Geographic destiny trumps taxonomy in the Roundtail Chub, Gila robusta species complex (Teleostei, Leuciscidae).

The Gila robusta species complex in the lower reaches of the Colorado River includes three nominal and contested species (G. robusta, G. intermedia, and G. nigra) originally defined by morphological and meristic characters. In subsequent investigations, none of these characters proved diagnostic, and species assignments were based on capture location. Two recent studies applied conservation genomics to assess species boundaries and reached contrasting conclusions: an ezRAD phylogenetic study resolved 5 lineages with poor alignment to species categories and proposed a single species with multiple population partitions. In contrast, a dd-RAD coalescent study concluded that the three nominal species are well-supported evolutionarily lineages. Here we developed a draft genome (~ 1.229 Gbp) to apply genome-wide coverage (10,246 SNPs) with nearly range-wide sampling of specimens (G. robusta N = 266, G. intermedia N = 241, and G. nigra N = 117) to resolve this debate. All three nominal species were polyphyletic, whereas 5 of 8 watersheds were monophyletic. AMOVA partitioned 23.1% of genetic variance among nominal species, 30.9% among watersheds, and the Little Colorado River was highly distinct (FST ranged from 0.79 to 0.88 across analyses). Likewise, DAPC identified watersheds as more distinct than species, with the Little Colorado River having 297 fixed nucleotide differences compared to zero fixed differences among the three nominal species. In every analysis, geography explains more of the observed variance than putative taxonomy, and there are no diagnostic molecular or morphological characters to justify species designation. Our analysis reconciles previous work by showing that species identities based on type location are supported by significant divergence, but natural geographic partitions show consistently greater divergence. Thus, our data confirm Gila robusta as a single polytypic species with roughly a dozen highly isolated geographic populations, providing a strong scientific basis for watershed-based future conservation.

Targeting protein kinase C in sarcoma.

Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure-function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic.

Socioeconomic variation in diet and activity-related behaviours of Australian children and adolescents aged 2-16 years.

BACKGROUND: Evidence for age-related variation in the relationship between obesity-related behaviours and socioeconomic position may assist in the targeting of dietary and physical activity interventions among children. OBJECTIVE: To investigate the relationship between different indicators of socioeconomic position and obesity-related behaviours across childhood and adolescence. METHODS: Data were from 4487 children aged 2 to 16 years participating in the cross-sectional 2007 Australian National Children's Nutrition and Physical Activity Survey. Socioeconomic position was defined by the highest education of the primary or secondary carer and parental income. Activity was assessed using recall methods with physical activity also assessed using pedometers. Intake of energy-dense drinks and snack foods, fruits and vegetables was assessed using 2 × 24-h dietary recalls. RESULTS: A socioeconomic gradient was evident for each dietary measure (although in age-specific analyses, not for energy-dense snacks in older children), as well as television viewing, but not physical activity. Whether each behaviour was most strongly related to parental income or education of the primary or secondary carer was age and sex dependent. The socioeconomic gradient was strongest for television viewing time and consumption of fruit and energy-dense drinks. CONCLUSIONS: A strong socioeconomic gradient in eating behaviours and television viewing time was observed. Relationships for particular behaviours differed by age, sex and how socioeconomic position was defined. Socioeconomic indicators define different population groups and represent different components of socioeconomic position. These findings may provide insights into who should be targeted in preventive health efforts at different life stages.

Television viewing time and mortality: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).

BACKGROUND: Television viewing time, the predominant leisure-time sedentary behavior, is associated with biomarkers of cardiometabolic risk, but its relationship with mortality has not been studied. We examined the associations of prolonged television viewing time with all-cause, cardiovascular disease (CVD), cancer, and non-CVD/noncancer mortality in Australian adults. METHODS AND RESULTS: Television viewing time in relation to subsequent all-cause, CVD, and cancer mortality (median follow-up, 6.6 years) was examined among 8800 adults > or =25 years of age in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). During 58 087 person-years of follow-up, there were 284 deaths (87 CVD deaths, 125 cancer deaths). After adjustment for age, sex, waist circumference, and exercise, the hazard ratios for each 1-hour increment in television viewing time per day were 1.11 (95% confidence interval [CI], 1.03 to 1.20) for all-cause mortality, 1.18 (95% CI, 1.03 to 1.35) for CVD mortality, and 1.09 (95% CI, 0.96 to 1.23) for cancer mortality. Compared with a television viewing time of <2 h/d, the fully adjusted hazard ratios for all-cause mortality were 1.13 (95% CI, 0.87 to 1.36) for > or =2 to <4 h/d and 1.46 (95% CI, 1.04 to 2.05) for > or =4 h/d. For CVD mortality, corresponding hazard ratios were 1.19 (95% CI, 0.72 to 1.99) and 1.80 (95% CI, 1.00 to 3.25). The associations with both cancer mortality and non-CVD/noncancer mortality were not significant. CONCLUSIONS: Television viewing time was associated with increased risk of all-cause and CVD mortality. In addition to the promotion of exercise, chronic disease prevention strategies could focus on reducing sitting time, particularly prolonged television viewing.

HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study.

AIMS/HYPOTHESIS: We assessed whether the relationships between insulin sensitivity and all-cause mortality as well as fatal or non-fatal cardiovascular disease (CVD) events are independent of elevated blood glucose, high blood pressure, dyslipidaemia and body composition in individuals without diagnosed diabetes. METHODS: Between 1999 and 2000, baseline fasting insulin, glucose and lipids, 2 h plasma glucose, HbA(1c), anthropometrics, blood pressure, medication use, smoking and history of CVD were collected from 8,533 adults aged >35 years from the population-based Australian Diabetes, Obesity and Lifestyle study. Insulin sensitivity was estimated by HOMA of insulin sensitivity (HOMA-%S). Deaths and fatal or non-fatal CVD events were ascertained through linkage to the National Death Index and medical records adjudication. RESULTS: After a median of 5.0 years there were 277 deaths and 225 CVD events. HOMA-%S was not associated with all-cause mortality. Compared with the most insulin-sensitive quintile, the combined fatal or non-fatal CVD HR (95% CI) for quintiles of decreasing HOMA-%S were 1.1 (0.6-1.9), 1.4 (0.9-2.3), 1.6 (1.0-2.5) and 2.0 (1.3-3.1), adjusting for age and sex. Smoking, CVD history, hypertension, lipid-lowering medication, total cholesterol and waist-to-hip ratio moderately attenuated this relationship. However, the association was rendered non-significant by adding HDL. Fasting plasma glucose, but not HOMA-%S significantly improved the prediction of CVD, beyond that seen with other risk factors. CONCLUSIONS/INTERPRETATION: In this cohort, HOMA-%S showed no association with all-cause mortality and only a modest association with CVD events, largely explained by its association with HDL. Fasting plasma glucose was a better predictor of CVD than HOMA-%S.

Protein kinases, from B to C.

The PKB (protein kinase B) and PKC (protein kinase C) families display highly related catalytic domains that require a largely conserved series of phosphorylations for the expression of their optimum activities. However, in cells, the dynamics of these modifications are quite distinct. Based on experimental evidence, it is argued that the underlying mechanisms determining these divergent behaviours relate to the very different manner in which their variant regulatory domains interact with their respective catalytic domains. It is concluded that the distinct behaviours of PKB and PKC proteins are defined by the typical ground states of these proteins.

Management of a parturient with respiratory failure secondary to cystic fibrosis.

A 21-year-old with end-stage respiratory failure and cor pulmonale due to cystic fibrosis became pregnant. Her forced expiratory volume in 1 s (FEV1) was 17% of that predicted antenatally, and termination was strongly advised on the grounds that continuing pregnancy was likely to be fatal. She elected to continue with the pregnancy and gave birth by lower segment caesarean section at 29 weeks and 5 days' gestation. Despite a problematic postnatal course, she was successfully discharged home and, 7 months postnatally, continues to live at home with her partner and their baby. There are no previous reports of cystic fibrosis patients with this level of respiratory impairment surviving pregnancy.

Differential recruitment of accessory molecules by FcgammaRI during monocyte differentiation.

Aggregation of the human high-affinity receptor for immunoglobulin G, FcgammaRI, results in initiation of intracellular signaling cascades. However, as the receptor contains no known signaling motif, it is required to recruit an accessory molecule. The gamma chain has been proposed to fulfil this role. Here, we show that in U937 cells differentiated to a more macrophage-like phenotype with dibutyryl cAMP, FcgammaRI no longer signals through the gamma chain but rather uses FcgammaRIIa to initiate tyrosine phosphorylation. Expression of the gamma chain is, however, increased in the dbcAMP-induced cells, but here the gamma chain specifically associates with the IgA receptor, FcalphaRI. Recruitment of the gamma chain either by FcgammaRI in cytokine-primed cells or by FcalphaRI in dbcAMP-induced cells couples ligand binding to the activation of phosphatidyl choline-specific phospholipase D.

Secular trends in the epidemiology and outcome of Barrett's oesophagus in Olmsted County, Minnesota.

BACKGROUND: The incidence of oesophageal adenocarcinoma has increased greatly. Barrett's oesophagus is a known risk factor. AIMS: To identify changes in the incidence, prevalence, and outcome of Barrett's oesophagus in a defined population. SUBJECTS: Residents of Olmsted County, Minnesota, with clinically diagnosed Barrett's oesophagus, or oesophageal or oesophagogastric junction adenocarcinoma. METHODS: Cases were identified using the Rochester Epidemiology Project medical records linkage system. Records were reviewed with follow up to 1 January 1998. RESULTS: The incidence of clinically diagnosed Barrett's oesophagus (>3 cm) increased 28-fold from 0.37/100 000 person years in 1965-69 to 10.5/100 000 in 1995-97. Of note, gastroscopic examinations increased 22-fold in this same time period. The prevalence of diagnosed Barrett's oesophagus increased from 22.6 (95% confidence interval (CI) 11.7-33.6) per 100 000 in 1987 to 82.6/100 000 in 1998. The prevalence of short segment Barrett's oesophagus (<3 cm) in 1998 was 33.4/ 100 000. Patients with Barrett's oesophagus had shorter than expected survival but only one patient with Barrett's oesophagus died from adenocarcinoma. Only four of 64 adenocarcinomas occurred in patients with previously known Barrett's oesophagus. CONCLUSIONS: The incidence and prevalence of clinically diagnosed Barrett's oesophagus have increased in parallel with the increased use of endoscopy. We infer that the true population prevalence of Barrett's oesophagus has not changed greatly, although the incidence of oesophageal adenocarcinoma increased 10-fold. Many adenocarcinomas occurred in patients without a previous diagnosis of Barrett's oesophagus, suggesting that many people with this condition remain undiagnosed in the community.

The history of Barrett esophagus.

The term Barrett esophagus has become well established in the medical literature to indicate columnar metaplasia of the distal esophagus associated with chronic gastroesophageal reflux disease. However, the historical events that led to the use of this term have become obscured. Here, the historical aspects of Barrett esophagus are reviewed, providing insight not only to this condition but also to the evolution of medical thought in general.

Barrett's esophagus: prevalence and size of hiatal hernia.

OBJECTIVE: Barrett's esophagus is caused by gastroesophageal reflux and predisposes to adenocarcinoma. Hiatal hernia may cause reflux. The prevalence and size of hernias in patients with Barrett's esophagus was investigated. METHODS: Axial hernia length and the width of the diaphragmatic hiatus were measured prospectively at endoscopy. RESULTS: A 2-cm or longer hernia was found in 96% of 46 patients with Barrett's esophagus, in 42% of 103 controls (p < 0.001), and in 72% of 18 patients with short segment Barrett's esophagus (p < 0.05 vs controls). A hernia was found in 71% of 31 controls with esophagitis and in 29% of 72 controls without esophagitis (p < 0.001). Of 54 controls with neither esophagitis or reflux symptoms, 20% had a hernia. Mean hernia length was 3.95 cm in Barrett's esophagus, and 2.81 cm in controls (p < 0.005). Mean hiatus width was 3.52 cm in patients with Barrett's esophagus and hernia, and 2.24 cm in controls with hernia. Hernia length was similar in patients with and without esophagitis, and in short segment Barrett's esophagus. CONCLUSIONS: Most patients with Barrett's esophagus have hiatal hernia; their hernias are longer and the hiatal openings wider than in controls with or without esophagitis. Hiatal hernia likely contributes to the development of Barrett's esophagus.

The human high-affinity immunoglobulin G receptor activates SH2-containing inositol phosphatase (SHIP).

On cytokine-primed U937 cells, aggregation of the human high-affinity immunoglobulin receptor, FcgammaRI, initiates signal transduction cascades which lead to the release of calcium from intracellular stores and no significant calcium influx. In these cells, aggregation of FcgammaRI results in no significant increase in inositol trisphosphate production, but rather phospholipase D is activated. Here we show that, in interferon-gamma (IFN-gamma)-primed cells, the SH2 containing inositol 5' phosphatase, SHIP, is constitutively associated with the membrane fraction. Following aggregation of FcgammaRI, SHIP is rapidly and transiently tyrosine phosphorylated and becomes associated with the adapter molecule Shc. Shc also becomes tyrosine phosphorylated and translocates from the cytoplasm to the membrane fraction concomitant with the association between Shc and SHIP. Further, SHIP and Shc appear to be recruited to membrane-associated immune complexes following FcgammaRI aggregation. As no immunoreceptor inhibitory motif has been demonstrated to associate with FcgammaRI, these data suggest that SHIP may be recruited to the receptor through an SH2 domain interaction with Shc.

Videoendoscopic diagnosis of esophageal motility disorders.

BACKGROUND: Esophageal motility disorders are usually diagnosed by manometry. We evaluated videoendoscopy as a diagnostic test. METHODS: In this study, 20 patients with achalasia, 13 with scleroderma, and 33 control subjects had a standard endoscopic examination followed by protocol videotaping of swallows to observe contractions in the esophagus and in the lower esophageal sphincter. Tapes were later reviewed by 2 blinded observers who recorded their motility findings and diagnoses. RESULTS: In the mid esophagus at 25 cm, lumen-occluding peristaltic contractions were identified in 26 of 33 control subjects versus 1 of 20 achalasia (p < 0.001) and 3 of 13 scleroderma patients (p < 0.005). As viewed in the lower esophagus, the lower esophageal sphincter opened normally in 31 of 33 control subjects versus 1 of 20 achalasia (p < 0.001). In scleroderma, the sphincter never closed in 12 of 13 patients (p < 0. 001 versus control subjects). A diagnostic sequence of sphincter opening followed by contraction in the esophageal body and subsequent sphincter closing was seen in 33 of 33 control subjects, 2 of 20 achalasia, and 1 of 13 scleroderma patients (both, p < 0. 001). The observers made the correct diagnosis in 96% of cases. CONCLUSIONS: Achalasia and esophageal scleroderma can be identified by endoscopic observation of motility. This procedure may represent an adjunctive diagnostic test to manometry.

Esophageal lichen planus: the Mayo Clinic experience.

Lichen planus (LP) is an inflammatory papulosquamous disease which may affect the squamous epithelium of the esophagus. We reviewed six patients with esophageal lichen planus (ELP) seen at Mayo Clinic Rochester between 1984 and 1998. The presenting symptoms were dysphagia (in all six patients) and odynophagia (two patients). Cervical esophageal strictures were seen in four patients; average number of esophageal dilatations required was 15 (range, 10-18). Esophageal biopsies demonstrated the classical histologic findings of ELP in two patients, and a lymphocytic infiltrate in the other four. Concomitant lichen planus (LP) was seen at other sites in five patients: all five had oral LP preceeded by ELP symptoms in all five; three had genital LP preceeded by ELP symptoms in all three; two had dermal LP, preceeded by ELP symptoms in one. Proton pump inhibitors were tried unsuccessfully in all patients. Four patients were started on systemic steroid medication; three had resolution of symptoms within 1 month.

Management of Barrett's esophagus.

In Barrett's esophagus, the squamous lining of the lower esophagus is replaced by columnar epithelium. Barrett's esophagus is associated with gastroesophageal reflux and an increased risk of the development of esophageal cancer. Endoscopy shows red columnar epithelium in the lower esophagus. Biopsy is needed to confirm intestinal metaplasia. Some cases progress from dysplasia to invasive adenocarcinoma. Medical or surgical antireflux treatment controls symptoms and esophagitis, but Barrett's esophagus remains. Patients are usually followed up by endoscopy for detection of dysplasia or early cancer. For patients with low-grade dysplasia, follow-up is adequate; however, for those with high-grade dysplasia, esophagectomy or experimental endoscopic mucosal ablation is advised.

A molecular switch changes the signalling pathway used by the Fc gamma RI antibody receptor to mobilise calcium.

BACKGROUND: Leukocytes express Fc gamma receptors, which are specific for the constant region of immunoglobulin G. Aggregation of these receptors activates a repertoire of responses that can lead to targeted cell killing by antibody-directed cellular cytotoxicity. The nature of the myeloid response to Fc gamma receptor aggregation is highly variable and depends on the maturation state of the cell, but little is known about the signalling mechanisms underlying this variability. RESULTS: We show here that differentiation of a monocytic cell line, U937, to a more macrophage phenotype resulted in an absolute and fundamental switch in the nature of the phospholipid signalling pathway recruited following Fc gamma receptor aggregation. In cytokine-primed monocytes, aggregation of the high-affinity receptor Fc gamma RI resulted in the activation of phospholipase D and sphingosine kinase, which in turn led to the transient release of stored calcium; these effects were mediated by the gamma chain, an Fc gamma RI accessory protein. In contrast, in cells differentiated to a more macrophage type, aggregation of Fc gamma RI resulted in the Fc gamma RIIa-mediated activation of phospholipase C, and the resulting calcium response was prolonged as calcium entry was stimulated. CONCLUSIONS: The switch in Fc gamma RI signalling pathways upon monocyte differentiation is mediated by a switch in the accessory molecule recruited by Fc gamma RI, which lacks its own intrinsic signal transduction motif. As many immune receptors have separate polypeptide chains for ligand binding and signal transduction (allowing a similar switch in signalling pathways), the mechanism described here is likely to be widely used.

Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma.

BACKGROUND & AIMS: Barrett's esophagus and adenocarcinoma are complications of gastroesophageal reflux disease. The aim of this study was to look for evidence of a familial predisposition to reflux. METHODS: Index patients with adenocarcinoma (n = 27), Barrett's esophagus (n = 40), and reflux esophagitis (n = 55) were recruited from tertiary care and community populations. Parents and siblings of patients (n = 243) and their spouses' relatives (n = 230) completed reflux symptom questionnaires (response rate, 86%). RESULTS: Reflux symptoms were significantly more prevalent among parents and siblings of patients with adenocarcinoma (43% vs. 23%) and Barrett's esophagus (46% vs. 27%) than spouse control relatives. No significant difference was found for the reflux esophagitis group (33% vs. 29%). Reflux was more prevalent in siblings than spouses of patients with Barrett's esophagus (41% vs. 12%) and adenocarcinoma (40% vs. 6%), a difference that was not found with reflux esophagitis (24% vs. 32%). Reflux was associated with obesity, 41% vs. 28% in the nonobese; smoking, 45% vs. 31% in nonsmokers; and men, 39% vs. 27% in women. CONCLUSIONS: There may be a genetic predisposition to the development of reflux in families of patients with Barrett's esophagus and esophageal adenocarcinoma. For uncomplicated reflux esophagitis, environmental factors appear more important.