Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective [beta]-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 ± 26 versus 425 ± 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 ± 0.6 versus 5.8 ± 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 ± 0.9 versus 5.6 ± 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca2+ loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.http://www.sciencedirect.com/science/article/B6WXH-47G34FR-7/1/591ea3d1072dcf2971b640191c05679

Delayed ethylene glycol poisoning presenting with abdominal pain and multiple cranial and peripheral neuropathies: a case report

<p>Abstract</p> <p>Introduction</p> <p>Ethylene glycol poisoning may pose diagnostic difficulties if the history of ingestion is not volunteered, or if the presentation is delayed. This is because the biochemical features of high anion-gap metabolic acidosis and an osmolar gap resolve within 24 to 72 hours as the ethylene glycol is metabolized to toxic metabolites. This case illustrates the less well-known clinical features of delayed ethylene glycol poisoning, including multiple cranial and peripheral neuropathies, and the clinical findings which may point towards this diagnosis in the absence of a history of ingestion.</p> <p>Case presentation</p> <p>A 53-year-old Afro-Caribbean man presented with vomiting, abdominal pain and oliguria, and was found to have acute renal failure requiring emergency hemofiltration, and raised inflammatory markers. Computed tomography imaging of the abdomen revealed the appearance of bilateral pyelonephritis, however he failed to improve with broad-spectrum antibiotics, and subsequently developed multiple cranial neuropathies and increasing obtundation, necessitating intubation and ventilation. Computed tomography of the brain showed no focal lesions, and a lumbar puncture revealed a raised cerebrospinal fluid opening pressure and cyto-albuminological dissociation. Nerve conduction studies revealed a sensorimotor radiculoneuropathy mimicking a Guillain-Barre type lesion with an atypical distribution. It was only about two weeks after presentation that the history of ethylene glycol ingestion one week before presentation was confirmed. He had a slow recovery on the intensive care unit, requiring renal replacement therapy for eight weeks, and complicated by acute respiratory distress syndrome, neuropathic pain and a slow neurological recovery requiring prolonged rehabilitation.</p> <p>Conclusions</p> <p>Although neuropathy as a result of ethylene glycol poisoning has been described in a few case reports, all of these were in the context of a known history of ingestion. As the diagnosis may well be obscured if the history of ingestion is not elucidated, it is important to be aware of this possibility especially if presentation is delayed.</p

Asymptomatic <i>Plasmodium falciparum</i> carriage at the end of the dry season is associated with subsequent infection and clinical malaria in Eastern Gambia

BACKGROUND: Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear.METHODS: In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria.RESULTS: Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p &lt; 0.0001) and clinical malaria (HR = 1.561, p = 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season.CONCLUSION: Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.</p

Asymptomatic <i>Plasmodium falciparum</i> carriage at the end of the dry season is associated with subsequent infection and clinical malaria in Eastern Gambia

Background: Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear. Methods: In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria. Results: Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p &lt; 0.0001) and clinical malaria (HR = 1.561, p = 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season. Conclusion: Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.</p

Physical Activity and Pediatric Obesity:A Quantile Regression Analysis

PURPOSE: We aimed to determine if moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) were independently associated with body mass index (BMI) and waist circumference (WC) in children and adolescents. METHODS: Data from the International Children’s Accelerometry Database (ICAD) were used to address our objectives (N=11,115; 6-18y; 51% female). We calculated age and gender specific body mass index (BMI) and waist circumference (WC) Z-scores and used accelerometry to estimate MVPA and total SB. Self-reported television viewing was used as a measure of leisure time SB. Quantile regression was used to analyze the data. RESULTS: MVPA and total SB were associated with lower and higher BMI and WC Z-scores, respectively. These associations were strongest at the higher percentiles of the Z-score distributions. After including MVPA and total SB in the same model the MVPA associations remained, but the SB associations were no longer present. For example, each additional hour per day of MVPA was not associated with BMI Z-score at the 10(th) percentile (b=-0.02, P=0.170), but was associated with lower BMI Z-score at the 50(th) (b=-0.19, P<0.001) and 90(th) percentiles (b=-0.41, P<0.001). More television viewing was associated with higher BMI and WC and the associations were strongest at the higher percentiles of the Z-score distributions, with adjustment for MVPA and total SB. CONCLUSIONS: Our observation of stronger associations at the higher percentiles indicate that increasing MVPA and decreasing television viewing at the population-level could shift the upper tails of the BMI and WC frequency distributions to lower values, thereby lowering the number of children and adolescents classified as obese

Objectively measured time spent sedentary is associated with insulin resistance independent of overall and central body fat in 9- to 10-year-old Portuguese children

OBJECTIVE — We examined the independent relationships between objectively measured physical activity and insulin resistance in Portuguese children. RESEARCH DESIGN AND METHODS — This is a school-based, cross-sectional study in 147 randomly selected girls (aged 9.8 0.3 years; 27.8 9.3% body fat) and 161 boys (aged 9.8 0.3 years; 22.0 9.2% body fat). Physical activity was assessed by the Actigraph accel erometer for 4 days and summarized as time spent sedentary (accelerometer counts 500/min), in light-intensity (accelerometer counts 500–2,000/min), and in moderate- and vigorous intensity activity (accelerometer counts 2,001/min). We measured total and central fat mass by dual-energy X-ray absorptiometry. Insulin resistance was expressed as the homeostasis model assessment score. RESULTS — Time (min/day) spent sedentary was significantly and positively associated with insulin resistance ( -coefficient 0.001 [95% CI 0.0002–0.002]; P 0.013). Time spent in moderate- and vigorous-intensity physical activity ( 0.002 [ 0.003 to 0.001]; P 0.0009) and overall physical activity ( 0.001 [ 0.008 to 0.003]; P 0.0001) were significantly and inversely associated with insulin resistance. All associations remained statistically significant, although they were attenuated after further adjustments for sex, birth weight, sexual maturity, and total or central fat mass (P 0.03). CONCLUSIONS — Physical activity is associated with insulin resistance independent of total and central fat mass in children. Our results emphasize the importance of decreasing sedentary behavior and increasing time spent in moderate- and vigorous-intensity activity in children, which may have beneficial effects on metabolic risk factors regardless of the degree of adiposity.info:eu-repo/semantics/publishedVersio

Transhiatal vs extended transthoracic resection in oesophageal carcinoma: patients' utilities and treatment preferences

To assess patients' utilities for health state outcomes after transhiatal or transthoracic oesophagectomy for oesophageal cancer and to investigate the patients' treatment preferences for either procedure. The study group consisted of 48 patients who had undergone either transhiatal or transthoracic oesophagectomy. In an interview they were presented with eight possible health states following oesophagectomy. Visual Analogue Scale and standard gamble techniques were used to measure utilities. Treatment preference for either transhiatal or transthoracic oesophagectomy was assessed. Highest scores were found for the patients' own current health state (Visual Analogue Scale: 0.77; standard gamble: 0.97). Lowest scores were elicited for the health state ‘irresectable tumour’ (Visual Analogue Scale: 0.13; standard gamble: 0.34). The Visual Analogue Scale method produced lower estimates (P<0.001) than the standard gamble method for all health states. Most patient characteristics and clinical factors did not correlate with the utilities. Ninety-five per cent of patients who underwent a transthoracic procedure and 52% of patients who underwent a transhiatal resection would prefer the transthoracic treatment. No significant associations between any patient characteristics or clinical characteristics and treatment preference were found. Utilities after transhiatal or transthoracic oesophagectomy were robust because they generally did not vary by patient or clinical characteristics. Overall, most patients preferred the transthoracic procedure

Regulation of CCL2 Expression by an Upstream TALE Homeodomain Protein-Binding Site That Synergizes with the Site Created by the A-2578G SNP

CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16– and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins. © 1999 Cancer Research Campaig

Light and Heavy Fractions of Soil Organic Matter in Response to Climate Warming and Increased Precipitation in a Temperate Steppe

Soil is one of the most important carbon (C) and nitrogen (N) pools and plays a crucial role in ecosystem C and N cycling. Climate change profoundly affects soil C and N storage via changing C and N inputs and outputs. However, the influences of climate warming and changing precipitation regime on labile and recalcitrant fractions of soil organic C and N remain unclear. Here, we investigated soil labile and recalcitrant C and N under 6 years' treatments of experimental warming and increased precipitation in a temperate steppe in Northern China. We measured soil light fraction C (LFC) and N (LFN), microbial biomass C (MBC) and N (MBN), dissolved organic C (DOC) and heavy fraction C (HFC) and N (HFN). The results showed that increased precipitation significantly stimulated soil LFC and LFN by 16.1% and 18.5%, respectively, and increased LFC∶HFC ratio and LFN∶HFN ratio, suggesting that increased precipitation transferred more soil organic carbon into the quick-decayed carbon pool. Experimental warming reduced soil labile C (LFC, MBC, and DOC). In contrast, soil heavy fraction C and N, and total C and N were not significantly impacted by increased precipitation or warming. Soil labile C significantly correlated with gross ecosystem productivity, ecosystem respiration and soil respiration, but not with soil moisture and temperature, suggesting that biotic processes rather than abiotic factors determine variations in soil labile C. Our results indicate that certain soil carbon fraction is sensitive to climate change in the temperate steppe, which may in turn impact ecosystem carbon fluxes in response and feedback to climate change