National guidelines may reduce socioeconomic disparities in treatment selection for esophageal cancer.

The 2011 National Comprehensive Cancer Network guidelines first incorporated the results of the landmark CROSS trial, establishing induction therapy (chemotherapy ± radiation) and surgery as the treatment standard for locoregional esophageal cancer in the United States. The effect of guideline publication on socioeconomic status (SES) inequalities in cancer treatment selection remains unknown. Patients diagnosed with Stage II/III esophageal cancer between 2004 and 2013 who underwent curative treatment with definitive chemoradiation or multimodality treatment (induction and surgery) were identified from the Surveillance, Epidemiology and End Results (SEER)-Medicare registry. Clinicopathologic characteristics were compared between the two therapies. Multivariable regression analysis was used to adjust for known factors associated with treatment selection. An interaction term with respect to guideline publication and SES was included Of the 2,148 patients included, 1,478 (68.8%) received definitive chemoradiation and 670 (31.2%) induction and surgery. Guideline publication was associated with a 16.1% increase in patients receiving induction and surgery in the low SES group (21.4% preguideline publication vs. 37.5% after). In comparison, a 4.5% increase occurred during the same period in the high SES status group (31.8% vs. 36.3%). After adjusting for factors associated with treatment selection, guideline publication was associated with a 78% increase in likelihood of receiving induction and surgery among lower SES patients (odds ratio 1.78; 95% confidence interval (CI): 1.05,3.03). Following the new guideline publication, patients living in low SES areas were more likely to receive optimal treatment. Increased dissemination of guidelines may lead to increased adherence to evidence-based treatment standards.

Microbiological impact of three commercial laying hen housing systems.

Hen housing for commercial egg production continues to be a societal and regulatory concern. Controlled studies have examined various aspects of egg safety, but a comprehensive assessment of commercial hen housing systems in the US has not been conducted. The current study is part of a holistic, multidisciplinary comparison of the diverse aspects of commercial conventional cage, enriched colony cage, and cage-free aviary housing systems and focuses on environmental and egg microbiology. Environmental swabs and eggshell pools were collected from all housing systems during 4 production periods. Total aerobes and coliforms were enumerated, and the prevalence of Salmonella and Campylobacter spp. was determined. Environmental aerobic and coliform counts were highest for aviary drag swabs (7.5 and 4.0 log cfu/mL, respectively) and enriched colony cage scratch pad swabs (6.8 and 3.8 log cfu/mL, respectively). Aviary floor and system wire shell pools had the greatest levels of aerobic contamination for all eggshell pools (4.9 and 4.1 log cfu/mL, respectively). Hens from all housing systems were shedding Salmonella spp. (89-100% of manure belt scraper blade swabs). The dry belt litter removal processes for all housing systems appear to affect Campylobacter spp. detection (0-41% of manure belt scraper blade swabs) considering detection of Campylobacter spp. was much higher for other environmental samples. Aviary forage area drag swabs were 100% contaminated with Campylobacter spp., whereas enriched colony cage scratch pads had a 93% positive rate. There were no differences in pathogen detection in the shell pools from the 3 housing systems. Results indicate egg safety is enhanced when hens in alternative housing systems use nest boxes. Additionally, current outcomes indicate the use of scratch pads in hen housing systems needs to be more thoroughly investigated for effects on hen health and egg safety.

Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites.

1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1'-hydroxylation, diltiazem N-demethylation and testosterone 6beta-hydroxylation with K(i) ranging from 3 to 37 micro M in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6beta-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding k(inact) and K(i) of 0.04 min(-1) and 0.2 micro M for tamoxifen and 0.08 min(-1) and 2.6 micro M for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.

Involvement of the nuclear matrix in the control of skeletal genes: the NMP1 (YY1), NMP2 (Cbfa1), and NMP4 (Nmp4/CIZ) transcription factors.

The functional role of the osteoblast nuclear matrix has been a matter of supposition. Its presumed function as an architectural agent of transcription derives primarily from the low solubility of nuclear matrix proteins and their typical localization into discrete subnuclear domains. In addressing how the nuclear matrix regulates skeletal genes, the authors compare Nmp4, Cbfal, and YY1 for the purpose of profiling osteoblast nuclear matrix transcription factors. All three proteins contribute to the transcription of ECM genes and partition into the osteoblast nuclear matrix via a nuclear matrix targeting domain. The authors propose that osteoblast nuclear matrix transcription factors involved in ECM regulation generally have the capacity to alter DNA geometry and reciprocally respond to DNA as an allosteric ligand. This may allow these proteins to adapt to the local nuclear architecture and generate the pattern of regulation specified by that architecture via unmasking of the appropriate transactivation domains. Osteoblast nuclear matrix transcription factors may also act as transcriptional adaptor molecules by supporting the formation of higher order protein complexes along target gene promoters. The genes encoding all three proteins considered here have trinucleotide repeat domains, although the significance of this is unclear. There is no canonical nuclear matrix binding motif, but finger-like structures may be suited for anchoring proteins to discrete subnuclear domains. Finally, the ability to leave the osteoblast nuclear matrix may be as important to the function of some nuclear matrix transcription factors as their association with this subcompartment.

Why do in utero stem cell transplants sometimes fail?

In utero stem cell transplantation promises a novel therapeutic approach to those genetic disorders that can be diagnosed in early pregnancy and that could lead to either severe disability or death. Available scientific evidence suggests that such procedures could achieve clinically relevant levels of engraftment with donor cells and that the resulting sustained chimerism is potentially long lived. However, the relatively few cases performed so far have not borne out initial hopes, and both the source and the type of cell preparation to be transplanted and the choice of disorders to target with this therapy remain controversial.

Affective and physiological responses to racism: the roles of afrocentrism and mode of presentation.

Recent experiments have examined the subjective and physiological responses of African Americans to racism using video-taped vignettes or emotional imagery. These studies reported changes in mood and increases in cardiovascular (CV) and electromyographic (EMG) activity when analogs of the stressful situations were encountered. In addition, individual differences in responses were found to be related to various personality measures. The present study examined the mood, CV and EMG responses of 60 African-American women as they encountered social situations that included blatant and more subtle forms of racism. Half of the sample viewed both vignettes while the remainder imagined them. The relationship between responses and Afrocentrism, a measure related to black identity, was examined. Significant changes in heart rate, digital blood flow and facial muscle activity in the corrugator regions resulted. The most pronounced changes occurred when blatantly racist material was encountered. Mood changes tended to be stronger when material was imagined versus viewed. In general, Afrocentricity was not related to physiological responses to the scripts, though mood responses and Afrocentricity were related in several instances. The findings indicate that CV, as well as EMG and mood responses, are sensitive to various forms of racism presented in imagery and video modes.

Metabolic responses to forced dives in Pekin duck measured by indirect calorimetry and 31P-MRS.

We tested the hypothesis that forced-dived ducks experience a reduction in metabolic rate during prolonged submergence. Unidirectionally ventilated conscious ducks were subjected to forced dives by temporarily stopping the airflow in the ventilation system and simultaneously filling a face mask with cold water. A typical cardiovascular response to submergence was observed: bradycardia and maintained arterial blood pressure. Phosphorylated metabolite concentrations in the pectoral muscle were measured noninvasively by phosphorus magnetic resonance spectroscopy (31P-MRS). ATP content was constant, and phosphocreatine was depleted via the creatine kinase reaction at a rate similar to the resting rate of ATP turnover, which was estimated to be 0.9 mumol.min-1 x g-1 in resting perfused pectoral muscle of pentobarbital-anesthetized ducks. Oxygen from myoglobin supplied at most 12% of the ATP required by the resting muscle during dives. Whole animal postdive excess oxygen consumption and blood lactic acid accumulation suggested that the shortfall in aerobic metabolism during forced dives was compensated by an increase in anaerobic metabolism.

Separan AP-273 and renal function: a novel natriuretic substance.

Recent studies have demonstrated that an anionic polyacrylamide (Separan, Union Carbide Corp.) decreased the formation of atherosclerotic lesions in the rabbit (Separan AP-30) and increased cardiac output (Separan AP-273) in the rat. Since the effect of these compounds on renal function was unknown, we investigated the dose-response relationship between Separan AP-273 and the renal excretion of electrolytes and water. In the anesthetized rat, intravenous injections of Separan at 0.01, 0.03, 0,10, and 0.30 mg/kg produced a dose-related increase in urine volume, sodium excretion, and osmolar clearance. Potassium excretion was increased less than twofold only at the maximal dose tested. At this high dose, the effect on sodium and water excretion was greater (five- and seven-fold, respectively). Creatinine clearance was not altered by these interventions. As well, the maximal dose studied was previously shown to have no effect on blood flow. These results indicate that Separan AP-273 is a potent diuretic and natriuretic substance. Taken together with similar studies using the poly(ethylene oxide) Polyox WSR N-60K, these results suggest that drag-reducing polymers may represent a novel group of compounds with diuretic and natriuretic effects.

The contribution of nasal receptors to the cardiac response to diving in restrained and unrestrained redhead ducks (Aythya americana).

In restrained redhead ducks, forced submergence caused heart rate to fall from 100 +/- 3 beats min-1 (mean +/- S.E.M., N = 12) to a stable underwater rate of 35 +/- 4 beats min-1 (N = 12) within 5 s after submergence. Bradycardia was unaffected by breathing oxygen before a dive, but was virtually eliminated by local anaesthesia of the narial region. In contrast, in a dabbling duck (Anas platyrhynchos) bradycardia in short dives was eliminated by breathing oxygen before a dive. In unrestrained diving, on a man-made pond, heart rate in redheads diving voluntarily (y) was related to pre-dive heart rate (x) by the equation y = 76 + 0.29 +/- 0.05x +/- 17 (r2 = 0.71). Chasing, to induce submergence, had variable effects on this relationship. Local anaesthesia of the narial region inhibited voluntary diving but heart rates in chase-induced dives after nasal blockade were significantly higher, by 10-30%, than those obtained from untreated ducks in chase-induced dives. Breathing oxygen before voluntary dives had no apparent effect on heart rate after 2-5 s submergence. Voluntary head submersion by dabbling ducks caused no change in heart rate. We conclude that nasal receptors make only a minor contribution to cardiac responses in unrestrained dives, compared with forced dives, in diving ducks. Furthermore, these results show that little can be learned about cardiac responses in free diving ducks from studies of forced dives in dabblers or divers.

Self-control of psychophysiologic response to motion stress: using biofeedback to treat airsickness.

Investigators of the Neuropsychiatry Branch, Clinical Sciences Division, U.S. Air Force School of Aerospace Medicine (USAFSAM), provided biofeedback-moderated behavioral treatment to 53 fliers grounded for chronic, severe motion sickness, and followed each flier for 2 years after treatment completion. Success was defined as returning to and maintaining satisfactory operational flying status. Of these, 42 fliers (79%) met this criterion; 3 (6%) were partially successful, and 8 (15%) were subsequently grounded for recurrent airsickness. Follow-on studies will investigate psychophysiological mechanisms through which this method of treatment works.

Biofeedback rehabilitation of airsick aircrew.

The biofeedback treatment of 20 aircrew, disabled by chronic severe airsickness, is reported. The USAF School of Aerospace Medicine (SAM) Airsick Rehabilitation Program requires careful selection to insure high motivation and thorough medical screening to rule out intercurrent medically disqualifying conditions. Patients are trained in relaxation techniques and placed in a modified Barany chair, capable of tilting as well as rotating. Psychological responses to motion stimulation are constantly monitored by both patient and investigators. Motion sickness is provoked, which the patient learns to control and abort through exercising autonomic control. Of 19 eligible, 16 have been returned to fully flying duties.