Some intrusions in dietary reports by fourth-grade children are based on specific memories: data from a validation study of the effect of interview modality

In dietary recall for a specified target period, an intrusion denotes an item reported eaten that was not consumed during that period. Intrusions may denote items available during the specified period, items consumed during other periods, or items from general knowledge of dietary intake. To investigate a cognitive basis of intrusions, we analyzed data from a dietary-reporting validation study in which 69 fourth-grade children were observed eating 2 school meals (breakfast and lunch) and interviewed that evening about that day's intake in person or by telephone. Of 450 items reported eaten for school meals, 82 were intrusions. Observations and school food service production records were used to determine whether items denoted by intrusions were available in school food service environments on the interview day, as many as 3 school days prior to the interview day, and the day following the interview. Availability of items denoted by intrusions decreased backward over days from the interview day, and decreased from the interview day to the following day. Among 40 children who reported at least 1 intrusion, mean number of intrusions (controlling for number of items reported) increased as interviews occurred later in the week. These results are consistent with the idea that some intrusions are based on specific memories of items encountered but not eaten during the target period, or encountered before the target period. Other intrusions are likely based on general dietary knowledge. It may be possible to design interview techniques to reduce the occurrence of intrusions that are incorrectly based on specific memories.     

Common variation in the BRCA1 gene and prostate cancer risk.

Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding (and including) the BRCA1 gene. We also used the Genotype-Identity-by-Descent Sharing Test to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln(356)Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (P = 0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval, 1.21-4.20). Notably, BRCA1 Gln(356)Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, Genotype-Identity-by-Descent Sharing Test results suggest that Gln(356)Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (P = 0.022). Thus, we have identified a common, nonsynonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.     

Microenvironmental transformations by VEGF- and EGF-receptor inhibition and potential implications for responsiveness to radiotherapy.

The microregional distribution and dynamics of tumor cell hypoxia and proliferation are important determinants of tumor aggressiveness and resistance to treatment. Modulation of these elements by biological targeted drugs such as EGFR- and VEGFR-inhibitors may improve the effect of radiotherapy significantly. These combinations are being evaluated in clinical trials and evidence of their effectiveness is accumulating. However, the mechanistic basis of this cooperative effect and the role and behavior of the microregional tumor phenotype under EGF- and VEGF-blockage is poorly understood. Unfolding of these interactions and effects further downstream is necessary to exploit these biological modifiers most profitably to unravel questions such as: (1) can microregional phenotypes be modulated by EGFR- or VEGFR-blockage and how do downstream effects in the signaling pathways relate to these changes? (2) How do the microregional changes induced by EGFR- and VEGF-blockage affect the responsiveness of tumors to ionizing radiation? Answering these questions will improve our understanding of tumor growth related phenotypic transformations at the microregional level and how these can be influenced by modulation of the EGF- and VEGF-signaling pathways. This knowledge can be used to identify and improve therapeutic combinations with the novel biological modifiers and test a variety of biological-based treatment approaches.     

A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy.

PURPOSE: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points. EXPERIMENTAL DESIGN: Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. RESULTS: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. CONCLUSIONS: Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.     

Uniform procedure of (1)H NMR analysis of rat urine and toxicometabonomics Part II: comparison of NMR profiles for classification of hepatotoxicity.

A procedure of nuclear magnetic resonance (NMR) urinalysis using pattern recognition is proposed for early detection of toxicity of investigational compounds in rats. The method is applied to detect toxicity upon administration of 13 toxic reference compounds and one nontoxic control compound (mianserine) in rats. The toxic compounds are expected to induce necrosis (bromobenzene, paracetamol, carbon tetrachloride, iproniazid, isoniazid, thioacetamide), cholestasis (alpha-naphthylisothiocyanate (ANIT), chlorpromazine, ethinylestradiol, methyltestosterone, ibuprofen), or steatosis (phenobarbital, tetracycline). Animals were treated daily for 2 or 4 days except for paracetamol and bromobenzene (1 and 2 days) and carbon tetrachloride (1 day only). Urine was collected 24 h after the first and second treatment. The animals were sacrificed 24 h after the last treatment, and NMR data were compared with liver histopathology as well as blood and urine biochemistry. Pathology and biochemistry showed marked toxicity in the liver at high doses of bromobenzene, paracetamol, carbon tetrachloride, ANIT, and ibuprofen. Thioacetamide and chlorpromazine showed less extensive changes, while the influences of iproniazid, isoniazid, phenobarbital, ethinylestradiol, and tetracycline on the toxic parameters were marginal or for methyltestosterone and mianserine negligible. NMR spectroscopy revealed significant changes upon dosing in 88 NMR biomarker signals preselected with the Procrustus Rotation method on principal component discriminant analysis (PCDA) plots. Further evaluation of the specific changes led to the identification of biomarker patterns for the specific types of liver toxicity. Comparison of our rat NMR PCDA data with histopathological changes reported in humans and/or rats suggests that rat NMR urinalysis can be used to predict hepatotoxicity.     

Detection of haptenated proteins in organotypic human skin explant cultures exposed to dapsone.

Bioactivation of parent drug to reactive metabolite(s) followed by protein haptenation has been suggested to be a critical step in the elicitation of cutaneous drug reactions. Although liver is believed to be the primary organ of drug bioactivation quantitatively, other organs including skin may also metabolize drugs. Cultured human epidermal keratinocytes and dermal fibroblasts have been shown to be capable of bioactivating sulfonamides and sulfones, giving rise to haptenated proteins. It is, however, unclear whether metabolic events in these isolated cells reflect bioactivation in vivo. Hence, split-thickness human skin explants were exposed to dapsone (DDS) or its arylhydroxylamine metabolite (dapsone hydroxylamine, D-NOH) and probed for protein haptenation. DDS and D-NOH were applied either epicutaneously or mixed in the medium (to mimic its entry into skin from the systemic circulation). DDS-protein adducts were readily detected in skin explants exposed to either DDS or D-NOH. Adducts were detected mainly in the upper epidermal region in response to epicutaneous application, whereas adducts were formed all over the explants when DDS/D-NOH were mixed in the culture medium. In addition, adducts were visible in HLA-DR+ cells, indicating their presence in the dendritic cell population in the skin. Our results demonstrate the ability of intact human skin to bioactivate DDS leading to protein haptenation.     

Pseudoexfoliation as a risk factor for prevalent open‐angle glaucoma

Purpose: To estimate the risk of open‐angle glaucoma (OAG) associated with exposure to pseudoexfoliation (PEX) and increased intraocular pressure (IOP). Methods: In 1984?86, a cross‐sectional, population‐based survey was conducted in the municipality of Tierp, central Sweden. Its target population comprised 2429 residents aged 65–74 years. In addition to a sample of 760 people, patients previously diagnosed with glaucoma were examined. The prevalence of OAG in the target population was estimated from the prevalence in the sample and patients already diagnosed. A review of prevalent cases in 1984–86 was undertaken in 2006. Results: Definite OAG was established in 77 cases, corresponding to a prevalence of 5.3% (95% confidence interval [CI] 4.4–6.2). Of these, 23 represented newly detected cases. The prevalence of PEX was 17.2% (95% CI 14.6–19.9), calculated from 134 cases in the population sample. When adjusting for gender, PEX was associated with a 4.7‐fold (95% CI 2.2–9.4) increased risk of OAG. For clinical cases only, the risk was 16‐fold (95% CI 4.8–56) greater in subjects with PEX, compared with those without PEX. In individuals without a previous diagnosis of glaucoma, an IOP ≥ 20 mmHg was associated with a 9.7‐fold (95% CI 3.7–27) increased risk, but PEX alone was not a risk factor for OAG (adjusted odds ratio = 0.96). Conclusions: Pseudoexfoliation was associated with OAG only in people previously diagnosed with the disease. In cases detected in the population‐based survey, increased IOP was a serious risk factor.