Overexpression of cell cycle regulatory proteins correlates with advanced tumor stage in head and neck squamous cell carcinomas

Squamous cell carcinoma of the head and neck region (HNSCC) is the sixth most frequent cancer worldwide. In the USA, 30,000 new cases and 8,000 deaths are reported each year. Differences between normal epithelium and cancer cells from the upper aerodigestive tract arise from alterations in expression of specific genes controlling proliferation and immortalization. The protein products of these genes include growth factor receptors, cell cycle regulators, and tumor suppressors which affect a variety of intracellular signaling pathways. To determine how altered expression of these gene products contribute to HNSCC progression, we examined expression of epidermal growth factor receptor (EGFR), cyclins, p16INK4A, c-myc, proliferating cell nuclear antigen (PCNA), and telomerase in archival pathology specimens by immunohistochemistry. A substantial majority of HNSCC tumors showed loss of p16INK4A expression and dramatic overexpression of EGFR. Overexpression of this receptor correlated with increased cyclin A levels and high mitotic index. EGFR, cyclins A, -B1, -E, and c-myc overexpression was significantly increased in stage III and IV tumors compared to early stage cancers. hTERT was expressed in all tumors and primarily in the basal layer cells of dysplastic epithelial lesions. Suprabasal expression of hTERT was found in a significantly higher number of HNSCC cases than in dysplastic lesions. These results indicate that overexpression of cell cycle regulatory proteins correlates with advanced tumor stage in HNSCC.     

3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.     

Cement pressurization after provisional repair of femoral cortical defects

Cortical defects are common and problematic in cemented revision hip arthroplasty. Extruded cement can cause thermal injury, pain, and impingement. Decreased cement pressure limits bony interdigitation and leads to loosening. Historically, surgeons have used a finger to contain cement and improve pressure, and decrease porosity, but, with large or multiple defects, fingers are ineffective. Novel solutions--such as wrapping foil suture packaging or half a syringe barrel around the defects--have been previously published. In the study reported here, we used modern cementing techniques, continuous pressure monitoring, and porosity calculations to analyze the utility of the 3 provisional defect-fixation techniques. The foil and the hemisyringe worked as well as a finger (P > .05). All 3 techniques enhanced pressurization and maintained the porosity reduction. Although manually pressurizing cement and feeling resistance provide the surgeon with more tactile feedback, using the gun and a proximal adapter was more effective in improving pressure. Using these provisional defect-fixation techniques as well as a cement gun and proximal adapter can improve cement pressure and decrease porosity. These techniques are particularly useful with large or multiple cortical defects encountered in revision arthroplasty or total hip arthroplasty after open reduction.     

Isolation and molecular characterization of nalidixic acid-resistant extraintestinal pathogenic Escherichia coli from retail chicken products

Fluoroquinolone use in poultry production may select for resistant Escherichia coli that can be transmitted to humans. To define the prevalence and virulence potential of poultry-associated, quinolone-resistant E. coli in the United States, 169 retail chicken products from the Minneapolis-St. Paul area (1999 to 2000) were screened for nalidixic acid (Nal)-resistant E. coli. Sixty-two (37%) products yielded Nal-resistant E. coli. From 55 products that yielded both Nal-resistant and susceptible E. coli, two isolates (one resistant, one susceptible) per sample were further characterized. Twenty-three (21%) of the 110 E. coli isolates (13 resistant, 10 susceptible) satisfied criteria for extraintestinal pathogenic E. coli (ExPEC), i.e., exhibited >or=2 of pap (P fimbriae), sfa/foc (S/F1C fimbriae), afa/dra (Dr binding adhesins), iutA (aerobactin receptor), and kpsMT II (group 2 capsule synthesis). Compared with other isolates, ExPEC isolates more often derived from virulence-associated E. coli phylogenetic groups B2 or D (74% versus 32%; P < 0.001) and exhibited more ExPEC-associated virulence markers (median, 10.0 versus 4.0; P < 0.001). In contrast, the Nal-resistant and -susceptible populations were indistinguishable according to all characteristics analyzed, including pulsed-field gel electrophoresis profiles. These findings indicate that Nal-resistant E. coli is prevalent in retail poultry products and that a substantial minority of such strains represent potential human pathogens. The similarity of the Nal-resistant and -susceptible populations suggests that they derive from the same source population, presumably the avian fecal flora, with Nal resistance emerging by spontaneous mutation as a result of fluoroquinolone exposure.     

An overview of methodologies,proficiencies, and training resources for controlled feeding studies

Dietary intervention studies of human beings produce valuable information regarding dietary effects on biological processes and risk factors for chronic diseases. Using the well-controlled feeding approach, participants consume only foods that have been precisely prepared in a research kitchen, whereas in behavioral counseling studies, participants self-select their foods within guidelines. Because controlled feeding studies meticulously control experimental diets, they are intellectually and logistically challenging to conduct. They afford exciting opportunities for dietetic professionals in designing protocols, developing budgets, and collaborating in multidisciplinary research teams. Research dietitians use food composition data and chemical analysis of menus to prepare research diets with precision. They determine the energy requirements of subjects and adjust diets as required, most often for weight maintenance, throughout the study. All people involved in research must be attentive to the ethical treatment of the study participants while motivating them to adhere to the protocol requirements. Dietitians possess many of these skills, but may require training specific to well-controlled feeding studies. Information related to the conduct of controlled feeding studies has recently become more accessible. We provide an overview of well-controlled feeding study methodologies, proficiencies for planning and implementing these studies, and training resources.     

Managing children with acute non‐traumatic limp: the utility of clinical findings,laboratory inflammatory markers and X‐rays

Objectives: To examine the utility of clinical findings, laboratory markers and X‐ray radiographs (X‐ray) in the assessment of children presenting with an acute non‐traumatic limp. Methods: A retrospective review of all children who received hip X‐rays over a 2 year period in the Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand. Children were identified from the radiology database and clinical notes reviewed. Children aged 0–12 years old were included if the limp was acute (less than 2 weeks of duration) with no history of trauma. X‐rays were reported by a consultant paediatric radiologist. Univariate and multivariate analysis was performed to determine predictors of osteomyelitis and septic arthritis. Receiver operator curves were used to assess the optimum cut‐off points for C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white cell count (WCC). Results: A total of 350 patients were enrolled. There were 21 (6%) abnormal X‐rays . Fever, non‐weight bearing, raised white cell count, raised erythrocyte sedimentation rate and raised CRP were all associated with increased risk of septic hip or osteomyelitis. The optimum inflammatory marker cut‐off was a CRP of 12 with a sensitivity of 87% and specificity of 91%. Conclusion: In acute non‐traumatic limp, X‐rays of the hips diagnose slipped upper femoral epiphysis, as such they should be routinely used from the age of 9 years upwards. Below this age they are of little value. Inflammatory markers have utility in risk‐stratifying children and selecting a group in whom to proceed with definitive tests to exclude osteomyelitis or septic hip. Children with a short history and minimal symptoms can be managed with appropriate follow up and no investigations.     

Electronic Medical Record Adoption in Hospitals That Care for Children

ObjectiveHospitals that care for children face unique barriers in electronic medical records (EMR) use that may affect their ability to meaningfully use EMR. The purpose of this study was to investigate hospitals that care for children, both freestanding and adult hospitals with children's services, to determine progress toward advanced stages of EMR use.MethodsThe American Hospital Association survey described hospitals across the United States. Healthcare Information and Management Systems Society 2006 and 2010 databases identified hospitals' EMR use. EMR stage was classified according to previous studies. Multivariable analysis was used to determine independent predictors of EMR use.ResultsThe analysis included 2794 hospitals. During the study time frame, a significant increase occurred for hospitals moving into any stage of EMR in adult hospitals with children's services (47% to 75%; P < .001), while improvements for freestanding children's hospitals were modest at best (46% to 59%; P = .3). Conversely, freestanding children's hospitals had the largest gain in advance stage 3 adoption (6% to 39%; P < .001) compared to adult hospitals with children's services (6% to 23%; P < .001). Freestanding children's hospitals were less likely to use pharmacy information systems but more likely to use computerized provider order entry.ConclusionsIn 2010, freestanding children's hospitals had the highest percentage use of advanced stage EMR (39%), but the lowest improvements in percentage of hospitals entering into any stage of adoption over the study period. This trend created a digital divide among freestanding children's hospitals that may improve with pediatric-specific electronic medication management products.     

Personalized Medicine for Diabetes: Environmental Influences on Development of Type 2 Diabetes and Obesity: Challenges in Personalizing Prevention and Management

Recent epidemic increases in the U.S. prevalence of obesity and diabetes are a consequence of widespread environmental changes affecting energy balance and its regulation. These environmental changes range from exposure to endocrine disrupting pollutants to shortened sleep duration to physical inactivity to excess caloric intake. Overall, we need a better understanding of the factors affecting individual susceptibility and resistance to adverse exposures and behaviors and of determinants of individual response to treatment. Obesity and diabetes prevention will require responding to two primary behavioral risk factors: excess energy intake and insufficient energy expenditure. Adverse food environments (external, nonphysiological influences on eating behaviors) contribute to excess caloric intake but can be countered through behavioral and economic approaches. Adverse built environments, which can be modified to foster more physical activity, are promising venues for community-level intervention. Techniques to help people to modulate energy intake and increase energy expenditure must address their personal situations: health literacy, psychological factors, and social relationships. Behaviorally oriented translational research can help in developing useful interventions and environmental modifications that are tailored to individual needs.