The effect of trimodal prehabilitation on the physical and psychological health of patients undergoing colorectal surgery: a randomised clinical trial.

Prehabilitation aims to increase the endurance capacity of patients who are awaiting major surgery. However, there are no studies investigating the implementation of this demanding and expensive intervention in low-income countries. This study aimed to assess the impact of a 4-week trimodal prehabilitation program on the physical and psychological health of patients waiting for colorectal surgery compared with a control group managed according to enhanced recovery after surgery principles supplemented by nutritional care. This study was a single-centre, randomised controlled trial. The primary outcome measures for the physical aspects were 6-minute walking distance (6MWD) and incentive spirometry, whereas the psychological elements were measured using the 36-item short form survey questionnaire and the hospital anxiety and depression score. In total, data from 149 patients were analysed (77 in the prehabilitation group and 72 in the control group). At the time of surgery, patients in the prehabilitation group had improved 6MWD and incentive spirometry compared with the control group (median (IQR [range]) percentage improvement 131% (112-173 [68-376]) vs. 107% (99-120 [63-163]); p < 0.001 and 113% (100-125 [75-200]) vs. 100% (100-112 [86-167]); p < 0.001 respectively). Patients in the prehabilitation group also had reduced anxiety scores compared with the control group (mean (SD) anxiety score (4 (3) vs. 5 (3) respectively; p = 0.032). However, these effects did not translate into improvements in postoperative mortality and morbidity, or a reduction in duration of hospital stay. Trimodal (physical, emotional and nutritional) prehabilitation is able to improve functional status as well as some parameters of emotional and physical well-being of patients waiting for colorectal surgery.

Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy to induce rapid regeneration of the remnant liver. The technique has been associated with high mortality and morbidity rates. This study aimed to evaluate mitochondrial function, biogenesis and morphology during ALPPS-induced liver regeneration. METHODS: Male Wistar rats (n = 100) underwent portal vein ligation (PVL) or ALPPS. The animals were killed at 0 h (without operation), and 24, 48, 72 or 168 h after intervention. Regeneration rate and proliferation index were assessed. Mitochondrial oxygen consumption and adenosine 5'-triphosphate (ATP) production were measured. Mitochondrial biogenesis was evaluated by protein level measurements of peroxisome proliferator-activated receptor γ co-activator (PGC) 1-α, nuclear respiratory factor (NRF) 1 and 2, and mitochondrial transcription factor α. Mitochondrial morphology was evaluated by electron microscopy. RESULTS: Regeneration rate and Ki-67 index were significantly raised in the ALPPS group compared with the PVL group (regeneration rate at 168 h: mean(s.d.) 291·2(21·4) versus 245·1(13·8) per cent, P < 0·001; Ki-67 index at 24 h: 86·9(4·6) versus 66·2(4·9) per cent, P < 0·001). In the ALPPS group, mitochondrial function was impaired 48 h after the intervention compared with that in the PVL group (induced ATP production); (complex I: 361·9(72·3) versus 629·7(165·8) nmol per min per mg, P = 0·038; complex II: 517·5(48·8) versus 794·8(170·4) nmol per min per mg, P = 0·044). Markers of mitochondrial biogenesis were significantly lower 48 and 72 h after ALPPS compared with PVL (PGC1-α at 48 h: 0·61-fold decrease, P = 0·045; NRF1 at 48 h: 0·48-fold decrease, P = 0·028). Mitochondrial size decreased significantly after ALPPS (0·26(0·05) versus 0·40(0·07) µm2 ; P = 0·034). CONCLUSION: Impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS. Surgical relevance Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a well known surgical strategy that combines liver partition and portal vein ligation. This method induces immense regeneration in the future liver remnant. The rapid volume increase is of benefit for resectability, but the mortality and morbidity rates of ALPPS are strikingly high. Moreover, lagging functional recovery of the remnant liver has been reported recently. In this translational study, ALPPS caused an overwhelming inflammatory response that interfered with the peroxisome proliferator-activated receptor γ co-activator 1-α-coordinated, stress-induced, mitochondrial biogenesis pathway. This resulted in the accumulation of immature and malfunctioning mitochondria in hepatocytes during the early phase of liver regeneration (bioenergetic destabilization). These findings might explain some of the high morbidity if confirmed in patients.

Statistical complexity of the time dependent damped L84 model.

We consider the concept of statistical complexity to writing the time-dependent damped systems applying the snapshot attractors. This allows us to understand the behavior of these dynamical systems by the probability distribution of the points on the Poincaré section at a given time making a difference between the regular, random, and structural complexity on finite simulation. We interpreted the statistical complexity on the snapshot attractor and determined it in the L84 model, especially the chaotic behavior of the system and on the neighbor range of standard parameter values considering the effect of periodic damping.

SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. PATIENTS AND METHODS: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. RESULTS: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. CONCLUSION: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. TRIAL IDENTIFIER: Clinicaltrials.gov NCT01750281.

Experimental models of hemorrhagic shock: a review.

Massive blood loss leading to hypovolemic shock is still a life-threatening situation. Recently, a great number of investigations have been conducted in order to understand the pathophysiological and immunological changes taking place during shock and to develop treatment strategies. These preclinical trials are based on animal studies. Although a wide spectrum of species and experimental models are available to researchers, it is rather difficult to create an ideal animal model to study hemorrhagic shock. A major challenge for investigators is the generation of a system which is simple, easily reproducible and standardized, while being an accurate replica of the clinical situation. The goal of this review is to summarize the current experimental models of hemorrhagic shock, highlighting their advantages and disadvantages to help researchers find the most appropriate model for their own experiments on hypovolemic shock.

Mechanistic insights into the bleaching of melanin by alkaline hydrogen peroxide.

This work aims to determine the roles of reactive oxygen species HO∙ and HO2- in the bleaching of melanins by alkaline hydrogen peroxide. Experiments using melanosomes isolated from human hair indicated that the HO∙ radical generated in the outside solution does not contribute significantly to bleaching. However, studies using soluble Sepia melanin demonstrated that both HO2- and HO∙ will individually bleach melanin. Additionally, when both oxidants are present, bleaching is increased dramatically in both rate and extent. Careful experimental design enabled the separation of the roles and effects of these key reactive species, HO∙ and HO2-. Rationalisation of the results presented, and review of previous literature, allowed the postulation of a simplified general scheme whereby the strong oxidant HO∙ is able to pre-oxidise melanin units to o-quinones enabling more facile ring opening by the more nucleophilic HO2-. In this manner the efficiency of the roles of both species is maximised.

Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice.

Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition to its principal role in immediate type hypersensitivity has been described to modulate IL-6 production and expression of IL-6 receptor. In this study, the IL-6 and IL-6 receptor expression was examined in histamine deficient histidine decarboxylase (HDC) knock-out mouse model. Our data suggest that in histamine deficient mice the inducibility of IL-6 is significantly reduced, whilst more IL-6 receptor/gp130 mRNA expresses in the liver than in wild type (HDC(+/+)) mice. These in vivo findings confirm earlier in vitro results and emphasize the efficacy of antihistamines in local IL-6 related processes.

Insulin pretreatment (imprinting) produces elevated capacity in the insulin binding of Tetrahymena. Different binding by the cilia of the body and oral field.

Gold-labeled insulin is bound first of all to the cilia of the oral field of Tetrahymena. A primary treatment (hormonal imprinting) with insulin increases the binding capacity even after 24h and makes it more sensitive for appearance a week later, within a minute of giving insulin-gold. The food vacuoles contain insulin-gold in pretreated cells or without pretreatment as well, though in imprinted situations the label can be found in pinocytotic vesicles at the bases of cilia in the oral field. Altogether, a functional difference can be observed between the cilia of the oral and non-oral surfaces of Tetrahymena and hormonal imprinting has a specifying effect on the binding of labeled hormone.

The binding of diazepam in the mitochondria of Tetrahymena pyriformis as detected by quantitative high resolution autoradiography.

Tritiated diazepam accumulates mainly in the mitochondria of the unicellular Tetrahymena. This is the case in both a single (the first encounter) and a repeated (one day or a week after the first) administration of the drug. When imprinting of Tetrahymena by diazepam (the first encounter) is followed a week later by the administration of the labelled drug, the membranes of the vesicles, too, show the appearance of label. Regarding the studies presented here, the unicellular Tetrahymena also contain diazepam receptors in the mitochondria as suggested for cells of higher rank animals.

Elevated hepatic glucocorticoid receptor expression during liver regeneration in rats.

In rats within the first week of partial hepatectomy reconstruction of the normal histological structure of the liver already starts. To approach the possible role of endogenous glucocorticoids in the process of regeneration we measured the changes in the expression of steroid glucocorticoid receptor gene after various regeneration intervals. After partial hepatectomy, between 0.5 168 hours from the surgery, the gene expression (mRNA) of glucocorticoid receptor was determined by reverse transcription followed by PCR and normalized to that of glycerolphoshate dehydrogenase. Two peaks of glucocorticoid receptor mRNA were detected first, between 3 and 6 hours (first peak) and a second between 24 and 36 hours. Immunoreactive glucocorticoid receptor was detected by immunohistochemistry using monoclonal anti-glucocorticoid receptor. Three days after the surgery immunohistochemical studies showed substantially more immunoreactive GcR protein in the regenerated liver than in the controls. These semiquantitative data provide evidence suggesting elevation of glucocorticoid receptor expression during regeneration of liver at mRNA and protein levels.

Phenylhydrazine is a mitogen and activator of lymphoid cells.

Rats were administered a single injection of phenylhydrazine (PHZ) which induced an hemolytic anemia that reached maximal levels two to four days following injection. This was accompanied by a leukocytosis which was most pronounced four to six days after injection; lymphocytes and monocytes accounted for 75 percent to 80 percent of the leukocyte count, respectively. All peripheral blood cell values, including the red cell count and hematocrit, returned to their pre-injection levels by the 11th post-injection day. Analysis by flow cytometry of peripheral blood mononuclear cells (PBMC) isolated from PHZ-treated rats by Ficoll-Hypaque gradient separation showed a marked increase in the B cell population of the peripheral blood. This was also seen in cultures of PBMC obtained from untreated rats following incubation with PHZ. Cultures of PBMC obtained from rats four to five days after PHZ injection which were incubated with pokewood mitogen (PWM) or phytohemagglutinin (PHA) showed significant increases in blastogenesis as indicated by [3H] thymidine incorporation when compared to cultures of PBMC obtained from untreated rats incubated with these mitogens. Incubation of cultures of PBMC obtained from untreated rats with PHZ significantly increased blastogenesis in cultures of five day duration. Atypical and blastic lymphoid cells were evident in cytosmears of PBMC isolated from PHZ-treated rats and also in sections of PBMC pellets studied using the transmission electron microscope. Serum of the PHZ-treated rats contained elevated immunoglobulin titers as measured by radial immunodiffusion. The results show that PHZ stimulates lymphoid cell blastogenesis and can sensitize circulating lymphoid cells to PHA and PWM indicating that PHZ is capable of stimulating the immune system of the rat.

Effects of a non-starch polysaccharidase enzyme preparation from Thermomyces lanuginosus on energy and protein metabolism and milk yield of dairy cattle.

Non-starch polysaccharides (NSPs) form an integral part of the cell walls in plants and represent considerable available energy when degraded into absorbable mono-, di-, tri- and oligosaccharides. The ruminal microflora hydrolyses a good part of NSPs, however, recently there have been attempts to enhance the rate of utilisation by using external polysaccharidase enzymes. In the present study the effects of an enzyme preparation (Rumino-Zyme) high in xylanase activity were studied on ruminal volatile fatty acid (VFA) concentration, parameters of energy and protein metabolism, milk yield, feed conversion ratio (FCR) and body condition score of high-yielding dairy cows. A lignolytic enzyme preparation produced by the thermophilic fungus Thermomyces lanuginosus was applied in the present experiment and fed to dairy cows at 34 g/day dosage in the period between calving and the 110th day of lactation. This preparation increased VFA concentration in the rumen from about 32 days after calving and onward. Increased VFA concentration was followed by an about 5 to 10% increase in milk production and an almost 0.1% increase in butterfat production. Increased VFA concentration produced more balanced energy metabolism in the experimental cows as indicated by the lower incidence rate of hyperketonaemia, and lower acetoacetic acid and non-esterified fatty acid (NEFA) concentration in the blood of the experimental cows. Aspartate aminotransferase (AST) activity was tendentiously higher in the control group and the proportion of cows that had AST activity higher than 100 U/l was also higher in the control group. Both control and experimental cows showed balanced protein and acid-base metabolism throughout the experiment. Enhanced VFA concentration contributed to an improvement in energy balance in the experimental cows with a resultant improvement of feed intake and feed utilisation. Due to the more balanced energy metabolism postparturient body condition loss of the treated cows was reduced.

Use of rhythm in acquisition of a computer-generated tracking task.

This research assessed whether rhythm aids acquisition of motor skills by providing cues for the timing of those skills. Rhythms were presented to participants visually or visually with auditory cues. It was hypothesized that the auditory cues would facilitate recognition and learning of the rhythms. The three timing principles of rhythms were also explored. It was hypothesized that rhythms that satisfied all three timing principles would be more beneficial in learning a skill than rhythms that did not satisfy the principles. Three groups learned three different rhythms by practicing a tracking task. After training, participants attempted to reproduce the tracks from memory. Results suggest that rhythms do help in learning motor skills but different sets of timing principles explain perception of rhythm in different modalities.

Non-conventional locations of hormone receptors (binding sites). A review.

Recent findings on the noncanonical positions of some well-known extracellular mediators and their receptors are reviewed. Peptide hormones (insulin) and/or their binding sites (cell membrane insulin receptor, nuclear insulin receptor); steroid hormones (corticosteroids and estrogens) and their putative membrane receptors are in the scope of this paper. The possible roles of these unusually located receptors in the intracellular signal propagation and physiological responses are also discussed.

Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease.

Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post-infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD).

Anaerobic regulation of hydrogenase transcription in different bacteria.

Hydrogen metabolism is closely related to other important metabolic and energetic processes of bacterial cells, such as photosynthesis, anaerobic respiration and sulphur metabolism. Even small environmental changes influence these networks through different regulatory systems. The presence or absence of oxygen is one of the most important signals; how the cascades evolved to transmit this signal in different bacteria is summarized. In many instances, hydrogen is released only under anoxic conditions, because of bioenergetic considerations. Most [NiFe] hydrogenases are inactivated by oxygen, but many of them can be re-activated under reducing conditions. In addition to direct inactivation of the hydrogenases, oxygen can also regulate their expression. The global regulatory systems [FNR (fumarate and nitrate reduction regulator), ArcAB (aerobic respiratory control) and RegAB], which respond to alterations in oxygen content and redox conditions of the environment, have an important role in hydrogenase regulation of several bacteria. FNR-like proteins were shown to be important for the regulation of hydrogenases in Escherichia coli, Thiocapsa roseopersicina and Rhizobium leguminosarum, whereas RegA protein modulates the expression of hupSL genes in Rhodobacter capsulatus.

The hydrogenases of Thiocapsa roseopersicina.

The purple sulphur phototrophic bacterium, Thiocapsa roseopersicina BBS, contains several NiFe hydrogenases. One of these enzymes (HynSL) is membrane associated, remarkably stable and can be used for practical applications. HupSL is also located in the photosynthetic membrane, its properties are similar to other known Hup-type NiFe hydrogenases. A third hydrogenase activity was located in the soluble fraction and was analogous to the NAD-reducing hydrogenases of cyanobacteria. The hoxEFUYH genes are transcribed together. HoxE is needed for the in vivo electron flow to and from the soluble hydrogenase. Some of the accessory genes were identified using random mutagenesis, and sequencing of the T. roseopersicina genome is in progress. The HupD, HynD and HoxW gene products corresponded to the proteases processing the C-termini of the three NiFe hydrogenases respectively. HypF and HupK mutants displayed significant in vivo H(2) evolution, which could be linked to the nitrogenase activity for the DeltahypF and to the bidirectional Hox activity in the DeltahupK strain. Both HypC proteins are needed for the biosynthesis of each NiFe hydrogenase. The hydrogenase expression is regulated at the transcriptional level through distinct mechanisms. The expression of hynSL is up-regulated under anaerobic conditions with the participation of an FNR (fumarate and nitrate reduction regulator)-type protein, FnrT. Although the genes encoding a typical H(2) sensor (hupUV) and a two-component regulator (hupR and hupT) are present in T. roseopersicina, the system is cryptic in the wild-type BBS strain. The hupR gene was identified in the gene cluster downstream from hupSL. Introduction of actively expressed hupT repressed the hupSL gene expression as expected by analogy with other bacteria.

Possibilities and results in the wide-scale genomic analysis of inflammation. Looking for the child among many midwives.

Only recently, available microarray methods have been extended to the investigation of such complex pathophysiological conditions as inflammatory disease. Genome analysis gives the possibility of looking for susceptibility gene loci and their allelic combinations. By the analysis of mRNAs (transcriptome), novel players, functional groups of participants and regulatory pathways involved in the inflammation can be revealed. The possibility of comparing several samples is ideal to increase our knowledge about the kinetics of inflammation. The effects and post-receptor signalling events of individual pro- or anti-inflammatory mediators can also be tested. The use of human post mortem samples could yield otherwise inaccessible information on molecular mechanisms of chronic inflammatory diseases. However, the analysis and interpretation of a huge amount of data, the selection of appropriate experimental systems and time points may hide some pitfalls, which emphasize the need to confirm results with independent methods such as e.g. semi-quantitative Northern, real time PCR, RNA-ase protection assay as well as functional studies.

Turnover and intranuclear localization of 125I-insulin in Tetrahymena. An autoradiographic study.

The unicellular Tetrahymena first internalized, then partly released the labelled insulin. Insulin-pretreated (imprinted) Tetrahymena cells behaved differently from non-pretreated cells, in that they retained a greater part of internalized insulin in the cytoplasm. Additional exposure to excessive non-labelled (cold) insulin caused a decrease in intracellular labelled insulin retention. Internalized insulin also entered the nucleus of Tetrahymena, where it was found in a heterochromatic localization.