The effect of acute physical exercise on cytokine levels in patients with systemic lupus erythematosus.

BACKGROUND: Acute exercise increases IL-6, IL-10 and TNF-α levels in healthy subjects. There is no study evaluating the effect of exercise on cytokines level in systemic lupus erythematosus (SLE) patients. OBJECTIVE: Our aim was to assess IL-10, IL-6 and TNF-α levels at baseline and after acute physical exercise in patients with SLE. METHODS: In total, 27 female SLE patients and 30 healthy controls were evaluated. Serum levels of IL-10, IL-6 and TNF-α at baseline and soon after the ergospirometric test were measured by ELISA test. Student's t-tests and Mann-Whitney test were used for intra- and inter-group comparisons; p values <0.05 were considered significant. RESULTS: Patients with SLE presented worse ergospirometric parameters compared with controls: VO2max (25.78 ± 5.51 vs. 32.74 ± 5.85 ml/kg/min, p < 0.001); maximum heart rate (174.18 ± 12.36 vs. 185.15 ± 2.07 bpm, p = 0.001); maximum ventilation (65.51 ± 15.68 vs. 80.48 ± 18.98 l/min, p = 0.001) and maximum speed (7.70 ± 1.24 vs. 9.40 ± 1.22 km/h, p < 0.001). At baseline, SLE patients presented higher levels of IL-6 (2.38 ± 1.70 vs. 1.71 ± 0.29 pg/ml, p = 0.035) and IL-10 (1.09 ± 1.55 vs. 0.30 ± 0.11 pg/ml, p = 0.037) than controls. Acute exercise in controls increased IL-6 level (1.71 ± 0.29 vs. 2.01 ± 0.27 pg/ml, p = 0.003) without change in IL-10 and TNF-α levels. However, no significant change in cytokine levels was observed in SLE patients after acute exercise. CONCLUSION: This is the first study evaluating the effect of acute exercise on cytokine levels in patients with SLE. In contrast to healthy controls, acute physical exercise did not increase the levels of IL-6 in patients with SLE, and seems to be safe in those patients with inactive or mild active disease.

Comparison of linear and non-linear decision boundaries to detect feedlot bloat using intensive data collection systems on Angus × Hereford steers.

Ruminal tympany (bloat) has long been an issue for large and small livestock operations. Though improvements in feedlot management practices have reduced its occurrence, it is still highly prevalent and is known to detrimentally affect animal performance, welfare, and in many instances, lead to animal death. Current decision support systems and diet formulation software omit the inclusion of bloat prediction based on animal performance. Here, we aim to predict bloat incidence in implanted and non-implanted feedlot steers from performance data comparing linear (LDB) and non-linear decision boundaries. Eighteen crossbred Angus × Hereford steers: BW (491.13 ± 25.78 kg) and age (12 ± 1 mo) were randomly distributed into implanted and non-implanted treatments. All animals were randomly assigned to one of two pens fit with automated monitoring systems for BW, freshwater intake, and water intake behavior: water intake event visit, no water intake event visit (NWIE), and time spent drinking. DM intake (DMI) was individually recorded from all animals through the Calan Gate system for 135 d (30 d adaptation, 105 d experimental diet). Incidences of bloat were recorded as bloat instances regardless of severity to ensure that early onset detection of bloat was recorded and properly identified in predictive models. Logistic regression with a binomial distribution and a logit link function was utilized to predict the incidences of bloat through LDB. Feature selection and penalization of coefficients were explored through L1 (sum of absolute values) and L2 (sum of squares) penalization to avoid overfitting of models. Additional NLDB and a non-parametric LDB are examined for prediction. Accuracy, specificity, and sensitivity were high for the models reported. No significant differences were observed between LDB and NLDB, with the highest specificity (predicting bloat) value of 0.820 for stepwise feature selection algorithms, and a value of 0.832 for the artificial neural network. Highest accuracy was 0.829 for ridge regression, and 0.847 for the random forest with hyperparameter tuning. DM intake, BW, and NWIE were the three most important variables for the prediction of feedlot bloat showing clear drops in DMI and BW and increases in NWIE when animals bloated. The lack of difference in predictive performance between LDB and NLDB highlights the often-overlooked concept that machine learning algorithms are not always the only/best modeling technique. Additionally, the models reported herein carry acceptable predictive performance for inclusion into management decisions that reduce bloat incidences in feedlot cattle.

Effects of lipid and starch supplementation as water intake mitigation techniques on performance and efficiency of nursing Holstein calves.

Exploring alternative supplementation sources capable of maximizing feed and water efficiency in nursing Holstein calves is often ignored. The goals herein involve investigating the effects of two isoenergetic supplements on a nonmedicated milk replacer diet on total water intake, milk water intake, fresh water intake, feed intake parameters, and performance of Holstein nursing bull calves. Twenty-three animals (body weight [BW] = 94.67 ± 12.07 kg, age = 67 days old) were randomly assigned to one of three treatments for 68 days: control (CON; ad libitum milk replacer, n = 7), carbohydrate supplement (CHO; corn starch on top of ad libitum milk replacer-based diet, n = 8), or lipid supplement (FAT; menhaden fish oil on top of ad libitum milk replacer-based diet, n = 8). The isoenergetic supplementation consisted of 3% menhaden fish oil addition on DM basis for FAT. This was matched energetically with corn starch for the CHO group resulting in a 7% composition in DM basis. All animals were provided free access to mineral mix and 120 g daily dried microbrewer's spent grains (BG). Data were analyzed with the GLMMIX procedure of SAS in a completely randomized design with the diets as a fixed effect. Dry matter intake (DMI) adjusted by average daily gain (ADG; DMI/ADG) resulted in significantly lower values for supplemented groups with CON = 2.48, CHO = 2.38, and FAT = 2.27 kg/kg (ADG) (P = 0.033). Energy intake values were lower for CON when analyzing metabolizable energy intake (P < 0.0001), net energy intake for maintenance (P < 0.0001), and net energy intake for gain (P < 0.0001), followed by CHO, and then FAT. Total water intake (P < 0.0001), milk water intake (P < 0.0001), and fresh water intake (P < 0.0001) all resulted in CHO consuming 0.5 L or less water than the other two treatments. Energy requirements as digestible energy (P < 0.0001), metabolizable energy (P < 0.0001), net energy for maintenance (P < 0.0001), and net energy for gain (P < 0.0001) were lower for CHO, followed by CON, and then FAT having the highest requirements. Similar results were observed for residual feed (RFI; P = 0.006) and residual water intakes (RTWI; P = 0.902). Ultimately, no performance differences were detected with regards to BW (CON = 146.71, CHO = 146.25, and FAT = 150.48 kg; P > 0.1). These results indicate that lipid-based and starch-based supplementation can potentially increase feed efficiency and decrease voluntary water intake without adversely affecting performance.

Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity.

Bcr-Abl is one of the most potent antiapoptotic molecules and is the tyrosine-kinase implicated in Philadelphia (Ph) chromosome-positive leukemia. It is still obscure how Bcr-Abl provides the leukemic cell a strong resistance to chemotherapeutic drugs. A rational drug development produced a specific inhibitor of the catalytic activity of Bcr-Abl called STI571. This drug was shown to eliminate Bcr-Abl-positive cells both in vitro and in vivo, although resistant cells may appear in culture and relapse occurs in some patients. In the study described here, Bcr-Abl-positive cells treated with tyrosine-kinase inhibitors such as herbimycin A, genistein or STI571 lost their phosphotyrosine-containing proteins, but were still extremely resistant to apoptosis. Therefore, in the absence of tyrosine-kinase activity, Bcr-Abl-positive cells continue to signal biochemically to prevent apoptosis induced by chemotherapeutic drugs. We propose that secondary antiapoptotic signals are entirely responsible for the resistance of Bcr-Abl-positive cells. Precise determination of such signals and rational drug development against them should improve the means to combat Ph chromosome-positive leukemia.

Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release.

A growing body of evidence suggests that the pineal hormone, melatonin, has immunomodulatory properties, although very little is known about its effect on leukocytes. Therefore, we aimed to investigate the effect of melatonin and its oxidation product N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) on cytokine production by neutrophils and peripheral blood mononuclear cells (PBMCs). AFMK (0.001-1 mM) inhibits the lipopolysaccharide (LPS)-mediated production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) more efficiently in neutrophils than PBMCs. Moreover, the inhibitory activity of AFMK is stronger than that of melatonin. Interestingly, monocytes efficiently oxidize melatonin to AFMK. We conclude that neutrophils are one of the main targets for melatonin and that at least part of the effects described for melatonin on immune cells may be due to its oxidation product, AFMK. We also consider that the oxidation of melatonin may be an important event in the cross-talking between neutrophils and monocytes.

[Atrioventricular septal defect with associated tetralogy of Fallot. Clinico-morphological aspects and surgical considerations]. / Defecto del septo atrioventricular con tetralogía de Fallot asociada. Aspectos clinicomorfológicos y consideraciones quirúrgicas.

In this work the clinical features, diagnostic methods, surgical procedures and postoperative follow-up are reviewed in 19 cases of atrioventricular septal defect with associated tetralogy of Fallot. The clinical situation was always related to the degree of pulmonary ischemia, that pointed out the urgency and need for a palliative surgical procedure before corrective surgery. There was no data in the ECG for the differential diagnosis of isolated forms of atrioventricular septal defect. In 50% of the cases the cardio-thoracic index was increased by right atrial enlargement. The diagnosis of the malformation was made in every case by means of 2D echocardiography. In 16 cases palliative surgery was done (aortic-pulmonary shunts), with one death (6.2%) due to facts unrelated to the technique. Of the 6 cases with corrective surgery (5 cases with previous shunts), one needed a mitral valve replacement (St Jude prosthesis). There was no mortality in this group and the functional status in the long-term follow-up was: 3 cases were in the functional class I and 3 cases in class II. The overall mortality for all surgical procedures carried out was 4.3%. In conclusion, we consider the use of the corrective surgery adequate to the clinical stability of the patients with atrioventricular septal defect with associated Fallot's tetralogy.

BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients.

Tumor necrosis factor-related apoptosis-inducing ligand-TNFSF10 (TRAIL), a member of the TNF-α family and a death receptor ligand, was shown to selectively kill tumor cells. Not surprisingly, TRAIL is downregulated in a variety of tumor cells, including BCR-ABL-positive leukemia. Although we know much about the molecular basis of TRAIL-mediated cell killing, the mechanism responsible for TRAIL inhibition in tumors remains elusive because (a) TRAIL can be regulated by retinoic acid (RA); (b) the tumor antigen preferentially expressed antigen of melanoma (PRAME) was shown to inhibit transcription of RA receptor target genes through the polycomb protein, enhancer of zeste homolog 2 (EZH2); and (c) we have found that TRAIL is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients. Thus, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is upregulated in BCR-ABL cells and is associated with the progression of disease in CML patients. There is a positive correlation between PRAME and BCR-ABL and an inverse correlation between PRAME and TRAIL in these patients. Importantly, knocking down PRAME or EZH2 by RNA interference in a BCR-ABL-positive cell line restores TRAIL expression. Moreover, there is an enrichment of EZH2 binding on the promoter region of TRAIL in a CML cell line. This binding is lost after PRAME knockdown. Finally, knocking down PRAME or EZH2, and consequently induction of TRAIL expression, enhances Imatinib sensibility. Taken together, our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML.

Conversion of CD95 (Fas) Type II into Type I signaling by sub-lethal doses of cycloheximide.

CD95 (Fas/Apo-1)-mediated apoptosis was shown to occur through two distinct pathways. One involves a direct activation of caspase-3 by large amounts of caspase-8 generated at the DISC (Type I cells). The other is related to the cleavage of Bid by low concentration of caspase-8, leading to the release of cytochrome c from mitochondria and the activation of caspase-3 by the cytochrome c/APAF-1/caspase-9 apoptosome (Type II cells). It is also known that the protein synthesis inhibitor cycloheximide (CHX) sensitizes Type I cells to CD95-mediated apoptosis, but it remains contradictory whether this effect also occurs in Type II cells. Here, we show that sub-lethal doses of CHX render both Type I and Type II cells sensitive to the apoptogenic effect of anti-CD95 antibodies but not to chemotherapeutic drugs. Moreover, Bcl-2-positive Type II cells become strongly sensitive to CD95-mediated apoptosis by the addition of CHX to the cell culture. This is not the result of a restraint of the anti-apoptotic effect of Bcl-2 at the mitochondrial level since CHX-treated Type II cells still retain their resistance to chemotherapeutic drugs. Therefore, CHX treatment is granting the CD95-mediated pathway the ability to bypass the mitochondria requirement to apoptosis, much alike to what is observed in Type I cells.

The Stresst'er ergometer as an alternative to treadmill testing in patients with claudication.

OBJECTIVES: To compare a new pedal ergometer (the Stresst'er) with conventional treadmill examination in patients with leg pain on exercise. DESIGN: Patients presenting with claudication were assessed by standard treadmill test and by the new device in two District General Hospitals. METHODS: Ninety-four subjects were studied. Symptoms induced by both types of exercise were compared. Distance walked on the treadmill was compared to the number of pumps using the Stresst'er. The percentage change in ankle systolic pressure produced by the two tests was compared. RESULTS: Subjective symptoms induced by the tests were similar. Distance walked did correlate with pumps on the ergometer, as did change in systolic pressure. Analysis of a subgroup of 41 cases with receiver operator curve (ROC) tests showed that the new device is sensitive and specific. CONCLUSION: This new device is comparable with treadmill testing, but being easier to use, may have a place in the vascular clinic.

Butyrate increases apoptosis induced by different antineoplastic drugs in monocytic leukemia cells.

BACKGROUND: Apoptosis is an essential form of cell death, the failure of which can lead to cancer development. Cancer including leukemia is usually treated with chemotherapeutic drugs that can be effective, but frequently problems are encountered that impair the success of the treatment. Butyrate is a short-chain fatty acid that can have many effects on different cells, including apoptosis. METHODS: The effect of a combination treatment with butyrate and antineoplastic agents Ara-C, etoposide and vincristine is evaluate on the leukemic cell line THP-1. RESULTS: We show that butyrate increased apoptosis induced by the three agents as seen by measurement of DNA content, annexin exposure and morphological characteristics. We also demonstrate that the process of apoptosis induced by butyrate and chemotherapeutic drugs involves the participation of caspases and induced activation of caspase-3, -8 and -9. CONCLUSIONS: We believe that butyrate could be a promising therapeutic agent for the treatment of leukemia in combination with other antineoplastic drugs.