting clinical side effects consistent with a serum sickness-like immune reaction were observed in 5 of 12 patients.

A new agent originally introduced for localizing inflammatory lesions is Tc-99m human immunoglobulin G (HIG). Recently, focal uptake of this agent was seen in malignant lesions in a limited number of patients during inflammation imaging studies. In this prospective clinical study, the authors aimed to evaluate the uptake of Tc-99m HIG in malignant lesions. Nineteen patients with histopathologically proven malignant tumors were studied (seven had distant metastases, the primary tumor was surgically removed in two). There was no evidence of inflammation or infection in any patient. The authors imaged patients at 1, 4, and 24 hours after injection. The dose was 15-20 mCi (555-740 MBq). Focal uptake was detected in the primary tumor in six patients and in the metastases in five patients, raising some question about the specificity of Tc-99m HIG imaging for the detection of inflammation and infection.

We have examined the expression of the c-erbB-3 protein in a wide range of tumours of the gastrointestinal (GI) tract using immunocytochemical staining. Two antibodies were employed, a polyclonal antibody, 49.3, and a new monoclonal antibody, RTJ1, both raised to a synthetic peptide from the cytoplasmic domain of the human c-erbB-3 protein. The antibodies recognize c-erbB-3 by immunoprecipitation and Western blotting of lysate prepared from a cell line engineered to overexpress the protein. Both antibodies also detect expression of the protein in formalin-fixed, paraffin-embedded human tissues. The RTJ1 monoclonal antibody gave superior staining, showing lower background and more pronounced cell surface immunoreactivity. The c-erbB-3 protein was found in normal epithelial cells throughout the GI tract, in squamous epithelium of the oropharanyx and oesophagus, in the parietal cells of the stomach, and in the surface enterocytes of the small and large bowel. Seventy-six tumours arising at these sites were examined for c-erbB-3 protein expression. Widely varying levels of expression were seen, from absent to intense staining with cell membrane accentuation.

The development of stable immunoconjugates by the advent of macrocyclic metal chelating agents (DOTA) has enabled us to study the ability of 111In-DOTA-labeled monoclonal antibodies to detect tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered 90Y-DOTA-labeled murine monoclonal antibody in a Phase I/II clinical trial of advanced ovarian cancer. The development of serum sickness-like reactions in three of six treated patients, in the absence of previous monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate. Six patients with ovarian cancer received 25 mg of HMFG1 monoclonal antibody coupled with 90Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant tumors received low doses (220 micrograms to 1 mg) of monoclonal antibodies, labeled with 111In-DOTA, i.v. for imaging studies. Using a solid-phase enzyme-linked immunosorbent assay method, the immunogenicity of DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or therapy with DOTA-coupled monoclonal antibodies, as well as sera from patients who did not receive DOTA-coupled antibody, were screened on enzyme-linked immunosorbent assay plates coated with human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p. monoclonal antibody developed anti-DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of DOTA-coupled monoclonal antibody developed antibodies against DOTA. The levels of anti-DOTA response correlated with the amount of injected radioimmunoconjugate (r = 0.889, P less than 0.001). None of the patients who received DOTA-coupled antibody had detectable antibodies against the macrocycle before immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to DOTA. Most, if not all, of the immune response is directed against the DOTA ring structure. Affinity purification of anti-DOTA antibody from serum enabled quantitation of these antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to DOTA, by HSA-2-iminothiolane-DOTA (100 micrograms/ml) and the level of anti-DOTA immunoglobulin in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)