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Exercise intensity is prone to be self-regulated in horses exercising freely. The main drivers include social, feeding and escape behaviors, as well as the operant conditioning. We hypothesized that self-regulated exercise intensity may increase due to the presence of another horse exercising ahead. Seven horses were assigned to a 2x2 crossover trial following treadmill familiarization. Video images of a trotting horse were displayed on the wall in front of the experimental unit (Visual), which was positioned in the treadmill. Physiological and behavioral markers were further compared with a control visual stimulus (Co), comprising a racetrack image without horses. Horses were sampled during a constant load exercise test (1) at rest (baseline), (2) after the warm-up (0 - 10th minute) and (3) after visual stimulation or control (10th- 12th minutes of the SET) to quantify plasma lactate and glucose concentration, heart rate, head angle, as well as behavioral markers. Following visual stimulation, heart rate (130.8 ± 27.8 b.p.m.) was higher than control (84.7 ± 15.1 b.p.m., P = .017), as was plasma lactate (Visual - 5.28 ± 1.48 mg/dl; Co -3.27 ± 1.24 mg/dl, P = .042) and head angle (Visual - 36.43 ± 3.69°; Co -25.14 ± 4.88°, P = .003). The prevalence of "ears forward" behavior was also higher following Visual (100% - 7/7) than Co (14% - 1/7, P = .004). These results suggest that visual stimulus (1) was safe and well tolerated and (2) prompted the anaerobic lactic pathways and shifted the behavior to a vigilant state. In conclusion, horses were able to perceive and adapt to a social environment. Our findings validate the use of social facilitation of trotting to encourage horses to move forward avoiding the use of the whip., Competing Interests: The authors declare that there is no conflict of interest., (Copyright: © 2024 Bogossian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to evaluate the effects of essential oils from the fruits of Citrus sinensis and Xylopia aromatica , included in broiler feed, on blood parameters, the biometrics of digestive organs, bone analyses, and the biochemical profiles of the viscera, as well as the histomorphometry of the small intestine. In this study, 180 one-day-old male chicks of the Cobb 500 strain were fed a corn and soybean meal over three treatments and six replications, and the experimental design was completely randomized. The data were subjected to an analysis of variance and a Tukey test at a 5% significance level. The effect of the experimental diets on performance, blood parameters, biometrics of the digestive organs, bone analysis, and biochemical profiles of the viscera, as well as the histomorphometry of the small intestine, were evaluated. The compounds identified in the essential oil of X. aromatica were sylvestrene, α-pinene, and β-pinene, while in C. sinensis they were limonene and myrcene. The essential oils of C. sinensis and X. aromatica had no significant effect on performance at 14 days. The effects of the presence of the essential oils of C. sinensis and X. aromatica on the response were beneficial: there were reductions in liver lipids, cholesterol, and triglycerides, and in the depths of the crypts in the jejunum of chickens. So, the essential oils from the fruits of C. sinensis and X. aromatica can be used in broiler chickens to improve the lipid profiles of birds without affecting their performance.

Objective: To analyze different anatomical sites in the abdominal region, in order to determine the positional parameter that identifies a higher level of visceral adipose tissue (VAT) and confers a greater cardiometabolic risk., Materials and Methods: This is a methodological study in which VAT was evaluated by ultrasonography (USG) in three anatomical sites in the abdomen, while the abdominal circumference (AC) was measured using seven different protocols. Additionally, the glycemic and lipid profile, C-reactive protein, and the presence of systemic arterial hypertension were evaluated., Results: One hundred and six individuals with an average age of 42 (36.8-46.2) years were included. The evaluation of the calibration of the ultrasound procedure for the analysis of VAT by intra- and inter-evaluators showed high reproducibility. The pattern of abdominal fat distribution differed between sexes, with higher mean VAT in males (p < 0.05) and higher mean SAT (subcutaneous adipose tissue) in females (p < 0.005). In the abdominal scan applied to women, higher levels of VAT and lower levels of SAT were observed in the narrower waist region, between the iliac crest and the last rib (p < 0.001). In males, the profile of adipose disposition along the abdomen was uniform (p > 0.05). Correlations between VAT measured by USG and cardiometabolic parameters were relatively stronger in the upper abdomen (p < 0.05)., Conclusion: Women accumulate more VAT in the narrower waist region, while men accumulate VAT uniformly across the abdomen. There was relative superiority in predicting cardiometabolic risk in the upper abdomen for both sexes.

Adsorption is a promising technology for removing several contaminants from aqueous matrices. In the last years, researchers worldwide have been working on developing composite adsorbents to overcome some limitations and drawbacks of conventional adsorbent materials, which depend on various factors, including the characteristics of the adsorbents. Therefore, it is essential to characterize the composite adsorbents to describe their properties and structure and elucidate the mechanisms, behavior, and phenomenons during the adsorption process. In this sense, this work aimed to review the main methods used for composite adsorbent characterization, providing valuable information on the importance of these techniques in developing new adsorbents. In this paper, we reviewed the following methods: X-Ray diffraction (XRD); spectroscopy; scanning electron microscopy (SEM); N 2 adsorption/desorption isotherms (BET and BJH methods); thermogravimetry (TGA); point of zero charge (pH PZC ); elemental analysis; proximate analysis; swelling and water retention capacities; desorption and reuse., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/objectives: Handgrip strength (HGS) is a potential predictor of outcomes in cancer setting. However, reference values for this population are lacking. The study aimed to describe reference values and cutoff point for HGS in adults with incurable cancer in Brazil and to verify the association of reference values with prognostic., Methods: Secondary analysis of a prospective cohort, conducted with 1,868 patients at the National Cancer Institute in Brazil were analyzed. HGS (kg) data were obtained with a Jamar ® hydraulic dynamometer. Description of percentile values of HGS was stratified by sex and age groups. Receiver operating characteristic curve was performed to determine the optimal HGS cutoff point by sex and age according to performance status. Kaplan-Meier curves was used to analyze the probability of survival and Cox's proportional model used to identify whether HGS predict 180-d mortality., Results: HGS value was significantly higher in male than in female and decreased with increasing age. Sex-specific HGS cutoff values ranged from 32.5 to 24.5 kg in males and 20.5 to 18.5 kg in females (with younger adults stronger than the older ones). When compared to HGS ≥50th, patients with HGS ≤10th percentile had significantly lower survival, as well as patients classified below the HGS cutoff point. In addition, patients with lower HGS percentiles showed increased risk of mortality regardless of sex and age., Conclusion: Reference values can inform the clinical assessment of HGS, which is recognized as an important part of the identification of patients with incurable cancer with reduced physical function and short survival., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Appropriate dietary recommendations represent a key part of secondary prevention in cardiovascular disease (CVD). We evaluated the effectiveness of the implementation of a nutritional program on quality of diet, cardiovascular events, and death in patients with established CVD., Methods: In this open-label, multicenter trial conducted in 35 sites in Brazil, we randomly assigned (1:1) patients aged 45 years or older to receive either the BALANCE Program (experimental group) or conventional nutrition advice (control group). The BALANCE Program included a unique nutritional education strategy to implement recommendations from guidelines, adapted to the use of affordable and regional foods. Adherence to diet was evaluated by the modified Alternative Healthy Eating Index. The primary end point was a composite of all-cause mortality, cardiovascular death, cardiac arrest, myocardial infarction, stroke, myocardial revascularization, amputation, or hospitalization for unstable angina. Secondary end points included biochemical and anthropometric data, and blood pressure levels., Results: From March 5, 2013, to Abril 7, 2015, a total of 2534 eligible patients were randomly assigned to either the BALANCE Program group (n = 1,266) or the control group (n = 1,268) and were followed up for a median of 3.5 years. In total, 235 (9.3%) participants had been lost to follow-up. After 3 years of follow-up, mean modified Alternative Healthy Eating Index (scale 0-70) was only slightly higher in the BALANCE group versus the control group (26.2 ± 8.4 vs 24.7 ± 8.6, P < .01), mainly due to a 0.5-serving/d greater intake of fruits and of vegetables in the BALANCE group. Primary end point events occurred in 236 participants (18.8%) in the BALANCE group and in 207 participants (16.4%) in the control group (hazard ratio, 1.15; 95% CI 0.95-1.38; P = .15). Secondary end points did not differ between groups after follow-up., Conclusions: The BALANCE Program only slightly improved adherence to a healthy diet in patients with established CVD and had no significant effect on the incidence of cardiovascular events or death., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the influence of socioeconomic factors (age, gender, and occupation) on the local knowledge of medicinal plants in the Araripe National Forest, Brazil, and the priority of conservation of the species as perceived by people. Additionally, priority species for in situ conservation were identified by calculating conservation priority (CP). Initially, free lists were developed with 152 informants in order to identify the plants known and used by them. Based on the most cited plants in these lists, a salience analysis was performed to identify the ten most prominent tree species. In a second moment, through a participatory workshop, these ten species were classified by the perception of local experts as to their environmental availability and intensity of exploitation. Then, the population size of the forest plant species was quantified through a phytosociological sampling and the conservation priority index (CP) of the species was calculated. A total of 214 ethnospecies were cited by the informants, which were identified in 167 species. Local knowledge was influenced by socioeconomic factors, with positive correlation between age and local knowledge and difference in knowledge among professions. Among the ten most prominent tree species in terms of their medicinal importance, Hancornia speciosa was highlighted as a priority for conservation in the experts' perception because it has low environmental availability and a high exploitation rate. The ten species were ordered by the CP differently from the ordering made by the local experts' perception, indicating that people's perception of species conservation status may not correspond to the actual situation in which they are found in the forests. Conservationist measures based on the perception of informants need complementary ecological studies on the species accessed.

The current study aimed to investigate the perceptions and expectations of family members/caregivers regarding nursing care provided to psychiatric inpatients in a general hospital. The study was a descriptive-exploratory study with a qualitative approach. Data were collected through open interviews with 10 relatives of patients hospitalized in the psychiatric unit and analyzed using content analysis. Participants reported that nursing care was good and emphasized a good relationship between the patient and nursing staff marked by professionalism, care, and dedication. Participants' expectations highlighted staff's need for relational skills, represented by patience, attention, and interaction, and for meeting the basic human needs of patients. Most participants did not have higher expectations regarding the care provided. Future studies should address the family/caregiver's point of view, as psychiatric hospitalizations in general hospitals are a recent practice that should be the subject of further reflection and discussion to improve the quality of care. [Journal of Psychosocial Nursing and Mental Health Services, 56(8), 31-36.]., (Copyright 2018, SLACK Incorporated.)

The extent to which pre-Columbian societies altered Amazonian landscapes is hotly debated. We performed a basin-wide analysis of pre-Columbian impacts on Amazonian forests by overlaying known archaeological sites in Amazonia with the distributions and abundances of 85 woody species domesticated by pre-Columbian peoples. Domesticated species are five times more likely than nondomesticated species to be hyperdominant. Across the basin, the relative abundance and richness of domesticated species increase in forests on and around archaeological sites. In southwestern and eastern Amazonia, distance to archaeological sites strongly influences the relative abundance and richness of domesticated species. Our analyses indicate that modern tree communities in Amazonia are structured to an important extent by a long history of plant domestication by Amazonian peoples., (Copyright © 2017, American Association for the Advancement of Science.)

Objective: to evaluate the effect of physical therapy on the range of motion of the shoulders and perimetry of the upper limbs in women treated with radiotherapy for breast cancer., Methods: a total of 35 participants were randomized into two groups, with 18 in the control group (CG) and 17 in the study group (SG). Both of the groups underwent three evaluations to assess the range of motion of the shoulders and perimetry of the upper limbs, and the study group underwent supervised physical therapy for the upper limbs., Results: the CG had deficits in external rotation in evaluations 1, 2, and 3, whereas the SG had deficits in flexion, abduction, and external rotation in evaluation 1. The deficit in abduction was recovered in evaluation 2, whereas the deficits in all movements were recovered in evaluation 3. No significant differences in perimetry were observed between the groups., Conclusion: the applied supervised physical therapy was effective in recovering the deficit in abduction after radiotherapy, and the deficits in flexion and external rotation were recovered within two months after the end of radiotherapy. Registration number of the clinical trial: NCT02198118., Objetivo: avaliar o efeito da fisioterapia na amplitude de movimento do ombro e na perimetria do membro superior, aplicada durante o período da radioterapia nas mulheres em tratamento para o câncer de mama., Métodos: 35 voluntárias foram randomizadas em dois grupos, 18 para o grupo controle e 17 para o grupo de estudo. Os dois grupos foram submetidos a três avaliações da amplitude de movimento do ombro e perimetria do membro superior, sendo o grupo de estudo também submetido à fisioterapia supervisionada para os membros superiores., Resultados: o grupo controle apresentou déficit entre os membros para o movimento de rotação externa nas avaliações 1, 2 e 3. O grupo de estudo apresentou déficit entre os membros para os movimentos de flexão, abdução e rotação externa na avaliação 1. Houve recuperação do déficit de movimento de abdução na avaliação 2 e, na avaliação 3, os déficits de todos os movimentos estavam recuperados. Na análise da perimetria não foi observada diferença significativa., Conclusão: o protocolo fisioterapêutico supervisionado aplicado foi efetivo na recuperação do déficit de abdução pós-radioterapia e de flexão e rotação externa quando avaliados até 2 meses após o término da radioterapia. Número do registro do ensaio clínico: NCT02198118., Objetivo: evaluar el efecto de la terapia física en el rango de movimiento de los hombros y la perimetría de las extremidades superiores en mujeres tratadas con radioterapia debido a cáncer de mama., Métodos: un total de 35 participantes fueron aleatorizadas en dos grupos, 18 en el grupo control y 17 en el grupo de estudio. Ambos grupos fueron sometidos a tres evaluaciones para evaluar el rango de movimiento de los hombros y la perimetría de las extremidades superiores, y el grupo de estudio fue sometido a terapia física supervisada de las extremidades superiores., Resultados: el grupo de control tuvo déficits en la rotación externa en la evaluación 1, 2, y 3, mientras que el grupo de estudio tuvo déficits en la flexión, abducción y rotación externa en la evaluación 1. El déficit en la abducción fue recuperado en la evaluación 2, mientras que los déficits en todos los movimientos fueron recuperados en la evaluación 3. No se observaron diferencias significativas en la perimetría., Conclusión: la terapia física supervisada aplicada fue efectiva en la recuperación del déficit en la abducción después de la radioterapia y los déficits en flexión y rotación externa fueron recuperados dos meses después de terminada la radioterapia. Número de registro del ensayo clínico: NCT02198118.

Estimates of extinction risk for Amazonian plant and animal species are rare and not often incorporated into land-use policy and conservation planning. We overlay spatial distribution models with historical and projected deforestation to show that at least 36% and up to 57% of all Amazonian tree species are likely to qualify as globally threatened under International Union for Conservation of Nature (IUCN) Red List criteria. If confirmed, these results would increase the number of threatened plant species on Earth by 22%. We show that the trends observed in Amazonia apply to trees throughout the tropics, and we predict that most of the world's >40,000 tropical tree species now qualify as globally threatened. A gap analysis suggests that existing Amazonian protected areas and indigenous territories will protect viable populations of most threatened species if these areas suffer no further degradation, highlighting the key roles that protected areas, indigenous peoples, and improved governance can play in preventing large-scale extinctions in the tropics in this century.

Adopting a critical perspective of the social sciences, this study initially analyzes some aspects of the technicism of the Brazilian Civil Defense to have it as a benchmark of the usual indifference of its technical and operational personnel to the multidimensional social suffering of the groups affected by disasters. The analytical framework is based on documentary research, especially of official records, and also a review of the literature of the main authors in the field as well as recent studies about the most emblematic recent disasters in Brazil. The conclusion reached is that concern about the multidimensional social suffering of the social groups affected by disasters is absent in the institutional framework.

Transformations of natural landscapes and their biodiversity have become increasingly dramatic and intense, creating a demand for rapid and inexpensive methods to assess and monitor ecosystems, especially the most vulnerable ones, such as aquatic systems. The speed with which surveys can collect, identify, and describe ecological patterns is much slower than that of the loss of biodiversity. Thus, there is a tendency for higher-level taxonomic identification to be used, a practice that is justified by factors such as the cost-benefit ratio, and the lack of taxonomists and reliable information on species distributions and diversity. However, most of these studies do not evaluate the degree of representativeness obtained by different taxonomic resolutions. Given this demand, the present study aims to investigate the congruence between species-level and genus-level data for the infraorder Nepomorpha, based on taxonomic and numerical resolutions. We collected specimens of aquatic Nepomorpha from five streams of first to fourth order of magnitude in the Pindaíba River Basin in the Cerrado of the state of Mato Grosso, Brazil, totaling 20 sites. A principal coordinates analysis (PCoA) applied to the data indicated that species-level and genus-level abundances were relatively similar (>80% similarity), although this similarity was reduced when compared with the presence/absence of genera (R = 0.77). The presence/absence ordinations of species and genera were similar to those recorded for their abundances (R = 0.95 and R = 0.74, respectively). The results indicate that analyses at the genus level may be used instead of species, given a loss of information of 11 to 19%, although congruence is higher when using abundance data instead of presence/absence. This analysis confirms that the use of the genus level data is a safe shortcut for environmental monitoring studies, although this approach must be treated with caution when the objectives include conservation actions, and faunal complementarity and/or inventories.

Background: The Calcium Hydroxide has been widely used as an intracanal dressing and in combination with restorative and endodontic materials and its main goal is the tissue reparation. However, when the patient has chronic stress, the immunological response and tissue repair decreases in both the epithelial and connective tissue. Therefore, the aim was to analyze the effect of chronic stress on the tissue response in rats exposed to calcium hydroxide (CH)., Materials and Methods: A total of 60 wistar rats were anesthetized, and a polyethylene tube containing CH was inserted under the skin. After 24 h, they were divided into two groups: Calcium hydroxide + stress (CHSG) n = 30 and calcium hydroxide (CHG) n = 30. They were stressed by physical restraint, for 12 h each day for periods of 7, 15 and 30 days when 10 animals from each group were euthanized. The tissues surrounding the polyethylene tubes were removed, and slides were prepared and stained with hematoxylin and eosin. The analysis was performed with an optical microscope with magnification of 4-400 times by a blinded senior examiner. The sample slides were classified according to the following scores 0 - absent/1 - present/2 - infiltrate to: Inflammatory infiltrate containing fibrous condensation, lymphocytes, plasmacytes, macrophages, neutrophils, and eosinophils. The data were statistically analyzed using the Student's t-test (P < 0.05) for paired samples., Results: The exposure time of 7 days elicited no statistical difference between groups (P > 0.05). The 15 days exposure group had higher averages for CHG to eosinophils and inflammatory infiltrate (P < 0.05). In 30 days, CHG showed higher averages to inflammatory infiltrate and lower averages to FC (P < 0.05)., Conclusions: Some modified patterns of responses in the CHSG were observed at 15 days and 30 days.

The infraorder Gerromorpha comprises semiaquatic bugs, most of which spend much of their lifetime on the water surface, between floating plants, or on the margins of water bodies. Based on literature and collections made on streams and lakes on municipalities of eastern Mato Grosso, Brazil, a list has been elaborated with 52 species, including several new records. Out of the recorded species, 26 belong to the family Veliidae, 20 to Gerridae, three to Hydrometridae, two to Mesoveliidae, and one to Hebridae. The modeling of the potential geographical distribution is also presented for the 20 species that have been recorded for the first time from the state.

In mammalian, several evidences suggest that central serotonin participates in thermoregulation. Nucleus raphe obscurus (NRO), a serotonergic nucleus, has been recognized to be the source of generation of various hemodynamic patterns in different behavioral conditions, but its involvement in thermoregulation is unclear. In the present study, extracellular action potentials of NRO neurons were recorded in anesthetized rats, which were submitted to cold and warm stimuli in the tail. The firing rate of the neurons was compared before and after each stimulation. It was found that 59% of the neurons submitted to a cold stimulus trial had a significant increase in their firing frequency, while 48% of the neurons submitted to warm stimulation trial were inhibited. The opposite responses in neuronal activity of NRO units to cooling or heating suggest that these cells are involved in producing the homoeothermic vascular adaptations secondary to changes in cutaneous temperature in the rat tail.

Background: Pythiosis is a life-threatening disease caused by Pythium insidiosum. Photodynamic therapy (PDT) is an alternative treatment to surgery that uses the interaction of a photosensitizer, light and molecular oxygen to cause cell death., Objectives: To evaluate the effect of PDT on the in vitro growth of P. insidiosum and in an in vivo model of pythiosis., Methods: For in vitro studies, two photosensitizers were evaluated: a haematoporphyrin derivative (Photogem(®)) and a chlorine (Photodithazine(®)). Amphotericin B was also evaluated, and the control group was treated with sterile saline solution. All experiments (PDT, porphyrin, chlorine and light alone, amphotericin B and saline solution) were performed as five replicates. For in vivo studies, six rabbits were inoculated with 20,000 zoospores of P. insidiosum, and an area of 1 cm(3) was treated using the same sensitizers. The PDT irradiation was performed using a laser emitting at 660 nm and a fluence of 200 J/cm(2) . Rabbits were clinically evaluated daily and histopathological analysis was performed 72 h after PDT., Results: For in vitro assays, inhibition rates for PDT ranged from 60 to 100% and showed better results in comparison to amphotericin B. For the in vivo assays, after PDT, histological analysis of lesions showed a lack of infection up to 1 cm in depth., Conclusions and Clinical Importance: In vitro and in vivo studies showed that PDT was effective in the inactivation of P. insidiosum and may represent a new approach to treating pythiosis., (© 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.)

Complexes [Bi(2Fo4Ph)Cl(2)] (1), [Bi(2Ac4Ph)Cl(2)] (2), [Bi(2Bz4Ph)Cl(2)] (3), [Bi(H(2)Gy3DH)Cl(3)] (4), [Bi(H(2)Gy4Et)(OH)(2)Cl] (5), and [Bi(H(2)Gy4Ph)Cl(3)] (6) were prepared with pyridine-2-carbaldehyde 4-phenylthiosemicarbazone (H2Fo4Ph), 1-(pyridin-2-yl)ethanone 4-phenylthiosemicarbazone (H2Ac4Ph), phenyl(pyridin-2-yl)methanone 4-phenylthiosemicarbazone (H2Bz4Ph), as well as with glyoxaldehyde bis(thiosemicarbazone) (H(2)Gy4DH) and its 4-Et (H(2)Gy4Et) and 4-Ph (H(2)Gy4Ph) derivatives. The complexes exhibited antibacterial activities against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Pseudomonas aeruginosa. Coordination to Bi(III) proved to be an effective strategy to increase the antibacterial activity of the thiosemicarbazones and bis(thiosemicarbazones)., (Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.)

South Asians have a higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) than white Caucasians, for a given BMI. Premature biological ageing, assessed by reduction in telomere length (TL), may be mediated by factors resulting from altered metabolic profiles associated with obesity. We hypothesise that ethnicity and metabolic status represent detrimental factors contributing to premature biological ageing. Therefore we assessed TL in two South Asian, age and BMI-matched cohorts [T2DM (n = 142) versus non-T2DM (n = 76)] to determine the effects of BMI, gender, lipid and CVD profile on biological ageing. Genomic DNA was obtained from the UKADS cohort; biochemical and anthropometric data was collected and TL was measured by quantitative real-time PCR. Our findings indicated a gender-specific effect with reduced TL in T2DM men compared with non-T2DM men (P = 0.006). Additionally, in T2DM men, TL was inversely correlated with triglycerides and total cholesterol (r = -0.419, P < 0.01; r = -0.443, P < 0.01). In summary, TL was reduced amongst South Asian T2DM men and correlated with triglycerides and total cholesterol. This study highlights enhanced biological ageing among South Asian, T2DM men, which appears to be tracked by changes in lipids and BMI, suggesting that raised lipids and BMI may directly contribute to premature ageing.

Ghrelin, an orexigenic hormone of gastric origin that stimulates growth hormone secretion, may modulate inflammation. This experimental study examines the effect of ghrelin on NFκB (p65 subunit), a transcriptional factor involved in inflammation on a human B-lymphocyte cell (WILCL). After confirming the expression of ghrelin receptor protein using western blotting the cells were transferred to wells maintaining a density of 1 × 10(6) cells per ml and a proportion activated with phytohaemagluttinin. Activated and resting cells were exposed to octanoyl-, desoctanoyl ghrelin and a non-peptide ghrelin agonist (Pfizer CP-464709) in increasing concentrations for 6 h. Cell protein extracts were analyzed for NFκB activation using Trans AM NFκB p65 assay. IL-6, IL-8, IL-10, IL-13 and TNFα were measured in the media using Lincoplex human cytokine assay. In octanoyl ghrelin treated resting cells, NFκB activity (Optical Density OD(450 nm)) (mean ± SEM) in control cells was 0.42 ± 0.10 and increased to 0.61 ± 0.20 (P = 0.044), 0.54 ± 0.10 (P = 0.043), 0.52 ± 0.08 at 1, 10 and 100 nM concentrations respectively. No effect was detected with desoctanoyl ghrelin or ghrelin agonist and no specific change in cytokine production. In conclusion, Octanoyl ghrelin increased NFκB activation by up to 50% in a B-lymphocyte cell line suggesting an effect on the inflammatory process.

Visfatin has been proposed as an insulin-mimicking adipocytokine, predominantly secreted from adipose tissue and correlated with obesity. However, recent studies suggest visfatin may act as a proinflammatory cytokine. Our studies sought to determine the significance of this adipocytokine and its potential role in the pathogenesis of T2DM. Firstly, we examined the effects of diabetic status on circulating visfatin levels, and several other adipocytokines, demonstrating that diabetic status increased visfatin*, TNF-α*** and IL-6*** compared with non-diabetic subjects (*p<0.05, **p<0.01, ***p<0.001, respectively). We then assessed the effects of an insulin sensitizer, rosiglitazone (RSG), in treatment naïve T2DM subjects, on circulating visfatin levels. Our findings showed that visfatin was reduced post-RSG treatment [vs. pre-treatment (*p<0.05)] accompanied by a reduction in HOMA-IR**, thus implicating a role for insulin in visfatin regulation. Further studies addressed the intracellular mechanisms by which visfatin may be regulated, and may exert pro-inflammatory effects, in human abdominal subcutaneous (Abd Sc) adipocytes. Following insulin (Ins) and RSG treatment, our in vitro findings highlighted that insulin (100 nM), alone, upregulated visfatin protein expression whereas, in combination with RSG (10 nM), it reduced visfatin*, IKKβ** and p-JNK1/2*. Furthermore, inhibition of JNK protein exacted a significant reduction in visfatin expression (**p<0.01), whilst NF-κB blockade increased visfatin (*p<0.05), thus identifying JNK as the more influential factor in visfatin regulation. Additional in vitro analysis on adipokines regulating visfatin showed that only Abd Sc adipocytes treated with recombinant human (rh)IL-6 increased visfatin protein (*p<0.05), whilst rh visfatin treatment, itself, had no influence on TNF-α, IL-6 or resistin secretion from Sc adipocytes. These data highlight visfatin's regulation by insulin and RSG, potentially acting through NF-κB and JNK mechanisms, with only rh IL-6 modestly affecting visfatin regulation. Taken together, these findings suggest that visfatin may represent a pro-inflammatory cytokine that is influenced by insulin/insulin sensitivity via the NF-κB and JNK pathways.

Background: Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status., Methods: Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8)., Results: Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively., Conclusions: Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.

Breast cancer is the second most frequent cancer among women. Surgery is part of the therapeutic process to prevent metastases, but it can also cause some complications, including lymphedema. Physiotherapy contributes to its treatment, using different techniques that have been developed over the years. This systematic literature review aims to present physiotherapy modalities applied for lymphedema therapy. The literature review was conducted using textbooks and Lilacs, Pubmed and Scielo databases, from 1951 to 2009. Physiotherapy resources used for lymphedema treatment include complex decongestive therapy (CDT), pneumatic compression (PC), high voltage electrical stimulation (HVES) and laser therapy. The analyzed literature shows that better results are obtained with combined techniques. CDT is the most used protocol, and its association with PC has demonstrated efficacy. The new techniques HVES and laser present satisfactory results.

Introduction: Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue., Aims: The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles., Methods: Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 +/- (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-alpha, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined., Results: Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 +/- 1.7 EU/ml, RSG: 5.6 +/- 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall., Conclusion: We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity.

Context: Visceral adipose tissue (AT) is known to confer a significantly higher risk of type 2 diabetes and cardiovascular disease. Epicardial AT has been shown to be related to cardiovascular disease and myocardial function through unidentified mechanisms. Epicardial AT expresses an inflammatory profile of proteins; however, the mechanisms responsible are yet to be elucidated., Objectives: The objectives of the study were to: 1) examine key mediators of the nuclear factor-kappaB (NFkappaB) and c-Jun N-terminal kinase (JNK) pathways in paired epicardial and gluteofemoral (thigh) AT from coronary artery disease (CAD) and control patients and 2) investigate circulating endotoxin levels in CAD and control subjects., Design: Serums and AT biopsies (epicardial and thigh) were obtained from CAD (n = 16) and non-CAD (n = 18) patients. Inflammation was assessed in tissue and serum samples through Western blot, real-time PCR, ELISAs, and activity studies., Results: Western blotting showed epicardial AT had significantly higher NFkappaB, inhibitory-kappaB kinase (IKK)-gamma, IKKbeta, and JNK-1 and -2 compared with thigh AT. Epicardial mRNA data showed strong correlations between CD-68 and toll-like receptor-2, toll-like receptor-4, and TNF-alpha. Circulating endotoxin was elevated in patients with CAD compared with matched controls [CAD: 6.80 +/- 0.28 endotoxin unit(EU)/ml vs. controls: 5.52 +/- 0.57 EU/ml; P<0.05]., Conclusion: Epicardial AT from patients with CAD shows increased NFkappaB, IKKbeta, and JNK expression compared with both CAD thigh AT and non-CAD epicardial AT, suggesting a depot-specific as well as a disease-linked response to inflammation. These studies implicate both NFkappaB and JNK pathways in the inflammatory profile of epicardial AT and highlight the role of the macrophage in the inflammation within this tissue.

Background: Ghrelin, a potent orexigenic peptide produced by the stomach, may be affected by circulating inflammatory mediators., Aim: To assess the effect of an anti-TNFα antibody on ghrelin in patients with Crohn's disease (CD)., Methods: Fifteen patients with Crohn's receiving infliximab were studied before and 1 week after infusion. Following an overnight fast, blood was sampled before a meal and then every 20 min for 2 h. Total ghrelin and CRP were measured using ELISA. Acylated ghrelin and TNFα, IFNγ, IL-1β and IL-6 were measured with bioplex. Harvey Bradshaw Activity Index was assessed., Results: Median (95% CI) 2-h integrated plasma total ghrelin increased from 162 (99-311) before infliximab to 200 (128-387) pg/mL h, (P = 0.02) after. Following infliximab, 20 min postmeal, median acylated ghrelin decreased from 50.3 (24-64) to 38.6 (26-82) pg/mL, (P = 0.04) thus reverting to a traditional meal related ghrelin curve. Median (range) disease activity decreased from 5 (2-28) before to 3 (0-22), (P = 0.0001) and Median (95% CI) TNFα decreased from 2.8 (1.89-4.48) to 1.31 (0.73-2.06) pg/mL (P = 0.002)., Conclusions: Infliximab increases circulating total ghrelin by 25% in CD and restores the postprandial response of acylated ghrelin to food intake. Acylated and de-sacyl ghrelin remain unchanged, suggesting that an alternate isoform could be affected by infliximab., (© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd.)

Unlabelled: Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, CONTROL: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha,, Control: 1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes (, Control: 2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.

Context: The adipokine leptin has critical importance in central appetite regulation. In contrast to some suggestion of adiponectin influencing energy homeostasis in rodents, there is no evidence for adiponectin or resistin entering the human blood-brain barrier., Objective: The objective was to establish the presence of adiponectin or resistin in human cerebrospinal fluid (CSF) and to compare their distribution with leptin. Furthermore, we wished to examine the expression of the adiponectin receptors 1 and 2 (AdipR1, AdipR2) in the human hypothalamus., Methods: For this purpose, serum and CSF samples were collected from 20 men and 19 women matched for age [men, 69.8 +/- 8.6 yr (mean +/- SD); women, 69.4 +/- 4.3 yr] and BMI (men, 29.4 +/- 3.4 kg/m(2); women, 27.3 +/- 4.8 kg/m(2)) undergoing elective surgery under spinal anesthesia., Results: Adiponectin was identified in CSF with levels 1000-fold less than serum, whereas resistin and leptin levels were 100-fold less. Unlike their serum levels, adiponectin CSF levels showed no gender difference or correlation with insulin resistance, which is similar to resistin CSF levels. The adiponectin and leptin CSF/serum ratios in our study exhibit the same pattern of gender-specific BMI association with inverse correlation in women (r = -0.61; P = 0.02) and no correlation in men (r = 0.026; P = not significant). Furthermore, immunostaining established AdipR1 and -2 in the hypothalamus and increased AdipR2 expression in the paraventricular nucleus, which is involved in energy regulation., Conclusion: In summary, our findings show both the presence of adiponectin and resistin in human CSF, with no effect of insulin resistance on CSF levels. The CSF entry of adiponectin and leptin in women appears to be impaired in obesity.

Context: Obesity-associated inflammation is a contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM); the mechanisms underlying the progression to T2DM are unclear. The adipokine resistin has demonstrated proinflammatory properties in relation to obesity and T2DM., Objectives: The objectives of this study were to characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway; to examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin, and rosiglitazone in human adipocytes; and, finally, to analyze the effect of rhResistin on the expression of components of the nuclear factor-kappaB pathway and insulin signaling cascade., Methods: Abdominal sc adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35; age, 36-49 yr; body mass index, 26.5 +/- 5.9 kg/m2). Isolated adipocytes were cultured with rhResistin (10-50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot., Results: In vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Proinflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific c-Jun NH2-terminal kinase (JNK) 1 and JNK2, were up-regulated in response to rhResistin., Conclusion: Resistin may participate in more than one mechanism to influence proinflammatory cytokine release from human adipocytes, potentially via the integration of nuclear factor-kappaB and JNK signaling pathways.

The aim of this study was to compare the use of several biomarkers to identify obese children and adolescents with increased metabolic risk. One hundred sixty-two Caucasian obese children and adolescents (41% males, 9-18 years old) referred to the Istituto Auxologico Italiano between 2003 and 2004 underwent an oral glucose tolerance test. Circulating levels of adiponectin (AD), plasminogen activator inhibitor 1 (PAI-1), interleukin 18 (IL-18), C-reactive protein (CRP), fibrinogen, uric acid, lipids and insulin were measured. Twenty five percent of obese children had the MS defined using World Health Organization-derived child specific criteria. MS subjects had significantly lower AD (p<0.01) and higher log-PAI-1 (p<0.001), uric acid (p<0.0001), and IL-18 (p<0.001). Subjects with AD levels

The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

Germline mutations in the BHD gene cause the dominantly inherited cancer susceptibility disorder, Birt-Hogg-Dubé (BHD) syndrome. Individuals with BHD are reported to have an increased risk of renal cell carcinoma (RCC) and of colorectal polyps and cancer. The BHD gene maps to 17p11.2, and to investigate whether somatic inactivation of the BHD gene region is implicated in the pathogenesis of sporadic RCC and colorectal cancer (CRC), we performed mutation analysis in 30 RCC primary tumours and cell lines, and 35 CRCs and cell lines. A somatic missense mutation (Ala444Ser) with loss of the wild type allele (consistent with a two hit mechanism of tumorigenesis) was detected in a primary clear cell RCC, and a further missense mutation (Ala238Val) was identified in a clear cell RCC cell line for which matched normal DNA was not available. A somatic missense substitution (Arg392Gly) was identified in a primary CRC, and the same change was detected in three RCCs (all oncocytomas) for which matched normal DNA was not available. A germline Arg320Gln missense variant detected in a primary CRC was not detected in 40 control individuals or in a further 159 familial and sporadic CRC cases. However, AA homozygotes for an intronic single nucleotide polymorphism (c.1517+6 G-->A) were under-represented in familial cases compared with controls (p = 0.03). For some tumour suppressor genes, epigenetic silencing is a more common mechanism of inactivation than somatic mutations. However, we did not detect evidence of epigenetic silencing of BHD in 19 CRC and RCC cell lines, and BHD promoter region hypermethylation was not detected in 20 primary RCCs. These findings suggest that BHD inactivation occurs in a subset of clear cell RCC and CRC.

Slit2 plays a vital role in axon guidance by signaling through Robo receptors. Recent evidence suggests that Slit2 protein may function in other settings because human and Xenopus Slit2 has been shown to inhibit leukocyte chemotaxis. SLIT2 protein is a putative ligand for the ROBO receptors. We recently demonstrated that ROBO1 is inactivated by promoter region hypermethylation in <20% of human cancers; furthermore, tumor suppressor activity has not been shown. Thus, the importance of ROBO1 inactivation in human cancer is uncertain. Therefore, we investigated the status of SLIT2 located at 4p15.2 in lung and breast cancers. Although somatic SLIT2 mutations were not detected, epigenetic inactivation was common. SLIT2 promoter methylation was detected in 59% of breast cancer, 77% of non-small cell lung cancer, and 55% of small cell lung cancer cell lines. In these tumor lines, SLIT2 expression was restored by treatment with a demethylating agent. SLIT2 promoter methylation was detected in 43% of breast cancer, 53% of non-small cell lung cancer, and 36% of small cell lung cancer primary tumors. The majority of methylated tumors demonstrated allelic loss at 4p15.2. In addition, SLIT2 expression was down-regulated in methylated breast tumors, relative to normal control, as demonstrated by quantitative real-time reverse transcription-PCR. Overexpression of SLIT2 suppressed >70% of colony growth in each of three breast tumor lines (with either absent or low SLIT2 expression). Because SLIT2 is primarily a secreted protein, SLIT2-conditioned medium suppressed the growth of several breast cancer lines (with absent or weak SLIT2expression) by 26-51% but had no significant effect on a breast tumor cell line that expresses normal levels of SLIT2. These findings demonstrate that SLIT2 is frequently inactivated in lung and breast cancer by promoter region hypermethylation and allele loss and is an excellent candidate for the lung and breast tumor suppressor gene previously mapped to 4p15.2.

Germ-line mutations in the von Hippel-Lindau (VHL) tumor suppressor disease are associated with a high risk of retinal and cerebellar hemangioblastomas, renal cell carcinoma (RCC), and, in some cases, pheochromocytoma (PHE). In addition, somatic mutation or epigenetic inactivation of the VHL gene occurs in most clear cell RCCs. VHL protein (pVHL) has a critical role in regulating proteasomal degradation of the HIF transcription factor, and VHL inactivation results in overexpression of many hypoxia-inducible mRNAs including vascular endothelial growth factor (VEGF). To identify novel pVHL target genes we investigated the effect of wild-type (WT) pVHL on the expression of 588 cancer-related genes in two VHL-defective RCC cell lines. Expression array analysis identified nine genes that demonstrated a >2-fold decrease in expression in both RCC cell lines after restoration of WT pVHL. Three of the nine genes (VEGF, PAI-1, and LRP1) had been reported previously as pVHL targets and are known to be hypoxia-inducible. In addition, six novel targets were detected: cyclin D1 (CCND1), cell division protein kinase 6, collagen VIII alpha 1 subunit, CD59 glycoprotein precursor, integrin beta8, and interleukin 6 precursor IFN-beta2. We found no evidence that CCND1, cell division protein kinase 6, CD59, and integrin beta8 expression was influenced by hypoxia suggesting that pVHL down-regulates these targets by a HIF-independent mechanism. A type 2C pVHL mutant (V188L), which is associated with a PHE only phenotype (and had been shown previously to retain the ability to promote HIF ubiquitylation), retained the ability to suppress CCND1expression suggesting that loss of pVHL-mediated suppression of cyclin D1 is not necessary for PHE development in VHL disease. Other studies have suggested that: (a) genetic modifiers influence the phenotypic expression of VHL disease; and (b) polymorphic variation at a CCND1 codon 242 A/G single nucleotide polymorphism (SNP) may influence cancer susceptibility or prognosis in some situations. Therefore, we analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease. There was an association between the G allele and multiple retinal angiomas (P = 0.04), and risk of central nervous system hemangioblastomas (P = 0.05). These findings suggest that a variety of HIF-independent mechanisms may contribute to pVHL tumor suppressor activity and that polymorphic variation at one pVHL target influences the phenotypic expression of VHL disease.

The objective of the present study was to determine whether there is a synergistic effect of malnutrition and ethanol exposure on neuromotor development. Ethanol (E) (6 g/kg) or sucrose (S) (isocaloric to ethanol) was administered by gavage to ad libitum-fed (A) and malnourished (M) pregnant rats on days 18, 19 and 20 of pregnancy. Malnutrition was produced by food restriction to 50% of control intake. At birth, the offspring were weighed and transferred to surrogate mothers. Performance in the rim-escape test and on the rotating rod were evaluated on days 19 and 28 of life, respectively. Development of the adult swimming pattern was also studied. The results indicated that: 1) malnutrition alone decreased birth weight (g) significantly (AE, 5.56 +/- 0.36; AS, 6.31 +/- 1.05; ME, 4.81 +/- 0.73; MS, 5.23 +/- 0.57); 2) a synergistic interaction between alcohol exposure and malnutrition was observed only in the rim escape test (percent of falling rats: AE, 9; AS, 5; ME, 24; MS, 5); 3) only malnutrition retarded development of swimming; 4) malnourished dams gained more weight (g) than controls during treatment with ethanol (AE, 2.6 +/- 8.4, N = 6; AS, 3.1 +/- 8.4, N = 4; ME, 23.0 +/- 6.3, N = 7; MS, 29.0 +/- 9.0, N = 8). These results indicate a possible synergistic action between malnutrition and ethanol on neuromotor development and point to the importance of ethanol as a calorie source for malnourished animals.