Search

Alexander von Humboldt, 1769-1859, scientific explorer of the eighteenth and nineteenth centuries, wrote with a rational mind as well as a romantic spirit. Humboldt's Personal Narrative of a Journey to the Equinoctial Regions of the New Continent during the Years 1799-1804 is a blend of the objective/rational and subjective/romantic, so much so that this work can be considered an early form of science writing in the tradition of literary journalism. Personal Narrative reveals that Humboldt drew on and combined his empirical, rational, and romantic backgrounds to inform and inspire the public and his fellow researchers. The strongest case for Humboldt's work being considered an early form of literary journalism is his consistent use of the picturesque, of which his particular use in Personal Narrative operates at the crossroads between an Age of Reason and Romanticism. In so doing, Humboldt uses the picturesque to entertain as well as inform his audience. Analyses looking for only objectivity, or only subjectivity, in Humboldt's work fall short because he actively uses both in his writing. His scientific philosophy and epistemology create a dynamic feedback loop between objectivity and subjectivity. Further analysis of Humboldt's work as a literary journalistic piece will shed more light on the methodological holism of his epistemology. Recognizing Personal Narrative as an early form of literary journalism opens the door to the works of other authors who were inspired by Humboldt's work to write in ways that could also be considered forms of literary journalism. [ABSTRACT FROM AUTHOR]

Cardiovascular adaptations to exercise, particularly at the individual level, remain poorly understood. Previous group level research suggests the relationship between cardiac output and oxygen consumption (-) is unaffected by training as submaximal is unchanged. We recently identified substantial inter-individual variation in the exercise - relationship that was correlated to stroke volume (SV) as opposed to arterial oxygen content. Therefore we explored the effects of sprint interval training (SIT) on modulating - given an individual’s specific - relationship. 22 (21±2 yrs) healthy, recreationally active males participated in a 4-week SIT (8, 20 second sprints; 4x/week, 170% of the work rate at peak) study with progressive exercise tests (PET) until exhaustion. Cardiac output ( L/min; inert gas rebreathe, Finometer Modelflow™), oxygen consumption ( L/min; breath-by-breath pulmonary gas exchange), quadriceps oxygenation (near infrared spectroscopy) and exercise tolerance (6–20; Borg Scale RPE) were measured throughout PET both before and after training. Data are mean Δ from bsl±SD. Higher () and lower () responders were identified post hoc (n = 8/group). SIT increased the - post-training in (3.8±0.2 vs. 4.7±0.2; P = 0.02) while was unaffected (5.8±0.1 vs. 5.3±0.6; P = 0.5). was elevated beyond 80 watts in due to a greater increase in SV (all P<0.04). Peak (ml/kg/min) was increased in (39.7±6.7 vs. 44.5±7.3; P = 0.015) and (47.2±4.4 vs. 52.4±6.0; P = 0.009) following SIT, with having a greater peak both pre (P = 0.02) and post (P = 0.03) training. Quadriceps muscle oxygenation and RPE were not different between groups (all P>0.1). In contrast to , responders are capable of improving submaximal - in response to SIT via increased SV. However, the increased submaximal exercise does not benefit exercising muscle oxygenation. [ABSTRACT FROM AUTHOR]

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: This study investigated whether VO2peak is reproducible across repeated tests before (PRE) and after (POST) training, and whether variability across tests impacts how individual responses are classified following 3 weeks of aerobic exercise training (cycle ergometry). Data from 45 young healthy adults (age: 20·1 ± 0·9 years; VO2peak, 42·0 ± 6·7 ml·min−1) from two previously published studies were utilized in the current analysis. Non‐responders were classified as individuals who failed to demonstrate an increase or decrease in VO2peak that was greater than 2·0 times the typical error of measurement (107 ml·min−1) away from zero, while responders and adverse responders were above and below this cut‐off, respectively. VO2peak tests at PRE (three total) and POST (three total) were highly reproducible (PRE and POST average and single measures ICCs: range 0·938–0·992), with low coefficients of variation (PRE:4·9 ± 3·1%, POST: 4·8 ± 2·7%). However, a potential learning effect was observed in the VO2peak tests prior to training, as the initial pretraining test was significantly lower than the third (p = 0·010, PRE 1: 2 946 ± 924 ml·min−1, PRE 3: 3 042 ± 919 ml·min−1). This resulted in fewer individuals classified as adverse responders for Test 3 compared to any combination of tests that included Test 1, suggesting that a single ramp test at baseline may not be sufficient to accurately classify the VO2peak response in young recreationally active individuals. Thus, it is our recommendation that the initial VO2peak test be used as a familiarization visit and not included for analysis. [ABSTRACT FROM AUTHOR]

Considerable interindividual differences in the Ȯ-VO2 relationship during exercise have been documented but implications for submaximal exercise tolerance have not been considered. We tested the hypothesis that these interindividual differences were associated with differences in exercising muscle deoxygenation and ratings of perceived exertion (RPE) across a range of submaximal exercise intensities. A total of 31 (21± 3 years) healthy recreationally active males performed an incremental exercise test to exhaustion 24 h following a resting muscle biopsy. Cardiac output (±Q L/min; inert gas rebreathe), oxygen uptake (±V O2 L/min; breath-by-breath pulmonary gas exchange), quadriceps saturation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured. The Ȯ-VO2 relationship from 40 to 160 W was used to partition individuals post hoc into higher (n = 10; 6.3 - 0.4) versus lower (n = 10; 3.7± 0.4, P < 0.001) responders. The Ȯ-VO2 difference between responder types was not explained by arterial oxygen content differences (P = 0.5) or peripheral skeletal muscle characteristics (P from 0.1 to 0.8) but was strongly associated with stroke volume (P < 0.05). Despite considerable Ȯ-VO2 difference between groups, no difference in quadriceps deoxygenation was observed during exercise (all P > 0.4). Lower cardiac responders had greater leg (P = 0.027) and whole body (P = 0.03) RPE only at 185 W, but this represented a higher %peak V- O2 in lower cardiac responders (87± 15% vs. 66± 12%, P = 0.005). Substantially lower Ȯ-VO2 in the lower responder group did not result in altered RPE or exercising muscle deoxygenation. This suggests substantial recruitment of blood flow redistribution in the lower responder group as part of protecting matching of exercising muscle oxygen delivery to demand. [ABSTRACT FROM AUTHOR]

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be ‘created’ on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions. [ABSTRACT FROM AUTHOR]

Background. Tumor hypoxia contributes to loco-regional failure, and for optimal treatment planning, knowledge about tumor hypoxia in individual patients is required. Nitroimidazole-based tracers, which are retained in hypoxic cells, allow PET-based assessment of tumor hypoxia, but current tracers are characterized by slow tracer retention and clearance, resulting in low inter-tissue contrast. Pimonidazole is an immune detectable hypoxia marker widely used for detection of hypoxia in tumor samples. Pimonidazole has excellent chemical properties for hypoxia imaging, but labeling for non- invasive assay has not been attempted. Here we labeled pimonidazole with 18F ([18F]FPIMO). Material and methods. [18F]FPIMO was produced by fluorination of 1-[2- O-tosyl-3-(2-nitroimidazole-1-yl)-propyl]-piperidine, which resulted in two isomeric interchangeable forms (named '5' and '6') with a radiochemical purity of 91-100%. [18F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [18F]FPIMO was also administered to tumor-bearing mice and tracer retention in tumors, non-hypoxic reference tissues and tissues involved in drug metabolism/clearance was evaluated by various techniques. Results and conclusions. Retention of [18F]FPIMO was strongly hypoxia-driven in vitro, but isomeric form '5' was particularly promising and reached impressive anoxic-to-oxic retention ratios of 36 and 102, in FaDuDD and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [18F]FAZA. [18F]FPIMO also accumulated in tumors grown in mice, and reached tumor levels that were two to six-fold higher than in muscle three hours post-administration. Furthermore, the intra-tumoral distribution of [18F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [18F]FPIMO proved inferior to [18F]FAZA, since absolute tumor signal and intra-tumoral contrast was low, thus compromising PET imaging. Low tumor signal was coupled to extensive tracer accumulation in liver and kidneys, and analysis of blood metabolites revealed that [18F]FPIMO was metabolized rapidly, with little parent compound remaining 15 minutes post-administration. Ongoing work focuses on the possibility of labeling pimonidazole in different positions with 18F to improve tracer stability in vivo. [ABSTRACT FROM AUTHOR]

Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2α or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities. [ABSTRACT FROM AUTHOR]

Examines the protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo. Reduction of renal injury caused by ischemia-reperfusion; Measurement on postischemic glomerular filtration rate; Evaluation of urinary lactate dehydrogenase concentration by ischemia-reperfusion in control groups.

We describe our preliminary studies on the development of methods to measure hypoxia in standard paraffin sections of human tumors. Three parameters were investigated. First, image analysis of tumor vascularity yielded the parameter diffusion limited fraction (DLF), which is the amount of tumor tissue greater than a fixed distance from the nearest blood vessel. Secondly, the amount of tumor tissue stained with antibodies against bound reduced products of the bioreductive marker pimonidazole was assessed. Finally, the fraction of blood vessels showing no surrounding tumor tissue labeled with IUdR, a cell kinetic marker, was measured. DLF and pimonidazole monitor primarily chronic hypoxia, while it is hypothesized that the IUdR-negative fraction monitors acute hypoxia. Feasibility was demonstrated in a series of 10 esophageal and 10 rectal tumors (no drug administration), 10 cervix tumors (pimonidazole) and 14 head and neck tumors (pimonidazole and IUdR). Significant differences between tumors were found for all parameters. DLF correlated significantly with the pimonidazole fraction when all images of all tumors were included, although mean values per tumor showed no correlation. The IUdR-negative fraction did not correlate with either of the other two parameters. We conclude that it is feasible to measure hypoxia-related, and possibly perfusion-related, parameters on paraffin sections for predictive purposes, although each method needs further validation. Each parameter will be correlated with outcome in a larger study on head and neck tumors treated with surgery with or without postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

Focuses on a study which investigated the hypothesis that hypokalemia might induce renal injury via a mechanism that involves subtle renal injury and alterations in local vasoactive mediators that would favor sodium retention. Methods of the study; Renal histology; Association of hypokalemic nephropathy with an alteration in vasoactive mediators that favors vasoconstriction.

Deals with a study which examined the validity of the hypothesis that organ manipulation activates Kupffer cells in the liver of rats. Release of toxic mediators which impair liver function; Hypermetabolic state in liver caused by gentle in situ organ manipulation; Relationship between gentle organ manipulation and graft viability.

Gentle in situ organ manipulation rapidly causes disturbances in the hepatic microcirculation, hypoxia, and activation of Kupffer cells. Because the mechanisms of Kupffer cell activation after organ manipulation remain unclear, the possible role of the autonomic nervous system and gut-derived endotoxin were assessed. To mimic what occurs with major abdominal surgery, livers from female Sprague-Dawley rats (200–230 g) underwent minimal dissection for 12 minutes and were manipulated gently or were left alone for 13 subsequent minutes. Kupffer cells were activated 2 hours after manipulation, reflected by a significant increase in intracellular calcium ([Ca2+]i) from about 90 nM in unmanipulated controls to more than 180 nM in response to lipopolysaccharide (LPS 100 ng/ml). Furthermore, Kupffer cells from manipulated rats produced about threefold more tumor necrosis factor-α after LPS (100 ng/ml) than did the unmanipulated controls. Moreover, O2 uptake of ex situ perfused liver was increased from about 110 μmol/g/hr in unmanipulated controls to more than 160 μmol/g/hr 2 hours after organ manipulation. Binding of pimonidazole (120 mg/kg IV), a 2-nitroimidazole hypoxia marker given 2 hours after manipulation, increased about 2.5-fold, and hepatic glycogen was depleted. Two hours after organ manipulation gut permeability to horseradish peroxidase was elevated and endotoxin in the portal venous blood was increased twofold. Microsurgical hepatic denervation, ganglionic blockade, adrenalectomy, and antibiotics to sterilize the gut before manipulation prevented activation of Kupffer cells by organ manipulation. Hexamethonium and adrenalectomy prevented increases in gut permeability caused by manipulation. Although antibiotics blunted the increase in portal venous endotoxin significantly, there was no effect on gut permeability. These data indicate for the first time that both the autonomic nervous system and gut-derived endotoxin are involved in activation of Kupffer cells after organ manipulation. [ABSTRACT FROM AUTHOR]

Two-hundred and fifteen isolates of Mycobacterium tuberculosis were evaluated with the BACTEC 460 radiometric method for susceptibility to isoniazid, rifampin, ethambutol, and streptomycin (SM); a revised protocol for inoculum preparation was used. Fresh clinical isolates were subcultured into 7H9 broth and then photometrically adjusted to the equivalent of a 0.5 McFarland standard, one-half the recommended inoculum density. This method produced an overall 98.3% correlation with a conventional agar method. The sensitivity of this procedure was good for all drugs tested except for the lowest concentration of SM (2 μg/ml). Specificity was excellent for all drugs tested. After repeat testing, only four discrepancies were found, yielding a 99.8% correlation between the two systems. The time required for susceptibility tests averaged 4.6 days. This method for inoculum preparation effectively minimized the number of susceptibility tests exceeding the threshold value before the fourth day of incubation. This allowed for definite trends of the growth index values to become established before interpretation of results. [ABSTRACT FROM AUTHOR]

2-Nitroimidazoles, such as pimonidazole, are reduced in cells with low oxygen tension and are, therefore, used as hypoxia markers. However, the effect of the pyridine nucleotide redox state on pimonidazole reduction is not known. Therefore, livers from fed or fasted rats were perfused with oxygen-saturated buffer containing pimonidazole (400 μM) in the presence and absence of an inhibitor of the mitochondrial respiratory chain, potassium cyanide; these treatments were used to modulate the mitochondrial and cytosolic pyridine nucleotide redox states. Pimonidazole-induced increases in oxygen uptake over basal values were as follows : fed, 15.1 ± 2.4; fasted, 4.2 ± 0.8; fed + KCN, 32.1 ± 0.9; fasted+KCN, 0.2 ± 0.2 μmol &timesd; g-1 &timesd; h-1. However, if NADPH was added in excess, microsomal oxygen uptake due to oxidative metabolism of pimonidazole was independent of treatment. These results indicate that pimonidazole-stimulated O2 uptake, due predominantly to N-oxidation and glucuronidation, is dependent on the NADPH redox state. In contrast, reduced pimonidazole adducts, detected immunochemically, accumulated in pericentral regions in liver. Increasing the NADH redox state by inhibiting the mitochondrial respiratory chain with KCN decreased protein-bound pimonidazole adducts. Concomitantly, the average O2 tension of the liver was increased at least 30 %. However, KCN had no effect on total pimonidazole adducts detected by ELISA, although both cytosolic (lactate/pyruvate) and mitochondrial (3-hydroxybutyrate/acetoacetate) NADH redox states were elevated by at least a factor of eight. These results indicate that, unlike oxidative metabolism, the pyridine nucleotide redox state does not determine the rate of reductive metabolism of pimonidazole. Instead, the cellular oxygen tension regulates this process. Therefore, even in cases where the supply of reducing equivalents is increased (e.g.,... [ABSTRACT FROM AUTHOR]

Determines if acute exposure to ethanol causes hypoxia directly in hepatocytes in vivo. Assessment of whether Kupffer cells play a role in this process.

Introduction: Hypoxia in solid tumors is associated with treatment resistance, resulting in poor prognosis. Tribbles homolog 3 (TRIB3) is induced during hypoxia and is involved in multiple cellular pathways involved in cell survival. Here, we investigated the role of TRIB3 in breast cancer.Methods: TRIB3 mRNA expression was measured in breast tumor tissue from 247 patients and correlated with clinicopathological parameters and clinical outcome. Furthermore, we studied TRIB3 expression regulation in cell lines, xenografts tissues and human breast cancer material using Reverse transcriptase, quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining. Finally, the effect of small interfering RNA (siRNA) mediated TRIB3 knockdown on hypoxia tolerance was assessed.Results: Breast cancer patients with low, intermediate or high TRIB3 expression exhibited a mean disease free survival (DFS) of 80 (95% confidence interval [CI] = 74 to 86), 74 (CI = 67 to 81), and 63 (CI = 55 to 71) months respectively (P = .002, Mantel-Cox log-rank). The prognostic value of TRIB3 was limited to those patients that had received radiotherapy as part of their primary treatment (n = 179, P = .005) and remained statistically significant after correction for other clinicopathological parameters (DFS, Hazard Ratio = 1.90, CI = 1.17 to 3.08, P = .009). In breast cell lines TRIB3 expression was induced by hypoxia, nutrient starvation, and endoplasmic reticulum stress in an hypoxia inducible factor 1 (HIF-1) independent manner. TRIB3 induction after hypoxia did not increase with decreasing oxygen levels. In breast tumor xenografts and human breast cancer tissues TRIB3 co-localized with the hypoxic cell marker pimonidazole. The induction of TRIB3 by hypoxia was shown to be regulated via the PERK/ATF4/CHOP pathway of the unfolded protein response and knockdown of TRIB3 resulted in a dose-dependent increase in hypoxia sensitivity.Conclusions: TRIB3 is independently associated with poor prognosis of breast cancer patients, possibly through its association with tumor cell hypoxia. [ABSTRACT FROM AUTHOR]