Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

Abnormal mismatch repair and other clinicopathologic predictors of poor response to progestin treatment in young women with endometrial complex atypical hyperplasia and well-differentiated endometrial adenocarcinoma: a consecutive case series.

OBJECTIVE: To report the response to progestin therapy in young women with endometrial complex atypical hyperplasia (CAH) or FIGO grade 1 endometrial adenocarcinoma (FIGO 1 EAC) based on clinicopathologic features, including abnormal DNA mismatch repair (MMR) by immunohistochemistry (IHC). DESIGN: Consecutive case series. SETTING: Olive View-UCLA Medical Center in Sylmar, CA, USA, and Cedars-Sinai Medical Center in Los Angeles, CA, USA. POPULATION: Women ≤55 years old with CAH or FIGO 1 EAC. METHODS: Response to progestin therapy in 84 consecutive patients was assessed based on clinicopathologic factors, including age, body mass index (BMI), initial histology, and IHC staining for MMR proteins. MAIN OUTCOME MEASURES: Rates of abnormal MMR protein expression and response to progestin therapy were determined. RESULTS: Six (7%) patients had abnormal IHC staining, of whom five (83%) had FIGO 1 EAC at initial diagnosis. Following progestin treatment, none of the endometrial lesions in patients with abnormal IHC for MMR proteins had resolution of hyperplasia or malignancy, in contrast to 41 (53%) with normal staining (P = 0.028). Age ≤40 years and initial lesion (CAH versus FIGO 1 EAC) were predictors of response to progestin; BMI was not. CONCLUSIONS: In this cohort, 7% of women ≤55 years of age with CAH or FIGO 1 EAC had loss of MMR proteins by IHC. These patients had a higher incidence of invasive cancer and a lower incidence of resolution with progestin therapy. TWEETABLE ABSTRACT: Abnormal MMR protein expression predicts poor response to progestins in young women with CAH or FIGO 1 EAC.

Assessment of DNA methylation status in early stages of breast cancer development.

BACKGROUND: Molecular pathways determining the malignant potential of premalignant breast lesions remain unknown. In this study, alterations in DNA methylation levels were monitored during benign, premalignant and malignant stages of ductal breast cancer development. METHODS: To study epigenetic events during breast cancer development, four genomic biomarkers (Methylated-IN-Tumour (MINT)17, MINT31, RARß2 and RASSF1A) shown to represent DNA hypermethylation in tumours were selected. Laser capture microdissection was employed to isolate DNA from breast lesions, including normal breast epithelia (n=52), ductal hyperplasia (n=23), atypical ductal hyperplasia (n=31), ductal carcinoma in situ (DCIS, n=95) and AJCC stage I invasive ductal carcinoma (IDC, n=34). Methylation Index (MI) for each biomarker was calculated based on methylated and unmethylated copy numbers measured by Absolute Quantitative Assessment Of Methylated Alleles (AQAMA). Trends in MI by developmental stage were analysed. RESULTS: Methylation levels increased significantly during the progressive stages of breast cancer development; P-values are 0.0012, 0.0003, 0.012, <0.0001 and <0.0001 for MINT17, MINT31, RARß2, RASSF1A and combined biomarkers, respectively. In both DCIS and IDC, hypermethylation was associated with unfavourable characteristics. CONCLUSION: DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential.

Diagnostic value of sentinel lymph node biopsy in head and neck cancer: a meta-analysis.

This study aimed to evaluate the diagnostic reliability of sentinel lymph node biopsy in patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx by reviewing the published literature. A systematic literature review was performed using MEDLINE from 1970 to 2011. With Boolean search strings, search terms included sentinel node, supraglottic, supraglottis, tongue, head and neck, oral, pharynx, laryngeal, and larynx. Additional studies were identified through article references. Duplicate data and articles were excluded based on treating institution and study inclusion time period. Additional studies were excluded if the head and neck subsite or tumor stage was not specifically identified or if the sentinel lymph node biopsy occurred in previously treated necks. All patients had sentinel lymph node biopsy performed followed by a concurrent neck dissection. Twenty-six studies met our inclusion criteria (n = 766 patients). The pooled sensitivity and negative predictive value of SLNB for all head and neck tumors was 95 % (95 % CI 91-99 %) and 96 % (95 %CI 94-99 %), respectively. The overall sensitivity and negative predictive value of SLNB in the subset of oral cavity tumors (n = 631) was 94 % (95 % CI 89-98 %) and 96 % (95 % CI 93-99 %), respectively. One-hundred percent of oropharyngeal (n = 72), hypopharyngeal (n = 5), and laryngeal (n = 58) tumor sentinel lymph biopsy results correlated with subsequent neck dissections giving a negative predictive value of 100 %, showing that, sentinel lymph node biopsy is a valid diagnostic technique to correctly stage regional metastases in patients with head and neck squamous cell carcinoma.

Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies.

BACKGROUND: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. METHODS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. RESULTS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. CONCLUSION: In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.

Modifiable lifestyle factors associated with metabolic syndrome in patients with psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, which is associated with obesity and with cardiovascular morbidity and mortality. AIM: To evaluate modifiable lifestyle factors including stress level, physical activity and nutrition, which may be associated with metabolic syndrome in patients with psoriasis. METHODS: In total, 65 patients with psoriasis and 52 control subjects from our university dermatology clinic were enrolled in this case-control pilot study. The study questionnaire included the Perceived Stress Scale (PSS), the Godin Leisure-Time Exercise Questionnaire (GLTEQ) and the Rapid Eating Assessment for patients (REAP). For subjects with psoriasis, the Psoriasis Area and Severity Index (PASI) was measured. RESULTS: Subjects with psoriasis (mean BMI 27.72) displayed a trend towards a higher BMI compared with controls (mean BMI 25.67). Subjects with psoriasis were not found to have an increased prevalence of self-reported metabolic syndrome-associated diseases including diabetes, heart disease, high cholesterol, hypertension or stroke compared with controls (P=0.25, P=0.46, P=0.96, P=0.26, and P=0.16, respectively). There was no significant difference in exercise or stress between patients with psoriasis and controls (P=0.06 and P=0.26, respectively). However, compared with controls, subjects with psoriasis (mean REAP score=2.23) did report poorer overall nutrition as assessed by the REAP score (mean=2.38, P<0.01). Among subjects with psoriasis, the factors of stress, smoking and systemic therapy were associated with increased PASI (r=0.13, r=3.47 and r=3.19, respectively). CONCLUSIONS: Our study suggests that poor dietary and exercise habits may be factors contributing to obesity and metabolic syndrome in patients with psoriasis. Further studies with larger numbers are needed to confirm these results.

Distinct gene signature revealed in white blood cells, CD4(+) and CD8(+) T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide.

Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4(+)CD25(+)Foxp3+ and CD8(+)Foxp3+ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4(+) T cells, and CD8(+) T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naïve mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8(+)T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4(+) T cells and CD8(+) T cells, to detect the effects of TGF-beta, known to be the major cytokine that accounts for the suppressive capacity of CD8(+) Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8(+) T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1-all of which are involved in the suppressive capacity of CD8(+) Treg in this model.

Differences in presentation of younger and older systemic sclerosis patients in clinical trials.

OBJECTIVES: To compare the characteristics of younger and older subjects with diffuse cutaneous systemic sclerosis (SSc) entering clinical trials. METHODS: Subjects were participants in three randomised interventional trials that shared relative uniformity of demographics and disease characteristics. Only subjects with diffuse cutaneous systemic sclerosis were evaluated. To maximise possible differences, the lowest (age<38 years) and highest quartiles (age>53 years) were used, and a total of 264 diffuse cutaneous SSc (dcSSc) subjects were identified. For the comparison between the two age groups, generalised linear mixed or linear models with adjustment for population norms, demographics and medications were employed to assess differences attributable to subject age. RESULTS: After adjustment for population norms and study effects, differences in diastolic blood pressure, alkaline phosphatase, AST, and creatinine phosphokinase (CK) were found between the two age groups. After further adjustment for demographics, disease duration and medications, older SSc patients still had significantly higher alkaline phosphatase (11 U/L higher), and lower CK (76 U/L lower) than younger patients (p<0.003 for all). All other variables were not significantly different in the two age groups. CONCLUSIONS: Clinical baseline differences exist between younger and older patients with SSc. However, after adjustment for population norms and potential confounders, including medications, only differences in alkaline phosphatise (only 11U/L) and CK (76 U/L) remain. Overall, older patients with SSc in clinical trials seem to be more similar to younger patients than was previously thought.

The American English version of the validated French Flare Assessment in RA Questionnaire (FLARE-RA).

OBJECTIVE: To evaluate use of a British English version of the validated French FLARE-RA questionnaire among American English speaking patients. In addition, to create a culturally adapted American English (AmE) FLARE-RA questionnaire and to examine its attributes of patient-reported RA flare status. METHODS: Using standardized cultural adaptation guidelines, we cognitively debriefed 25 American English speaking rheumatoid arthritis (RA) outpatients and created AmE-FLARE-RA with their input. One hundred three additional RA patients were recruited. Patients completed the Routine Assessment of Patient Index Data 3 (RAPID3), patient global visual analogue scale (VAS), AmE-FLARE-RA, and self-reports of flare. Physician global VAS, physician-assessed flare, swollen and tender joint count (TJC), and clinical disease activity index (CDAI) were documented. AmE-FLARE-RA and disease activity measures were compared between patient-reported and physician-reported flare categories. RESULTS: Patients were female (89%), with mean (SD) age 51.1 (± 15.3) years and mean disease duration (SD) 11.9 (± 10.1) years, with 26% in remission/low disease activity. Total AmE-FLARE-RA scores, RAPID3, CDAI, and patient global VAS were significantly higher for both patient-reported flares and physician-reported flares compared with non-flaring patients by self- or physician report (p < 0.05). Total AmE-FLARE-RA scores correlated significantly with RAPID3 (corr = 0.50, p < 0.0001) and with CDAI (corr = 0.45, p < 0.0001). Across "no flares," "one flare," and "several flare" groups, there was a non-significant increase in AmE-FLARE-RA scores (p = 0.07). CONCLUSION: The British English FLARE-RA was successfully adapted for AmE-speaking RA patients. AmE-FLARE-RA significantly correlated with RAPID3 and CDAI and distinguished between patient-reported and physician-reported flares, making it useful to detect flares in American RA patients.Key Points• The American English FLARE-RA (AmE-FLARE-RA) questionnaire is the result of cognitive debriefing with American RA patients using the British English version of the validated French FLARE-RA and incorporates patient-recommended language modifications..• Patients self-reporting flares had significantly higher AmE-FLARE-RA scores, compared with those without flares at the time of visit. AmE-FLARE-RA scores correlate with RAPID3 and CDAI.• There was a non-statistically significant trend using the AmE-FLARE-RA scores when examining patients with no flare, one flare, or several flares.• AmE-FLARE-RA total scores are uniformly elevated (~ 6.0 on a 0-10 scale), regardless of discordance between patient and MD assessment of flare at time of visit (~ 30%).

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo.

Mitochondrial complex I inhibition has been implicated in the degeneration of midbrain dopaminergic (DA) neurons in Parkinson's disease. However, the mechanisms and pathways that determine the cellular fate of DA neurons downstream of the mitochondrial dysfunction have not been fully identified. We conducted cell-type specific gene array experiments with nigral DA neurons from rats treated with the complex I inhibitor, rotenone, at a dose that does not induce cell death. The genome wide screen identified transcriptional changes in multiple cell death related pathways that are indicative of a simultaneous activation of both degenerative and protective mechanisms. Quantitative PCR analyses of a subset of these genes in different neuronal populations of the basal ganglia revealed that some of the changes are specific for DA neurons, suggesting that these neurons are highly sensitive to rotenone. Our data provide insight into potentially defensive strategies of DA neurons against disease relevant insults.

Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft.

Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long-term survival post-lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation. We conducted a single-center, retrospective study and examined the presence of PH and vasculopathy in patients with pathologic OB/BOS. Fifty-two pathologic specimens post-LT were recovered from January 10, 1997 to January 5, 2007 and divided into two groups, those with and without pathologic OB/BOS.PH was defined as a mean pulmonary artery pressure (mPAP) > 25 mmHg by right heart catheterization (RHC) or right ventricular systolic pressure (RVSP) > or = 45 mmHg by transthoracic echocardiogram (TTE). PH was more prevalent in those LT recipients with pathologic OB/BOS (72% vs. 0%, p = 0.003). Furthermore, pulmonary arteriopathy and venopathy were more prevalent in patients with pathologic OB/BOS (84% vs. 4%, p < 0.0001, and 77% vs. 35%, p = 0.004, respectively). PH is common in LT recipients with pathologic OB/BOS and is associated with a vasculopathy of the allograft pulmonary circulation.

Improving the Prediction of Mortality in the High Model for End-Stage Liver Disease Score Liver Transplant Recipient: A Role for the Left Atrial Volume Index.

Left atrial volume index (LAVI) is an echocardiographic measurement used in assessing diastolic dysfunction, and is associated with mortality in many populations. In this retrospective cohort study including 254 patients, we investigated whether LAVI is an independent predictor of post-liver transplantation mortality using multivariable Cox regression. We found that elevated LAVI was associated with increased mortality among patients with high Model for End-Stage Liver Disease (MELD) scores, but not among those with lower MELD scores, indicating that recipients with high LAVI values and high MELD scores may represent patients at an increased risk of post-transplantation mortality. Specifically, there was a statistically significant interaction between LAVI and MELD score (P = .006) such that for patients with MELD scores ≥33, LAVI >27 mL/m2 was associated with increased mortality (hazard ratio = 2.3; 95% confidence interval, 1.04-5.20; P = .04.) We further show that the inclusion of LAVI in a multivariable model led to a statistically significant improvement in the ability to predict post-liver transplantation mortality, with an increase in the model's C-statistic from 0.68 to 0.71. The incorporation of LAVI in multivariable risk models may be useful in the selection of transplant recipients with high MELD scores, and may be helpful in decreasing the probability of futile transplantation.

Effect of lifestyle exposures on sperm aneuploidy.

Lifestyle exposures including cigarette smoke, alcohol, and caffeine have all been studied in relationship to male reproductive health. Over the years the focus has primarily been on semen quality and/or fertility. More recently, literature evaluating direct adverse effects of lifestyle exposures on sperm chromosomes and chromatin has grown due to concern that induced damage could be transmitted to offspring causing transgenerational health effects. In this paper we present a new analysis that summarizes published studies of smoking effects on sperm chromosome number and demonstrates a statistically significant increase in sperm disomy among smokers compared to nonsmokers (P < 0.001). In addition, new data on the effect of alcohol intake on sperm chromosome number are presented showing a rate ratio of 1.38 (95% CI 1.2, 1.6) for XY frequency in sperm of alcohol drinkers compared to nondrinkers.

Predictive value of cord blood bilirubin for hyperbilirubinemia in neonates at risk for maternal-fetal blood group incompatibility and hemolytic disease of the newborn.

OBJECTIVE: To determine the predictive ability of cord blood bilirubin (CBB) for hyperbilirubinemia in a population at risk for maternal-fetal blood group incompatibility and hemolytic disease of the newborn. STUDY DESIGN: This is a single center retrospective case-control study. Cases received phototherapy; controls did not. Cases were matched 1:3 to controls by gender and treating physician. Inclusion criteria included: ≥35 weeks gestation, CBB, and one or more total serum bilirubin (TSB) concentrations. The primary outcome was CBB. Secondary outcomes were a TSB >75th percentile, length of stay, and neonatal intensive care unit admission. The prognostic ability of CBB for phototherapy and TSB >75th percentile was assessed using area under the receiver operating characteristic (ROC) curve. Logistic regression analyses were performed to determine predictors for phototherapy and TSB >75th percentile. RESULT: When compared to controls (n = 142), cases (n = 54) were more likely to have a positive Coombs' test (82% vs. 41% , p <  0.001) and TSB >75th percentile (85% vs. 21% , p <  0.001). When compared to controls, cases had a higher mean (±SD) CBB (2.5 ± 0.5 vs. 1.8 ± 0.4 mg/dL, p <  0.001). The area under the ROC curve (±SEM) for CBB for phototherapy and TSB >75th percentile was 0.87 ± 0.03 (p <  0.001, 95% CI 0.82, 0.93) and 0.87 ± 0.03 (p <  0.001, 95% CI 0.82, 0.92), respectively. CONCLUSION: In this study, the mean CBB concentration was higher in neonates who received phototherapy compared to those who did not. CBB concentrations may help predict severe hyperbilirubinemia and phototherapy in a population at risk for hemolytic disease of the newborn.

The administration of intranasal live attenuated influenza vaccine induces changes in the nasal microbiota and nasal epithelium gene expression profiles.

BACKGROUND: Viral infections such as influenza have been shown to predispose hosts to increased colonization of the respiratory tract by pathogenic bacteria and secondary bacterial pneumonia. To examine how viral infections and host antiviral immune responses alter the upper respiratory microbiota, we analyzed nasal bacterial composition by 16S ribosomal RNA (rRNA) gene sequencing in healthy adults at baseline and at 1 to 2 weeks and 4 to 6 weeks following instillation of live attenuated influenza vaccine or intranasal sterile saline. A subset of these samples was submitted for microarray host gene expression profiling. RESULTS: We found that live attenuated influenza vaccination led to significant changes in microbial community structure, diversity, and core taxonomic membership as well as increases in the relative abundances of Staphylococcus and Bacteroides genera (both p < 0.05). Hypergeometric testing for the enrichment of gene ontology terms in the vaccinated group reflected a robust up-regulation of type I and type II interferon-stimulated genes in the vaccinated group relative to controls. Translational murine studies showed that poly I:C administration did in fact permit greater nasal Staphylococcus aureus persistence, a response absent in interferon alpha/beta receptor deficient mice. CONCLUSIONS: Collectively, our findings demonstrate that although the human nasal bacterial community is heterogeneous and typically individually robust, activation of a type I interferon (IFN)-mediated antiviral response may foster the disproportionate emergence of potentially pathogenic species such as S. aureus. TRIAL REGISTRATION: This study was registered with Clinicaltrials.gov on 11/3/15, NCT02597647 .

Comparing 3T and 1.5T MRI for mapping hippocampal atrophy in the Alzheimer's Disease Neuroimaging Initiative.

BACKGROUND AND PURPOSE: Prior MR imaging studies, primarily at 1.5T, established hippocampal atrophy as a biomarker for Alzheimer disease. 3T MR imaging offers a higher contrast and signal-to-noise ratio, yet distortions and intensity uniformity are harder to control. We applied our automated hippocampal segmentation technique to 1.5T and 3T MR imaging data, to determine whether hippocampal atrophy detection was enhanced at 3T. MATERIALS AND METHODS: We analyzed baseline MR imaging data from 166 subjects from the Alzheimer's Disease Neuroimaging Initiative-1 (37 with Alzheimer disease, 76 with mild cognitive impairment, and 53 healthy controls) scanned at 1.5T and 3T. Using multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for sex. 3D statistical maps were adjusted for multiple comparisons by using permutation-based statistics at a threshold of P < .01. RESULTS: Bilaterally significant radial distance differences in the areas corresponding to the cornu ammonis 1, cornu ammonis 2, and subiculum were detected for Alzheimer disease versus healthy controls and mild cognitive impairment versus healthy controls at 1.5T and more profoundly at 3T. Comparison of Alzheimer disease with mild cognitive impairment did not reveal significant differences at either field strength. Subjects who converted from mild cognitive impairment to Alzheimer disease within 3 years of the baseline scan versus nonconverters showed significant differences in the area corresponding to cornu ammonis 1 of the right hippocampus at 3T but not at 1.5T. CONCLUSIONS: While hippocampal atrophy patterns in diagnostic comparisons were similar at 1.5T and 3T, 3T showed a superior signal-to-noise ratio and detected atrophy with greater effect size compared with 1.5T.

Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.

BACKGROUND: We examined the cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-wk controlled trial at a university research center. OBJECTIVE: We evaluated the lipid-lowering effects of this red-yeast-rice dietary supplement in US adults separate from effects of diet alone. DESIGN: Eighty-three healthy subjects (46 men and 37 women aged 34-78 y) with hyperlipidemia [total cholesterol, 5.28-8.74 mmol/L (204-338 mg/dL); LDL cholesterol, 3.31-7.16 mmol/L (128-277 mg/dL); triacylglycerol, 0.62-2.78 mmol/L (55-246 mg/dL); and HDL cholesterol 0.78-2.46 mmol/L (30-95 mg/dL)] who were not being treated with lipid-lowering drugs participated. Subjects were treated with red yeast rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat, and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL and LDL cholesterol measured at weeks 8, 9, 11, and 12. RESULTS: Total cholesterol concentrations decreased significantly between baseline and 8 wk in the red-yeast-rice-treated group compared with the placebo-treated group [(x+/-SD) 6.57+/-0.93 mmol/L (254+/-36 mg/dL) to 5.38+/-0.80 mmol/L (208+/-31 mg/dL); P < 0.001]. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. CONCLUSIONS: Red yeast rice significantly reduces total cholesterol, LDL cholesterol, and total triacylglycerol concentrations compared with placebo and provides a new, novel, food-based approach to lowering cholesterol in the general population.

The bronchoalveolar lavage fluid of cystic fibrosis lung transplant recipients demonstrates increased interleukin-8 and elastase and decreased IL-10.

Cystic fibrosis (CF) patients continue to have reservoirs of Pseudomonas aeruginosa infection in their sinuses and trachea after transplantation, and studies indicate that nontransplanted CF patients have high bronchoalveolar lavage (BAL) levels of proinflammatory factors, interleukin-8 (IL-8), and elastase and decreased airway lavage levels of IL-10. The aims of our study were to measure the IL-8 and IL-10 levels and elastase activity in the BAL of lung transplant patients, with correlation to microbiologic and pathologic findings, and to identify any differences in the findings between CF and non-CF patients. Fifty serial BAL samples were collected from 38 lung transplant recipients over 8 months. The BAL supernatant fluid was cultured for bacterial, viral, and fungal organisms. Histologic tissue analysis was performed as indicated. The fluid IL-10 and IL-8 levels were measured in duplicate using ELISA techniques. Elastase activity was measured using a colorimetric assay system. The mean IL-8, IL-10, and elastase levels for the group studied were 1894 pg/ml, 394 pg/ml, and 4.2 U/ml, respectively. The CF patients had significantly higher levels of IL-8, with a mean value of 4093 pg/ml (p < 0.02), and lower IL-10, mean 217 pg/ml (n = 9). Elastase activity correlated strongly with IL-8 level (p < 0.04). Pseudomonas growth was associated with higher elastase and IL-8 concentrations (p < 0.02). There was no association between allograft rejection and the markers studied. CF transplanted patients have higher airway lavage concentrations of IL-8 and elastase correlated to the presence of Pseudomonas in the lower airway. They also have lower BAL levels of anti-inflammatory cytokine IL-10.

Individualized prognosis for melanoma patients.

The clinical course of malignant melanoma is notoriously variable. Current approaches to prognostication allow assignment to risk categories but do not permit accurate assessment of prognosis on an individual patient basis. We analyzed a melanoma histology database that comprises 1,042 sequential melanoma patients evaluated by A.J.C. at UCLA between 1980 and 1990 for 30 separate variables according to a standard protocol. After censoring for absent data, a univariate Cox model analysis was performed that showed 20 individual variables that were significantly linked to clinical outcome. A step-up multivariate analysis was then performed. The combined analysis shows 5 variables: gender, site of primary, age relative to 60 years, Breslow thickness, and presence and width of ulceration to be linked to survival. Probability of survival is calculated using a 2-step approach. The survival-linked variables are multiplied to give an individualized risk score. This is converted into probability of survival by the formula .987 (risk score) for 3-year survival, .975 (risk score) for 5-year survival, and .960 (risk score) for 10-year survival. Thus, a 55-year-old woman with a 1.8-mm nonulcerated melanoma on the leg would have a risk score of (1 x 1 x 1 x 2 x 1) = 2 and a predicted probability of survival at 5 years of .9752 (95%) and at 10 years of .9602 (92%). We used similar techniques to develop individualized risk scores for likelihood of recurrence. The significant variables in this case are anatomic site of the primary melanoma, melanoma subtype, Breslow thickness, and presence and width of ulceration. The formulae for likelihood of recurrence at different periods after initial surgical removal of the primary melanoma are at 3 years, .979(risk score); at 5 years, .971(risk score); and at 10 years, .957(risk score). This relatively simple approach to prognostication uses readily available demographic information and is likely to be more accurate than single-factor analysis.