Aeolian sediments on the Tibetan Plateau

Abstract HKT-ISTP 2013 B

Landscape and Lake-System Response to Late Quaternary Monsoon Dynamics on the Tibetan Plateau - Northern Transect

Abstract HKT-ISTP 2013 B

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer

Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel

Metabolic drift in the aging brain.

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication

Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent.

Countries in the Indian subcontinent have committed to reducing the incidence of kala-azar, a clinical manifestation of visceral leishmaniasis, to below 1 in 10,000 by 2020. We address the role of timing of use and accuracy of diagnostics in kala-azar control and elimination. We use empirical data on health-seeking behaviour and health-system performance from the Indian state of Bihar, Bangladesh and Nepal to parameterize a mathematical model. Diagnosis of cases is key to case management, control and surveillance. Treatment of cases prevents onward transmission, and we show that the differences in time to diagnosis in these three settings explain the observed differences in incidence. Shortening the time from health-care seeking to diagnosis is likely to lead to dramatic reductions in incidence in Bihar, bringing the incidence down to the levels seen in Bangladesh and Nepal. The results emphasize the importance of maintaining population and health-system awareness, particularly as transmission and disease incidence decline. We explore the possibility of diagnosing patients before the onset of clinical kala-azar (before 14 days fever), and show that this could have a marked impact on incidence, even for a moderately sensitive test. However, limited specificity (that results in false positives) is a major barrier to such a strategy. Diagnostic tests of high specificity used at an early stage of active infection, even if sensitivity is only moderate, could have a key role in the control of kala-azar, and prevent its resurgence when paired with the passive health-care system and tests of high sensitivity, such as the test for rK39 antibody response

Nine weeks of supplementation with a multi-nutrient product augments gains in lean mass, strength, and muscular performance in resistance trained men

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to compare the effects of supplementation with Gaspari Nutrition's SOmaxP Maximum Performance™ (SOmaxP) versus a comparator product (CP) containing an equal amount of creatine (4 g), carbohydrate (39 g maltodextrin), and protein (7 g whey protein hydrolysate) on muscular strength, muscular endurance, and body composition during nine weeks of intense resistance training.</p> <p>Methods</p> <p>Using a prospective, randomized, double-blind design, 20 healthy men (mean ± SD age, height, weight, % body fat: 22.9 ± 2.6 y, 178.4 ± 5.7 cm, 80.5 ± 6.6 kg, 16.6 ± 4.0%) were matched for age, body weight, resistance training history, bench press strength, bench press endurance, and percent body fat and then randomly assigned via the ABBA procedure to ingest 1/2 scoop (dissolved in 15 oz water) of SOmaxP or CP prior to, and another 1/2 scoop (dissolved in 15 oz water) during resistance exercise. Body composition (DEXA), muscular performance (1-RM bench press and repetitions to failure [RTF: 3 sets × baseline body weight, 60-sec rest between sets]), and clinical blood chemistries were measured at baseline and after nine weeks of supplementation and training. Subjects were required to maintain their normal dietary habits and follow a specific, progressive overload resistance training program (4-days/wk, upper body/lower body split) during the study. An intent-to-treat approach was used and data were analyzed via ANCOVA using baseline values as the covariate. Statistical significance was set <it>a priori </it>at p ≤ 0.05.</p> <p>Results</p> <p>When adjusted for initial differences, significant between group post-test means were noted in: 1-RM bench press (SOmaxP: 133.3 ± 1.3 kg [19.8% increase] vs. CP: 128.5 ± 1.3 kg [15.3% increase]; p < 0.019); lean mass (SOmaxP: 64.1 ± 0.4 kg [2.4% increase] vs. 62.8 ± 0.4 kg [0.27% increase], p < 0.049); RTF (SOmaxP: 33.3 ± 1.1 reps [44.8% increase] vs. 27.8 ± 1.1 reps [20.9% increase], p < 0.004); and fat mass (SOmaxP: 12.06 ± 0.53 kg [9.8% decrease] vs. 13.90 ± 0.53 kg [4.1% increase], p < 0.024). No statistically significant differences in vital signs (heart rate, systolic and diastolic blood pressures) or clinical blood chemistries were noted.</p> <p>Conclusions</p> <p>These data indicate that compared to CP, SOmaxP administration augments and increases gains in lean mass, bench press strength, and muscular performance during nine weeks of intense resistance training. Studies designed to confirm these results and clarify the molecular mechanisms by which SOmaxP exerts the observed salutary effects have begun. Both SOmaxP and the CP were well-tolerated, and no supplement safety issues were identified.</p

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer

Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel

Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function

Background &amp; Aims Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved. Methods The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)induced colitis was examined in mice. Results PHD1-/-, but not PHD2+/- or PHD3-/-, mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1-/- mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice. Conclusions These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD. © 2010 AGA Institute

Skin parasite landscape determines host infectiousness in visceral leishmaniasis

Increasing evidence suggests that the infectiousness of patients for the sand fly vector of visceral leishmaniasis is linked to parasites found in the skin. Using a murine model that supports extensive skin infection with Leishmania donovani, spatial analyses at macro-(quantitative PCR) and micro-(confocal microscopy) scales indicate that parasite distribution is markedly skewed. Mathematical models accounting for this heterogeneity demonstrate that while a patchy distribution reduces the expected number of sand flies acquiring parasites, it increases the infection load for sand flies feeding on a patch, increasing their potential for onward transmission. Models representing patchiness at both macro- and micro-scales provide the best fit with experimental sand fly feeding data, pointing to the importance of the skin parasite landscape as a predictor of host infectiousness. Our analysis highlights the skin as a critical site to consider when assessing treatment efficacy, transmission competence and the impact of visceral leishmaniasis elimination campaigns.Parasitemia has been considered the main determinant of visceral leishmaniasis transmission. By combining imaging, qPCR and experimental xenodiagnoses with mathematical models, Doehl et al. argue that the patchy landscape of parasites in the skin is necessary to explain infectiousness