A generic framework for modeling brain deformation as a constrained parametric optimization problem to aid non-diffeomorphic image registration in brain tumor imaging.

OBJECTIVES: In the present paper a novel computational framework for modeling tumor induced brain deformation as a biophysical prior for non-rigid image registration is described. More precisely, we aim at providing a generic building block for non-rigid image registration that can be used to resolve inherent irregularities in non-diffeomorphic registration problems that naturally arise in serial and cross-population brain tumor imaging studies due to the presence (or progression) of pathology. METHODS: The model for the description of brain cancer dynamics on a tissue level is based on an initial boundary value problem (IBVP). The IBVP follows the accepted assumption that the progression of primary brain tumors on a tissue level is governed by proliferation and migration of cancerous cells into surrounding healthy tissue. The model of tumor induced brain deformation is phrased as a parametric, constrained optimization problem. As a basis of comparison and to demonstrate generalizability additional soft constraints (penalties) are considered. A back-tracking line search is implemented in conjunction with a limited memory Broyden-Fletcher-Goldfarb-Shanno (LBFGS) method in order to handle the numerically delicate log-barrier strategy for confining volume change. RESULTS: Numerical experiments are performed to test the flexible control of the computed deformation patterns in terms of varying model parameters. The results are qualitatively and quantitatively related to patterns in patient individual magnetic resonance imaging data. CONCLUSIONS: Numerical experiments demonstrate the flexible control of the computed deformation patterns. This in turn strongly suggests that the model can be adapted to patient individual imaging patterns of brain tumors. Qualitative and quantitative comparison of the computed cancer profiles to patterns in medical imaging data of an exemplary patient demonstrates plausibility. The designed optimization problem is based on computational tools widely used in non-rigid image registration, which in turn makes the model generally applicable for integration into non-rigid image registration algorithms.

Decreased food intake is a risk factor for mortality in hospitalised patients: the NutritionDay survey 2006.

BACKGROUND & AIMS: Malnutrition is a known risk factor for the development of complications in hospitalised patients. We determined whether eating only fractions of the meals served is an independent risk factor for mortality. METHODS: The NutritionDay is a multinational one-day cross-sectional survey of nutritional factors and food intake in 16,290 adult hospitalised patients on January 19th 2006. The effect of food intake and nutritional factors on death in hospital within 30 days was assessed in a competing risk analysis. RESULTS: More than half of the patients did not eat their full meal provided by the hospital. Decreased food intake on NutritionDay or during the previous week was associated with an increased risk of dying, even after adjustment for various patient and disease related factors. Adjusted hazard ratio for dying when eating about a quarter of the meal on NutritionDay was 2.10 (1.53-2.89); when eating nothing 3.02 (2.11-4.32). More than half of the patients who ate less than a quarter of their meal did not receive artificial nutrition support. Only 25% patients eating nothing at lunch receive artificial nutrition support. CONCLUSION: Many hospitalised patients in European hospitals eat less food than provided as regular meal. This decreased food intake represents an independent risk factor for hospital mortality.

Hepatology - Guidelines on Parenteral Nutrition, Chapter 16.

Parenteral nutrition (PN) is indicated in alcoholic steatohepatitis (ASH) and in cirrhotic patients with moderate or severe malnutrition. PN should be started immediately when sufficientl oral or enteral feeding is not possible. ASH and cirrhosis patients who can be sufficiently fed either orally or enterally, but who have to abstain from food over a period of more than 12 hours (including nocturnal fasting) should receive basal glucose infusion (2-3 g/kg/d). Total PN is required if such fasting periods last longer than 72 h. PN in patients with higher-grade hepatic encephalopathy (HE); particularly in HE IV degrees with malfunction of swallowing and cough reflexes, and unprotected airways. Cirrhotic patients or patients after liver transplantation should receive early postoperative PN after surgery if they cannot be sufficiently rally or enterally nourished. No recommendation can be made on donor or organ conditioning by parenteral administration of glutamine and arginine, aiming at minimising ischemia/reperfusion damage. In acute liver failure artificial nutrition should be considered irrespective of the nutritional state and should be commenced when oral nutrition cannot be restarted within 5 to 7 days. Whenever feasible, enteral nutrition should be administered via a nasoduodenal feeding tube.

A phase I trial of pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer.

PURPOSE: Based on previous studies that demonstrated the safety profile and preliminary clinical activity of prostate specific antigen (PSA) targeted therapeutic vaccines, as well as recent laboratory data supporting the value of the addition of co-stimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM) to these vaccines, we conducted a Phase I study to evaluate the safety and immunogenicity of a novel vaccinia and fowlpox vaccine incorporating the PSA gene sequence and TRICOM. METHODS: In this study, ten patients with androgen independent prostate cancer with or without metastatic disease were enrolled. Patients were treated with 2 x l0(8) pfu of a recombinant vaccinia virus vaccine (PROSTVAC-V) followed by 1 x 10(9) pfu of the booster recombinant fowlpox virus (PROSTVAC-F) both with gene sequences for PSA and TRICOM. The mean age of patients enrolled in the study was 70 (range 63 to 79). The mean PSA at baseline was 434 (range 9-1424). RESULTS: There were no deaths, and no Grade 3 or 4 adverse events. The most commonly reported adverse events, regardless of causality, were injection site reactions and fatigue. One serious adverse event (SAE) occurred that was unrelated to vaccine; this patient developed progressive disease with a new sphenoid metastasis. PSA was measured at week 4 and week 8. Four patients had stable disease (with less than 25% increase in PSA) through the week 8 study period. Anti-PSA antibodies were not induced with therapy: however, anti-vaccinia titers increased in all patients. CONCLUSION: This study demonstrated that vaccination with PROSTVAC-V and PROSTVAC-F combined with TRICOM is well-tolerated and generated an immune response to vaccinia. Therefore, PROSTVAC-VF/TRICOM represents a feasible therapeutic approach for further phase II and III study in patients with prostate cancer.

Covered transjugular intrahepatic portosystemic stents maintain lower portal pressure and require fewer reinterventions than uncovered stents.

BACKGROUND: The purpose of this study was to evaluate the patency, functional and haemodynamic results of expanded-polytetrafluoroethylene (ePTFE)-covered transjugular intrahepatic portosystemic shunts in patients with liver cirrhosis. METHODS: Thirteen patients with an ePTFE-covered transjugular intrahepatic portosystemic shunt stent (TIPSS) were prospectively evaluated at 6 and 12 months and compared with matched controls with mesh-wire uncovered TIPSS. RESULTS: At 6 months, ePTFE-TIPSS showed a significantly lower porto-caval pressure gradient (PCPG) (9 (3-21) mmHg, P = 0.006), a lower rate of dysfunction (8% versus 54%, P = 0.03) and required fewer reinterventions (2 versus 13, P = 0.02); similar results were obtained after 12 months. This resulted in a reduction in the median cost for angiographic surveillance in the covered TIPSS group at 6 and 12 months (36% and 56% compared to the uncovered TIPSS group, P = 0.002), but total procedure-related costs were higher with the ePTFE-TIPSS (6 months: 3730 (3245-6759) versus 1850 (1466-5479) euro/patient; 12 months: 3945 (3460-6759) versus 2295 (1728-5694) euro/patient) due to the higher initial cost of the ePTFE-covered TIPSS. CONCLUSIONS: The insertion of ePTFE-covered TIPSS results in better maintenance of lowered portal pressure and fewer reinterventions in patients with liver cirrhosis. There is strong evidence that the use of ePTFE-TIPSS does not require regular surveillance to maintain primary patency, which may then improve cost-effectiveness.

Prevalence of malnutrition in 1760 patients at hospital admission: a controlled population study of body composition.

OBJECTIVE: Malnutrition, defined as low or excessive body weight, is associated with increased hospital length of stay and cost of care. The purpose of this study was to determine if fat-free mass (FFM) and body fat (BF) differed between patients at hospital admission in Geneva and Berlin and healthy volunteers, and if there is a difference in the prevalence of low FFM (percentile P<10) and high BF (percentile P>90) between patients and volunteers. METHODS: In total, 1760 patients (Geneva: 525 men, 470 women; Berlin: 397 men, 368 women) were evaluated for malnutrition by BMI, serum albumin, and FFM and BF, determined by bioelectrical impedance analysis (BIA), and compared to 1760 healthy volunteers matched for age and height, and further compared to FFM and BF percentiles, previously determined in 5225 healthy adults. RESULTS: The prevalence of FFM P<10 was greater in patients than controls. The prevalence of albumin<35 g/l (14.9% and 11.2% in Geneva and Berlin patients, respectively) and BMI<20.0 kg/m(2) was lower than the prevalence of low FFM (31.3% and 17.3%, respectively). The prevalence of high BF in Berlin patients was three-fold the prevalence of volunteers. Twelve and twenty percent of Geneva and Berlin patients, respectively, with normal BMI had high BF, compared to 4% of volunteers. CONCLUSIONS: Geneva and Berlin patients had lower FFM and higher BF than age-and height-matched volunteers and a higher prevalence of low FFM and high BF. Serum albumin and BMI underestimated the prevalence of malnutrition in patients at hospital admission. Body composition measurements identified patients with low FFM and low or high BF reserves.

Hypoxic Hypoperfusion Fails to Induce Myocardial Hibernation in Anesthetized Swine.

BACKGROUND: Congenital origin of the left coronary artery from the pulmonary artery (ALCAPA) results in chronically dysfunctional myocardium with the partial ability to recover after revascularization. We attempted to establish an ALCAPA syndrome in anesthetized pigs for 24 hours and to compare it with stunned and infarcted myocardium. METHODS AND RESULTS: In group 1 (n = 12), a bypass graft was interposed between the pulmonary artery and the left anterior descending coronary artery (LAD). Reduction of flow in the LAD with gradual increases in flow from the pulmonary artery resulted in an incremental reduction of segment shortening (8.9 +/- 5.3% at 24 hours vs 26.6 +/- 10% at baseline, P <.005). In group 3 (n = 5), 2 cycles of 10-minute LAD occlusion resulted in decreased segment shortening with slow recovery (at 24 hours 18.7 +/- 1.3% vs 24.2 +/- 4% at baseline, segment shortening with slow recovery (at 24 hours 18.7 +/- 1.3% vs 24.2 +/- 4% at baseline, P <.05). In group 3 (n = 6), 1-hour LAD occlusion reduced segment shortening at 24 hours to 4.7 +/- 5.2% (P <.005 vs baseline). Histological analysis of the LAD territory revealed severe degeneration, myolysis, and alteration of the chromatin structure in group 1 comparable to ischemic cell death in group 3, whereas control areas and the LAD area in group 2 showed only minor structural alterations. Infarct size/risk area, as measured by tetrazolium staining, was 49.8 +/- 11.2% in group 1, 9.3 +/- 8.1% in group 2 (P <.005), and 60.3 +/- 9% in group 3. CONCLUSION: Hypoxic myocardial hypoperfusion from the pulmonary artery results in myocardial necrosis in anesthetized pigs. These findings are in contrast to the concept of myocardial hibernation in the ALCAPA syndrome because in this model, hypoxic hypoperfusion failed to induce adaptation to preserve myocardial structure.

Infarct Size Reduction by Ischemic Preconditioning Is a Monophasic, Short-Lived Phenomenon in Anesthetized Pigs.

BACKGROUND: Controversy exists concerning the duration of infarct size reduction with ischemic preconditioning in different species. In the present study, we (a) evaluated the time course of protection with preconditioning and (b) sought to determine whether late protection (the "second window") after 24 hours is manifest in the open-chest pig model. METHODS AND RESULTS: Six groups of pentobarbital-anesthetized pigs underwent 1 hour of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Group 1 served as control, and pigs in group 2 received two 10-minute episodes of preconditioning ischemia followed by 30 minutes of reperfusion before the sustained 1-hour occlusion. In groups 3-6, the period of intervening reperfusion between the preconditioning stimulus and the index ischemia was extended to 60, 90, and 300 minutes and 24 hours, respectively. The area at risk was determined by fluorescein dye injection, and infarct size was measured by incubation in p-nitrobluetetrazolium and expressed as percent of the risk area. Infarct size in preconditioned pigs (group 2) was significantly reduced compared with controls (25.6 +/- 3.9% v 71.3 +/- 5.9%, P <.001). Extension of the intervening reperfusion to 60, 90, and 300 minutes and 24 hours resulted in infarct sizes of 64.5 +/- 5.5%, 67.2 +/- 8%, 62.6 +/- 6.1%, and 75.3 +/- 7%, respectively (P = NS v control). CONCLUSIONS: The infarct size-limiting effects of ischemic preconditioning last less than 1 hour in the pig model. Moreover, in contrast to other species, a late protection at 24 hours after the preconditioning stimulus was not detected. These results indicate that precondition-induced reduction of infarct size is monophasic in anesthetized pigs.

A heat shock-responsive domain of human HSF1 that regulates transcription activation domain function.

Human heat shock factor 1 (HSF1) stimulates transcription from heat shock protein genes following stress. We have used chimeric proteins containing the GAL4 DNA binding domain to identify the transcriptional activation domains of HSF1 and a separate domain that is capable of regulating activation domain function. This regulatory domain conferred heat shock inducibility to chimeric proteins containing the activation domains. The regulatory domain is located between the transcriptional activation domains and the DNA binding domain of HSF1 and is conserved between mammalian and chicken HSF1 but is not found in HSF2 or HSF3. The regulatory domain was found to be functionally homologous between chicken and human HSF1. This domain does not affect DNA binding by the chimeric proteins and does not contain any of the sequences previously postulated to regulate DNA binding of HSF1. Thus, we suggest that activation of HSF1 by stress in humans is controlled by two regulatory mechanisms that separately confer heat shock-induced DNA binding and transcriptional stimulation.

In vitro activation of purified human heat shock factor by heat.

A major regulatory step in the heat-induced transcription of heat shock protein (hsp) genes in eukaryotes is the activation of heat shock factor (HSF). In metazoans and Schizosaccharomyces pombe, HSF is present in unstressed cells but is unable to bind to its target DNA sequence element, the heat shock element (HSE). Heat induction of the DNA binding activity of HSF is a critical component required for activation of heat shock genes. Inactive HSF in extracts of non-heat shocked human cells can be heated in vitro to activate HSF, suggesting the factors required to sense temperature and activate HSF are soluble factors [Larson, J. S., Schuetz, T. J., & Kingston, R. E. (1988) Nature 335, 372-375]. We utilized the ability to purify human HSF in the active form to characterize further the in vitro activation of HSF. Here we have developed a procedure to deactivate the DNA binding ability of HSF. When purified and deactivated HSF is heated, the DNA binding ability of HSF is activated. This activation occurs most efficiently at 43 degrees C (heat shock temperature), but, in contrast to activation in the crude system, some activation of HSF is observed at 37 degrees C (non-heat shock temperature). We show that purified and deactivated HSF is similar to natural inactive HSF in both size and shape. Thus, the monomer to trimer transition that activates HSF can occur in a temperature-dependent fashion in the absence of other proteins. It is possible that these biochemical properties of HSF contribute to the ability of HSF to respond to heat in vivo.

Isolation of a cDNA for HSF2: evidence for two heat shock factor genes in humans.

The heat shock response is transcriptionally regulated by an evolutionarily conserved protein termed heat shock factor (HSF). We report the purification to homogeneity and the partial peptide sequence of HSF from HeLa cells. The peptide sequence was used to isolate a human cDNA with a predicted open reading frame that has homology to the DNA binding domains of both Saccharomyces cerevisiae and Drosophila HSFs. The cDNA directs the synthesis of a protein that binds to the heat shock element with specificity identical to HeLa HSF and stimulates transcription from a heat shock promoter. The expressed protein cross-reacts with anti-HSF antibodies. Surprisingly, however, this cDNA does not encode all of the peptides obtained from purified HeLa HSF. These peptides are encoded by a distinct human cDNA, HSF1, described by Rabindran et al. [Rabindran, S. K., Giorgi, G., Clos, J. & Wu, C. (1991) Proc. Natl. Acad. Sci. USA 88, 6906-6910.] It therefore appears that there is a human heat shock factor gene family and that at least two separate but related HSF proteins regulate the stress response in humans.

Facilitated binding of GAL4 and heat shock factor to nucleosomal templates: differential function of DNA-binding domains.

Regulatory factors must contend with chromatin structure to function. Although nucleosome structure and position on promoters can be important in determining factor access, the intrinsic ability of factors to bind to nucleosomal DNA might also play an essential regulatory role. We have used templates where nucleosomes were either randomly positioned or rotationally phased to demonstrate that two transcription factors, heat shock factor (HSF) and GAL4, differ significantly in their ability to bind to nucleosomes. GAL4 was able to bind to nucleosomal templates. Surprisingly, in contrast to its behavior on naked DNA, GAL4 bound better to multiple GAL4 sites than to a single GAL4 site on these templates. HSF alone was not able to bind to nucleosomal templates. HSF was able to bind to nucleosomal templates, however, when the TATA-binding factor TFIID was present. Consequently, binding to nucleosomal templates could be facilitated by adjacent binding of the same protein in the case of GAL4 but required binding of a second protein in the case of HSF. Taken together, these data demonstrate that regulatory factors differ in their inherent ability to bind to nucleosomal templates. These differences are likely to be important to the function of these factors in vivo.

Regulation of heat shock factor in Schizosaccharomyces pombe more closely resembles regulation in mammals than in Saccharomyces cerevisiae.

The heat shock response appears to be universal. All eucaryotes studied encode a protein, heat shock factor (HSF), that is believed to regulate transcription of heat shock genes. This protein binds to a regulatory sequence, the heat shock element, that is absolutely conserved among eucaryotes. We report here the identification of HSF in the fission yeast Schizosaccharomyces pombe. HSF binding was not observed in extracts from normally growing S. pombe (28 degrees C) but was detected in increasing amounts as the temperature of heat shock increased between 39 and 45 degrees C. This regulation is in contrast to that observed in Saccharomyces cerevisiae, in which HSF binding is detectable at both normal and heat shock temperatures. The S. pombe factor bound specifically to the heat shock element, as judged by methylation interference and DNase I protection analysis. The induction of S. pombe HSF was not inhibited by cycloheximide, suggesting that induction occurs posttranslationally, and the induced factor was shown to be phosphorylated. S. pombe HSF was purified to near homogeneity and was shown to have an apparent mobility of approximately 108 kDa. Since heat-induced DNA binding by HSF had previously been demonstrated only in metazoans, the conservation of heat-induced DNA binding by HSF among S. pombe and metazoans suggests that this mode of regulation is evolutionarily ancient.

Activation in vitro of sequence-specific DNA binding by a human regulatory factor.

The human heat-shock factor (HSF) regulates heat-shock genes in response to elevated temperature. When human cells are heated to 43 degrees C, HSF is modified post-translationally from a form that does not bind DNA to a form that binds to a specific sequence (the heat-shock element, HSE) found upstream of heat-shock genes. To investigate the transduction of the heat signal to HSF, and more generally, how mammalian cells respond at the molecular level to environmental stimuli, we have developed a cell-free system that exhibits heat-induced activation of human HSF in vitro. Comparison of HSF activation in vitro and in intact cells suggests that the response of human cells to heat shock involves at least two steps. First, an ATP-independent, heat-induced alteration of HSF allows it to bind the HSE; the temperature at which activation occurs in vitro implies that a human factor directly senses temperature. Second, HSF is phosphorylated. It is possible that similar multi-step activation mechanisms play a role in the response of eukaryotic cells to a variety of environmental stimuli, and that these mechanisms evolved to increase the range and flexibility of the response.

Heat-inducible human factor that binds to a human hsp70 promoter.

A factor found in nuclear extracts of human cells bound to the heat shock element of a human heat shock protein 70 gene. The level of this factor was significantly increased after heat shock. This induction was rapid and was not blocked by cycloheximide, suggesting that an initial event in the response of a human cell to heat is the activation of a preexisting regulatory factor.