Identification of protein expression signatures in gastric carcinomas using clustering analysis

Background and Aim: The identification of gastric carcinomas (GC) has traditionally been based on histomorphology. Recently, DNA microarrays have successfully been used to identify tumors through clustering of the expression profiles. Random forest clustering is widely used for tissue microarrays and other immunohistochemical data, because it handles highly-skewed tumor marker expressions well, and weighs the contribution of each marker according to its relatedness with other tumor markers. In the present study, we e identified biologically- and clinically-meaningful groups of GC by hierarchical clustering analysis of immunohistochemical protein expression. Methods: We selected 28 proteins (p16, p27, p21, cyclin D1, cyclin A, cyclin B1, pRb, p53, c-met, c-erbB-2, vascular endothelial growth factor, transforming growth factor [TGF]-beta I, TGF-beta II, MutS homolog-2, bcl-2, bax, bak, bcl-x, adenomatous polyposis coli, clathrin, E-cadherin, beta-catenin, mucin (MUC) 1, MUC2, MUC5AC, MUC6, matrix metalloproteinase [ MMP]-2, and MMP-9) to be investigated by immunohistochemistry in 482 GC. The analyses of the data were done using a random forest-clustering method. Results: Proteins related to cell cycle, growth factor, cell motility, cell adhesion, apoptosis, and matrix remodeling were highly expressed in GC. We identified protein expressions associated with poor survival in diffuse-type GC. Conclusions: Based on the expression analysis of 28 proteins, we identified two groups of GC that could not be explained by any clinicopathological variables, and a subgroup of long-surviving diffuse-type GC patients with a distinct molecular profile. These results provide not only a new molecular basis for understanding the biological properties of GC, but also better prediction of survival than the classic pathological grouping.

Isokinetic Strength and Endurance in Proximal and Distal Muscles in Patients With Peripheral Artery Disease

Background: The objective of this study was to analyze the muscle strength and endurance of the proximal and distal lower-extremity muscles in peripheral artery disease (PAD) patients. Methods: Twenty patients with bilateral PAD with symptoms of intermittent claudication and nine control subjects without PAD were included in the study, comprising 40 and 18 legs, respectively. All subjects performed an isokinetic muscle test to evaluate the muscle strength and endurance of the proximal (knee extension and knee flexion movements) and distal (plantar flexion and dorsiflexion movements) muscle groups in the lower extremity. Results: Compared with the control group, the PAD group presented lower muscle strength in knee flexion (-14.0%), dorsiflexion (-26.0%), and plantar flexion (-21.2%) movements (P < 0.05) but similar strength in knee extension movements (P > 0.05). The PAD patients presented a 13.5% lower knee flexion/extension strength ratio compared with the control subjects (P < 0.05), as well as lower muscle endurance in dorsiflexion (-28.1%) and plantar flexion (-17.0%) movements (P < 0.05). The muscle endurance in knee flexion and knee extension movements was similar between PAD patients and the control subjects (P > 0.05). Conclusion: PAD patients present lower proximal and distal muscle strength and lower distal muscle endurance than control patients. Therefore, interventions to improve muscle strength and endurance should be prescribed for PAD patients.

Exercício aeróbico ou com pesos melhora o desempenho nas atividades da vida diária de mulheres idosas

Este estudo aleatorizado não controlado teve como objetivo determinar o efeito de um protocolo de exercício com pesos ou aeróbico no desempenho das atividades da vida diária em mulheres idosas. Para tanto, a amostra foi constituída por 41 mulheres idosas aparentemente saudáveis na faixa etária de 60 a 85 anos de idade (x: 65,1 ± 7,9 anos) divididas aleatoriamente em grupo exercício com pesos (n: 22) ou aeróbico (n: 19). O grupo exercício com pesos consistiu na execução de três séries de oito a 12 repetições a 60% de uma repetição máxima no exercício leg press 45º. O grupo exercício aeróbico consistiu em pedalar em cicloergômetro durante 40 minutos a 60% da frequência cardíaca de reserva. Os dois protocolos foram realizados três vezes por semana durante cinco semanas. As atividades da vida diária selecionadas foram velocidade para se levantar de uma posição sentada (VLPS), velocidade para se levantar de uma posição deitada (VLPD), velocidade para subir escada (VSE) e velocidade para calçar e amarrar o tênis (VCAT). O grupo exercício aeróbico melhorou significativamente o desempenho em VCAT (19,1%), enquanto o exercício com pesos incrementou significativamente o desempenho em VSE (4,3%) e VLPS (8,9%). Os resultados deste estudo permitem concluir que tanto o exercício com pesos como o aeróbico induziram efeito positivo nas atividades da vida diária, sugerindo que ambas as modalidades de exercício devem ser associadas a um programa adequado de exercícios para a melhora da capacidade funcional de pessoas idosas.

Isokinetic analysis of ankle and ground reaction forces in runners and triathletes

OBJECTIVE: To analyze and compare the vertical component of ground reaction forces and isokinetic muscle parameters for plantar flexion and dorsiflexion of the ankle between long-distance runners, triathletes, and nonathletes. METHODS: Seventy-five males with a mean age of 30.26 (±6.5) years were divided into three groups: a triathlete group (n=26), a long-distance runner group (n = 23), and a non-athlete control group. The kinetic parameters were measured during running using a force platform, and the isokinetic parameters were measured using an isokinetic dynamometer. RESULTS: The non-athlete control group and the triathlete group exhibited smaller vertical forces, a greater ground contact time, and a greater application of force during maximum vertical acceleration than the long-distance runner group. The total work (180º/s) was greater in eccentric dorsiflexion and concentric plantar flexion for the non-athlete control group and the triathlete group than the long-distance runner group. The peak torque (60º/s) was greater in eccentric plantar flexion and concentric dorsiflexion for the control group than the athlete groups. CONCLUSIONS: The athlete groups exhibited less muscle strength and resistance than the control group, and the triathletes exhibited less impact and better endurance performance than the runners.

Association between muscle strength and the cardiopulmonary status of individuals living with HIV/AIDS

OBJECTIVE: The purpose of this study was to compare aerobic function [anaerobic threshold (%_VVO2-AT), respiratory compensation point (%_VVO2-RCP) and peak oxygen uptake (_VVO2peak)] between physically active patients with HIV/AIDS and matched controls and to examine associations between disease status, poor muscle strength, depression (as estimated by the profile of mood states questionnaire) and the aerobic performance of patients. METHODS: Progressive treadmill test data for %_VVO2-AT (V-slope method), RCP and (_VVO2peak) were compared between 39 male patients with HIV/AIDS (age 40.6¡1.4 years) and 28 male controls (age 44.4¡2.1 years) drawn from the same community and matched for habitual physical activity. Within-patient data were also examined in relation to CD4+ counts (nadir and current data) and peak isokinetic knee torque. RESULTS: AT, RCP and (_VVO2peak) values were generally similar for patients and controls.Within the patient sample, binary classification suggested that AT, RCP and (_VVO2peak) values were not associated with either the nadir or current CD4+ count, but treadmill test variables were positively associated with peak isokinetic knee torque. CONCLUSION: The aerobic performance of physically active patients with HIV/AIDS is generally well conserved. Nevertheless, poor muscle strength is observed in some HIV/AIDS patients, which is associated with lower anaerobic power and (_VVO2peak), suggesting the possibility of enhancing the aerobic performance of patients with weak muscles through appropriate muscle-strengthening activities.

Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume

[EN] Erythropoietin (Epo) has been suggested to affect plasma volume, and would thereby possess a mechanism apart from erythropoiesis to increase arterial oxygen content. This, and potential underlying mechanisms, were tested in eight healthy subjects receiving 5000 IU recombinant human Epo (rHuEpo) for 15 weeks at a dose frequency aimed to increase and maintain haematocrit at approximately 50%. Red blood cell volume was increased from 2933 +/- 402 ml before rHuEpo treatment to 3210 +/- 356 (P < 0.01), 3117 +/- 554 (P < 0.05), and 3172 +/- 561 ml (P < 0.01) after 5, 11 and 13 weeks, respectively. This was accompanied by a decrease in plasma volume from 3645 +/- 538 ml before rHuEpo treatment to 3267 +/- 333 (P < 0.01), 3119 +/- 499 (P < 0.05), and 3323 +/- 521 ml (P < 0.01) after 5, 11 and 13 weeks, respectively. Concomitantly, plasma renin activity and aldosterone concentration were reduced. This maintained blood volume relatively unchanged, with a slight transient decrease at week 11, such that blood volume was 6578 +/- 839 ml before rHuEpo treatment, and 6477 +/- 573 (NS), 6236 +/- 908 (P < 0.05), and 6495 +/- 935 ml (NS), after 5, 11 and 13 weeks of treatment. We conclude that Epo treatment in healthy humans induces an elevation in haemoglobin concentration by two mechanisms: (i) an increase in red cell volume; and (ii) a decrease in plasma volume, which is probably mediated by a downregulation of the rennin-angiotensin-aldosterone axis. Since the relative contribution of plasma volume changes to the increments in arterial oxygen content was between 37.9 and 53.9% during the study period, this mechanism seems as important for increasing arterial oxygen content as the well-known erythropoietic effect of Epo.

Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport?

[EN] This study was performed to test the hypothesis that administration of recombinant human erythropoietin (rHuEpo) in humans increases maximal oxygen consumption by augmenting the maximal oxygen carrying capacity of blood. Systemic and leg oxygen delivery and oxygen uptake were studied during exercise in eight subjects before and after 13 wk of rHuEpo treatment and after isovolemic hemodilution to the same hemoglobin concentration observed before the start of rHuEpo administration. At peak exercise, leg oxygen delivery was increased from 1,777.0+/-102.0 ml/min before rHuEpo treatment to 2,079.8+/-120.7 ml/min after treatment. After hemodilution, oxygen delivery was decreased to the pretreatment value (1,710.3+/-138.1 ml/min). Fractional leg arterial oxygen extraction was unaffected at maximal exercise; hence, maximal leg oxygen uptake increased from 1,511.0+/-130.1 ml/min before treatment to 1,793.0+/-148.7 ml/min with rHuEpo and decreased after hemodilution to 1,428.0+/-111.6 ml/min. Pulmonary oxygen uptake at peak exercise increased from 3,950.0+/-160.7 before administration to 4,254.5+/-178.4 ml/min with rHuEpo and decreased to 4,059.0+/-161.1 ml/min with hemodilution (P=0.22, compared with values before rHuEpo treatment). Blood buffer capacity remained unaffected by rHuEpo treatment and hemodilution. The augmented hematocrit did not compromise peak cardiac output. In summary, in healthy humans, rHuEpo increases maximal oxygen consumption due to augmented systemic and muscular peak oxygen delivery.

Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans

[EN] A universal O2 sensor presumes that compensation for impaired O2 delivery is triggered by low O2 tension, but in humans, comparisons of compensatory responses to altered arterial O2 content (CaO2) or tension (PaO2) have not been reported. To directly compare cardiac output (QTOT) and leg blood flow (LBF) responses to a range of CaO2 and PaO2, seven healthy young men were studied during two-legged knee extension exercise with control hemoglobin concentration ([Hb] = 144.4 +/- 4 g/l) and at least 1 wk later after isovolemic hemodilution ([Hb] = 115 +/- 2 g/l). On each study day, subjects exercised twice at 30 W and on to voluntary exhaustion with an FIO2 of 0.21 or 0.11. The interventions resulted in two conditions with matched CaO2 but markedly different PaO2 (hypoxia and anemia) and two conditions with matched PaO2 and different CaO2 (hypoxia and anemia + hypoxia). PaO2 varied from 46 +/- 3 Torr in hypoxia to 95 +/- 3 Torr (range 37 to >100) in anemia (P < 0.001), yet LBF at exercise was nearly identical. However, as CaO2 dropped from 190 +/- 5 ml/l in control to 132 +/- 2 ml/l in anemia + hypoxia (P < 0.001), QTOT and LBF at 30 W rose to 12.8 +/- 0.8 and 7.2 +/- 0.3 l/min, respectively, values 23 and 47% above control (P < 0.01). Thus regulation of QTOT, LBF, and arterial O2 delivery to contracting intact human skeletal muscle is dependent for signaling primarily on CaO2, not PaO2. This finding suggests that factors related to CaO2 or [Hb] may play an important role in the regulation of blood flow during exercise in humans.

Cardiovascular responses to dynamic exercise with acute anemia in humans

[EN] We hypothesized that reducing arterial O2 content (CaO2) by lowering the hemoglobin concentration ([Hb]) would result in a higher blood flow, as observed with a low PO2, and maintenance of O2 delivery. Seven young healthy men were studied twice, at rest and during two-legged submaximal and peak dynamic knee extensor exercise in a control condition (mean control [Hb] 144 g/l) and after 1-1.5 liters of whole blood had been withdrawn and replaced with albumin [mean drop in [Hb] 29 g/l (range 19-38 g/l); low [Hb]]. Limb blood flow (LBF) was higher (P < 0.01) with low [Hb] during submaximal exercise (i.e., at 30 W, LBF was 2.5 +/- 0.1 and 3.0 +/- 0.1 l/min for control [Hb] and low [Hb], respectively; P < 0.01), resulting in a maintained O2 delivery and O2 uptake for a given workload. However, at peak exercise, LBF was unaltered (6.5 +/- 0.4 and 6.6 +/- 0.6 l/min for control [Hb] and low [Hb], respectively), which resulted in an 18% reduction in O2 delivery (P < 0.01). This occurred despite peak cardiac output in neither condition reaching >75% of maximal cardiac output (approximately 26 l/min). It is concluded that a low CaO2 induces an elevation in submaximal muscle blood flow and that O2 delivery to contracting muscles is tightly regulated.

Hypoxia and the cardiovascular response to dynamic knee-extensor exercise

[EN] Hypoxia affects O2 transport and aerobic exercise capacity. In two previous studies, conflicting results have been reported regarding whether O2 delivery to the muscle is increased with hypoxia or whether there is a more efficient O2 extraction to allow for compensation of the decreased O2 availability at submaximal and maximal exercise. To reconcile this discrepancy, we measured limb blood flow (LBF), cardiac output, and O2 uptake during two-legged knee-extensor exercise in eight healthy young men. They completed studies at rest, at two submaximal workloads, and at peak effort under normoxia (inspired O2 fraction 0.21) and two levels of hypoxia (inspired O2 fractions 0.16 and 0.11). During submaximal exercise, LBF increased in hypoxia and compensated for the decrement in arterial O2 content. At peak effort, however, our subjects did not achieve a higher cardiac output or LBF. Thus O2 delivery was not maintained and peak power output and leg O2 uptake were reduced proportionately. These data are consistent then with the findings of an increased LBF to compensate for hypoxemia at submaximal exercise, but no such increase occurs at peak effort despite substantial cardiac capacity for an elevation in LBF.

ATG based combination therapy - a novel clinically relevant approach to promote regulation and induce long-term allograft survival

Regulatory T cells (Treg) actively regulate alloimmune responses and promote transplantation tolerance. Polyclonal anti-thymocyte globulin (ATG), a widely used induction therapy in clinical organ transplantation, depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T cell depleting strategies and is attributed to alterations in the balance of naïve, memory and regulatory T cells. Here we report a novel reagent, murine ATG (mATG), depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T cell repertoire toward T-effector-memory (Tem) phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and Sirolimus synergize to prolong graft survival by tipping the Treg/Tem balance further in favor of Tregs by preserving Tregs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation. These results provide the rationale for translating such novel combination therapies to promote tolerance in primate and human organ transplantation.

Il dialetto nell'"Alpenrock": proposta di traduzione di alcuni brani di Hubert Von Goisern

Il tema del presente elaborato riguarda la traduzione dal dialetto, di alcuni brani del cantautore austriaco Hubert von Goisern. Viene inoltre presentata una breve storia del fenomeno musicale "Alpenrock", una biografia del cantautore e un commento alle traduzioni svolte, con relativa analisi di uno dei brani tradotti.

Offline fusion of co-registered intravascular ultrasound and frequency domain optical coherence tomography images for the analysis of human atherosclerotic plaques

To demonstrate the feasibility and potential usefulness of an offline fusion of matched optical coherence tomography (OCT) and intravascular ultrasound (IVUS)/virtual histology (IVUS-VH) images.