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Objectives Small bowel adenocarcinoma (SBA) with peritoneal metastasis (PM) is rare and despite treatment with systemic chemotherapy, the prognosis is poor. However, there is emerging evidence that cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) may offer a survival benefit over systemic therapy alone. This systematic review will assess the effectiveness of CRS–HIPEC for SBA–PM. Content Three databases were searched from inception to 11/10/21. Clinical outcomes were extracted and analysed. Summary A total of 164 cases of SBA–PM undergoing CRS–HIPEC were identified in 12 studies. The majority of patients had neoadjuvant chemotherapy (87/164, 53%) and complete cytoreduction (143/164, 87%) prior to HIPEC. The median overall survival was 9–32 months and 5-year survival ranged from 25 to 40%. Clavien–Dindo grade III/IV morbidity ranged between 19.1 and 50%, while overall mortality was low with only 3 treatment-related deaths. Outlook CRS–HIPEC has the potential to improve the overall survival in a highly selected group of SBA–PM patients, with 5-year survival rates comparable to those reported in colorectal peritoneal metastases. However, the expected survival benefits need to be balanced against the intrinsic risk of morbidity and mortality associated with the procedure. Further multicentre studies are required to assess the safety and feasibility of CRS–HIPEC in SBA–PM to guide best practice management for this rare disease.

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Supplementary figures, results, and methods.

Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite graph–based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, that is, the candidate members of the pathway that regulate the transcriptomic module. Computational evaluations indicated that our methods-identified pathways were perturbed by SGA. In particular, our analyses revealed that SGA affecting TP53, PTK2, YWHAZ, and MED1 perturbed a set of signals that promote cell proliferation, anchor-free colony formation, and epithelial–mesenchymal transition (EMT). These proteins formed a signaling complex that mediates these oncogenic processes in a coordinated fashion. Disruption of this signaling complex by knocking down PTK2, YWHAZ, or MED1 attenuated and reversed oncogenic phenotypes caused by mutant p53 in a synthetic lethal manner. This signal-oriented framework for searching pathways and therapeutic targets is applicable to all cancer types, thus potentially impacting precision medicine in cancer. Cancer Res; 76(23); 6785–94. ©2016 AACR.

The vital process of intracellular calcium (Ca 2+ ) signaling in T-lymphocytes control complex immune responses, and disruptions can cause autoimmune and inflammatory disorders. The activation of T-cells is fine-tuned by various pathways interacting with membrane potential, messengers, and other enzymes that eventually trigger intracellular calcium release. In cardiac and skeletal muscle, ryanodine receptors (RyR) are crucial to the release of calcium, facilitating contractions and relaxations of striated muscle cells. However, RyR also plays an important role in human T-cell activation, regulating calcium release in activated T-cells through bidirectional coupling of calcium release-activated calcium (CRAC) channels. The mechanism of RyR has been demonstrated in vitro, but it is important to explore this system quantitatively to describe various interactions and modulations in the T-cell. We modified an existing T-cell model simulating the activation of CRAC channels with intracellular components, adding RyR1, RyR2, and RyR3 isoforms. Our model simulated the role of RyR in an activated and resting T-cell, potentially providing a tool to modulate immune responses in humans., Journal of Student-Scientists' Research, Vol. 3 (2021)

Writing on-demand, text-based analytical essays is a challenging skill to master. Novice writers, such as the sixth grade US students in this study, may lack background knowledge of how to compose an effective essay, the self-efficacy skills, and the goal setting skills that will help with completing this task in accomplished ways. This sequential mixed-method study explored the impact of guiding a predominantly Redesignated English Learner group of students in a large, urban, low-SES school district in a timed, on-demand essay into a multiple draft process paper through a self-assessment, planning and goal setting, and reflection process as they revised this process paper over a three week period. Both treatment and comparison students completed a pre-test on demand writing assessment, a pre and post self-efficacy in writing survey, and a post-test on demand writing assessment. Students in both conditions were participating in a year-long writing intervention called The Pathway to Academic Success, developed and implemented by the UC Irvine site of the National Writing Project (UCI Writing Project), during the 2017–2018 school year and received identical training from their teachers on how to revise a pre-test essay. However, only the treatment group engaged in self-assessment, planning and goal setting, and reflection during this revision process. Students in the treatment condition demonstrated improved self-efficacy in the writing sub-domain of revision (p p

Resection of diverticular disease can be technically challenging. Tissue planes can be difficult to identify intraoperatively due to inflammation or fibrosis. Robotic surgery may improve identification of tissue planes and dissection which can facilitate difficult minimally invasive resections. This systematic review and meta-analysis evaluates the role of robotic surgery compared to laparoscopic surgery in diverticular resection.A systematic review and meta-analysis was performed in accordance with the PRISMA statement. The search was completed using PubMed, OVID MEDLINE and EMBASE. A total of 490 articles were retrieved, and studies reporting primary outcomes for robotic diverticular resection were included in the final analysis. A meta-analysis of studies comparing robotic and laparoscopic surgery was performed on rate of conversion to open surgery and complications.Fifteen articles (8 cohort studies and 7 case series) reporting 3711 robotic diverticular resections were analysed. In comparison to laparoscopic, robotic surgery for diverticular disease was associated with a reduced conversion to open and a longer operating time. Meta-analysis showed robotic resection was associated with a lower conversion rate compared to laparoscopic surgery (OR: 0.57; 95% CI: 0.49-0.66, p 0.001). There was no significant difference in grade III and above complications (OR: 0.74; 95% CI: 0.49-1.13, p = 0.17). Operating time was longer with a robotic approach (Hedge's G: 0.43; 95% CI: 0.04-0.81, p = 0.03).Robotic resection is a feasible and safe option in diverticular disease. Although associated with a longer operating time, robotic surgery may render diverticular disease resectable with a minimally invasive approach that would have otherwise necessitated a laparotomy. Randomised controlled data is required to better define the role of robotic surgery for diverticular disease resections.

ObjectiveIllustrate that some neuroinflammatory diseases may respond best to antiproliferative therapies rather than immunomodulatory therapies.BackgroundGenomics are increasingly employed in the diagnostic armamentarium of refractory neuro-inflammatory diseases. Metagenomic next-generation sequencing is used to detect pathogens and germline genetic testing is used to detect inborn errors of the immune system. Genetic testing of tissue can identify somatic mutations for targeted treatment. MEK-inhibitors are an emerging treatment for RAS/MAPK pathway mutated diseases which include some neuro-inflammatory mimics like neuro-histiocytoses.Design/MethodsNA.ResultsPreviously healthy 12-year-old girl presented with 1 month of diplopia and headaches. Her brother has clinically diagnosed NF1 (café-au-lait macules, cutaneous neurofibromas). Exam notable for right third nerve palsy. MRI showed T2/FLAIR hyperintense lesions of the right temporal lobe, basal ganglia, and cervical through thoracic cord, nodular leptomeningeal enhancement along the entire spinal cord, and right middle cerebral artery vessel wall enhancement. CSF: WBC 6/mm3(62% lymphocytes 37% monocytes), protein 133 mg/dL. She improved with pulse methylprednisolone and maintenance steroids. At 5 months, she developed malignant elevated intracranial pressure with CSF OP >50 cm water, bradycardia, and encephalopathy requiring weekly LPs. Brain biopsy showed astrocytic and microglial activation without significant inflammation. No histiocytes were noted. There was no evidence of neoplasia or infection. She was tried on anakinra. At 6 months, she developed left third nerve palsy and seizures. For weeks, she required daily LPs for intracranial hypertension despite placement of ventriculoperitoneal shunt. Additional treatments included infliximab, steroids, and siltuximab. NGS from brain biopsy identified 2 NF1 mutations (nonsense, splicing). Allele fractions: 6% and 9%. Her mental status and need for frequent LP improved dramatically with trametinib.ConclusionsThis case illustrates the importance of considering somatic genomic testing of neural tissue even when the neuropathology is not suggestive of a malignancy or histiocytosis as this can inform newer molecularly targeted therapeutic options.

Objective: To evaluate whether outpatient cervical ripening with a balloon catheter results in a shorter amount of time in the labor and delivery unit when compared with use in the inpatient setting. Data sources: PubMed, Scopus, Cochrane Library, and ClinicalTrials.gov were searched from their inception until December 2020. No restrictions for language or geographic location were applied. Methods of study selection: Using a predefined protocol and search strategy, 1,152 titles were identified and screened. Randomized controlled trials that compared outpatient and inpatient cervical ripening with balloon catheters were included. Tabulation, integration, and results: Data extraction and risk of bias assessments were performed by two reviewers. Meta-analysis was performed to produce mean difference for continuous data and risk ratio (RR) for dichotomous data, both with a 95% CI. The primary outcome was the amount of time from admission to the labor ward until delivery. Additional secondary maternal and neonatal outcomes were evaluated. Eight trials (740 patients) were included; six studies (571 patients) reported on our primary outcome. Compared with the inpatient group, outpatient balloon cervical ripening was associated with significantly less time in the labor and delivery unit (outpatient 16.3±9.7 hours vs inpatient 23.8±14.0 hours; mean difference -7.24 hours, 95% CI -11.03 to -3.34). There were no differences in total induction time or total hospital admission. The outpatient group was significantly less likely than the inpatient group to undergo cesarean delivery (21% vs 27%), RR 0.76 (95% CI 0.59-0.98). There were no differences in other maternal or neonatal outcomes. There were no deliveries outside of the hospital and no stillbirths. Conclusion: Outpatient balloon cervical ripening in low-risk patients is associated with a decreased amount of time from admission to labor and delivery until delivery by more than 7 hours and a significant 24% decreased risk of cesarean delivery. Outpatient balloon cervical ripening is a safe alternative for low-risk patients and has the potential for significant benefits to patients, and labor and delivery units. Systematic review registration: PROSPERO, CRD42019140503.

The CO2CRC, in collaboration with The University of Melbourne (UoM) and the University of New South Wales (UNSW), tested two novel CO2 capture technologies aimed for both on-shore and off-shore natural gas applications. The tests involved materials testing in a state-of-the-art experimental capture rig at CO2CRC’s Otway International Test Centre followed by simulation and techno-economic activities for scaled up facilities. The goal was to develop robust and compact technology for high pressure natural gas separation over a range of adjusted high CO2 concentrations mimicking various gas field conditions. The tests were conducted for adsorbents and membranes in a high-pressure rig incorporating both pressure swing adsorption (PSA) and membrane technologies. It was found that adsorption, a second-generation technology with a low footprint is very suitable for natural gas separation with higher separation efficiency, contrary to the general perception. The stable separation performance of the thin film composite hollow fibre membranes was particularly encouraging among all membranes tested. This paper will discuss novel adsorbent and membrane development and their quantitative performance in the test campaigns followed by suggested next steps in the TRL towards commercial application. It is anticipated further research and testing at higher Technology Readiness Level (TRL) levels 5/6 would be necessary to make them commercial ready. These technologies, if successful, would facilitate developing new gas fields to recover methane in a cost-effective manner which is currently uneconomical with conventional technologies.

The diagnosis of focal segmental glomerulosclerosis (FSGS) requires a renal biopsy, which is invasive and can be problematic in children and in some adults. We used single cell RNA-sequencing to explore disease-related cellular signatures in 23 urine samples from 12 FSGS subjects. We identified immune cells, predominantly monocytes, and renal epithelial cells, including podocytes. Analysis revealed M1 and M2 monocyte subsets, and podocytes showing high expression of genes for epithelial-to-mesenchymal transition (EMT). We confirmed M1 and M2 gene signatures using published monocyte/macrophage data from lupus nephritis and cancer. Using renal transcriptomic data from the Nephrotic Syndrome Study Network (NEPTUNE), we found that urine cell immune and EMT signature genes showed higher expression in FSGS biopsies compared to minimal change disease biopsies. These results suggest that urine cell profiling may serve as a diagnostic and prognostic tool in nephrotic syndrome and aid in identifying novel biomarkers and developing personalized therapeutic strategies.

From literary canons all the way to the motion picture industry, the artistic and popular cultural experience of marginalized or nonmainstream groups has been one of being represented by the other. In this article, we explore how online fanfiction, as an audience-driven, interactive form of writing, may offer a way for members of nonmainstream groups to push back against and offer alternatives to stereotypical and normative discourses. We focus on how autistic people, family members, teachers, and advocates cast autistic characters in their fanfiction stories, how these stories represent autism and how, given the affordances of an online publishing platform, audience members respond to such representations. Findings suggest that these online narratives diversify available representations of autistic characters; moreover, the interactive nature of the online publishing forum allows readers to respond to and potentially disrupt stereotypical thinking and common fictional tropes surrounding autism.

Inflammatory bowel disease (IBD), majorly include Crohn’s disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg−1) and the positive drug Sulfasalazine (SASP, 200 mg kg−1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high-throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis.

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182-mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206(high) patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

Comparing diverse single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories remains a major challenge. Here we address the need for guidance in choosing algorithms leading to accurate biological interpretations of varied data types acquired with different platforms. Using two well-characterized cellular reference samples (breast cancer cells and B cells), captured either separately or in mixtures, we compared different scRNA-seq platforms and several preprocessing, normalization and batch-effect correction methods at multiple centers. Although preprocessing and normalization contributed to variability in gene detection and cell classification, batch-effect correction was by far the most important factor in correctly classifying the cells. Moreover, scRNA-seq dataset characteristics (for example, sample and cellular heterogeneity and platform used) were critical in determining the optimal bioinformatic method. However, reproducibility across centers and platforms was high when appropriate bioinformatic methods were applied. Our findings offer practical guidance for optimizing platform and software selection when designing an scRNA-seq study.

Since the discovery of autophagy in the mid-2000s, the interest in autophagy-related processes within the scientific community has been burgeoning. Countless authors have investigated its function in cellular homeostasis, but arguably of higher importance is its role during pathology. Although primarily a catabolic process, in cancer cells autophagy has numerous downstream effects, being observed to be both pro- and anti-apoptotic. One of the primary factors mediating this differential role of autophagy is the accumulation or sequestration of reactive oxygen species (ROS). Until recently, despite its increasing popularity in the Western world, the efficacy of herbal supplements has been largely anecdotal. Herein, we reviewed the ten most commonly studied herbs in cancer research and their impact on ROS regulation, on the activation and inhibition of autophagy, and ultimately on cancer cell death.

Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.

Author(s): Chen, Vicky | Abstract: This paper is a self-study that uses the lens of Vygotsky’s four phases of sign acquisition to examine one student writer’s development of voice through writing produced from 5th grade through her second year of graduate school (17 years). Growing up as a twin—and as a visually impaired individual—the author learned how to use the written word to help her imagine those aspects of the world that she could not physically see. Through excerpts from journal entries, planning documents, short stories, long fiction, poetry, school assignments, and fanfiction she traces her growth as a writer within the shifting context of experiences within and outside of school. Her sensitive exploration of varied sources of motivation and inspiration, along with her own changing attitudes towards and beliefs about writing, provide the reader with fresh insight into all that goes into one’s development as a writer.

The study's aim was to identify technical factors that are predictive of negative margins after breast-conserving surgery (BCS).This was a retrospective, cohort study of patients who underwent BCS for early-stage cancer from 2000 to 2002. Pathological and specific surgical factors were compared with margin status. Univariate and multivariate regression analyses were performed.Four hundred eighty-nine cases were reviewed. The positive margin rate after the initial surgery was 26%. In univariate analysis, lobular histology, size, grade, multifocality, and the presence of EIC and LVI were associated with positive margins (P.05). The absence of cavity margin dissection and specimen orientation labeling, the absence of a confirmed diagnosis, and smaller volumes of excision were also associated with positive margins (P.05). In multivariate analysis, confirmed diagnosis, small tumor size, ductal histology, absence of LVI and multifocality, palpability, cavity margin dissection, and larger volumes of excision were predictors of negative margins.This study shows that specific surgical factors are predictive of margin status. Both tumor and technical factors should be considered when planning BCS.

Acute apical abscesses and cellulitis are severe endodontic diseases caused by opportunistic bacteria with possible coinfection with latent herpesviruses. The objectives of this study are to identify herpesviruses, including human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), herpes simplex virus-1 (HSV-1), and Varicella zoster virus (VZV) in patients (n = 31) presenting with acute apical abscesses and cellulitis of endodontic origin. Primary and nested polymerase chain reaction (PCR) was conducted using virus-specific primers and DNA isolated from cell-free abscess fluid. From patients exhibiting concurrent spontaneous pain (n = 28), nine abscesses contained HCMV, two abscesses contained EBV, one abscess contained HSV-1, and no abscesses contained VZV. Control PCR using genomic or recombinant templates showed detection limits to a single genomic copy of HCMV, 100 genomic copies for EBV, and 1 to 10 copies for HSV-1 with no cross-amplification between herpesviral DNA targets. Nested PCR was required for detection of herpesviral DNA in the abscess specimens, indicating that these viruses were present in low copy number. Filtration of abscess specimens and virus transfer experiments using human fibroblastic MRC-5 cells confirmed the presence of HCMV particles in several abscess specimens. We conclude that herpesviruses are present but not required for the development of acute apical abscesses and cellulitis of endodontic origin.

Irreversible pulpitis and apical periodontitis are inflammatory diseases caused by opportunistic bacteria with possible co-infection with latent herpesviruses. The objectives of this study are to identify herpesviruses, including human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV-1), and Varicella zoster virus (VZV) in patients with irreversible pulpitis (n = 29) or apical periodontitis, either primary (n = 30) or previously treated (n = 23). Using primary and nested polymerase chain reaction (PCR) and reverse transcription-PCR, EBV DNA and RNA were present in endodontic pathoses in significantly higher percentages (43.9% and 25.6%, respectively) compared with healthy pulp controls (0% and 0%, respectively). HCMV DNA and RNA were found in measurable numbers in both endodontic patients (15.9% and 29.3%, respectively) and in healthy pulp controls (42.1% and 10.5%, respectively). HSV-1 DNA was found in low percentages in endodontic patients (13.4%), and only one patient showed the presence of VZV. In conclusion, EBV may be associated with irreversible pulpitis and apical periodontitis.

Heat-killed Saccharomyces cerevisiae (HKY) vaccination protects mice against aspergillosis, coccidioidomycosis, mucormycosis, or candidiasis. We studied HKY protection against murine cryptococcosis. Once weekly subcutaneous HKY doses (S, 6 × 10(7); 2S, 1.2 × 10(8); 3S, 2.4 × 10(8)) began 28 (×3), 35 (×4), or 42 (×6) days prior to intravenous Cryptococcus grubii infection. Survival through 28 days, and CFU in the organs of survivors, were compared to saline-vaccinated controls. In the initial experiment, S, S×4, or 2S reduced brain CFU; liver or spleen CFU was reduced by S×4 or 2S. In a more lethal second experiment, 2S×6, 2S, or 3S×4 improved survival, and HKY regimens reduced CFU in the brain, liver, or spleen, with 2S×6, 2S, or 3S×4 most efficacious. Dose size appears more important than the number of doses: RegimensS were superior, and 2S and 2S×6 were equivalent. 2S and 3S were equivalent, suggesting doses2S do not provide additional protection. HKY protects against Cryptococcus, supporting components of HKY as a basis for the development of a panfungal vaccine.

Previously we showed heat-killed yeast (HKY) of Saccharomyces cerevisiae administered as a vaccine are protective against systemic murine aspergillosis (and other mycoses) and that HKY induces antibody and cellular responses. To determine the role of antibodies in this protection, male antibody knockout mice (KO; strain B6.129S2-Igh-6 (tm1Cgn)/J) and C57BL/6 wild-type (WT) mice were vaccinated subcutaneously with 6 × 10(7) HKY or phosphate buffered saline (PBS) given three or four times. Mice were infected intravenously with 6 × 10(6) viable conidia of Aspergillus fumigatus 10AF and mortality tallied through 12 days post infection. HKY vaccination given four times proved protective in the prolongation of survival of WT and KO mice vs. the respective PBS-treated controls. In one study, survival was prolonged in vaccinated WT or KO mice (P < 0.0001). A second study confirmed these results (P < 0.0001). Additionally, a three-dose regimen of HKY was also effective, prolonging survival of WT or KO mice vs. controls (P = 0.0002); no difference was found when the effectiveness of three- or four-dose regimens was compared. No significant differences in survival were found between HKY-vaccinated WT and KO mice, nor were PBS-treated KO mice more susceptible to infection than PBS-treated WT mice. Similar results were noted in another study in which a higher infectious inoculum and a three-dose regimen were used. Overall, antibodies do not appear to play a significant role in HKY-induced prolongation of survival in systemic aspergillosis, nor do antibodies appear to play a role in the innate resistance of the mice to aspergillosis.

Although polymorphonuclear leukocytes (PMNs) are powerfully anti- Aspergillus , transfusion therapy remains controversial, with conflicting results, and experimental support has been lacking. We devised a pulmonary infection model in neutropenic BALB/c mice, used an antibacterial regimen to prevent confounding sepsis, and optimized PMN induction, purifications, and dose. Mice were given 150 mg/kg cyclophosphamide every 4 days and a gentamicin-vancomycin-clindamycin-imipenem regimen daily beginning 4 days before intranasal challenge with 5 × 10 5 Aspergillus conidia. This regimen produced leukopenia (∼10% of normal white blood cell [WBC] count; ≤10% PMNs) for 10 days, without bacterial superinfection. PMN donors given 100 μg/kg recombinant murine granulocyte colony-stimulating factor (G-CSF) for 10 days yielded 11 × 10 7 to 13.6 × 10 7 WBC/ml (81 to 87% PMNs). Infected mice were given PMN transfusions intravenously. In 2 experiments with up to 70% mortality of neutropenic controls, transfusion of 10 7 PMNs 1 and 4 days after challenge had negligible effects on peripheral WBC counts but improved survival ( P = 0.007, 0.02), decreased lung CFU ( P = 0.03, 0.005), and cleared infection in 28 to 50% of survivors. Transfusion of 5 × 10 6 PMNs showed partial protection. Transfusions given every other day did not improve protection. Our present results provide an experimental basis for enthusiasm for PMN transfusions in the therapy of aspergillosis in humans.

Shoppers have many avenues on where to purchase products, one of which is online. Many online retailers do not apply state and local sales taxes on products they sell, thus allowing them to sell their products cheaper than can be found at local retailers. If the physical presence nexus rule is altered and Internet sales tax is applied for all online transactions, it could potentially change online shopping. The results of a survey of 154 persons are presented, discussing the potential impact of the changing of the physical presence nexus rule and requiring Internet sales tax.

For patients with breast cancer, a negative surgical margin at first breast-conserving surgery (BCS) minimizes the need for reoperation and likely reduces postoperative anxiety. We assessed technical factors, surgeon and hospital case volume and margin status after BCS in early-stage breast cancer.We performed a retrospective cohort study using a regional cancer centre database of patients who underwent BCS for breast cancer from 2000 to 2002. We considered the influence of patient, tumour and technical factors (e.g., size of specimen and preoperative diagnosis of cancer available) and surgeon and hospital case volume on margin status at first and final operation. We performed univariate and multivariate regression analyses.We reviewed 489 cases. There were no differences in patient or tumour characteristics among the low-, medium- and high-volume surgeon groups. High-volume surgeons were significantly more likely than other surgeons to operate with a confirmed preoperative diagnosis and to resect a larger volume of tissue. In our univariate analysis and at first operation, the rates of positive margins were 16.4%, 32.9% and 29.1% for high-, medium- and low-volume surgeons, respectively (p = 0.002). In the multivariate analysis, tumour factors (palpability, size, histology), presence of a confirmed preoperative diagnosis and size of resection specimen significantly predicted negative margins. However, when we controlled for these and other factors, high surgeon volume was not a predictor of negative margins at first surgery (odds ratio 1.8, 95% confidence interval 0.9-3.8, p = 0.09). Increased hospital volume was not associated with a lower rate of positive margins at first surgery.Various tumour and technical factors were associated with negative margins at first BCS, whereas surgeon and hospital volume status were not. Technical steps that are under the control of the operating surgeon are likely effective targets for quality initiatives in breast cancer surgery.

Background: Positron emission tomography (PET) is a noninvasive imaging modality that can detect malignant lymph nodes. This study determined the sensitivity, specificity, predictive values, and likelihood ratios of PET scanning compared with standard axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) in staging the axilla in women with early stage breast cancer. Methods: Women with clinical stage I or II breast cancer had whole body PET scanning before ALND and SLNB, in a prospective, blinded protocol. ALND were evaluated by standard hematoxylin and eosin (H&E) staining techniques, while sentinel nodes were also examined for micrometastatic disease. Results: A total of 98 patients were recruited. PET compared with ALND demonstrated sensitivity of 0.40 (95% CI, 0.16, 0.68), specificity 0.97 (CI, 0.90, 0.99), positive likelihood ratio 14.4 (CI, 3.21, 64.5), positive predictive value 0.75 (CI, 0.35, 0.97), and false–negative rate of 0.60 (CI, 0.32, 0.84). Test properties were similar for PET compared with sentinel nodes positive by H&E staining. A few false–positive scans (0.028, CI, 0.003, 0.097) were seen. Multiple logistic regression analysis found that PET accuracy was better in patients with high grade and larger tumors. Increased size and number of positive nodes were also associated with a positive PET scan. Conclusions: The sensitivity of PET compared with ALND and SLNB was low, whereas PET scanning had high specificity and positive predictive values. The study suggests that PET scanning cannot replace histologic staging in early stage breast cancer. The low rate of false–positive findings suggests that PET can identify women who can forego SLNB and require full axillary dissection.

Binary aqueous solutions of bovine serum albumin (BSA) and beta-lactoglobulin (bLG) were subject to flux-stepping and constant flux ultrafiltration to identify the apparent critical flux and to study the mechanisms and factors affecting fouling when the membrane is permeable to one protein component. Membranes from these filtration experiments were analyzed using matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) to locate and quantify levels of fouling below and above the apparent critical flux. Hydrophilic (PLTK) regenerated cellulose and hydrophobic (PBTK) polysulfone asymmetric membranes were used, both of 30 kDa nominal molecular weight cut-off. For the hydrophilic PLTK membrane, protein deposition was shown to depend on electrostatic forces, exhibiting little or no fouling when the proteins had the same charge sign as that of the membrane. This was found to apply for both dilute equal mass-per-unit-volume and equimolar binary mixtures. For the PBTK membrane, hydrophobic protein-membrane attractive forces were sufficiently strong to cause deposition of bLG even in the presence of repulsive electrostatic forces. For the PBTK membrane deposition exceeded monolayer coverage below and above apparent critical flux conditions but for the PLTK membrane this generally occurred when the apparent critical flux was exceeded. MALDI-MS was shown to be a facile direct analytical technique for individually quantifying adsorbed proteins on membrane surfaces at levels as low as 50 fmol/mm(2). The high levels of compound specificity inherent to mass spectrometry make this approach especially suited to the quantification of individual components in mixed deposits. In this study, MALDI-MS was found to be successful in identifying and quantifying the protein species responsible for fouling.

In developing a computer technique to classify clustered microcalcifications as malignant or benign, we previously indicated manually the location of all individual calcifications to the computer and found the computer to be more accurate than radiologists. In this study, we investigate whether radiologists can be asked to provide minimal input to the computer and obtain consistent computer classification results. Radiologists were instructed to draw a rectangle that enclosed all calcifications, and indicate the approximate number of the calcifications (either 30). The computer used these two pieces of information to detect the individual calcifications and, subsequently, to classify the calcifications as malignant or benign based on only those calcifications detected by the computer. We showed at the 2002 RSNA conference 18 cases together with standard and magnification view mammograms to 38 self-reported breast-imaging radiologists (12 of whom read all 18 cases). The standard deviation in the location of their rectangles (averaged over all cases) was approximately 3 mm, the standard deviation in the linear dimension of the rectangles was 6 mm, and the standard deviation in the computer-estimated likelihood of malignancy was 17%. These results indicate that radiologists are able to provide consistent input to the computer, which in turn produces reasonably consistent computer classification results.

We read with interest the paper by Wu et al. ([1][1]) purporting to show that blockade of P-glycoprotein with verapamil or itraconazole increased brain concentrations of amphotericin B (AMB). Because virtually all P-glycoprotein blockers also block other transporters, we chose to compare P