Integrated care van delivery of evidence-based services for people who inject drugs: A cluster-randomized trial.

BACKGROUND AND AIMS: People who inject drugs (PWID) are at risk for adverse outcomes across multiple dimensions. While evidence-based interventions are available, services are often fragmented and difficult to access. We measured the effectiveness of an integrated care van (ICV) that offered services for PWID. DESIGN, SETTING AND PARTICIPANTS: This was a cluster-randomized trial, which took place in Baltimore, MD, USA. Prior to randomization, we used a research van to recruit PWID cohorts from 12 Baltimore neighborhoods (sites), currently served by the city's mobile needle exchange program. INTERVENTION AND COMPARATOR: We randomized sites to receive weekly visits from the ICV (n = 6) or to usual services (n = 6) for 14 months. The ICV offered case management; buprenorphine/naloxone; screening for HIV, hepatitis C virus and sexually transmitted infections; HIV pre-exposure prophylaxis; and wound care. MEASUREMENTS: The primary outcome was a composite harm mitigation score that captured access to evidence-based services, risk behaviors and adverse health events (range = 0-15, with higher numbers indicating worse status). We evaluated effectiveness by comparing changes in the composite score at 7 months versus baseline in the two study arms. FINDINGS: We enrolled 720 cohort participants across the study sites (60 per site) between June 2018 and August 2019: 38.3% women, 72.6% black and 85.1% urine drug test positive for fentanyl. Over a median of 10.4 months, the ICV provided services to 734 unique clients (who may or may not have been cohort participants) across the six intervention sites, including HIV/hepatitis C virus testing in 577 (78.6%) and buprenorphine/naloxone initiation in 540 (74%). However, only 52 (7.2%) of cohort participants received services on the ICV. The average composite score decreased at 7 months relative to baseline, with no significant difference in the change between ICV and usual services (difference in differences: -0.31; 95% confidence interval: -0.70, 0.08; P = 0.13). CONCLUSIONS: This cluster-randomized trial in Baltimore, MD, USA, found no evidence that weekly neighborhood visits from a mobile health van providing injection-drug-focused services improved access to services and outcomes among people who injected drugs in the neighborhood, relative to usual services. The van successfully served large numbers of clients but unexpectedly low use of the van by cohort participants limited the ability to detect meaningful differences.

Embolic Phenomena of Libman-Sacks Endocarditis and Antiphospholipid Syndrome.

Patients with systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are at high risk of developing arterial or venous thromboembolism and a state of systemic hypercoagulability. Libman-Sacks endocarditis (LSE) is a type of non-bacterial endocarditis usually seen in patients with systemic lupus erythematosus and antiphospholipid antibody syndrome. These vegetations dislodge easily and can cause profound neurological and systemic complications in the form of emboli. We describe one such case of a young woman with known SLE who presented with an acute middle cerebral artery (MCA) stroke and was found to have APS with extensive mitral valve vegetation, indicating Libman-Sacks endocarditis on echocardiography. Recognizing the increasing frequency of both APS and LSE in patients with SLE and screening patients, especially the younger population with SLE, for APS is vital. Furthermore, in those patients presenting with embolic events, echocardiography plays a key role as it can help expedite the diagnosis of LSE. Our case report also reiterates that warfarin, when compared to direct oral anticoagulants (DOAC), is superior in decreasing future embolic events.

Listeria peritonitis in a patient on hemodialysis for end-stage renal disease secondary to lupus nephritis-a case report.

Key Clinical Message: Patients with a recent history of peritoneal dialysis catheter removal in the setting of immunosuppression should be monitored for rare Listeria bacterial peritonitis. This infection should be managed with ampicillin and gentamicin. Abstract: There are scattered reports to date of patients with peritonitis caused by Listeria monocytogenes. Listeria peritonitis is more commonly reported in patients with cirrhosis and those receiving peritoneal dialysis. We present a case of L. monocytogenes peritonitis in a patient with end-stage renal disease due to lupus nephritis actively on hemodialysis months after peritoneal dialysis catheter removal.

Hyperammonemic Encephalopathy Secondary to Urinary Tract Infection.

Hyperammonemic encephalopathy (HE) refers to a clinical condition characterized by abrupt alteration in mental status (AMS) with markedly elevated plasma ammonia levels and frequently results in intractable coma and death. While hepatic cirrhosis is by far the most common etiology for hyperammonemia together with drugs such as valproic acid as well as urea cycle disorders, non-hepatic causes of hyperammonemia are rare and pose a clinical challenge. In this report, we describe a case of HE caused by obstructive urinary tract infection due to urease-producing bacteria in a 69-year-old man with two episodes of obstructive uropathy associated with AMS resolving with treatment with antibiotics and lactulose with normalization of ammonia level. We also provide a review of the literature with emphasis on the recognition of this serious entity of HE in the setting of obstructive uropathy to avoid the possible complications that include intractable coma and high mortality from this potentially treatable disorder.

Comorbilidades infecciosas en la gravedad y mortalidad por Covid-19: análisis del aporte científico en The Lancet Publishing Group / Infectious comorbidities in severity and mortality from Covid-19: analysis of the scientific contribution in The Lancet Publishing Group

El número de casos totales de la enfermedad coronavirus-2019 (Covid-19) sigue aumentando rápidamente, amenazando a miles o millones de personas con condiciones crónicas preexistentes que se ven afectados de manera desproporcionada. Hasta el 2020, el centro de recursos de coronavirus de la Universidad Johns Hopkins informó que en todo el mundo más de 180 países han sido afectados con Covid-19 con más de doce millones de casos confirmados y más de 500,000 muertes. A medida que continúa la investigación relacionada con los posibles factores de riesgo de mortalidad por Covid-19, se hace evidente que las personas con comorbilidades subyacentes, como enfermedades cardiovasculares, hipertensión, diabetes, insuficiencia cardíaca congestiva, enfermedad cerebrovascular, enfermedad renal crónica, enfermedad hepática crónica, cáncer, enfermedad pulmonar obstructiva crónica, el asma y el VIH/SIDA pueden tener un mayor riesgo de muerte por Covid-19. El objetivo de este trabajo es determinar las comorbilidades infecciosas en la gravedad y mortalidad por Covid-19 especialmente asociadas con VIH/SIDA y tubercolosis, respodiendo a la siguiente pregunta: ¿La comunidad científica mundial se ha preocupado por la comorbilidad infecciosa en casos de covid-19 severos y fatales?. Un análisis hecho al grupo de referencias The Lancet Publishing Group fue realizado para dar repuesta a dicha pregunta(AU)

The number of total cases of coronavirus disease-2019 (COVID-19) continues to rise rapidly, threatening thousands or millions of people with pre-existing chronic conditions who are disproportionately affected. As of 2020, the Johns Hopkins University Coronavirus Resource Center reported that worldwide more than 180 countries have been affected with COVID-19 with more than twelve million confirmed cases and more than 500,000 deaths. As research related to potential risk factors for mortality from COVID-19 continues, it becomes clear that people with underlying comorbidities, such as cardiovascular disease, hypertension, diabetes, congestive heart failure, cerebrovascular disease, chronic kidney disease, chronic liver disease, cancer, chronic obstructive pulmonary disease, asthma, and HIV/AIDS may be at increased risk of death from COVID-19. The objective of this work is to determine the infectious comorbidities in severity and mortality from Covid-19, especially associated with HIV/AIDS and tuberculosis, answering the following question: Has the world scientific community been concerned about infectious comorbidity in covid-19 severe and fatal cases? An analysis made to the reference group The Lancet Publishing Group was carried out to answer this question(AU)

Pharmacologic Treatments in Upper Extremity Complex Regional Pain Syndrome: A Review and Analysis of Quality of Evidence.

BACKGROUND: The purpose of this study was to assess the quality of evidence informing on common pharmacologic modalities used in upper extremity complex regional pain syndrome (CRPS). METHODS: A literature search was performed for primary prospective trials that reported on the pharmacologic treatment of CRPS type I and II specific to the upper extremity. Thirty-one trials were included and evaluated by 2 independent reviewers according to the Oxford Levels of Evidence (LOE), modified Coleman Methodology Score, and the revised Consolidated Standards of Reporting Trials (CONSORT) score. Cohen's kappa coefficient was calculated to measure interrater reliability. RESULTS: Twenty-two Oxford LOE I and 9 level II trials met the inclusion criteria. Overall, there was high interrater reliability in the Oxford LOE (100% agreement), modified Coleman Methodology Score (87% agreement), and CONSORT score (94% agreement). The pharmacologic interventions with the highest quality of evidence supporting use in treatment of upper extremity CRPS were bisphosphonates and ketamine. Interventions that lack high-quality evidence are tricyclic antidepressants (TCAs) and topical dimethyl sulfoxide (DMSO). Pharmacologic agents that remain inconclusive are calcitonin, gabapentin, mycophenolate, probiotics, steroids, nonsteroidal anti-inflammatory drugs, vitamin C, and N-acetylcysteine. Agents with limited benefit are mannitol, isosorbide dinitrate, guanethidine, and morphine. CONCLUSIONS: Based on the evidence evaluated in this study, bisphosphonates should be considered as a first-line medication in the treatment of CRPS. In patients presenting with chronic or refractory CRPS, strong consideration should be given for the use of ketamine. Adjunct treatment in the acute setting should include TCAs and/or topical DMSO.

Mentefactos conceptuales como estrategia para el aprendizaje de Estadística Inferencial en estudiantes universitarios / Conceptual diagrams used with university students as a strategy for learning Inferential Statistics

Introducción: Los mentefactos conceptuales como estrategia para el aprendizaje de la estadística inferencial desarrollan procesos cognitivos mediante diagramas, lo que estructura los temas conceptuales sobre la base de las operaciones intelectuales. Objetivo: Determinar el efecto de los mentefactos conceptuales como estrategia didáctica para el aprendizaje de Estadística Inferencial por estudiantes del IV ciclo de carrera profesional de psicología en la Universidad Peruana Los Andes. Métodos: Se ejecutaron una investigación experimental y un diseño pre experimental longitudinal con pre- y pos prueba. La muestra fue de 16 estudiantes del IV ciclo de la carrera profesional de psicología, matriculados en la asignatura de Estadística Inferencial. Se experimentaron los temas población y muestra y estimación estadística. Se aplicó una prueba objetiva de 10 ítems medidos en escala de razón. Los datos se procesaron mediante la estadística descriptiva y las pruebas de hipótesis. Resultados: En relación con el tema población y muestra, se demostró la significancia de la diferencia de medias en pre-y pos = 4,7 mayor que = 2,04 y α = 0,05; en la segunda fase el tema fue estimación estadística, en el cual la diferencia de medias en pre- y pos- resultaron significativos porque = 8,6 mayor que = 2,04, al aceptar la hipótesis alternativa. Conclusiones: Los mentefactos conceptuales como estrategia de aprendizaje de la Estadística Inferencial generó expectativas en estudiantes, quienes lograron su aprendizaje significativamente. Se reconoció la necesidad de aplicar sistemáticamente y con continuidad el modelo, dado que se obtiene mejor nivel de aprehensión de los conocimientos estadísticos(AU)

Introduction: Conceptual diagrams as a strategy for learning inferential statistics develop cognitive processes, structuring conceptual topics on the basis of intellectual operations. Objective: To determine the effect of conceptual diagrams as a didactic strategy for the learning of inferential statistics by students from the fourth cycle of the professional major of Psychology at Los Andes Peruvian University. Methods: An experimental research was carried out, together with a longitudinal, preexperimental, pre-test/post-test design. The sample consisted of sixteen students from the fourth cycle of the professional major in Psychology, enrolled in the Inferential Statistics subject. The topics about population and sample, as well as statistical estimation, were tested. An objective test of ten items measured on a ratio scale was applied. The data were processed using descriptive statistics and hypothesis testing. Results: Regarding the population and sample item, the significance of the difference in means between pre-test and post-test was demonstrated, being t cal =4.7, a value higher than t crit =2.04, and α=0.05. In the second phase, the topic was statistical estimation, for which the difference in means between pre-test and post-test resulted to be significant, because t cal =8.6, a value higher than t crit =2.04, by accepting the alternative hypothesis. Conclusions: Conceptual diagrams as a strategy for learning inferential statistics created expectations among students, who achieved their learning significantly. The need to apply the model systematically and continuously was recognized, given that a better level of apprehension of statistical knowledge is obtained(AU)

Management of Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device: A Systematic Review and Meta-Analysis.

BACKGROUND: Intracranial hemorrhage (ICH) has been reported to occur in up to 23% of patients with left ventricular assist devices (LVADs). Currently, limited data exists to guide neurosurgical management strategies to optimize outcomes in patients with an LVAD who develop ICH. METHODS: A systematic review and meta-analysis of the literature was performed to evaluate the mortality rate in these patients following medical and/or surgical management and to evaluate antithrombotic reversal and resumption strategies after hemorrhage. RESULTS: 17 studies reporting on 3869 LVAD patients and 545 intracranial hemorrhages spanning investigative periods from 1996 to 2019 were included. The rate of ICH in LVAD patients was 10.6% (411/3869) with 58.6% (231/394) being intraparenchymal hemorrhage (IPH), 23.6% (93/394) subarachnoid hemorrhage (SAH), and 15.5% (61/394) subdural hemorrhage (SDH). Total mortality rates for surgical management 65.6% (40/61) differed from medical management at 45.2% (109/241). There was an increased relative risk of mortality (RR=1.45, 95% CI: 1.10-1.91, p = 0.01) for ICH patients undergoing surgical intervention. The hemorrhage subtype most frequently managed with anticoagulation reversal was IPH 81.8% (63/77), followed by SDH 52.2% (12/23), and SAH 39.1% (18/46). Mean number of days until antithrombotic resumption ranged from 6 to 10.5 days. CONCLUSION: Outcomes remain poor, specifically for those undergoing surgery. As experience with this population increases, prospective studies are warranted to contribute to management and prognostication .

Phase I/II study of bendamustine in combination with ofatumumab, carboplatin, etoposide (BOCE) for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

We developed an outpatient salvage chemotherapy regimen using bendamustine, ofatumumab, carboplatin and etoposide (BOCE) to treat relapsed/refractory non-Hodgkin lymphoma (RR NHL) in a single-center phase I/II study. Primary objectives were safety, tolerability and overall response rate (ORR). Thirty-five RR NHL patients (57% de novo large cell [DLBCL] or grade 3B follicular [FL], 26% transformed DLBCL, 9% grade 3A FL, 3% mantle cell; median age = 62, median prior therapies = 1) were treated. Median follow-up was 24.1 months. ORR was 69% (CR = 49%, PR = 20% [ORR = 70%, CR = 50%, PR = 20% in the de novo DLBCL/grade 3B FL subgroup]). Median progression-free survival was 5.1 months and overall-survival 26.2 months. Twelve patients subsequently underwent stem cell transplantation. The most common non-hematologic grade 3-4 toxicities were neutropenic fever and hypophosphatemia. There were no treatment-related deaths. In conclusion, BOCE is a safe and effective outpatient salvage regimen for patients with RR NHL and serves as an effective bridge to stem cell transplantation.

Markedly elevated hepatic arterial velocity-HAV greater than 200 cm/s-is not specific to hepatobiliary disease.

OBJECTIVE: The aim of the study was to review the different etiologies and outcomes of patients with hepatic artery velocities greater than 200 cm/s. METHODS: This retrospective study included 88 hospitalized patients in whom angle-corrected proper hepatic artery flow velocities greater than 200 cm/s were obtained during an abdominal ultrasonographic examination. Peak systolic hepatic artery flow velocities, hepatic artery resistance index, and portal vein flow velocities were evaluated. The patients were then allocated to one of four groups based on their primary underlying diagnosis: structural liver disease, nonstructural liver disease, generalized infection, or miscellaneous. RESULTS: The median hepatic artery velocity was similar for all groups, ranging from 226 to 238 cm/s. The maximum portal venous velocities were not significantly different between groups. No lab values were statistically different between the groups, except total bilirubin that was greater in the nonstructural liver disease group (8 mg/dL). Overall, 9/88 (10.2%) of patients with elevated hepatic artery velocity died within 30 days of their ultrasonographic examination. CONCLUSION: Elevated hepatic artery velocity greater than 200 cm/s in hospitalized patients is not specific to primary hepatobiliary disease but may indicate acute hepatic dysfunction from other causes such as infection or sepsis.

Telomerase-Mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance.

Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities.

Three-dimensional image analysis for staging chronic rhinosinusitis.

BACKGROUND: Traditional methods of staging chronic rhinosinusitis (CRS) through imaging do not differentiate between degrees of partial mucosal sinus inflammation, thus limiting their utility as imaging biomarkers. We hypothesized that software-aided, quantitative measurement of sinus inflammation would generate a metric of disease burden that would correlate with clinical parameters in patients with suspected sinus disease. METHODS: Adults with rhinologic complaints undergoing computed tomography imaging were recruited at an urban, academic, tertiary care center (n = 45 with Lund-Mackay [LM] scores ≥4). Three-dimensional (3D) volumetric image analysis was performed using a semiautomated method to obtain a "Chicago-modified Lund-Mackay" (Chicago MLM) score, which provides a continuous scale to quantify extent of opacification. Linear regression was used to test the association of the Chicago MLM score with concurrent symptoms (Total Nasal Symptom Score [TNSS]) and disease-specific quality of life, based on the Sinonasal Outcome Test-22 (SNOT-22). RESULTS: Chicago MLM scores were significantly associated with both symptoms (p = 0.037) and disease-specific quality of life (p = 0.007). Inflammation in the ethmoid and sphenoid sinuses appeared to influence these associations. These findings were even more robust when analysis was limited to patients with more severe disease (LM >6). CONCLUSION: The quantitative measurement of sinus inflammation by computer-aided 3D analysis correlates modestly with both symptoms and disease-specific quality of life. Posterior sinuses appear to have the greatest impact on these findings, potentially providing an anatomic target for clinicians to base therapy. The Chicago MLM score is a promising imaging biomarker for clinical and research use.

Ecosystem carbon density and allocation across a chronosequence of longleaf pine forests.

Forests can partially offset greenhouse gas emissions and contribute to climate change mitigation, mainly through increases in live biomass. We quantified carbon (C) density in 20 managed longleaf pine (Pinus palustris Mill.) forests ranging in age from 5 to 118 years located across the southeastern United States and estimated above- and belowground C trajectories. Ecosystem C stock (all pools including soil C) and aboveground live tree C increased nonlinearly with stand age and the modeled asymptotic maxima were 168 Mg C/ha and 80 Mg C/ha, respectively. Accumulation of ecosystem C with stand age was driven mainly by increases in aboveground live tree C, which ranged from <1 Mg C/ha to 74 Mg C/ha and comprised <1% to 39% of ecosystem C. Live root C (sum of below-stump C, ground penetrating radar measurement of lateral root C, and live fine root C) increased with stand age and represented 4-22% of ecosystem C. Soil C was related to site index, but not to stand age, and made up 39-92% of ecosystem C. Live understory C, forest floor C, downed dead wood C, and standing dead wood C were small fractions of ecosystem C in these frequently burned stands. Stand age and site index accounted for 76% of the variation in ecosystem C among stands. The mean root-to-shoot ratio calculated as the average across all stands (excluding the grass-stage stand) was 0.54 (standard deviation of 0.19) and higher than reports for other conifers. Long-term accumulation of live tree C, combined with the larger role of belowground accumulation of lateral root C than in other forest types, indicates a role of longleaf pine forests in providing disturbance-resistant C storage that can balance the more rapid C accumulation and C removal associated with more intensively managed forests. Although other managed southern pine systems sequester more C over the short-term, we suggest that longleaf pine forests can play a meaningful role in regional forest C management.

Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.

Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a 'persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit--and may even provide a latent reservoir of cells for--the emergence of heterogeneous drug-resistance mechanisms.

Computer-assisted staging of chronic rhinosinusitis correlates with symptoms.

BACKGROUND: The Lund-Mackay (LM) staging system for chronic rhinosinusitis (CRS) does not correlate with clinical parameters, likely due to its coarse scale. We developed a "Modified Lund Mackay" (MLM) system, which uses a three-dimensional (3D), computerized method to quantify the volume of mucosal inflammation in the sinuses, and sought to determine whether the MLM would correlate with symptoms and disease-specific quality of life. METHODS: We obtained Total Nasal Symptom Score (TNSS) and 22-item Sino-Nasal Outcome Test (SNOT-22) data from 55 adult subjects immediately prior to sinus imaging. The volume of each sinus occupied by mucosal inflammation was measured using MATLAB algorithms created using customized, image analysis software after manual outlining of each sinus. Linear regression was used to model the relationship between the MLM and the SNOT-22 and TNSS. Correlation between the LM and MLM was tested using Spearman's rank correlation coefficient. RESULTS: Adjusting for age, gender, and smoking, a higher symptom burden was associated with increased sinonasal inflammation as captured by the MLM (ß = 0.453, p < 0.013). As expected due to the differences in scales, the LM and MLM scores were significantly different (p < 0.011). No association between MLM and SNOT-22 scores was found. CONCLUSION: The MLM is one of the first imaging-based scoring systems that correlates with sinonasal symptoms. Further development of this custom software, including full automation and validation in larger samples, may yield a biomarker with great utility for both treatment of patients and outcomes assessment in clinical trials.

Nuclear expression of ß-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells.

Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of ß-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of ß-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated ß-catenin. However, we found that HCT116 cells, which contain an activated allele of ß-catenin but do not express nuclear ß-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast, TNF did not induce RB cleavage in colon cancer cells expressing nuclear ß-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of ß-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of ß-catenin led to a reduction in the RB protein without affecting RB mRNA. Furthermore, ectopic expression of the caspase-resistant, but not the wild-type, RB re-established resistance to TNF-induced caspase activation in colon cancer cells without ß-catenin. Together, these results suggest that nuclear ß-catenin-dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8-positive colon cancer cells.

ß-Catenin-dependent lysosomal targeting of internalized tumor necrosis factor-α suppresses caspase-8 activation in apoptosis-resistant colon cancer cells.

The Wnt/ß-catenin pathway is constitutively activated in more than 90% of human colorectal cancer. Activated ß-catenin stimulates cell proliferation and survival, however, its antiapoptotic mechanisms are not fully understood. We show here that activated ß-catenin is required to suppress caspase-8 activation, but only in colon cancer cells that are resistant to tumor necrosis factor-α (TNF)-induced apoptosis. We found that lysosomal delivery of internalized TNF occurred at a faster pace in apoptosis-resistant than in apoptosis-sensitive colon cancer cells. Retardation of endosomal trafficking through vacuolar ATPase (V-ATPase) inhibition enhanced caspase-8 activation in apoptosis-resistant but not apoptosis-sensitive cells. Interestingly, knockdown of ß-catenin also prolonged TNF association with the early endosome and enhanced caspase-8 activation in apoptosis-resistant but not apoptosis-sensitive colon cancer cells. In a mouse model of inflammation-associated colon tumors, we found nuclear expression of ß-catenin, resistance to TNF-induced apoptosis, and reactivation of apoptosis in vivo after cotreatment of TNF with a V-ATPase inhibitor. Together these results suggest that activated ß-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer cells.

Sani-cloth wipe mimics rare enzyme deficiency malonic aciduria on newborn screen.

Within a 7-month period at our institution, newborn screening by tandem mass spectrometry revealed 10 cases with elevated levels of malonylcarnitine, which suggested malonic aciduria. Malonic aciduria is a rare autosomal recessive inborn error of metabolism. Confirmatory testing yielded normal results in all the newborns involved. The application of quality improvement practices dictated investigating the dried blood spot collection process, which revealed the use of multiple blood-collection techniques by newborn nursery staff, improper handling of the dried blood spot specimens, and sanitary wipe contamination as the causes of the aberrant false-positive results at our institution. This systematic evaluation identified the cause of the aberrant false-positive results and a strategy was implemented to avoid aberrant results in the future. Thus far, no false-positive results have occurred since the investigative process. False-positive results on a newborn screen can cause unnecessary emotional and economic stress on families, a finding that was identified at our institution. Historically, false-positive newborn screening results have been identified in infants born by cesarean delivery in which iodine antiseptic was used and in newborns who receive total parenteral nutrition, such as premature infants in the NICU. Therefore, if an unusually high number of false-positive results are found during the newborn screening process, contamination should be considered as a contributing factor.

Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice.

The taxane chemotherapeutic paclitaxel frequently produces peripheral neuropathy in humans. Rodent models to investigate mechanisms and treatments are largely restricted to male rats, whereas female mouse studies are lacking. We characterized a range of paclitaxel doses on cold and mechanical allodynia in male and female C57Bl/6 mice. Because the nonpsychoactive phytocannabinoid cannabidiol attenuates other forms of neuropathic pain, we assessed its effect on paclitaxel-induced allodynia. Paclitaxel produced allodynia that was largely dose independent and more robust in female mice, and this effect was prevented by treatment with cannabidiol. Our preliminary findings therefore indicate that cannabidiol may prevent the development of paclitaxel-induced allodynia in mice and therefore be effective at preventing dose-limiting paclitaxel-induced peripheral neuropathy in humans.

Stability and Morphology of Gold Nanoisland Arrays Generated from Layer-by-Layer Assembled Nanoparticle Multilayer Films: Effects of Heating Temperature and Particle Size.

This article reports the effects of heating temperature and composition of nanoparticle multilayer films on the morphology, stability, and optical property of gold nanoisland films prepared by nanoparticle self-assembly/heating method. First, nanoparticle-polymer multilayer films are prepared by the layer-by-layer assembly. Nanoparticle multilayer films are then heated at temperature ranging from 500 °C to 625 °C in air to induce an evaporation of organic matters from the films. During the heating process, the nanoparticles on the solid surface undergo coalescence, resulting in the formation of nanostructured gold island arrays. Characterization of nanoisland films using atomic force microscopy and UV-vis spectroscopy suggests that the morphology and stability of gold island films change when different heating temperatures are applied. Stable gold nanoisland thin film arrays can only be obtained after heat treatments at or above 575 °C. In addition, the results show that the use of nanoparticles with different sizes produces nanoisland films with different morphologies. Multilayer films containing smaller gold nanoparticles tend to produce more monodisperse and smaller island nanostructures. Other variables such as capping ligands around nanoparticles and molecular weight of polymer linkers are found to have only minimal effects on the structure of island films. The adsorption of streptavidin on the biotin-functionalized nanoisland films is studied for examining the biosensing capability of nanoisland arrays.