Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants

OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.     

Nutrient intake and body weight in a large HIV cohort that includes women and minorities

OBJECTIVE: Evaluate the baseline nutrient intake of an HIV positive population that includes significant representation from women and minorities, and determine the relationship between state of disease and nutritional intake. DESIGN: Baseline data from a prospective study (Nutrition for Healthy Living). SUBJECTS: Individuals with HIV in the Boston and Rhode Island area (n = 516); 25% were women and 30% were minorities. METHODS: Nutrient intakes from 3-day food records, which included vitamin/mineral supplements, were estimated by gender and nonwhite vs white categories, after grouping by CD4 lymphocyte counts. STATISTICAL ANALYSES: Spearman correlation coefficients, Wilcoxon signed rank test, Wilcoxon rank sum test, chi2 test, and restricted cubic spline model were used for data analyses as indicated. RESULTS: Macronutrient but not micronutrient intake was statistically and inversely associated with decreasing CD4 cell counts. The median intake of micronutrients was higher in the study sample compared with the same age and gender group in NHANES III data; however, 25% to 35% of the women in our study sample had dietary intakes of less than 75% of the DRIs for vitamins A, C, E and B-6, and iron and zinc. White men had statistically higher values of all micronutrients compared with nonwhite men. Body mass index for men and women ranged from 23 to 25. CONCLUSIONS/APPLICATIONS: Median values for micronutrient intake from food plus vitamin/mineral supplements were adequate in the overall population studied, but a large percent of women and minorities had inadequate nutrient intakes and would benefit from dietary assessment and counseling.     

Weight loss and body-composition changes in men and women infected with HIV

BACKGROUND: The nature of body-composition changes in HIV-associated weight loss is unclear. OBJECTIVE: We examined the relation between the initial percentage of body fat and the composition of weight loss in men and women with HIV infection. DESIGN: HIV-positive adults were seen at semiannual clinic visits, at which time weight, fat, and fat-free mass were determined. The unit of analysis was the person-interval. RESULTS: Five hundred fifty-one persons contributed 2266 intervals of data, of which 311 (14%) were intervals in which weight loss was >/= 5% of initial (start of interval) weight. Of these, 208 (67%) intervals met the criteria for analysis (123 from men and 85 from women). Loss of fat-free mass was dependent on the initial percentage of body fat in the men with < 32% body fat. A plot of the initial percentage of body fat compared with loss of fat-free mass (kg) suggested a nonlinear relation over the range of body fat examined. There was no clear relation between the initial percentage of body fat and loss of fat-free mass in the women. CONCLUSIONS: In men with HIV-associated weight loss, the weight lost as fat-free mass depends on the initial percentage of body fat at low levels of body fat but appears to be independent of initial percentage of body fat at high levels of body fat. In women with HIV-associated weight loss who have normal-to-high body fat stores, loss of fat-free mass is independent of the initial percentage of body fat.     

X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.

Seven boys with an apparently X-linked syndrome of dilated cardiomyopathy, growth retardation, neutropenia, and persistently elevated urinary levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate were studied. The natural history of the disorder was characterized by severe or lethal cardiac disease and recurrent infections during infancy and early childhood but relative improvement in later childhood. The initial presentation of the syndrome varied from congenital dilated cardiomyopathy to infantile congestive heart failure to isolated neutropenia without clinical evidence of heart disease. The excretion of 3-methylglutaconate and 3-methylglutarate appeared to be independent of the metabolism of leucine, the presumed precursor of these organic acids in humans. Although the cause of the organic aciduria remains obscure, the constellation of biochemical and clinical abnormalities forms a distinct syndrome that may be a relatively common cause of dilated cardiomyopathy or neutropenia in boys during infancy and childhood.     

Magnetic Resonance in Schizophrenia

In vivo magnetic resonance imaging (MRI) of schizophrenic patients permits the direct and noninvasive study of brain biochmeistry, structure, and function. During the last decade, a number of morphological abnormalities have been found in schizophrenic brains on the basis of qualitative and quantitative assessment of MRIs. Changes in ventricular volume, cortical volume, temporal lobe structures, and subcortical regions have been reported. The search for a precise and specific location underlying the pathophysiology of schizophrenia has led to the interpretation of imaging results in the context of interrelated systems of brain function, rather than isolated focal brain abnormalities. Furthermore, an important goal of imaging studies is to describe unusual features of schizophrenic brains that represent abnormalities central to the development of the disorder, including abnormalities that may represent vulnerabilities or risk factors, as well as those that are directly related to psychopathology. Identifying brain pathology that distinguishes schizophrenics' brains has proven difficult because it involves detecting rather subtle changes against a background of extensive normal variation. Application of powerful new magnetic resonance techniques continues to increase our understanding of these subtle changes. The importance of magnetic resonance spectroscopy is derived from the information it provides regarding the chemical content of the tissue being studied. Functional MRI provides a method for the assessment of functional architecture by measuring changes in oxidation and regional blood flow in discrete regions of the brain in response to challenge paradigms. These technologies promise to facilitate both the detection of cortical anomalies as well as provide the methods necessary for the systematic exploration of cortical structure and function needed to examine brain dysfunction from a network perspective.     

Primary cultures of prostate cells and their ability to activate carcinogens

Differences in the incidence of prostate cancer (CaP) amongst different migrant populations point to causative agents of dietary and/or environmental origin. Prostate tissues were obtained following transurethral resection of the prostate (TURP) or radical retropubic prostatectomy. After surgery, TURP-derived or tumour-adjacent tissue fragments were minced in warm PFMR-4A medium (37 degrees C) and suspensions pipetted into collagen-coated petri dishes. Non-adherent material was removed by washing with fresh medium after 12 h. Adhered cells subsequently reacted positively with monoclonal antibodies to prostate specific antigen (PSA). PSA was also detected in the medium. The genotoxicities of the chemical carcinogens 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), its N-hydroxy metabolite (N-OH-PhIP) and benzo[a]pyrene (B[a]P) in adherent cell populations from different donors (n=8) were examined. Cells were treated in suspension for 30 min at 37 degrees C in the presence of the DNA repair inhibitors hydroxyurea (HU) and cytosine arabinoside (ara-C). DNA single-strand breaks were detected in cells by the alkaline single cell-gel electrophoresis ('Comet') assay and quantified by measuring comet tail length (CTL) in microm. All three carcinogens induced dose-related increases in CTLs (P<0.0001) in cells from four donors 24 h post-seeding. However, in cells from a further two donors the genotoxic effects of PhIP, N-OH-PhIP and B[a]P were much less apparent after 48 h than after 24 h in culture. After 96 h in culture, cells from these donors appeared to be resistant to the comet-forming activity of the compounds. However, B[a]P-DNA adducts were still measurable by (32)P-postlabelling for up to 14 days following a 24-h exposure to 50 microM B[a]P in adhered cells from another two donors. This study shows that primary cultures of cells derived from the prostate can activate members of two classes of chemical carcinogens. Further development may provide a robust model system in which to investigate the aetiology of CaP.     

Provision of HPA-1a (PlA1)-negative platelets for neonatal alloimmune thrombocytopenia: screening, testing, and transfusion protocol

HPA-1a-negative platelet products are not routinely available for newborns with alloimmune thrombocytopenia. In this article we describe a program established to identify normal pheresis donors who are HPA-1a-negative and to organize their future donations so that our regional blood center would always have an HPA-1a-negative platelet product available. The solid phase red cell adherence assay was used for initial screening of platelet pheresis products. HPA-1a-negative donors were confirmed with the platelet suspension immunofluorescence test using three anti-HPA-1a sera. Screening of 2600 plateletpheresis donor samples identified 40 HPA-1a-negative donors. Of these, 36 are active and are coded for recognition on the daily pheresis inventory sheet. Theoretically, assuming four donations per year and donors' cooperation with scheduling, these 36 donors would enable us to have at least one HPA-1a-negative product available every day. In addition, a decision tree for patient management using platelet serology and availability of HPA-1a-negative products was developed. The GTI-PAK trade mark 12 is the major technique used for serologic screening of mothers of patients thought to have neonatal alloimmune thrombocytopenia. By screening pheresis donors and developing a clinical decision tree, HPA-1a-negative products, a rare resource, can be fully utilized.