Systematic review: pre- and post-operative prognostic value of cardiopulmonary exercise testing in liver transplant candidates.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is the gold standard for the objective assessment of functional status. In many conditions, CPET outperforms the traditional variables in predicting mortality. AIM: In patients with cirrhosis listed for liver transplantation, our primary aim was to determine the prognostic value of CPET for pre-and post-transplant mortality and, in particular, whether CPET remained predictive after adjustment for liver disease severity. METHODS: A systematic literature review was conducted in databases Medline, Scopus, Embase and PubMed. Where possible, data were pooled for meta-analyses using a DerSimonian and Laird random effects model. RESULTS: A total of seven studies were retrieved, including 1107 patients with a mean MELD of 14.2 (standard deviation 1.6) and peak baseline VO2 of 17.4 mL/kg/min. In all of the studies in which multivariable analysis was performed, CPET variables were independent predictors of pre-transplant mortality (three studies) and post-transplant mortality (four studies). In the three studies where we could aggregate post-transplant mortality data, post-transplant mortality was predicted by AT with a mean difference of 2.0 (95% confidence interval, CI: 0.42-3.59; Z = 2.48, P = 0.01) between survivors and nonsurvivors. The peak VO2 was not significant (0.77 95% CI: -1.36 to 2.90; Z = 0.71, P = 0.48). CONCLUSIONS: Patient's listed for liver transplant have significant functional limitations, with a weighted mean VO2 below the threshold level required for independent living. Although heterogeneity in study designs with respect to timing, CPET variables, and cut-off values precluded the determination of CPET mortality thresholds, the studies support CPET as an objective and independent predictor of pre- and post-transplant mortality.

Effects of confinement on anomalies and phase transitions of core-softened fluids.

We use molecular dynamics simulations to study how the confinement affects the dynamic, thermodynamic, and structural properties of a confined anomalous fluid. The fluid is modeled using an effective pair potential derived from the ST4 atomistic model for water. This system exhibits density, structural, and dynamical anomalies, and the vapor-liquid and liquid-liquid critical points similar to the quantities observed in bulk water. The confinement is modeled both by smooth and structured walls. The temperatures of extreme density and diffusion for the confined fluid show a shift to lower values while the pressures move to higher amounts for both smooth and structured confinements. In the case of smooth walls, the critical points and the limit between fluid and amorphous phases show a non-monotonic change in the temperatures and pressures when the nanopore size is increase. In the case of structured walls, the pressures and temperatures of the critical points varies monotonically with the pore size. Our results are explained on basis of the competition between the different length scales of the fluid and the wall-fluid interaction.

[Bisphosphonate-associated osteonecrosis of the jaw]. / Bisphosphonat-assoziierte Kiefernekrosen.

BACKGROUND: Bisphosphonates (BP) are used in the treatment of severe osteoporosis and metastasis of malignant diseases. A possible relationship between the occurrence of osteonecrosis of the jaw and BP therapy was first described in 2003. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is difficult to treat. In some cases the condition of the patients is so compromised that only minimally invasive surgery is possible. Histopathologically, osteonecrosis shows the features of chronic sequestered osteomyelitis, which can be found in different areas of the upper and lower jaw. Sometimes extensive resections of the jaw are necessary. Thus, BRONJ can cause mutilation, impairment of function and esthetics in the orofacial system and, thereby, compromise the life quality of the patients. Triggering factors are often tooth extraction without surgical plastic wound closure of the alveoli, but can also be associated with bruises from denture or other minor wounds. OBJECTIVES: The purpose of this article is to present results from our own patient collective, including therapy regime, success rate, and therapy recommendations. METHODS: The patient populations at three German hospitals were analyzed using a standard questionnaire. The patients in the study group, entered into a follow-up system for early detection of possible BRONJ, were evaluated for treatement outcome. RESULTS: The success rate for prophylactic surgery in asymptomatic patients was very high at 96 %. In the group with symptomatic BRONJ, the outcome was significantly lower (76.4 %). CONCLUSIONS: Because of the complex symptoms, close cooperation between oncologists, dentists, and maxillofacial surgeons is required in the treatment of BRONJ. Before starting therapy with bisphosphonates and during the therapy, dental treatment and monitoring of the patient' oral health is necessary.

Relation between occupation in the first coordination shells and Widom line in core-softened potentials.

Three core-softened families of potentials are checked for the presence of density and diffusion anomalies. These potentials exhibit a repulsive core with a softening region and at larger distances an attractive well. We found that the region in the pressure-temperature phase diagram in which the anomalies are present increases if the slope between the core-softened scale and the attractive part of the potential decreases. The anomalous region also increases if the range of the core-softened or of the attractive part of the potential decreases. We also show that the presence of the density anomaly is consistent with the non-monotonic changes of the radial distribution function at each one of the two scales when temperature and density are varied. Then, using this anomalous behavior of the structure we show that the pressure and the temperature at which the radial distribution function of one of the two length scales equals the radial distribution function of the other length scales identify the Widom line.

Meta-analysis: oral or enteral nutritional supplementation in cirrhosis.

BACKGROUND: Malnutrition is a common and clinically significant problem in patients with cirrhosis. The impact of nutritional therapy remains unclear. AIM: To provide an up-to-date systematic review and meta-analysis of RCTs of oral or enteral nutritional supplementation (ONS or ENS) on nutritional and clinical outcomes in adult patients with cirrhosis. METHODS: The primary outcome measure was survival. Included: full-text English language RCTs investigating ONS or ENS vs. a standard nonsupplemented diet in patients with cirrhosis. Excluded: parenteral or branched chain amino acids intervention; treatment duration ≤7 days, exclusive evaluation of posttransplant, postsurgical or quality of life outcomes. RESULTS: Six trials (4 ONS/2 ENS) and 470 patients were included with 71% males and median age 53 years. When all studies were combined, there was no reduction in mortality [Relative risk (RR): 0.75 (0.42, 1.32), P = 0.31]. Subgroup analysis of 3 of the 4 ONS studies did demonstrate a mortality reduction [RR: 0.40 (0.18, 0.90), P = 0.03]. Of the 2 ENS studies, one included the sickest patients in the meta-analysis (82% Child Pugh C) and the other had the shortest mean intervention duration (8.6 days), possibly impacting the potential for benefit. Study quality was suboptimal (median Jadad = 2). CONCLUSIONS: Although there is insufficient evidence to definitively state that oro-enteral nutritional supplementation impacts clinical outcomes, on the basis of this analysis, one can be cautiously optimistic that there is the potential for benefit without an increase in adverse events. Adequately powered, Child Pugh stratified studies of at least 1 month in duration are needed to clarify the impact on relevant clinical outcomes.

Thermodynamic, dynamic, structural, and excess entropy anomalies for core-softened potentials.

Using molecular dynamic simulations, we study three families of continuous core-softened potentials consisting of two length scales: a shoulder scale and an attractive scale. All the families have the same slope between the two length scales but exhibit different potential energy gap between them. For each family three shoulder depths are analyzed. We show that all these systems exhibit a liquid-liquid phase transition between a high density liquid phase and a low density liquid phase ending at a critical point. The critical temperature is the same for all cases suggesting that the critical temperature is only dependent on the slope between the two scales. The critical pressure decreases with the decrease of the potential energy gap between the two scales suggesting that the pressure is responsible for forming the high density liquid. We also show, using the radial distribution function and the excess entropy analysis, that the density, the diffusion, and the structural anomalies are present if particles move from the attractive scale to the shoulder scale with the increase of the temperature indicating that the anomalous behavior depends only in what happens up to the second coordination shell.

Core-softened fluids, water-like anomalies, and the liquid-liquid critical points.

Molecular dynamics simulations are used to examine the relationship between water-like anomalies and the liquid-liquid critical point in a family of model fluids with multi-Gaussian, core-softened pair interactions. The core-softened pair interactions have two length scales, such that the longer length scale associated with a shallow, attractive well is kept constant while the shorter length scale associated with the repulsive shoulder is varied from an inflection point to a minimum of progressively increasing depth. The maximum depth of the shoulder well is chosen so that the resulting potential reproduces the oxygen-oxygen radial distribution function of the ST4 model of water. As the shoulder well depth increases, the pressure required to form the high density liquid decreases and the temperature up to which the high-density liquid is stable increases, resulting in the shift of the liquid-liquid critical point to much lower pressures and higher temperatures. To understand the entropic effects associated with the changes in the interaction potential, the pair correlation entropy is computed to show that the excess entropy anomaly diminishes when the shoulder well depth increases. Excess entropy scaling of diffusivity in this class of fluids is demonstrated, showing that decreasing strength of the excess entropy anomaly with increasing shoulder depth results in the progressive loss of water-like thermodynamic, structural and transport anomalies. Instantaneous normal mode analysis was used to index the overall curvature distribution of the fluid and the fraction of imaginary frequency modes was shown to correlate well with the anomalous behavior of the diffusivity and the pair correlation entropy. The results suggest in the case of core-softened potentials, in addition to the presence of two length scales, energetic, and entropic effects associated with local minima and curvatures of the pair interaction play an important role in determining the presence of water-like anomalies and the liquid-liquid phase transition.

Thermodynamic, dynamic, and structural anomalies for shoulderlike potentials.

Using molecular dynamic simulations we study a family of continuous core-softened potentials consisting of a hard core, a shoulder at closest distances, and an attractive well at further distance. The repulsive shoulder and the well distances represent two length scales. We show that if the first scale, the shoulder, is repulsive or has a small well, the potential has a region in the pressure-temperature phase diagram with density, diffusion, and structural anomalies. However, if the closest scale becomes a deep well, the regions in the pressure-temperature phase diagram where the three anomalies are present shrink and disappear. This result helps in defining two length scales potentials that exhibit anomalies.

[Evaluation of the follow-up of women aged 50-74 years after cervical cytological Ascus abnormalities in cancer screening: adherence to clinical practice guidelines in Isere, France; 1991-2000]. / Evaluation de la prise en charge des femmes de 50 à 74 ans après frottis du col de l'utérus répondu Ascus dans un dépistage organisé en Isère 1991-2000 : application de la conduite à tenir de l'Agence nationale d'accréditation et d'évaluation en santé.

OBJECTIVES: The aim of this study is to compare to the guideline (1998 and 2001) the follow-up of Ascus cytological abnormalities among women aged 50-74 years who have participated at the combined breast, cervical and colorectal cancer screening programme from 1991 to 2000 in Isère, France. PATIENTS AND METHODS: The follow-up of 1154 women with Ascus smear was analysed. A woman was defined according follow-up if she have made a colposcopy or biopsy less than four months after one positive smear or if she has repeated three smears: 3-7 months and 10-14 months after the positive smear and 1 year after the last negative smear. RESULTS: The follow-up was according to guidelines for 28.4% of the 1154 women (150 women are unknowns), 58.6% had a follow-up with too long delay and 17.2% had an uncompleted follow-up. The follow-up did not differ before 1998. It did not differ from women age. Women who were treated by gynaecologist (548) had a better follow-up (according: 35.4%) than the women who were treated by a general practitioner (595). DISCUSSION AND CONCLUSION: The follow-up of Ascus cytological abnormalities is not according to guideline. The follow-up in the screening program will be intensified.

[Effect of tamoxifen on plasma proteins in diabetes mellitus type 1]. / Efeito do tamoxifeno no perfil das proteínas plasmáticas em condição de diabetes mellitus tipo 1.

PURPOSE: Considering that important scientific advances have been obtained through studies based on experimental Diabetes mellitus, and that tamoxifen action in humans remains unknown, the aim of the present work is to follow the modifications promoted by diabetes and tamoxifen in the electrophoretic profile of plasmatic proteins. METHODS: It was used 27 Wistar female rats (180-250 body weight), randomicaly divided into five groups: C1 (n = 3, received vehicle), C2 (n = 3, no treatment), T (n =5, treated with tamoxifen, 0.3mg/Kg/day), D (n = 8, experimental diabetes by estreptozotocin, 45mg/Kg and DT (n = 8, diabetic treated with tamoxifen). The electrophoresis was accomplished in cellulose acetate. pH 8.6-8.8, TECNOW chamber, and the strains were stained by Ponceau S. The total proteins were determined by the Biuret method (Labtest). Proteinograms were obtained in densitometer BioSystems BTS-235. RESULTS: Albumin decreased progressively in the groups T, D and DT; a1 fraction increased in groups T and DT; a2 fraction increased in groups T and D, including a synergic effect in group DT; a fraction increased in groups T and D; a fraction increased in groups T, D and DT. CONCLUSIONS: The results indicate an acute phase resposta, with synergic effect of tamoxifen and diabetes, suggesting a probable hepatic lesion.

Efeito do tamoxifeno no perfil das proteínas plasmáticas em condição de diabetes mellitus tipo 1 / Effect of tamoxifen on plasma proteins in diabetes mellitus type 1

OBJETIVO: Considerando-se que importantes avanços científicos têm sido obtidos através de estudos com Diabetes mellitus experimental, e que a ação do tamoxifeno em humanos permanece obscura, o presente trabalho objetiva acompanhar as modificações promovidas pelo diabetes e tamoxifeno no perfil eletroforético das proteínas plasmáticas. MÉTODOS: Foram utilizados 27 ratos fêmeas Wistar (180-220g peso corporal), divididos randomicamente em 5 grupos: C1 (n=3, receberam veículo), C2 (n=3, sem tratamento), T (n=5, tratados com tamoxifeno, 0,3mg/kg/dia), D (n=8, diabéticos experimentais por estreptozotocina, 45mg/Kg) e DT (n=8, diabéticos tratados com tamoxifeno). A eletroforese foi realizada em acetato de celulose, pH 8,6-8,8, cuba TECNOW, e as fitas foram coradas em Ponceau S. As proteínas totais foram determinadas pelo método do Biureto (Kit Labtest). Os proteinogramas foram obtidos em densitômetro BioSystems BTS-235. RESULTADOS: Albumina diminuiu progressivamente nos grupos T, D e DT; a fração a1 aumentou nos grupos T e DT; a fração a2 aumentou nos grupos T e D, havendo efeito aditivo no grupo DT; a fração b aumentou nos grupos T e D; a fração g aumentou nos grupos T, D e DT. CONCLUSÃO: Os resultados indicam uma resposta de fase aguda, com efeito aditivo do tamoxifeno e diabetes, sugerindo uma provável lesão hepática.

Excretion measurement of porphyrins and their precursors after topical administration of 5-aminolaevulinic acid for fluorescence endoscopy in head and neck cancer.

5-Aminolevulinic acid (5-ALA) is a useful agent to enhance the detection of early epithelial lesions in head and neck cancers. It is applied either topically or systemically and converted intracellular into photosensitive protoporphyrin IX (PpIX). By ultraviolet light illumination malignant and fast proliferating lesions are detected by a characteristic red fluorescence and delineated by the bluish fluorescence of healthy tissue. To assess the elimination patterns 5-ALA, porphobilinogen (PBG) and porphyrin were measured 12h and 36h after administration in urine, 12h and 24h after examination in blood and in feces 12h after endoscopy. 5-ALA was applied either by inhalation (250 mg) or mouth rinse (200 mg). After both administration routes, excretion levels in urine returned to background levels within 12 hours after administration and only in feces values are slightly increased for PpIX and total porphyrin. Concentrations in erythrocytes were elevated, but not in plasma. No side effects were observed. According to our results the topical administration of 5-ALA is a useful method with satisfying fluorescence imaging results. Levels of metabolites in urine and plasma return to normal within 12 hours so that skin photosensitization can be neglected.

Mast cells are present in epithelial layers of different tissues of the mollusc Anomalocardia brasiliana. In situ characterization of heparin and a correlation of heparin and histamine concentration.

Heparin, other sulphated glycosaminoglycans and histamine were extracted from various dissected organs of Anomalocardia brasiliana, a mollusc from the South Atlantic, and quantified. A good correlation between heparin and histamine content was found in the labial palp, intestine, ctenidium, mantle and foot tissues. The tissue location of metachromatic cells, putatively containing heparin, was identified histologically with Alcian Blue, Toluidine Blue, Masson trichrome, Haematoxylin-Eosin and PAS. Except for the foot, cells containing metachromatic granules were found in the epithelium surfaces of all the organs analysed. An in situ identification of heparin using nitrous acid and heparinase degradation has established unequivocally the presence of this compound in the metachromatic cells. The location of 'mast-like' cells at the epithelium surface of mollusc tissues exposed to the environment are very similar to the distribution of mammalian and other vertebrate mast cells and gives support to the suggestion for a role of mast cells in defense mechanisms.

CHOP/GADD153 gene expression response to cellular stresses inhibited by prior exposure to ultraviolet light wavelength band C (UVC). Inhibitory sequence mediating the UVC response localized to exon 1.

CHOP/GADD153 is both an activating and repressing transcription factor that is markedly induced in response to a variety of cellular stresses. The CHOP/GADD153 gene was originally cloned because of its inducibility by ultraviolet light wavelength band C (UVC) and has since been found to be activated in response to many different cellular stresses. Some of the recent studies have questioned the UVC responsiveness of the CHOP gene. Contradiction in our own data led us to reexamine the UVC effects on CHOP expression. UVC is capable of strongly activating the mouse CHOP promoter in stably transfected NIH 3T3 cells but has only a modest and transient effect on the level of the CHOP messenger RNA. In addition to its positive effect on CHOP promoter activity, we show that UVC negatively affects CHOP mRNA and protein expression. Pretreatment of NIH 3T3 cells with UVC markedly attenuates the subsequent induction of CHOP mRNA by the cellular stress activators methylmethane sulfate, tunicamycin, glucose deprivation, and methionine deprivation for as long as at least 16 h. This inhibitory effect of UVC on CHOP expression in response to stress is independent of the presence or absence of p53 and does not involve mRNA degradation as opposed to the UVC effect that inhibits p21 expression seen only in the absence of p53. The target of the inhibitory effect of UVC on CHOP expression is located in the first exon of the gene, a 5'-untranslated region that is unusually conserved between different species. These findings suggest that an unknown function encoded by the 5'-untranslated region somehow modifies the response of CHOP gene transcription to UVC.

CHOP/GADD153 and methionyl-tRNA synthetase (MetRS) genes overlap in a conserved region that controls mRNA stability.

The transcription factor CHOP is involved in the regulation of the cell division cycle and the control of programmed cell death in response to cellular stress. CHOP expression has been linked with several forms of cancer. A reciprocal translocation between the CHOP and TLS RNA-binding protein gene results in myxoid liposarcoma and amplifications of the CHOP gene are associated with solid tumors including several types of sarcomas. Here we report the mapping of the methionyl tRNA synthetase (MetRS) gene to the identical 12q13 locus where the CHOP gene had previously been mapped. PCR analysis demonstrates a tail-to-tail overlap of both genes over a 55-bp region. As a result the two mRNAs share a 3' UTR complementary sequence allowing an in vivo interaction between the two mRNAs. An AU-rich regulatory element (ARE) known to control mRNA stability resides in the overlapping sequence. To test for functional significance of the ARE a luciferase reporter plasmid containing the 3'UTR of CHOP was constructed. Transfection experiments in NIH-3T3 cells show that CHOP 3'UTR confers a significantly lower activity than a control reporter or a reporter in which the region overlapping the MetRS mRNA is deleted. The conservation of this overlapping of the CHOP and MetRS genes and the role of their complementary sequence in the control of mRNA stability suggest the existence of a functional link between the expression of these two genes.

Hematologic disorders in trauma patients during parenteral alimentation with lipids

Total parenteral nutrition with lipids is a well-accepted modality of metabolic support in seriously ill trauma patients. Intolerance to lipid administration is unusual when dosage limits are not exceeded, and few hematologic disturbances have been recorded with modern fat emulsions. In the course of intravenous alimentation of six adults admitted for traumatic lesions, eosinophilia with or without leukocytopenia was noticed after periods of four days to five weeks. Principal clinical events and hematologic derangements were documented in this population. Sepsis was not always present in the patients by the time of the complication, and in those that did require antibiotics and other drugs, the prescription remained unchanged along the episode. Discontinuation of the nutritional regimen with lipids was followed by normalization of the hematologic profile, suggesting that an acute or sub-acute allergic reaction was responsible. The appearance of skin rash in two occasions reinforces this hypothesis, and the possibility of hemophagocytosis merits consideration in two of the cases who displayed reversible acute leukocytopenia. It is concluded that blood cell aberrations are possible during intravenous feeding with lipids in trauma subjects, but tend to respond to suppression of the lipid-containing nutritional prescription.