Proton Pump Inhibitor Use and Iron Deficiency Anemia in Celiac Patients.

INTRODUCTION: We sought to evaluate the effect of proton pump inhibitor (PPI) use on the development and severity of iron deficiency anemia (IDA) in celiac disease (CD). METHODS: We conducted a retrospective chart review of patients older than 18 years of age at Milton S. Hershey Medical Center who were diagnosed with CD. We analyzed four cohorts of celiac patients: (1) IDA diagnosis with PPI usage, (2) no IDA diagnosis with PPI usage, (3) IDA diagnosis with no PPI usage, and (4) no IDA diagnosis with no PPI usage. We also stratified celiac patients with IDA by anemia severity. RESULTS: Of 366 celiac patients, 92 (25.1%) were diagnosed with IDA, of which 60 (65.2%) were on a PPI. The mean Hgb of celiac patients with IDA on a PPI was 11.1 g/dL and 12.1 g/dL for those without PPI (p = 0.04). For all celiac patients on a PPI without IDA, the mean was 13.3 g/dL and 13.7 g/dL for those without PPI (p = 0.02). PPI use occurred in 12 (70.6%) of the 17 patients with low severity anemia, 11 (64.7%) of the 17 patients with medium severity and 6 (85.7%) of the 7 patients with severe (p = 0.55). CONCLUSIONS: There is significant association between PPI use and IDA in celiac patients (p < 0.0001). Of those with IDA on PPIs, the distribution of the severity of anemia is not statistically different compared to those not on PPI. Discontinuation of PPIs or usage of alternative acid suppressive treatments may be indicated in patients with CD and iron deficiency anemia.

D-CRSE: Diminishing chemotherapy-related side effects through patient education, a mixed-methods pilot study.

OBJECTIVES: Patient education materials regarding self-management of chemotherapy-related side effects are limited, which may result in patients using disreputable sources. We created a brochure that educates patients on common side effects, tools to address problems themselves, and guidance on when to contact their oncologist or seek emergency care. This mixed-methods study conducted at Penn State Cancer Institute evaluates the feasibility of using an educational brochure to improve patient outcomes through education. METHODS: Chemotherapy naïve patients with breast or gastrointestinal (GI) cancer were enrolled in a single-arm clinical trial from December 2021 to 2022. Participants received the educational brochure and were asked to provide their initial impressions. They completed The Emotional Thermometer Scale (ETS) and the Memorial Symptom Assessment Scale (MSAS) to measure changes in patient symptoms and mental health throughout their chemotherapy course at 0, 6, and 12-week intervals. The drop-out rate was recorded as a measure of study feasibility. RESULTS: The study participants were split between the following cancer types: 77.8% breast and 22.2% GI cancer. A significant decrease in overall mean ETS score was observed between baseline and week 6 (p = 0.001) and 12 (p = 0.0004), respectively. Moreover, the mean MSAS psychological symptoms decreased significantly at week 12 compared to baseline (p = 0.005), while no change was observed in physical symptoms (p = 0.101). Of the 40 participants who completed baseline surveys, 37 had at least one additional visit for a drop-out rate of 7.5%. CONCLUSION: This mixed-methods pilot study was successful in demonstrating the feasibility of distributing a standardized educational brochure as an intervention for chemotherapy patients. While participants' emotional scores and psychological symptoms decreased over time, physical symptoms did not, which aligns with side effect progression from cumulative chemotherapy burden.

Empowering Psychiatric Inpatients to Vote: Perceptions of Voting and the Barriers Encountered.

Individuals with psychiatric illness believe that voting is important. However, these individuals have lower rates of voting when compared to the general population. A survey of psychiatrically hospitalized adult patients was conducted to assess perceptions of and barriers to voting in patients with psychiatric illness. Data from 113 surveys was analyzed. A majority of survey participants agreed that they cared about voting, that their vote made a difference, and that their vote was important. 74% of individuals reported previously experiencing at least one barrier when exercising their right to vote. The most commonly experienced barriers reported were not having enough information to make an informed choice, not knowing where to vote, not having transportation, and not being registered to vote. Individuals who encountered a higher number of barriers in the past had a higher chance of encountering barriers more often. In conclusion, a high percentage of individuals with mental illness severe enough to warrant hospitalization have experienced barriers to voting, with many experiencing multiple barriers. Reduction of these barriers is important, as voting and the resultant public policies can directly affect this population's mental health and access to both mental and physical healthcare services.

Characteristics and Outcomes of Intrahospital Transfers from Neonatal Intensive Care to Pediatric Intensive Care Units.

OBJECTIVE: Critically ill children may be transferred from the neonatal intensive care unit (NICU) to the pediatric intensive care unit (PICU) for further critical care, but the frequency and outcomes of this patient population are unknown. The aims of this study are to describe the characteristics and outcomes in patients transferred from NICU to PICUs. We hypothesized that a higher-than-expected mortality would be present for patients with respiratory or cardiovascular diagnoses that underwent a NICU to PICU transition and that specific factors (timing of transfer, illness severity, and critical care interventions) are associated with a higher risk of mortality in the cardiovascular group. STUDY DESIGN: Retrospective analysis of Virtual Pediatric Systems, LLC (2011-2019) deidentified cardiovascular and respiratory NICU to PICU subject data. We evaluated demographics, PICU length of stay, procedures, disposition, and mortality scores. Pediatric Index of Mortality 2 (PIM2) score was utilized to determine the standardized mortality ratio (SMR). RESULTS: SMR of 4,547 included subjects (3,607 [79.3%] cardiovascular and 940 [20.7%] respiratory) was 1.795 (95% confidence interval: 1.62-1.97, p < 0.0001). Multivariable logistic regression analysis demonstrated transfer age (cardiovascular: odds ratio, 1.246 [1.10-1.41], p = 0.0005; respiratory: 1.254 [1.07-1.47], p = 0.0046) and PIM2 scores (cardiovascular: 1.404 [1.25-1.58], p < 0.0001; respiratory: 1.353 [1.08-1.70], p = 0.0095) were significantly associated with increased odds of mortality. CONCLUSION: In this present study, we found that NICU to PICU observed deaths were high and various factors, particularly transfer age, were associated with increased odds of mortality. While the type of patients evaluated in this study likely influenced mortality, further investigation is warranted to determine if transfer timing is also a factor. KEY POINTS: · NICU patients may be transitioned to the PICU.. · NICU to PICU observed deaths were high.. · Transfer timing may be a factor..

Promoting Health Equity Through Voter Support Activities for the Inpatient Psychiatric Population.

Individuals with mental illness often face barriers to voting. One of the primary barriers is not being registered to vote. This paper describes voter support activities (VSAs) provided to hospitalized adults on the acute inpatient psychiatric units at Pennsylvania Psychiatric Institute. During the six weeks preceding the 2020 general election, adult inpatients were offered six VSAs and an optional survey examining previous voting behaviors and barriers encountered to voting. VSAs included checking voter registration status and polling location, completing a paper or electronic voter registration application, and requesting a mail-in ballot. Of 189 patients approached, 119 individuals participated in the survey and 60 individuals utilized at least one VSA. This project demonstrates that VSAs are a welcome and feasible resource for psychiatrically hospitalized adults. Psychiatric providers can serve an important role in promoting access to voting-related activities for their patients.

Rate of Rise of Platelet Count After IVIG for Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease causing platelet destruction, and is a common cause of symptomatic thrombocytopenia in children. Intravenous immune globulin (IVIG) is a treatment for ITP that increases the platelet counts of most patients within 24 to 48 hours. This study aimed to calculate the rate of rise in pediatric ITP after a dose of IVIG and to analyze if patient characteristics affected the rate. For 116 children treated for ITP with IVIG at Hershey Medical Center, the rate of rise of the platelet count for all patients was calculated. The rate of rise ranged from -0.1 to +4.2 K/µL/hour (average 1.3, median 1.2). 78% of patients had a rate of rise of over 0.5 K/µL/hour. There was a statistically significant correlation between the rate rise of the platelet count and the initial platelet count (P=0.0197), but rate was not affected by age or sex. This study was able to demonstrate that IVIG is effective in most patients and that demographic features do not affect the rate of rise. By providing a nomogram showing when to expect a meaningful rise in the platelet count after IVIG, we give guidance for timing of the postinfusion platelet count to avoid administering a second dose. Future studies are needed to test this nomogram prospectively.

Adult tonsillectomy: An evaluation of indications and complications.

OBJECTIVE: This study aimed to evaluate current adult tonsillectomy indications along with risk factors associated with postoperative complications. METHODS: In this retrospective chart review, demographic, clinical, and surgical data were collected from 2004 to 2020 of adult patients who underwent tonsillectomy. Indications for surgery were categorized as infectious etiology, biopsy, obstructive sleep apnea (OSA), and tonsillar stones. Data regarding postoperative hemorrhage, emergency department (ED) visits, and readmissions were collected. Multivariable logistic regression models were used to evaluate factors associated with postoperative complications. RESULTS: 574 adults (mean age 32 years, 69.9% F vs. 30.1% M) were included. The most common indication was infections (62.2%), followed by biopsy (26.5%), tonsillar stones (6.8%), and OSA (4.5%). The highest frequency of postoperative bleeds (17.9%) occurred in the tonsillar stones cohort; however, the indication for surgery was not a significant predictor on multivariate analysis. Male sex and younger age were independent predictors of postoperative bleeding, while younger age was a significant predictor of postoperative ED visits. There was a significant linear trend of an increasing proportion of tonsillectomies performed for tonsillar stones compared to other indications for 2011-2019. CONCLUSION: Infectious etiology was the most common indication for tonsillectomy. Indication for surgery was not a significant predictor of postoperative bleeding; however, male sex and younger age had higher odds of postoperative bleeding. The proportion of tonsillectomies performed for tonsillar stones was steadily increasing.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

Omega-3 Fatty Acids Responsive Proteins and Reduction in Breast Density in Obese Postmenopausal Women.

We reported that breast density (BD) was inversely correlated with the plasma level of DHA in postmenopausal obese, but not in nonobese, women given Lovaza (n-3FA). To identify protein biomarkers for the possible differential effect of n-3FA on BD between obese and nonobese women, an iTRAQ method was performed to analyze plasma from obese and lean women at each time point (baseline, 12 and 24-months, n = 10 per group); 173 proteins with >95% confidence (Unuses Score >1.3 and local false discovery rate estimation <5%) were identified. Comparative analysis between various groups identified several differentially expressed proteins (hemopexin precursor, vitamin D binding protein isoform 1 precursor [VDBP], fibronectin isoform 10 precursor [FN], and α-2 macroglobulin precursor [A2M]). Western blot analysis was performed to verify the differential expression of proteins in the iTRAQ study, and those found to be altered in a tumor protective fashion by an n-3FA rich diet in our previous preclinical study; gelsolin, VDBP, and FN were altered by n-3FA in a manner consistent with reduction in inflammation in obese women. To test the impact of our findings on breast cancer risk reduction by n-3FA, a posthoc analysis revealed that n-3FA administration reduced BD selectively in obese postmenopausal women.

Satellite and In-Transit Metastatic Disease in Melanoma Skin Cancer: A Retrospective Review of Disease Presentation, Treatment, and Outcomes.

BACKGROUND: Satellitosis and in-transit metastases (SITM) are uncommon in cutaneous melanoma and are associated with poor prognosis. However, the disease- and treatment-specific variables that predict outcomes among patients with SITM are poorly defined. OBJECTIVE: To identify factors that predict prognosis among patients with SITM. MATERIALS AND METHODS: Retrospective chart review of patients treated for melanoma at a large academic medical center in central Pennsylvania between 2000 and 2012. Patients with pathology reports containing "satellite lesions" or "in-transit metastases" were selected for analysis. Data were collected regarding tumor stage, the timing of SITM discovery, treatment, recurrence-free survival after SITM discovery, and overall survival (OS). RESULTS: We identified SITM in 32 (1.9%) of 1,650 patients with pathology-diagnosed melanoma over the study period. Reduced recurrence-free survival after SITM discovery was associated with higher pathologic stage, metastatic disease, lymph node dissection, and use of adjuvant chemotherapy. Reduced OS was associated with higher T, N, M, and overall prognostic stage; positive surgical margins; disease recurrence; and SITM on initial presentation. CONCLUSION: Our data support previous findings that higher stage disease confers a worse prognosis among patients with SITM. Patients with SITM on initial presentation had worse outcomes, suggesting SITM is indicative of more aggressive disease.

Nicotine dependence as an independent risk factor for atherosclerosis in the National Lung Screening Trial.

BACKGROUND: Atherosclerosis and COPD are systemic inflammatory diseases that share common risk factors including cigarette smoking. A high level of nicotine dependence is emerging as a recently identified risk factor for pulmonary impairment, chronic obstructive pulmonary disease and tobacco-related cancers. We hypothesized that nicotine dependence is associated with the risk of atherosclerosis in long-term cigarette smokers. METHODS: A nested case-control study was conducted within the National Lung Cancer Screening Trial- American College of Radiology Imaging Network. Cases were defined as having a new diagnosis of any type of atherosclerosis. Controls were matched on a 2:1 basis by age, sex, race, study center, smoking status, years of smoking, and frequency of smoking. Dependence was measured by the time to first cigarette after awakening (TTFC). RESULTS: The study included 166 cases and 286 controls. Compared to participants who smoked within 5 min after waking, the risk of atherosclerosis for participants who smoked an hour or more after waking was borderline non-significant (odds ratio = 0.49, 95% confidence intervals [CI] 0.23, 1.00). Findings were similar for men and women. For aortic atherosclerosis, the corresponding odds ratio was 0.24 (95% CI 0.08, 0.69). Hypertension was associated with an increased risk and body mass index was associated with a decreased risk of aortic atherosclerosis. The TTFC was unrelated to coronary atherosclerosis. CONCLUSIONS: Compared to smoking immediately after waking, delaying an hour or more reduces the risk of aortic atherosclerosis even among long-term heavy smokers. Possible mechanisms that explain this association are intensity of smoking, inflammation and oxidative stress, and elevated lipid levels.

Comparative Tumorigenicity and DNA Damage Induced by Dibenzo[ def,p]chrysene and Its Metabolites in the Mouse Ovary.

Ovarian cancer ranked second in incidence among gynecologic cancers, but it causes more deaths than any other gynecologic cancer; at present there is no curative treatment beyond surgery. Animal models that employ carcinogens found in the human environment can provide a realistic platform to understand the mechanistic basis for disease development and to design rational chemopreventive/therapeutic strategies. We and others have shown that the administration of the environmental pollutant and tobacco smoke constituent dibenzo[ def,p]chrysene (DBP) to mice by several routes of exposure can induce tumors in multiple sites including the ovary. In the present study we compared, for the first time, the tumorigenicity and DNA damage induced by DBP and its metabolites DBP-dihydrodiol (DBPDHD) and DBP-dihydrodiol epoxide (DBPDE) in the mouse ovary. Compounds were dissolved in dimethyl sulfoxide (DMSO) as the vehicle and administered by topical application into the mouse oral cavity three times per week for 38 weeks. No tumors were observed in mice treated with DMSO. At equal dose (24 nmol/30 µL DMSO), the incidence of ovarian tumors induced by DBPDHD was higher (60.7%), although not significantly, than that induced by DBP (44.8%). Similarly the levels of DNA damage induced by DBPDHD in the ovary were higher than those observed with DBP. We did not observe any histological abnormality in the ovary of mice treated with DBPDE, which is consistent with lack of DNA damage. Our results suggested that both DBP and DBPDHD can be metabolized in the mouse ovary leading to the formation of DBPDE that can damage DNA, which is a prerequisite step in the initiation stage of carcinogenesis.

An Analysis of Oncotype DX Recurrence Scores and Clinicopathologic Characteristics in Invasive Lobular Breast Cancer.

The Oncotype DX breast cancer assay (Genomic Health, Redwood City, CA) is increasingly being used to guide treatment decisions for patients with early stage, hormone-positive, Her-2-negative breast cancer. The utility of the Oncotype DX in decision making for treatment of invasive lobular carcinoma (ILC) has not been investigated as the results reported by Genomic Health are largely in a population with invasive ductal carcinoma (IDC). The authors hypothesized that the Oncotype DX recurrence score (RS) distribution for ILC is different than that for IDC. We performed a retrospective analysis of early stage breast cancer patients treated at Penn State Cancer Institute from 2001 to 2011 and identified 102 patients with ILC. We also pulled RS data from our institution's prospective registry of consecutive patients with early stage IDC treated during the same time period. Median follow-up was 55 months. We found that the RS distribution for ILC differed significantly from that of IDC (p = 0.024). We also found a statistically significant difference in the RS distribution between the pure ILC and pleomorphic ILC subtypes (p = 0.027). The Oncotype DX RS distribution in ILC is unique, differing significantly from that in ductal carcinoma. Consequently, the clinical usefulness and cost-effectiveness of the Oncotype DX in guiding treatment for ILC should be further investigated.

A two-site, two-arm, 34-week, double-blind, parallel-group, randomized controlled trial of reduced nicotine cigarettes in smokers with mood and/or anxiety disorders: trial design and protocol.

BACKGROUND: The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks. METHODS: Adult smokers (N = 200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms). DISCUSSION: Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes. TRIAL REGISTRATION: TRN: NCT01928758 , registered August 21, 2013.

Efficient replication of Epstein-Barr virus in stratified epithelium in vitro.

Epstein-Barr virus is a ubiquitous human herpesvirus associated with epithelial and lymphoid tumors. EBV is transmitted between human hosts in saliva and must cross the oral mucosal epithelium before infecting B lymphocytes, where it establishes a life-long infection. The latter process is well understood because it can be studied in vitro, but our knowledge of infection of epithelial cells has been limited by the inability to infect epithelial cells readily in vitro or to generate cell lines from EBV-infected epithelial tumors. Because epithelium exists as a stratified tissue in vivo, organotypic cultures may serve as a better model of EBV in epithelium than monolayer cultures. Here, we demonstrate that EBV is able to infect organotypic cultures of epithelial cells to establish a predominantly productive infection in the suprabasal layers of stratified epithelium, similar to that seen with Kaposi's-associated herpesvirus. These cells did express latency-associated proteins in addition to productive-cycle proteins, but a population of cells that exclusively expressed latency-associated viral proteins could not be detected; however, an inability to infect the basal layer would be unlike other herpesviruses examined in organotypic cultures. Furthermore, infection did not induce cellular proliferation, as it does in B cells, but instead resulted in cytopathic effects more commonly associated with productive viral replication. These data suggest that infection of epithelial cells is an integral part of viral spread, which typically does not result in the immortalization or enhanced growth of infected epithelial cells but rather in efficient production of virus.

Lysosomal degradation of CD44 mediates ceramide nanoliposome-induced anoikis and diminished extravasation in metastatic carcinoma cells.

The ceramide nanoliposome (CNL) has shown promise in being able to treat a variety of primary tumors. However, its potential for treating metastatic cancer remains unknown. In this study, we demonstrate that CNL increases anoikis while preventing cancer cell extravasation under both static and physiological fluid flow conditions. Mechanistically, CNL limits metastases by decreasing CD44 protein levels in human breast and pancreatic cancer cells via lysosomal degradation of CD44, independent of palmitoylation or proteasome targeting. siRNA down-regulation of CD44 mimics CNL-induced anoikis and diminished extravasation of cancer cells. Taken together, our data indicate that ceramide limits CD44-dependent cancer cell migration, suggesting that CNL could be used to prevent and treat solid tumor metastasis.

Comparison of Puff Volume With Cigarettes per Day in Predicting Nicotine Uptake Among Daily Smokers.

The role of inhalation behaviors as predictors of nicotine uptake was examined in the Pennsylvania Adult Smoking Study (2012-2014), a study of 332 adults whose cigarette smoking was measured in a naturalistic environment (e.g., at home) with portable handheld topography devices. Piecewise regression analyses showed that levels of salivary cotinine, trans-3'-hydroxycotinine, and total salivary nicotine metabolites (cotinine + trans-3'-hydroxycotinine) increased linearly up to a level of about 1 pack per day (20 cigarettes per day (CPD)) (P < 0.01). Total daily puff volume (TDPV; in mL) (P < 0.05) and total daily number of puffs (P < 0.05), but not other topographical measures, increased linearly with CPD up to a level of about 1 pack per day. The mean level of cotinine per cigarette did not change above 20 CPD and was 36% lower in heavy smokers (≥20 CPD) than in lighter smokers (<20 CPD) (15.6 ng/mL vs. 24.5 ng/mL, respectively; P < 0.01). Mediation models showed that TDPV accounted for 43%-63% of the association between CPD and nicotine metabolites for smokers of <20 CPD. TDPV was the best predictor of nicotine metabolite levels in light-to-moderate smokers (1-19 CPD). In contrast, neither CPD, total daily number of puffs, nor TDPV predicted nicotine metabolite levels above 20 CPD (up to 40 CPD). Finally, although light smokers are traditionally considered less dependent on nicotine, these findings suggest that they are exposed to more nicotine per cigarette than are heavy smokers due to more frequent, intensive puffing.

Epstein-Barr virus nuclear antigen 3A promotes cellular proliferation by repression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1.

Latent infection by Epstein-Barr virus (EBV) is highly associated with the endemic form of Burkitt lymphoma (eBL), which typically limits expression of EBV proteins to EBNA-1 (Latency I). Interestingly, a subset of eBLs maintain a variant program of EBV latency - Wp-restricted latency (Wp-R) - that includes expression of the EBNA-3 proteins (3A, 3B and 3C), in addition to EBNA-1. In xenograft assays, Wp-R BL cell lines were notably more tumorigenic than their counterparts that maintain Latency I, suggesting that the additional latency-associated proteins expressed in Wp-R influence cell proliferation and/or survival. Here, we evaluated the contribution of EBNA-3A. Consistent with the enhanced tumorigenic potential of Wp-R BLs, knockdown of EBNA-3A expression resulted in abrupt cell-cycle arrest in G0/G1 that was concomitant with conversion of retinoblastoma protein (Rb) to its hypophosphorylated state, followed by a loss of Rb protein. Comparable results were seen in EBV-immortalized B lymphoblastoid cell lines (LCLs), consistent with the previous observation that EBNA-3A is essential for sustained growth of these cells. In agreement with the known ability of EBNA-3A and EBNA-3C to cooperatively repress p14(ARF) and p16(INK4a) expression, knockdown of EBNA-3A in LCLs resulted in rapid elevation of p14(ARF) and p16I(NK4a). By contrast, p16(INK4a) was not detectably expressed in Wp-R BL and the low-level expression of p14(ARF) was unchanged by EBNA-3A knockdown. Amongst other G1/S regulatory proteins, only p21(WAF1/CIP1), a potent inducer of G1 arrest, was upregulated following knockdown of EBNA-3A in Wp-R BL Sal cells and LCLs, coincident with hypophosphorylation and destabilization of Rb and growth arrest. Furthermore, knockdown of p21(WAF1/CIP1) expression in Wp-R BL correlated with an increase in cellular proliferation. This novel function of EBNA-3A is distinct from the functions previously described that are shared with EBNA-3C, and likely contributes to the proliferation of Wp-R BL cells and LCLs.

JOURNAL CLUB: Scatter Radiation Dose From Digital Screening Mammography Measured in a Representative Patient Population.

OBJECTIVE: The purpose of this study was to quantify the amount of scatter radiation received at the skin surface overlying the thyroid gland, salivary gland, lens of the eye, sternum, and uterus during a routine screening digital mammographic examination measured in a representative patient population. SUBJECTS AND METHODS: The subjects were 207 women without symptoms with varied body mass indexes who underwent annual screening mammography while wearing six optically stimulated luminescence dosimeters placed at the bridge of the nose, right submandibular gland, right and left thyroid lobes, mid sternum, and 2 cm caudal to the umbilicus to assess scatter radiation dose to the skin. RESULTS: The average scatter radiation doses at the skin surface during digital screening mammography in the representative population of women were as follows: overlying the right lobe of the thyroid, 0.24 mGy; left lobe of the thyroid, 0.25 mGy; salivary gland, 0.2 mGy; bridge of the nose, 0.025 mGy; sternum, 0.87 mGy; and umbilicus, 0.011 mGy. The scatter radiation doses at the umbilicus and the bridge of the nose were too low to measure with statistical confidence. Scatter radiation dose increased with increasing body mass index and increasing breast compression thickness. CONCLUSION: Scatter radiation dose at the skin overlying organs of interest is a small fraction of the entrance skin dose to the breast. The low levels of scatter radiation measured do not support delaying clinically indicated mammography during early pregnancy.