Trade-offs direct the evolution of coloration in Galápagos land snails.

Increasingly, multiple selective factors are recognized as jointly contributing to the evolution of morphology. What is not clear is how these forces vary across communities to promote morphological diversification among related species. In this study of Galápagos endemic snails (genus Naesiotus), we test several hypotheses of colour evolution. We observe mockingbirds (genus Mimus) predating live snails and find that avian predation selects against conspicuous shells. The evolutionary outcome of this selection is a diversity of shell colours across snails of the archipelago, each closely matching local backgrounds. We also find that snails more regularly exposed to the hot, equatorial sun reflect more light than shells of species from shadier habitats, suggesting a role for thermoregulatory constraints directing colour evolution. The signature of thermoregulatory selection is most clear in comparatively young communities (on the youngest islands), while the signature of selection from predators is most evident in older communities (on the older islands). Together, our findings point to a scenario of shifting selective forces along island ontogeny and community maturity that lead to the distribution of snail coloration we observe in Galápagos. Complex selective regimes such as these may have more responsibility for morphological diversity than is currently recognized.

Batesian mimics influence the evolution of conspicuousness in an aposematic salamander.

Conspicuousness, or having high contrast relative to the surrounding background, is a common feature of unpalatable species. Several hypotheses have been proposed to explain the occurrence of conspicuousness, and while most involve the role of conspicuousness as a direct signal of unpalatability to potential predators, one hypothesis suggests that exaggerated conspicuousness may evolve in unpalatable species to reduce predator confusion with palatable species (potential Batesian mimics). This hypothesis of antagonistic coevolution between palatable and unpalatable species hinges on the 'cost of conspicuousness', in which conspicuousness increases the likelihood of predation more in palatable species than in unpalatable species. Under this mimicry scenario, four patterns are expected: (i) mimics will more closely resemble local models than models from other localities, (ii) there will be a positive relationship between mimic and model conspicuousness, (iii) models will be more conspicuous in the presence of mimics, and (iv) when models and mimics differ in conspicuousness, mimics will be less conspicuous than models. We tested these predictions in the salamander mimicry system involving Notophthalmus viridescens (model) and one colour morph of Plethodon cinereus (mimic). All predictions were supported, indicating that selection for Batesian mimicry not only influences the evolution of mimics, but also the evolution of the models they resemble. These findings indicate that mimicry plays a large role in the evolution of model warning signals, particularly influencing the evolution of conspicuousness.

The disease burden of hepatitis B, influenza, measles and salmonellosis in Germany: first results of the burden of communicable diseases in Europe study.

Setting priorities in the field of infectious diseases requires evidence-based and robust baseline estimates of disease burden. Therefore, the European Centre for Disease Prevention and Control initiated the Burden of Communicable Diseases in Europe (BCoDE) project. The project uses an incidence- and pathogen-based approach to measure the impact of both acute illness and sequelae of infectious diseases expressed in disability-adjusted life years (DALYs). This study presents first estimates of disease burden for four pathogens in Germany. The number of reported incident cases adjusted for underestimation served as model input. For the study period 2005-2007, the average disease burden was estimated at 33 116 DALYs/year for influenza virus, 19 115 DALYs/year for Salmonella spp., 8708 DALYs/year for hepatitis B virus and 740 DALYs/year for measles virus. This methodology highlights the importance of sequelae, particularly for hepatitis B and salmonellosis, because if omitted, the burden would have been underestimated by 98% and 56%, respectively.

Esophagojejunostomy after total gastrectomy for caustic injuries.

The objective of the study was to compare outcomes of emergency esophagogastrectomy (EGT) and total gastrectomy with immediate esophagojejunostomy (EJ) in patients with full-thickness caustic necrosis of the stomach and mild esophageal injuries. After caustic ingestion, optimal management of the esophageal remnant following removal of the necrotic stomach remains a matter of debate. Between 1987 and 2012, 26 patients (men 38%, median age 44 years) with isolated transmural gastric necrosis underwent EGT (n = 14) or EJ (n = 12). Early and long-term outcomes of both groups were compared. The groups were similar regarding age (P = 0.66), gender (0.24), and severity of esophageal involvement. Functional success was defined as nutritional autonomy after removal of the jejunostomy and tracheotomy tubes. Emergency morbidity (67% vs. 64%, P = 0.80), mortality (17% vs. 7%, P = 0.58), and reoperation rates (25% vs.14%, P = 0.63) were similar after EJ and EGT. One patient (8%) experienced EJ leakage. One patient in the EJ group and 13 patients in the EGT group underwent esophageal reconstruction (P < 0.0001). Aggregate in hospital length of stay was significantly longer in patients who underwent EGT (median 83 [33-201] vs. 36 [10-82] days, P = 0.001). Functional success after EJ and EGT was similar (90% vs.69%, P = 0.34). Immediate EJ can be safely performed after total gastrectomy for caustic injuries and reduces the need of further esophageal reconstruction.

Clinical signs, therapy and zoonotic risk of pet guinea pigs with dermatophytosis.

Systematic studies about pet guinea pigs with dermatophytosis are rare. The aim of this study was to evaluate clinical signs, therapy and zoonotic risk of pet guinea pigs with dermatophytosis. Questionnaires from both owners (n = 74) of pet guinea pigs with dermatophytosis and their veterinarians (n = 101) were analysed regarding clinical signs, therapy and data pertinent to zoonotic potential. Trichophyton (T.) mentagrophytes was found in 97% of cases. In the weeks preceding the onset of the clinical signs, a new guinea pig joined the household in 43% of cases. One third of the affected guinea pigs had lived in the household for less than 3 months. Predominant clinical signs were alopecia (83%), scaling (73%) and crusting (70%). The most commonly affected body site was the head (75%). In approximately one quarter of the cases humans showed clinical signs of dermatophytosis, in half the households, only children were affected. Skin lesions were seen most often on the face, the neck and the arms. Pet guinea pigs carrying dermatophytes must be considered a serious zoonotic risk for their owners, especially for children. A major risk factor for dermatophytosis seems to be a recent acquisition of a new guinea pig.

Roux-en-Y Gastric Bypass Reversal for Severe Malnutrition and Cirrhosis.

BACKGROUND: Severe post-operative malnutrition (SM) is a dreaded complication after gastric bypass often related to the short bowel syndrome consecutive limb length mismeasurement or intestinal resections. Patients with rapid weight loss or malnutrition can experience liver failure with cirrhosis and require liver transplantation (LT). Malnutrition can constitute a contraindication to LT since it negatively impacts on postoperative morbidity. RYGB reversal is an effective option to consider when nutritional support has failed. We describe the performance of a RYGB reversal in a pre-LT setting. MATERIAL AND METHODS: A 36-year-old patient with morbid obesity (weight, 140 kg; BMI, 50.1 kg/m2) underwent a RYGB 9 years ago. She presented with 85 kg weight loss (i.e., 60.7% total body weight loss) associated with SM and hepatocellular insufficiency. LT was considered but contraindicated because of SM. An intensive nutritional support was attempted but failed and the RYGB reversal was recommended. RESULTS: Laparoscopic exploration revealed ascites, cirrhosis, and splenomegaly. The whole small bowel measurement revealed a short gut. Alimentary, biliary, and common channel limb lengths were 250 cm, 150 cm, and 30 cm long. The alimentary limb was stapled off the gastric pouch and the gastrojejunostomy was resected. After resection of the gastrojejunostomy, linear stappled gastro-gastrostomy and jéjuno-jejunostomy were performed to restore the normal anatomy. At 1 year, malnutrition was resolved and the cirrhosis was stabilized. CONCLUSION: Reversal to normal anatomy appeared effective and safe in this setting but must be considered only after failure of intensive medical management. Careful bowel measurement is mandatory to prevent patients from this complication.

[Autoimmune pancreatitis mimicking an intra-ductal papillary mucinous neoplasm of the pancreas: an original case]. / Pancréatite auto-immune mimant une tumeur intracanalaire papillaire et mucineuse : une observation originale et trompeuse.

In recent years, autoimmune pancreatitis (AIP) has been increasingly recognized. It can be associated with diabetes mellitus and other systemic autoimmune diseases, or with bile ducts lesions, which are also responsive to steroid therapy as pancreatic lesions. We report the case of a 34-year-old man with a history of a first acute pancreatitis, attributed to an intraductal papillary-mucinous neoplasm of the pancreas (IPMN) with segmental involvement of the main pancreatic duct. A spleno-pancreatectomy was performed, and pathological examination of the specimen diagnosed autoimmune pancreatitis. A treatment with corticosteroids was carried out. To our knowledge, this is the first reported case of AIP mimicking IPMN of the main pancreatic duct.

Conformational switch and role of phosphorylation in PAK activation.

p21-activated protein kinases (PAKs) are involved in signal transduction processes initiating a variety of biological responses. They become activated by interaction with Rho-type small GTP-binding proteins Rac and Cdc42 in the GTP-bound conformation, thereby relieving the inhibition of the regulatory domain (RD) on the catalytic domain (CD). Here we report on the mechanism of activation and show that proteolytic digestion of PAK produces a heterodimeric RD-CD complex consisting of a regulatory fragment (residues 57 to 200) and a catalytic fragment (residues 201 to 491), which is active in the absence of Cdc42. Cdc42-GppNHp binds with low affinity (K(d) 0.6 microM) to intact kinase, whereas the affinity to the isolated regulatory fragment is much higher (K(d) 18 nM), suggesting that the difference in binding energy is used for the conformational change leading to activation. The full-length kinase, the isolated RD, and surprisingly also their complexes with Cdc42 behave as dimers on a gel filtration column. Cdc42-GppNHp interaction with the RD-CD complex is also of low affinity and does not dissociate the RD from the CD. After autophosphorylation of the kinase domain, Cdc42 binds with high (14 nM) affinity and dissociates the RD-CD complex. Assuming that the RD-CD complex mimics the interaction in native PAK, this indicates that the small G protein may not simply release the RD from the CD. It acts in a more subtle allosteric control mechanism to induce autophosphorylation, which in turn induces the release of the RD and thus full activation.

Dynamic interaction of cAMP with the Rap guanine-nucleotide exchange factor Epac1.

Epac1 is a Rap-specific guanine-nucleotide exchange factor (GEF) which is activated by the binding of cAMP to a cyclic nucleotide monophosphate (cNMP)-binding domain. We investigated the equilibrium and dynamics of the interaction of cAMP and Epac1 using a newly designed fluorescence analogue of cAMP, 8-MABA-cAMP. We observed that the interaction of cAMP, measured by competition with 8-MABA-cAMP, with an isolated cNMP binding domain of Epac1 has an overall equilibrium constant (Kd) of 4 microM and that the kinetics of the interaction are highly dynamic. The binding properties of cAMP are apparently not affected when the catalytic domain is present, despite the fact that binding of cAMP results in activation of Epac1. This indicates that for the activation process, no appreciable binding energy is required. However, when bound to Rap1b, the apparent Kd of Epac to cAMP was about fivefold lower, suggesting that substrate interaction stabilizes cAMP binding. Since the fluorescent analogues used here were either less able or unable to induce activation of Epac1, we concluded that the binding of nucleotide to Epac and the activation of GEF activity are uncoupled processes and that thus appropriate cAMP analogues can be used as inhibitors of the Epac1-mediated signal transduction pathway of Rap.

High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma.

The aim of this study was to define prognostic factors that might be predictive for response to thalidomide (Thal) in progressive multiple myeloma (n = 54). We examined the concentration of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), two potent heparin-binding mediators of angiogenesis in peripheral blood (PB; PB-VEGF and PB-bFGF) and bone marrow (BM; BM-VEGF and BM-bFGF), in combination with well-characterized predictors for response and survival to chemotherapy. After a median follow-up time of 15 months (range, 0.3-20), 29 patients (pts.) showed at least a minimal response to Thal therapy, whereas 25 pts. were nonresponsive. As shown by univariate analysis, responsive pts. had statistically significant higher concentrations of PB-bFGF (P = 0.009) and beta2-microglobulin (P = 0.03) before therapy, as well as lower hemoglobin (P = 0.008) and albumin (P = 0.02) levels, whereas no statistically significant difference was found for PB-VEGF (P = 0.93). When a multiple logistic regression analysis was performed, PB-bFGF was the only statistically significant predictor for response to therapy (P = 0.01). None of these variables was associated with a prolonged progression-free survival. In conclusion, our findings indicate that high pretreatment plasma bFGF levels in pts. with progressive multiple myeloma are associated with unfavorable parameters of response and survival but nevertheless predict for response to Thal therapy.

Aneuploidy precedes and segregates with chemical carcinogenesis.

A century ago, Boveri proposed that cancer is caused by aneuploidy, an abnormal balance of chromosomes, because aneuploidy correlates with cancer and because experimental aneuploidy generates "pathological" phenotypes. Half a century later, when cancers were found to be nonclonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result, aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer. However, we have recently proposed a two-stage mechanism of carcinogenesis that resolves the discrepancy between clonal mutation and nonclonal karyotypes. The proposal is as follows: in stage 1, a carcinogen "initiates" carcinogenesis by generating a preneoplastic aneuploidy; in stage 2, aneuploidy causes asymmetric mitosis because it biases balance-sensitive spindle and chromosomal proteins and alters centrosomes both numerically and structurally (in proportion to the degree of aneuploidy). Therefore, the karyotype of an initiated cell evolves autocatalytically, generating ever-new chromosome combinations, including neoplastic ones. Accordingly, the heterogeneous karyotypes of "clonal" cancers are an inevitable consequence of the karyotypic instability of aneuploid cells. The notorious long latent periods, of months to decades, from carcinogen to carcinogenesis, would reflect the low probability of evolving by chance karyotypes that compete favorably with normal cells, in principle analagous to natural evolution. Here, we have confirmed experimentally five predictions of the aneuploidy hypothesis: (1) the carcinogens dimethylbenzanthracene and cytosine arabinoside induced aneuploidy in a fraction of treated Chinese hamster embryo cells; (2) aneuploidy preceded malignant transformation; (3) transformation of carcinogen-treated cells occurred only months after carcinogen treatment, i.e., autocatalytically; (4) preneoplastic aneuploidy segregated with malignant transformation in vitro and with 14 of 14 tumors in animals; and (5) karyotypes of tumors were heterogeneous. We conclude that, with the carcinogens studied, aneuploidy precedes cancer and is necessary for carcinogenesis.

[Description of a special form of postprandial hyperlipidemia: possible cause of premature coronary heart disease]. / Beschreibung einer besonderen Form von post-prandialer Hyperlipidämie: mögliche Ursache einer frühzeitigen koronaren Herzkrankheit.

We have studied the metabolism of post-prandial lipoproteins in four male patients who suffered from premature (less than 60 years) angiographically proven coronary heart disease. They had normal to low total and low density lipoprotein cholesterol levels. Other risk factors were absent. Using the vitamin A fat loading test we were able to show that the clearance of chylomicron remnants was delayed compared to three healthy control subjects. Since these postprandial lipoproteins have been implicated in atherogenesis, we conclude that this defect contributed to the development of coronary heart disease in these patients.

Dermatophytes in pet Guinea pigs and rabbits.

PROBLEM ADDRESSED: The frequency of dermatophytes in pet Guinea pigs and rabbits. OBJECTIVES: To determine the frequency and types of dermatophytes in pet Guinea pigs and rabbits. METHODS AND APPROACH: First, 2153 samples collected from pet Guinea pigs (n=1132) and rabbits (n=1021) with suspected dermatophytosis and submitted to three different laboratories for fungal culture were analysed. Subsequently, healthy Guinea pigs and rabbits, animals with skin lesions and with noncutaneous diseases were examined prospectively for dermatophytes. RESULTS: Trichophyton (T.) mentagrophytes was the most common fungal species isolated (91.6% and 72.3% of positive cultures from Guinea pigs (n=431) and rabbits (n=83), respectively). Animals with positive fungal culture did not show any gender predisposition, but affected animals were younger than those with negative fungal culture (P<0.0001) or than healthy animals of the prospective part of the study. Dermatophytes were isolated from 14/164 healthy Guinea pigs and 0/140 healthy rabbits. In addition, fungal cultures of Guinea pigs with skin lesions (n=26) and other diseases (n=25) were positive in 7.7% and 8.0% respectively. Samples collected from 17 rabbits with skin lesions and 32 rabbits with noncutaneous disease were all negative in culture. CONCLUSIONS: T. mentagrophytes is the most common dermatophyte in pet Guinea pigs and rabbits, asymptomatic carriers are regularly seen in Guinea pigs, but not in rabbits.

The WST survival assay: an easy and reliable method to screen radiation-sensitive individuals.

An easy, fast and reliable method was developed to screen hundreds of Epstein-Barr virus-transformed cell lines (lymphoblastoid cell lines, LCLs) for radiation sensitivity that were generated from lymphocytes isolated from young lung cancer patients. The WST-1 test explores the metabolic activity of the mitochondria as an indicator for the vital status of cells. Cell proliferation as well as indirect cell death can be quantified by this method on a large scale in microtiter plates. Cell survival was measured at 24- and 48-h post-irradiation with 10 Gy ((137)Cs source) by the WST-1 assay and Trypan blue staining. To set up the experimental screening conditions and to establish a positive and a negative control, an ATM-mutated cell line from a radiation-sensitive ATM patient and an ATM proficient cell line from a healthy brother were compared. An optimal differentiation between the two cell lines was demonstrated for 10 Gy and 24- and 48-h cell growth after irradiation. Upon screening 120 LCLs of young lung cancer patients under these conditions, 5 of them were found to be radiation sensitive to a high degree of statistical significance. The results have been confirmed by a second laboratory by means of Trypan blue testing. The WST-1 test represents an efficient and reliable method by means of screening for radiation-sensitive cell lines.

Factors associated with being underweight, overweight and obese among ever-married non-pregnant urban women in Bangladesh.

UNLABELLED: Extremes of body mass index (BMI), viz. underweight, overweight and obese categories, are associated with a variety of adverse health outcomes such as diabetes mellitus, cardiovascular diseases, low birth weight, poor quality of life and higher mortality. In Bangladesh, the prevalence of underweightness is very high with an increasing trend of overweightness and obesity. This is a serious public health concern as it indicates a dual burden of disease. The present study assessed the associations of being underweight, overweight and obese with socioeconomic, demographical and migration variables among ever-married non-pregnant urban Bangladeshi women aged 13-49 years. METHODS: The data was extracted from the Bangladesh Demographic and Health Survey 2004. Bivariable, factor and multinomial logistic regression analyses were performed in this study. RESULTS: The prevalence of being underweight, overweight and obese among ever-married non-pregnant urban women in Bangladesh was 25.2 percent, 15.7 percent and 3.9 percent, respectively. Age, education, region of residence, marital status, current use of contraception and type of occupation were significantly associated with BMI categories. Adjusted multinomial logistic regression analysis indicated that women with a high socioeconomic status were significantly negatively associated with being underweight (odds ratio [OR] 0.55, 95 percent confidence interval [CI] 0.48-0.63) but positively associated with being overweight (OR 1.70, 95 percent CI 1.48-1.96) and obese (OR 2.48, 95 percent CI 1.89-3.26), as compared to the women with normal BMI. In contrast, women who migrated from rural to urban areas showed a significantly positive association with being underweight (OR 1.15, 95 percent CI 1.04-1.27) but negative associations with being overweight (OR 0.80, 95 percent CI 0.71-0.89) and obese (OR 0.75, 95 percent CI 0.62-0.92), when compared with women who did not migrate. CONCLUSION: Suitable interventions based on further studies are needed to reduce the prevalence of being underweight and overweight among ever-married non-pregnant urban women in Bangladesh. Factors, viz. socioeconomic status, rural-urban migration and education, should be considered while developing interventional strategies to reduce the prevalence of extreme BMIs among women living in urban areas of Bangladesh.

Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins.

Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.

Associations between obesity and developmental functioning in pre-school children: a population-based study.

OBJECTIVE: To examine associations between obesity and impairment in developmental functioning in a general population sample of pre-school children. METHOD: Standardized medical examinations were conducted in nine consecutive cohorts of male and female children (n=9415) aged between 4.4 and 8.6 years (mean=6.0, s.d.=0.37) residing in the Lower Bavaria region of Germany. Tests designed to assess performance in subdivisions representing four broad developmental domains, namely, motor development, speech development, cognitive development and psycho-social development, were completed by all participants. RESULTS: Boys had significantly higher rates of impairment than girls. The prevalence of obesity in boys was 2.4%, whereas in girls it was 4.3% (chi (2)=21.51, P< 0.01). After controlling for age, gender, year of recruitment and other potential covariates, the prevalence of impairment in gross motor skills was higher among obese male children than normal-weight male children (adjusted odds ratio=1.76, 95% confidence interval (CI)=1.02, 3.01, P< 0.05), whereas the prevalence of impairment in the ability to focus attention was higher in obese female children than normal-weight female children (adjusted odds ratio=1.86, 95% CI=1.00, 3.44, P< 0.05). CONCLUSIONS: The findings suggest that gender-specific associations between obesity and impairment in specific aspects of developmental functioning may be evident in younger children.

The influence of ethics on leadership.

Value driven ethical leadership is needed today. The housekeeping field employs a diverse work force, and managers must develop and empower workers to attain organization goals. As managers, we must understand and develop our personal value structures that affect our decision making. This paper reviews Lawrence Kohlberg's study of moral behavior and how those stages are relevant to ethical management practices. It also addresses ways to overcome some obstacles in understanding and dealing with personal values that may threaten moral and ethical practices. Mature ethical principles and good communication are the foundation for and foster strong leadership for the future.

Permits and effluent charges in the water pollution control policies of France, West Germany, and the Netherlands.

In this article the water pollution control policies of these countries and their effects on emitters are analyzed. In the Netherlands, local water control boards levy pollution charges on both direct and indirect emitters. The charges are based upon measured emissions and actual treatment costs and they vary among the boards. Discharges into surface waters are by permission only. West German law sets nationally uniform rates only for direct emitters and some pollutants, irrespective of treatment costs. The States (Länder), however, may make indirect emitters liable to pay as well. In France, river basin agencies charge emitters and grant discounts where abatement facilities have been installed. Further policy instruments are tax cuts, subsidies, and standards set on local and national levels. France, in this complex policy, also uses contrats de branche where government and industries agree by contract on pollution abatement. Evidence shows that all these policies have reduced water pollution. As emissions decrease, problems of overcapacity might occur where collective water treatment plants have been installed already. Moreover, investment in additive abatement technology may inhibit the introduction of low-waste, integrated technologies. Yet the development of the latter, though expensive in the short run, should enable industry to meet more stringent standards in the future.