Exercise and intestinal polyp development in APCMin mice

PURPOSE: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms. METHODS: Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice. RESULTS: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01). CONCLUSION: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.     

Snowmobile injuries and fatalities in children

Background/Purpose: Snowmobiling is a popular form of wintertime recreation but can be associated with significant morbidity and mortality. To better understand snowmobile trauma in children, medical records were reviewed, evaluating the relationships between demographic data, mechanisms, and resultant injuries. In addition, because prior studies of childhood snowmobile fatalities have reviewed only national databases, state and national data were combined to evaluate possible underreporting. Methods: Medical records were reviewed of children [le ]17 years old admitted to one trauma center between 1991 and 2000 with snowmobile-related injuries. Demographics, helmet usage, driver versus passenger, mechanism, injuries, injury severity score (ISS), and outcome data were recorded. Statistical analyses were performed to identify relationships between potential causative factors and ISS. State mortality data were acquired from state agencies and 2 databases of the U.S. Consumer Product Safety Commission (CPSC). Data from the 3 sources were compared, and a single list of fatalities was compiled and evaluated. Results: Thirty-one children (65% boys; mean age, 12 years) were admitted with snowmobile-related injuries. Fifty-two percent were driving the snowmobile. Helmet usage was 68%. The most common mechanisms were collisions with a fixed object (42%) and with a motor vehicle (35%). The head was the most commonly injured site (71%) followed by the extremities (58%). ISS ranged from 1 to 38 (median, 10). Increased age and the child driving were the only factors associated with increased ISS (P [lt ] .05). One child died of a massive head injury. Twenty-two fatalities (70% boys; mean age, 14 years) statewide were identified from state and national databases, only 12 of which were identified by the CPSC Death Certificate file. Head injury was the most common cause of death. Conclusions: Reckless snowmobiling leads to significant morbidity and mortality among children. Prior reports based on CPSC data likely underestimated the number of snowmobile-related fatalities. Our findings support previous American Academy of Pediatrics recommendations, including the restriction of snowmobile driving by children under 16, graduated licensing for older children, and universal helmet usage. J Pediatr Surg 38:784-787. [copy ] 2003 Elsevier Inc. All rights reserved.     

Detection and diagnosis of oral cancer by light-induced fluorescence

BACKGROUND AND OBJECTIVE: New techniques for non-invasive early detection and diagnosis of oral dysplasia and carcinoma are required. Our objective was to determine in the hamster cheek pouch model whether differentiation between the healthy tissue and the different stages of oral premalignancy and malignancy is possible using laser-induced fluorescence after tissue exposure to 5-Aminolevulinic acid (ALA). STUDY DESIGN/MATERIALS AND METHODS: DMBA carcinogenesis was applied to one cheek pouch in 18 hamsters for 0-20 weeks. Prior to sacrifice, 20% ALA was applied to the cheek tissues. Excised cheek tissues were cryosectioned and imaged using fluorescence microscopy with excitation at 405 nm, detection at 635 nm. After fluorescence measurement, H&E staining and histopathological evaluation were performed. RESULTS: Fluorescence intensity was significantly lower in healthy tissue than in pathological tissues. Significantly higher intensities and more "fluorescence hot spots" occurred in severe dysplasia and carcinoma than in healthy tissue, hyperkeratosis, mild and moderate dysplasia. CONCLUSIONS: Light-induced fluorescence after ALA exposure can differentiate between the different stages of premalignancy and malignancy. Its ability to differentiate between healthy tissue and early pathology is particularly interesting     

Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1

BACKGROUND: Previous linkage studies have suggested prostate cancer susceptibility genes located on chromosomes 1, 20, and X. Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2. Presently, these linkage regions and candidate genes appear to explain only a small proportion of hereditary prostate cancer cases suggesting the need for additional whole genome analyses. METHODS: A genome-wide mode-of-inheritance-free linkage scan, using 405 genetic markers, was conducted on 175 pedigrees, the majority containing three or more affected individuals diagnosed with prostate cancer. Stratified linkage analyses were performed based on previously established criteria. RESULTS: Results based on the entire set of 175 pedigrees showed strong suggestive evidence for linkage on chromosome 17q (LOD = 2.36), with strongest evidence coming from the subset of pedigrees with four or more affected individuals (LOD = 3.27). Race specific analyses revealed strong suggestive evidence for linkage in our African-American pedigrees on chromosome 22q (LOD = 2.35). CONCLUSIONS: Genome-wide analysis of a large set of prostate cancer families indicates new areas of the genome that may harbor prostate cancer susceptibility genes. Specifically, our linkage results suggest that there is a prostate cancer susceptibility gene on chromosome 17 that is independent of ELAC2. Further research including combined analyses of independent genome-wide scan data may clarify the most important regions for future investigation.     

Prenatal ultrasound: detection and diagnosis of limb abnormalities

Many cases of congenital limb abnormalities referred for orthopaedic treatment are not diagnosed prenatally, despite routine ultrasound scanning. The authors aimed to study the detection rate and diagnostic accuracy of prenatal scans. Data concerning two groups of patients were collected. First, the authors followed-up 26,203 babies that had been scanned prenatally. Sixty had limb abnormalities; 15 of the abnormalities were detected prenatally (sensitivity 25%, 95% confidence interval 14%-36%). Second, the authors studied 67 cases from the Wessex Antenatally Detected Anomalies Register that had been identified prenatally. The diagnosis was confirmed postnatally in 56 cases (positive predictive value 84%, 95% confidence interval 75%-93%).     

Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxyadenosine

N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 0.6 mM) was allowed to react with 2'-deoxyadenosine (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were followed by HPLC-MS and HPLC-MS/MS techniques. Although the predominant reaction observed was chlorambucil hydrolysis, ca. 7% of 1 reacted with various heteroatoms of the nucleoside. The principal site of alkylation was N1. Several other adducts were also detected. The N1, N6, N3, and N7 derivatives were characterized by means of MS/MS, UV, and (1)H NMR. The N6 adduct is derived directly from alkylation of N6 of 2'-dAdo. Dimroth rearrangement of the N1 adduct to the N6 adduct was very slow under the reaction conditions employed. Minor adducts such as a carbohydrate derivative were tentatively characterized by MS/MS. No cross-links were detected. The role of chlorambucil-2'-deoxyadenosine adducts in the cytotoxicity and mutagenicity of 1 is also discussed.     

Antioxidant properties of newly synthesized N-propargylamine derivatives of nitroxyl: a comparison with deprenyl

In our search for novel, low-toxic, cell-penetrable and neuroprotective antioxidants, we have designed a number of novel N-propargylamine derivatives of nitroxyl, named "JSAKs". The reactivity and antioxidative potency of two selected JSAKs and their parent nitroxyl against reactive oxygen species (ROS) were examined in vitro, in a cell-free gamma-radiolysis and in model Fenton-type reaction systems and compared with those of deprenyl, the investigated member of adjunct therapies in clinical neurology. The efficiency of JSAKs to suppress the oxidative degradation of a model target (deoxyribose), deprenyl and dopamine, caused by hydroxyl radical (*OH) was also investigated. The data demonstrated that the novel compounds, JSAKs, can act as promising antioxidants and protectors of targets against ROS toxicity, thus, providing a sound chemical basis for further comparative investigations of their activity in vivo. The findings were discussed from a mechanistic point of view as well as in terms of the structure-dependent, comprehensive properties of JSAKs as dual-function compounds: antioxidants and anti-apoptotic propargylamines. The novel class of N-propargylamine nitroxyls, JSAKs, may have potential implications for the experimental therapies of Parkinson's disease, where ROS mediate deleterious effects, because these compounds have an ability to either block or reduce the progression of neurotoxic cascade of brain damage.     

TGF-betal/Smad signaling in prostate cancer

Adenocarcinoma of the prostate is the most common type of cancer, excluding skin cancer, and the second leading cause of cancer death in adult men in the United States. The lifetime risk for developing symptomatic prostate cancer is one in five for an American man. A pivotal step in carcinogenesis is a shift in the balance between proliferation, differentiation, and apoptosis that favors cell proliferation. Transforming growth factor-beta (TGF-beta) is a key negative growth regulator in the normal prostate. Although TGF-beta) inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Elevated expression of TGF-beta in prostate cancer cells is associated with poor clinical outcome. Over-expression of TGF-beta aids tumorigenesis by not only stimulating angiogenesis and suppressing the immune system, but also by acting directly on the prostate tumor cells. While prostate cancer cells become resistant to TGF-beta-induced growth inhibition and apoptosis, they retain other TGF-beta-induced responses that enhance tumorgenicity. such as induction of extracellular matrix proteins, cell adhesion proteins and proteases. These direct tumor effects are mediated primarily through Smad signaling. This review addresses the mechanisms by which prostate cancer cells may acquire TGF-beta resistance and promote tumorgenicity. Understanding the mechanisms underlying TGF-beta resistance is important for the identification and development of better diagnostic markers and more effective strategies for treating prostate cancer.     

Quality improvement for pressure ulcer care in the nursing home setting: the Northeast Pressure Ulcer Project

OBJECTIVES: The objectives of this study were to evaluate the impact of a collaborative model of quality improvement in nursing homes on processes of care for the prevention and treatment of pressure ulcers. STUDY DESIGN: The study design was experimental. SETTING: We studied 29 nursing homes in New Jersey, Pennsylvania, and Rhode Island. PARTICIPANTS: Participants consisted of pressure ulcer quality improvement teams in 29 nursing homes. INTERVENTION: Quality improvement teams attended a series of workshops to review clinical guidelines and quality improvement principles and to share best practices, and worked one-on-one with mentors to implement quality improvement techniques and to collect data independently. MEASUREMENTS: We calculated process measures based on the Agency for Healthcare Research and Quality (AHRQ) guidelines. Process measures addressed each facility's processes of care for the prevention and treatment of pressure ulcers at baseline and after 12 months of intervention. Prevention measures focused on recent admissions and high-risk residents; treatment measures focused on patients newly diagnosed with pressure ulcers and all patients with pressure ulcers. RESULTS: Overall, 6 of 8 prevention process measures improved significantly, with percent difference between baseline and follow up ranging from 11.6% to 24.5%. Three of 4 treatment process measures improved significantly, with 5.0%, 8.9%, and 25.9% difference between baseline and follow up. For each process measure, between 5 and 12 facilities demonstrated significant improvement between baseline and follow up, and only 2 or fewer declined for each process measure. CONCLUSION: Improvement in processes of care after the use of a structured collaborative quality improvement approach is possible in the nursing home setting.     

Effects of cataractogenesis on the CDP-choline pathway: changes in ATP concentration and phosphocholine synthesis during and after exposure of rat lenses to sugars in vitro and in vivo

We measured choline influx and phosphorylation, ATP concentration ([ATP]), choline kinase activity and lens swelling during formation and partial reversal of sugar cataracts in rat lenses incubated with xylose or galactose and in lenses of galactosemic rats. [ATP] and phosphocholine (P-Cho) synthesis decreased about 60 and 40% after 4 h in normal rat lenses incubated up to 24 h in medium containing 30 mM xylose and partially recovered when the lenses were then removed from the xylose. Incubation with the somewhat less cataractogenic sugar galactose decreased P-Cho synthesis but had little effect on [ATP]. P-Cho synthesis decreased rapidly in the lenses of rats fed a 50% galactose diet, but began recovery by the third day on this diet. [ATP] decreased for at least 10 days during the galactose diet and did not recover, even with resumption of the control diet (50% starch) after 4 or 7 days. The results of in vitro and in vivo sugar cataractogenesis differed from each other in several respects, including effects on choline influx and the degree to which the changes were reversible. The in vitro and in vivo sugar cataracts, however, could both produce swelling and opacification of the lens and decreased P-Cho synthesis and [ATP]. Neither model caused a substantial change in the choline kinase activity (as measured in cell-free assays). The data did not generally support the hypothesis that decreased [ATP] causes decreased P-Cho synthesis.