Low Rates of Colorectal Cancer Screening in First-Degree Relatives of Our Patients: Are We Failing Them?

BACKGROUND: Guidelines recommend screening those with a family history of early-onset colorectal cancer at age 40 years or 10 years before the age of their relative's diagnosis. Currently, there is no literature reporting the screening rate in these individuals, and no protocols are in place to identify and target this population for screening awareness. OBJECTIVE: This study aimed to assess adherence to current screening guidelines among first-degree relatives of patients with early-onset colorectal cancer. DESIGN: Retrospective and qualitative study involving a telephone survey where patients were asked about relative's screening status and barriers to screening. SETTINGS: Two community-based institutions between January 2018 and December 2021. PATIENTS: Individuals diagnosed with early-onset colorectal cancer who had undergone surgery at our institutions. MAIN OUTCOME MEASURES: Rate of screening in first-degree relatives of our patients with early-onset colorectal cancer. Other factors measured included demographics, clinicopathologic characteristics, and screening barriers. RESULTS: Thirty-six patients were identified. The survey response rate was 66.6% (n = 24). A total of 88 first-degree relatives who met the screening criteria resulted in 67.1% of patients (n = 59) having a known screening status. Of the 59 patients with known screening status, only 44% (n = 26) had undergone screening. Patients of Black race, having stage III/IV disease, having Medicare/Medicaid insurance, and living within Baltimore City County were more likely to have family members with unknown or no screening. Lack of insurance coverage was the most common barrier, which was noted in 12.5% of patients (n = 3), whereas 54.1% of patients (n = 13) reported no barriers to screening. LIMITATIONS: Retrospective design. CONCLUSIONS: Most first-degree relatives of patients diagnosed with early-onset colorectal cancer do not undergo colorectal cancer screening. This could be attributed to the lack of protocols that could guarantee these individuals are informed of their elevated risk and the different options available for screening. Furthermore, our study suggests that racial and socioeconomic disparities exist among high-risk patients who should pursue screening. See Video Abstract . BAJAS TASAS DE DETECCIN DEL CNCER COLORRECTAL EN LOS FAMILIARES DE PRIMER GRADO DE NUESTROS PACIENTES LES ESTAMOS FALLANDO: ANTECEDENTES:Las directrices recomiendan realizar pruebas de detección a las personas con antecedentes familiares de cáncer colorrectal de aparición temprana a los 40 años o 10 años antes de la edad del diagnóstico de su familiar. Actualmente, no hay literatura que informe la tasa de detección en estos individuos y no existen protocolos para identificar y dirigirse a esta población para concientizar sobre la detección.OBJETIVO:Evaluar el cumplimiento de las pautas de detección actuales entre los FDR de pacientes con cáncer colorrectal de aparición temprana.DISEÑO:Estudio retrospectivo y cualitativo que incluyó una encuesta telefónica en la que se preguntó a los pacientes sobre el estado de detección de sus familiares y las barreras para la detección.AJUSTES:Dos instituciones comunitarias entre enero de 2018 y diciembre de 2021.PACIENTES:Personas diagnosticadas con cáncer colorrectal de inicio temprano que habían sido intervenidas quirúrgicamente en nuestras instituciones.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de detección en familiares de primer grado de nuestros pacientes con cáncer colorrectal de aparición temprana. Otros factores medidos incluyeron datos demográficos, características clínico-patológicas y barreras de detección.RESULTADOS:Se identificaron treinta y seis pacientes. La tasa de respuesta a la encuesta fue del 66,6% (n = 24). Resultaron un total de 88 familiares de primer grado que cumplieron con los criterios para la detección, y el 67,1% (n = 59) tenía un estado de detección conocido. De los 59 con estado de detección conocido, se informó que solo el 44% (n = 26) se había sometido a pruebas de detección. Los pacientes de raza afroamericana, enfermedad en etapa III/IV, Medicare/Medicaid y que vivían dentro del condado de la ciudad de Baltimore tenían más probabilidades de tener familiares con pruebas de detección desconocidas o sin ellas. La falta de cobertura de seguro fue la barrera más común observada por el 12,5% (n = 3); mientras que el 54,1% (n = 13) no informó ninguna barrera para el cribado.LIMITACIONES:Diseño retrospectivo.CONCLUSIONES:La mayoría de los familiares de primer grado de pacientes diagnosticados con cáncer colorrectal de aparición temprana no se someten a pruebas de detección de cáncer colorrectal. Esto podría atribuirse a la falta de protocolos que garanticen que estas personas estén informadas sobre su elevado riesgo y las diferentes opciones disponibles para el cribado. Además, nuestro estudio sugiere que existen disparidades raciales y socioeconómicas entre los pacientes de alto riesgo que deberían someterse a pruebas de detección. (Traducción-Dr. Francisco M. Abarca-Rendon).

Toxicological Effects of Inhaled Crude Oil Vapor.

PURPOSE OF REVIEW: The purpose of this review is to assess the toxicological consequences of crude oil vapor (COV) exposure in the workplace through evaluation of the most current epidemiologic and laboratory-based studies in the literature. RECENT FINDINGS: Crude oil is a naturally occuring mixture of hydrocarbon deposits, inorganic and organic chemical compounds. Workers engaged in upstream processes of oil extraction are exposed to a number of risks and hazards, including getting crude oil on their skin or inhaling crude oil vapor. There have been several reports of workers who died as a result of inhalation of high levels of COV released upon opening thief hatches atop oil storage tanks. Although many investigations into the toxicity of specific hydrocarbons following inhalation during downstream oil processing have been conducted, there is a paucity of information on the potential toxicity of COV exposure itself. This review assesses current knowledge of the toxicological consequences of exposures to COV in the workplace.

Clinical, economic, and health-related quality of life outcomes in patients with overweight or obesity in the United States: 2016-2018.

Objectives: This study aimed to estimate clinical, economic (including productivity), and health-related quality of life (HRQoL) outcomes and associated individual characteristics among adults with overweight (OW) or obesity in the United States. Methods: This study included adult respondents with body mass index (BMI) ≥18.5 kg/m2 in the 2017-2018 National Health and Nutrition Examination Survey (NHANES) and 2016 Medical Expenditure Panel Survey. Respondents were classified according to BMI. Individual characteristics were described by BMI categories. Multivariable regression models estimated the association between BMI categories and outcomes, adjusting for individual characteristics. Results: Nearly three-quarters (73.7%) of NHANES participants were OW or obese. Relative to Normal weight (NW), respondents with Class 3 obesity had more obesity-related complications (2.07 vs. 4.62, p < 0.001). Higher BMI was associated with significantly lower HRQoL, lower productivity, and higher healthcare expenditures as well as more frequent weight loss attempts in the previous 12 months. Weight loss surgery and prescription anti-obesity medications (AOMs) were used only by a very small proportion of individuals. Despite frequent weight loss attempts, most respondents did not achieve clinically meaningful weight loss. Conclusions: Adults with OW or obesity experienced worse clinical, economic and HRQoL outcomes than those with NW. Better use of evidence-based obesity treatments, including prescription AOMs, should be considered to achieve more clinically meaningful weight reduction and improved outcomes in individuals with OW or obesity.

EXIST: EXamining rIsk of excesS adiposiTy-Machine learning to predict obesity-related complications.

Background: Obesity is associated with an increased risk of multiple conditions, ranging from heart disease to cancer. However, there are few predictive models for these outcomes that have been developed specifically for people with overweight/obesity. Objective: To develop predictive models for obesity-related complications in patients with overweight and obesity. Methods: Electronic health record data of adults with body mass index 25-80 kg/m2 treated in primary care practices between 2000 and 2019 were utilized to develop and evaluate predictive models for nine long-term clinical outcomes using a) Lasso-Cox models and b) a machine-learning method random survival forests (RSF). Models were trained on a training dataset and evaluated on a test dataset over 100 replicates. Parsimonious models of <10 variables were also developed using Lasso-Cox. Results: Over a median follow-up of 5.6 years, study outcome incidence in the cohort of 433,272 patients ranged from 1.8% for knee replacement to 11.7% for atherosclerotic cardiovascular disease. Harrell C-index averaged over replicates ranged from 0.702 for liver outcomes to 0.896 for death for RSF, and from 0.694 for liver outcomes to 0.891 for death for Lasso-Cox. The Harrell C-index for parsimonious models ranged from 0.675 for liver outcomes to 0.850 for knee replacement. Conclusions: Predictive modeling can identify patients at high risk of obesity-related complications. Interpretable Cox models achieve results close to those of machine learning methods and could be helpful for population health management and clinical treatment decisions.

Weight management treatment modalities in patients with overweight or obesity: A retrospective cohort study of administrative claims data.

Background: The purpose of this study was to describe demographic and clinical characteristics among patients who have medical encounters for weight management treatments and to investigate the association of those characteristics with treatment modality. Methods: This was a retrospective database study using medical claims, pharmacy claims, and enrollment information from commercial and Medicare Advantage with Part D members in the Optum Research Database from 01/01/2011-2/29/2020. Adult patients with a claim for a weight management treatment from 01/01/2012-2/28/2019 were categorized into cohorts according to the highest intensity intervention received. To examine the association between patient characteristics and treatment modality received, a multinomial logit model was performed. Results: Cohorts by increasing intensity included lifestyle intervention (LSI, n = 67,679), weight reduction pharmacotherapy (WRRx) with an anti-obesity medication (AOM, n = 6,905), weight reduction procedure (WRP, n = 1,172), and weight reduction surgery (WRS, n = 18,036). Approximately 32.1% and 16.6% of patients who received WRS or WRP had an LSI during the 12-month baseline, and only 0.6% and 0.4% had treatment with long-term AOMs. In a multinomial logit model, patients with type 2 diabetes (not including WRRx cohort), respiratory disorders, cardiovascular risk factors, pain disorders, and mental health conditions had increased odds of treatment with higher intensity intervention versus LSI. Patients who were male, received an intervention more recently (2016-2019), or had a Charlson comorbidity score of 1 (compared to 0) had decreased odds of treatment with higher intensity interventions. Conclusion: In this study, age, sex, body mass index, obesity-related complications, and Charlson comorbidity score appeared to influence the type of weight management treatment modality received. This study improves understanding of weight management treatment utilization and identifies gaps and opportunities to improve obesity care with the appropriate use of different treatment modalities.

Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison.

AIM: To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison. MATERIALS AND METHODS: Using SURMOUNT-1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points. RESULTS: Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: -4.67% [95% CI -5.91%, -3.43%]; tirzepatide 15 mg mean difference: -5.92% [95% CI -7.16%, -4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074). CONCLUSIONS: Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching-adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.

Bilateral common carotid artery mycotic aneurysms in the setting of intravenous drug abuse.

Carotid mycotic aneurysms are rare, and fewer than five case reports have described carotid mycotic aneurysms due to intravenous drug abuse. Rare bilateral intracranial mycotic carotid aneurysms have been reported, although a review of literature revealed no cases of bilateral extracranial carotid aneurysms. We have reported the case of a 41-year-old man who had presented with intermittent fevers, headaches, and myalgias of 2 weeks' duration. He was found to have bilateral carotid artery mycotic aneurysms after intravenous drug abuse with neck injections. We used a management strategy entailing unilateral endovascular balloon control with open surgical resection followed by placement of a saphenous vein graft. The contralateral aneurysm was managed nonoperatively with antibiotics.

Biological effects of crude oil vapor. IV. Cardiovascular effects.

Workers in the oil and gas extraction industry are at risk of inhaling volatile organic compounds. Epidemiological studies suggest oil vapor inhalation may affect cardiovascular health. Thus, in this hazard identification study we investigated the effects of inhalation of crude oil vapor (COV) on cardiovascular function. Male rats were exposed to air or COV (300 ppm) for 6 h (acute), or 6 h/day × 4 d/wk. × 4 wk. (sub-chronic). The effects of COV inhalation were assessed 1, 28, and 90 d post-exposure. Acute exposure to COV resulted in reductions in mean arterial and diastolic blood pressures 1 and 28 d after exposure, changes in nitrate-nitrite and H2O2 levels, and in the expression of transcripts and proteins that regulate inflammation, vascular remodeling, and the synthesis of nitric oxide (NO) in the heart and kidneys. The sub-chronic exposure resulted in a reduced sensitivity to α1-adrenoreceptor-mediated vasoconstriction in vitro 28 d post-exposure, and a reduction in oxidative stress in the heart. Sub-chronic COV exposure led to alterations in the expression of NO synthases and anti-oxidant enzymes, which regulate inflammation and oxidative stress in the heart and kidneys. There seems to be a balance between changes in the expression of transcripts associated with the generation of reactive oxygen species (ROS) and antioxidant enzymes. The ability of antioxidant enzymes to reduce or inhibit the effects of ROS may allow the cardiovascular system to adapt to acute COV exposures. However, sub-chronic exposures may result in longer-lasting negative health consequences on the cardiovascular system.

Previously unrecognized risk factors for severe hypoglycaemia requiring emergency medical care in insulin-treated type 2 diabetes: Results from a real-world nested case-control study.

AIM: Several risk factors for severe hypoglycaemia (SH) are associated with insulin-treated diabetes. This study explored potential risk factors in adults with insulin-treated type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this case-control study, adults with T2DM initiating insulin were identified in the IQVIA PharMetrics® Plus database. The index date was the date of the first SH event (cases). Using incidence-density sampling, controls were selected from those who had been exposed 'at risk' of SH for the same amount of time as each case. After exact-matching on the well-established factors, previously unreported risk factors were evaluated through conditional logistic regression. RESULTS: In 3153 case-control pairs, pregnancy [odds ratios (OR) = 3.20, p = .0003], alcohol abuse (OR = 2.43, p < .0001), short-/rapid-acting insulin (OR = 2.22/1.47, p < .0001), cancer (OR = 1.87, p < .0001), dementia/Alzheimer's disease (OR = 1.73, p = .0175), peripheral vascular disease (OR = 1.59, p < .0001), antipsychotics (OR = 1.59; p = .0059), anxiolytics (OR = 1.51, p = .0012), paralysis/hemiplegia/paraplegia (OR = 1.51, p = .0416), hepatitis (OR = 1.50, p = .0303), congestive heart failure (OR = 1.47, p = .0002), adrenergic-corticosteroid combinations (OR = 1.45, p = .0165), ß-adrenoceptor agonists (OR = 1.40, p = .0225), opioids (OR = 1.38, p < .0001), corticosteroids (OR = 1.35, p = .0159), cardiac arrhythmia (OR = 1.29. p = .0065), smoking (OR = 1.28, p = .005), Charlson Comorbidity Index score 2 (OR = 1.28, p = .0026), 3 (OR = 1.41, p = .0016) or ≥4 (OR = 1.57, p = .0002), liver/gallbladder/pancreatic disease (OR = 1.26, p = .0182) and hypertension (OR = 1.19, p = .0164) were independently associated with SH. CONCLUSIONS: Although all people with insulin-treated diabetes are at risk of SH, these results have identified some previously unrecognized risk factors and sub-groups of insulin-treated adults with T2DM at greater risk. Scrutiny of current therapies and comorbidities are advised as well as additional glucose monitoring and education, when identifying and managing SH in vulnerable populations.

Caffeine intake from coffee and tea and invasive breast cancer incidence among postmenopausal women in the Women's Health Initiative.

Research findings remain inconsistent whether caffeine consumption is associated with invasive breast cancer. We aimed to examine the association between caffeine intake from coffee and tea and incident invasive breast cancer among postmenopausal women. We included 79 871 participants in the Women's Health Initiative Observational Study in the current analysis. Incident invasive breast cancers were identified through September 30, 2015. Caffeine intake (mg/day) from caffeinated and decaffeinated coffee and tea was estimated based on self-reported frequency (cups/day) and average caffeine amount in each beverage. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses were conducted to explore whether associations of caffeine intake from coffee and tea with invasive breast cancer were different by age, race and ethnicity, smoking status, body mass index, history of hormone therapy use, alcohol intake and subtypes of breast cancer. During a median follow-up of 16.0 years, 4719 incident invasive breast cancers were identified. No significant association was found between caffeine intake from coffee and tea and invasive breast cancer incidence after adjusting for demographic, lifestyle and reproductive factors: HRs (95% CIs) for increasing quartiles of caffeine intake compared to the lowest were 1.03 (0.94, 1.12), 1.04 (0.95, 1.13) and 1.03 (0.94, 1.13), respectively (P-for-trend = .54). No significant associations of coffee and tea intake (cups/day) with overall breast cancer risk were found. Our findings are consistent with others showing no clear association of caffeine consumption with invasive breast cancer among postmenopausal women.

Antioxidant Activity Evaluation of Oviductus Ranae Protein Hydrolyzed by Different Proteases.

As nutrition and a health tonic for both medicine and food, the protein content of Oviductus Ranae is more than 40%, making it an ideal source to produce antioxidant peptides. This work evaluated the effects of six different proteases (pepsin, trypsin, papain, flavourzyme, neutral protease and alcalase) on the antioxidant activity of Oviductus Ranae protein, and analyzed the relationship between the hydrolysis time, the degree of hydrolysis (DH) and the antioxidant activity of the enzymatic hydrolysates. The results showed that the antioxidant activity of Oviductus Ranae protein was significantly improved and the optimal hydrolysis time was maintained between 3-4 h under the action of different proteases. Among them, the protein hydrolysate which was hydrolyzed by pepsin for 180 min had the strongest comprehensive antioxidant activity and was most suitable for the production of antioxidant peptides. At this time, the DH, the DPPH radical scavenging activity, the absorbance value of reducing power determination and the hydroxyl radical scavenging activity corresponding to the enzymatic hydrolysate were 13.32 ± 0.24%, 70.63 ± 1.53%, 0.376 ± 0.009 and 31.96 ± 0.78%, respectively. Correlation analysis showed that there was a significant positive correlation between the hydrolysis time, the DH and the antioxidant activity of the enzymatic hydrolysates, further indicating that the hydrolysates of Oviductus Ranae protein had great antioxidant potential. The traditional anti-aging efficacy of Oviductus Ranae is closely related to the scavenging of reactive oxygen species, and its hydrolysates have better antioxidant capacity, which also provides support for further development of its traditional anti-aging efficacy.

The Prognostic Value of Deficient Mismatch Repair in Stage II-IVa Nasopharyngeal Carcinoma in the Era of IMRT.

In the era of intensity-modulated radiotherapy (IMRT), it is important to analyse the prognostic value of deficient mismatch repair (dMMR) in nasopharyngeal carcinoma (NPC). In this study, in pretreatment biopsies of 69 patients with stage II-IVa NPC, the expression levels of MMR proteins, including MLH1, MSH2, MSH6 and PMS2, were assessed by immunohistochemistry (IHC). The median follow-up time was 37.5 months (3.1-87.4 months). 50.7% of cases (35/69) showed preserved expression of all 4 MMR proteins, which was interpreted as proficient mismatch repair (pMMR). Only 1.5% of cases (1/69) lost expression of all 4 MMR proteins, 26.1% of cases (18/69) have PMS2 loss alone and 21.7% of cases (15/69) lost expression of both PMS2 and MLH1. Thus, 49.3% of cases (34/69) lost expression of one or more MMR proteins, which was interpreted as dMMR. There was no significant difference (P > 0.05) in terms of sex, age, clinical stage, T category, N category or therapy regimens between the dMMR and pMMR groups. The multivariate Cox regression analysis revealed that dMMR was an independent significant prognostic factor for distant metastasis-free survival (DMFS) (dMMR vs pMMR: P = 0.01, HR = 0.25, 95% CI: 0.09~0.75). Therefore, NPC patients with dMMR had significantly superior DMFS compared with patients with pMMR. It can be expected that dMMR will become a new independent prognostic factor for NPC.

Magnetic resonance imaging-navigated argon-helium cryoablation therapy against a rabbit VX2 brain tumor.

The aim of the present study was to investigate the feasibility of interventional magnetic resonance imaging (MRI)-guided and monitored argon-helium cryoablation for the treatment of brain tumors in rabbits. In addition, the present study evaluated the associations between imaging and pathology, the therapeutic effects and the effects on the surrounding normal tissues. A total of 14 rabbits were equally divided into groups C and D. Under general anesthesia, the skull was drilled and tumor blocks were implanted. Subsequently, a New Zealand rabbit VX2 brain tumor model was successfully established. Rabbits in group C were treated with argon-helium cryoablation and those in group D did not undergo any treatment (control). Regular postoperative MRI scanning was performed to observe the changes in tumor size, and the survival times of the rabbits in groups C and D were recorded. The extent of necrosis in the brain tumor exhibited a significant correlation with the freezing time of cryoablation, and the necrotic region was shown to be the same size as the ice ball. The survival times of the rabbits in the treatment group (group C) were significantly prolonged. Therefore, the observations of the present study demonstrated that the VX2 brain tumor model, produced using an improved tumor block implantation method, was stable and suitable for MRI observation and interventional study. In addition, argon-helium cryoablation was shown to be a safe and feasible therapeutic method for the treatment of brain tumors, and was demonstrated to significantly increase the survival times of the brain tumor-bearing rabbits.

Alterations in cardiomyocyte function after pulmonary treatment with stainless steel welding fume in rats.

Welding fume is composed of a complex of different metal particulates. Pulmonary exposure to different welding fumes may exert a negative impact on cardiac function, although the underlying mechanisms remain unclear. To explore the effect of welding fumes on cardiac function, Sprague-Dawley rats were exposed by intratracheal instillation to 2 mg/rat of manual metal arc hard surfacing welding fume (MMA-HS) once per week for 7 wk. Control rats received saline. Cardiomyocytes were isolated enzymatically at d 1 and 7 postexposure. Intracellular calcium ([Ca(2+)]i) transients (fluorescence ratio) were measured on the stage of an inverted phase-contrast microscope using a myocyte calcium imaging/cell length system. Phosphorylation levels of cardiac troponin I (cTnI) were determined by Western blot. The levels of nonspecific inflammatory marker C-reactive protein (CRP) and proinflammatory cytokine interleukin-6 (IL-6) in serum were measured by enzyme-linked immunosorbent assay (ELISA). Contraction of isolated cardiomyocytes was significantly reduced at d 1 and d 7 postexposure. Intracellular calcium levels were decreased in response to extracellular calcium stimulation at d 7 postexposure. Changes of intracellular calcium levels after isoprenaline hydrochloride (ISO) stimulation were not markedly different between groups at either time point. Phosphorylation levels of cTnI in the left ventricle were significantly lower at d 1 postexposure. The serum levels of CRP were not markedly different between groups at either time point. Serum levels of IL-6 were not detectable in both groups. Cardiomyocyte alterations observed after welding fume treatment were mainly due to alterations in intracellular calcium handling and phosphorylation levels of cTnI.

Evaluation of Pulmonary and Systemic Toxicity of Oil Dispersant (COREXIT EC9500A(®)) Following Acute Repeated Inhalation Exposure.

INTRODUCTION: Oil spill cleanup workers come into contact with numerous potentially hazardous chemicals derived from the oil spills, as well as chemicals applied for mitigation of the spill, including oil dispersants. In response to the Deepwater Horizon Macondo well oil spill in the Gulf of Mexico in 2010, a record volume of the oil dispersant, COREXIT EC9500A, was delivered via aerial applications, raising concern regarding potential health effects that may result from pulmonary exposure to the dispersant. METHODS: The current study examined the effects on pulmonary functions, cardiovascular functions, and systemic immune responses in rats to acute repeated inhalation exposure of COREXIT EC9500A at 25 mg/m(3), five hours per day, over nine work days, or filtered air (control). At one and seven days following the last exposure, a battery of parameters was measured to evaluate lung function, injury, and inflammation; cardiovascular function; peripheral vascular responses; and systemic immune responses. RESULTS: No significant alterations in airway reactivity were observed at one or seven days after exposure either in baseline values or following methacholine (MCh) inhalation challenge. Although there was a trend for an increase in lung neutrophils and phagocyte oxidant production at one-day post exposure, there were no significant differences in parameters of lung inflammation. In addition, increased blood monocytes and neutrophils, and decreased lymphocyte numbers at one-day post exposure also did not differ significantly from air controls, and no alterations in splenocyte populations, or serum or spleen immunoglobulin M (IgM) to antigen were observed. There were no significant differences in peripheral vascular responsiveness to vasoconstrictor and vasodilator agonists or in blood pressure (BP) responses to these agents; however, the baseline heart rate (HR) and HR responses to isoproterenol (ISO) were significantly elevated at one-day post exposure, with resolution by day 7. CONCLUSIONS: In summary, acute repeated exposure to COREXIT EC9500A did not alter pulmonary function, lung injury/inflammation, systemic immune responses, or vascular tone, but did cause transient chronotropic effects on cardiac function.

miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.

The role of trivalent arsenic (As(3+)) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As(3+) is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As(3+) is concentration dependent and associated with the expression of the host gene of miR-190, talin 2, a gene encoding a high-molecular-weight cytoskeletal protein. The elevated level of miR-190 induced by As(3+) is capable of downregulating the translation of the PH domain leucine-rich repeat protein phosphatase (PHLPP), a negative regulator of Akt signaling. Such a downregulation is occurred through direct interaction of the miR-190 with the 3'-UTR region of the PHLPP mRNA, leading to a diminished PHLPP protein expression and consequently, an enhanced Akt activation and expression of vascular endothelial growth factor, an Akt-regulated protein. Overexpression of miR-190 itself is able to enhance proliferation and malignant transformation of the cells as determined by anchorage-independent growth of the cells in soft agar. Accordingly, the data presented suggest that induction of miR-190 is one of the key mechanisms in As(3+)-induced carcinogenesis.

Rescue of a trafficking defective human pacemaker channel via a novel mechanism: roles of Src, Fyn, and Yes tyrosine kinases.

Therapeutic strategies such as using channel blockers and reducing culture temperature have been used to rescue some long QT-associated voltage-gated potassium Kv trafficking defective mutant channels. A hyperpolarization-activated cyclic nucleotide-gated HCN4 pacemaker channel mutant (D553N) has been recently found in a patient associated with cardiac arrhythmias including long QT. D553N showed the defective trafficking to the cell surface, leading to little ionic current expression (loss-of-function). We show in this report that enhanced tyrosine phosphorylation mediated by Src, Fyn, and Yes kinases was able to restore the surface expression of D553N for normal current expression. Src or Yes, but not Fyn, significantly increased the current density and surface expression of D553N. Fyn accelerated the activation kinetics of the rescued D553N. Co-expression of D553N with Yes exhibited the slowest activation kinetics of D553N. Src, Fyn, and Yes significantly enhanced the tyrosine phosphorylation of D553N. A combination of Src, Fyn, and Yes rescued the current expression and the gating of D553N comparable with those of wild-type HCN4. In conclusion, we demonstrate a novel mechanism using three endogenous Src kinases to rescue a trafficking defective HCN4 mutant channel (D553N) by enhancing the tyrosine phosphorylation of the mutant channel protein.

Incidence and costs of treatment-related complications among patients with advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To evaluate the incidence and costs of complications due to radiotherapy alone vs platinum-based chemoradiotherapy among patients diagnosed as having advanced squamous cell carcinoma of the head and neck (ASCCHN) from a payer perspective. DESIGN: Retrospective cohort study. SETTING: Data from the PharMetrics Patient-Centric Database from June 2000 through June 2006. PATIENTS: The study included patients with ASCCHN and an indication of a secondary malignant neoplasm (both identified based on International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes), 124 of whom were treated with radiotherapy alone and 77 of whom were treated with chemoradiotherapy (including 53 with cisplatin plus radiotherapy, 26 with carboplatin plus radiotherapy, and 2 with cisplatin and carboplatin plus radiotherapy). The patients were assigned to 1 of 2 cohorts based on treatment type-radiotherapy only and platinum-based chemoradiotherapy-and were followed up for 6 months. MAIN OUTCOME MEASURES: Incidence and costs of treatment-related complications associated with chemotherapy in ASCCHN. RESULTS: We found significantly (P < .001) higher rates of treatment-related complications among patients receiving chemoradiotherapy (86%) than among patients receiving only radiotherapy (51%). The mean per-patient costs associated with treatment-related complications were approximately $10 000 higher among patients who received chemoradiotherapy than among those treated with radiotherapy alone (P < .001). These costs represented 17% of the total costs during follow-up for patients who received chemoradiotherapy and 11% of costs for those who received radiotherapy. The most expensive complications were dehydration and/or electrolyte imbalance and oral complications. CONCLUSIONS: Our study results suggest that the attributable incidence and costs of treatment-related complications associated with chemotherapy in ASCCHN are substantial. The emergence of safer treatments may have the advantage of alleviating this cost burden.

Prevalence and the associated burden of illness of symptoms of diabetic peripheral neuropathy and diabetic retinopathy.

BACKGROUND: We estimated the prevalence and the associated burden of illness of symptoms of diabetic peripheral neuropathy (SDPN), diabetic retinopathy (DR), and comorbid SDPN and DR among people with diabetes in the United States aged > or =40 years. METHODS: Analyses were conducted on 850 respondents aged > or =40 years with diagnosed diabetes from the combined 1999-2000 and 2001-2002 National Health and Nutrition Examination Surveys. Sampling weights were used to estimate the number of people with diabetes who have SDPN, DR, or comorbid SDPN and DR. Multivariate regression models were used to assess the effects of SDPN, DR, and comorbid SDPN and DR on burden-of-illness measures. RESULTS: Approximately 11.9 million adults in the United States aged > or =40 years have diagnosed diabetes. Of those, 3.9 million (32.7%) have SDPN, 3.3 million (27.4%) have DR, and 1.6 million (13.1%) have comorbid SDPN and DR. Among our sample, those with SDPN [odds ratio (OR)=2.25; 95% confidence interval (95% CI)=1.32-3.83], DR (OR=1.68; 95% CI=1.08-2.61), or comorbid SDPN and DR (OR=2.84; 95% CI=1.26-6.41) were more likely than those without the corresponding condition to have four or more health care visits in the past year. Those of working age (40-65 years) with SDPN (OR=3.23; 95% CI=1.60-6.52), DR (OR=2.94; 95% CI=1.45-5.97), or comorbid SDPN and DR (OR=4.32; 95% CI=2.17-8.63) were more likely unable to work due to physical limitations. CONCLUSIONS: SDPN, DR, and comorbid SDPN and DR are prevalent among people with diabetes in the United States aged > or =40 years; each of these complications appears to significantly increase the burden of illness.