Carbon and oxygen isotope study of hydrothermal carbonates in the zinc-lead deposits of the San Vicente district, central Peru: A quantitative modeling on mixing processes and CO2 degassing

Carbon and oxygen isotope studies of the host and gangue carbonates of Mississippi Valley-type zinc-lead deposits in the San Vicente District hosted in the Upper Triassic to Lower Jurassic dolostones of the Pucara basin (central Peru) were used to constrain models of the ore formation. A mixing model between an incoming hot saline slightly acidic radiogenic (Pb, Sr) fluid and the native formation water explains the overall isotopic variation (delta(13)C = - 11.5 to + 2.5 parts per thousand relative to PDB and delta(18)O = + 18.0 to + 24.3 parts per thousand relative to SMOW) of the carbonate generations. The dolomites formed during the main ore stage show a narrower range (delta(13)C = - 0.1 to + 1.7 parts per thousand and delta(18)O = + 18.7 to + 23.4 parts per thousand) which is explained by exchange between the mineralizing fluids and the host carbonates combined with changes in temperature and pressure. This model of fluid-rock interaction explains the pervasive alteration of the host dolomite I and precipitation of sphalerite I. The open-space filling hydrothermal white sparry dolomite and the coexisting sphalerite II formed by prolonged fluid-host dolomite interaction and limited CO2 degassing. Late void-filling dolomite III (or calcite) and the associated sphalerite III formed as the consequence of CO2 degassing and concomitant pH increase of a slightly acidic ore fluid. Widespread brecciation is associated to CO2 outgassing. Consequently, pressure variability plays a major role in the ore precipitation during the late hydrothermal events in San Vicente. The presence of native sulfur associated with extremely carbon-light calcites replacing evaporitic sulfates (e.g., delta(13)C = - 11.5 parts per thousand), altered native organic matter and heavier hydrothermal bitumen (from - 27.0 to - 23.0 parts per thousand delta(13)C) points to thermochemical reduction of sulfate and/or thiosulfate. The delta(13)C- and delta(18)O-values of the altered host dolostone and hydrothermal carbonates, and the carbon isotope composition of the associated organic matter show a strong regional homogeneity. These results coupled with the strong mineralogical and petrographic similarities of the different MVT occurrences perhaps reflects the fact that the mineralizing processes were similar in the whole San Vicente belt, suggesting the existence of a common regional mineralizing hydrothermal system with interconnected plumbing.

Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.

Audit report on the Wayne-Ringgold-Decatur County Solid Waste Management Commission for the year ended June 30, 2008

Audit report on the Wayne-Ringgold-Decatur County Solid Waste Management Commission for the year ended June 30, 2008

Identification of optimal structural connectivity using functional connectivity and neural modeling.

The complex network dynamics that arise from the interaction of the brain's structural and functional architectures give rise to mental function. Theoretical models demonstrate that the structure-function relation is maximal when the global network dynamics operate at a critical point of state transition. In the present work, we used a dynamic mean-field neural model to fit empirical structural connectivity (SC) and functional connectivity (FC) data acquired in humans and macaques and developed a new iterative-fitting algorithm to optimize the SC matrix based on the FC matrix. A dramatic improvement of the fitting of the matrices was obtained with the addition of a small number of anatomical links, particularly cross-hemispheric connections, and reweighting of existing connections. We suggest that the notion of a critical working point, where the structure-function interplay is maximal, may provide a new way to link behavior and cognition, and a new perspective to understand recovery of function in clinical conditions.

Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process. [Authors]

Characterization of CD4+ CD25+ T cells in solid organ transplant recipients

Although important progresses have been achieved in the therapeutic management of transplant recipients, acute and chronic rejections remain the leading causes of premature graft loss after solid organ transplantation. This, together with the undesirable side effects of immunosuppressive drugs, has significant implications for the long-term outcome of transplant recipients. Thus, a better understanding of the immunological events occurring after transplantation is essential. The immune system plays an ambivalent role in the outcome of a graft. On one hand, some T lymphocytes with effector functions (called alloreactive) can mediate a cascade of events eventually resulting in the rejection, either acute or chronic, of the grafted organ ; on the other hand, a small subset of T lymphocytes, called regulatory T cells, has been shown to be implicated in the control of these harmful rejection responses, among other things. Thus, we focused our interest on the study of the balance between circulating effectors (alloreactive) and regulatory T lymphocytes, which seems to play an important role in the outcome of allografts, in the context of kidney transplantation. The results were correlated with various variables such as the clinical status of the patients, the immunosuppressive drugs used as induction or maintenance agents, and past or current episodes of rejection. We observed that the percentage of the alloreactive T lymphocyte population was correlated with the clinical status of the kidney transplant recipients. Indeed, the highest percentage was found in patients suffering from chronic humoral rejection, whilst patients on no or only minimal immunosuppressive treatment or on sirolimus-based immunosuppression displayed a percentage comparable to healthy non-transplanted individuals. During the first year after renal transplantation, the balance between effectors and regulatory T lymphocytes was tipped towards the detrimental effector immune response, with the two induction agents studied (thymoglobulin and basiliximab). Overall, these results indicate that monitoring these immunological parameters may be very useful for the clinical follow-up of transplant recipients ; these tests may contribute to identify patients who are more likely to develop rejection or, on the contrary, who tolerate well their graft, in order to adapt the immunosuppressive treatment on an individual basis.

Use of NIR spectroscopy and multivariate process spectra calibration methodology for pharmaceutical solid samples analysis

Accomplish high quality of final products in pharmaceutical industry is a challenge that requires the control and supervision of all the manufacturing steps. This request created the necessity of developing fast and accurate analytical methods. Near infrared spectroscopy together with chemometrics, fulfill this growing demand. The high speed providing relevant information and the versatility of its application to different types of samples lead these combined techniques as one of the most appropriated. This study is focused on the development of a calibration model able to determine amounts of API from industrial granulates using NIR, chemometrics and process spectra methodology.

Simple and fast methods based on solid-phase extraction coupled to liquid chromatography with UV detection for the monitoring of caffeine in natural and waste waters as marker of anthropogenic impact

Two concentration methods for fast and routine determination of caffeine (using HPLC-UV detection) in surface, and wastewater are evaluated. Both methods are based on solid-phase extraction (SPE) concentration with octadecyl silica sorbents. A common “offline” SPE procedure shows that quantitative recovery of caffeine is obtained with 2 mL of an elution mixture solvent methanol-water containing at least 60% methanol. The method detection limit is 0.1 μg L−1 when percolating 1 L samples through the cartridge. The development of an “online” SPE method based on a mini-SPE column, containing 100 mg of the same sorbent, directly connected to the HPLC system allows the method detection limit to be decreased to 10 ng L−1 with a sample volume of 100 mL. The “offline” SPE method is applied to the analysis of caffeine in wastewater samples, whereas the “on-line” method is used for analysis in natural waters from streams receiving significant water intakes from local wastewater treatment plants

Modeling the impact of lesions in the human brain.

Lesions of anatomical brain networks result in functional disturbances of brain systems and behavior which depend sensitively, often unpredictably, on the lesion site. The availability of whole-brain maps of structural connections within the human cerebrum and our increased understanding of the physiology and large-scale dynamics of cortical networks allow us to investigate the functional consequences of focal brain lesions in a computational model. We simulate the dynamic effects of lesions placed in different regions of the cerebral cortex by recording changes in the pattern of endogenous ("resting-state") neural activity. We find that lesions produce specific patterns of altered functional connectivity among distant regions of cortex, often affecting both cortical hemispheres. The magnitude of these dynamic effects depends on the lesion location and is partly predicted by structural network properties of the lesion site. In the model, lesions along the cortical midline and in the vicinity of the temporo-parietal junction result in large and widely distributed changes in functional connectivity, while lesions of primary sensory or motor regions remain more localized. The model suggests that dynamic lesion effects can be predicted on the basis of specific network measures of structural brain networks and that these effects may be related to known behavioral and cognitive consequences of brain lesions.

Can smaller-scale comprehensive cancer centers provide outstanding care in abdominal and thoracic pediatric solid tumor surgery? Results of a 14-year retrospective single-center analysis.

PURPOSE: Quality of care and its measurement represent a considerable challenge for pediatric smaller-scale comprehensive cancer centers (pSSCC) providing surgical oncology services. It remains unclear whether center size and/or yearly case-flow numbers influence the quality of care, and therefore impact outcomes for this population of patients. PATIENTS AND METHODS: We performed a 14-year, retrospective, single-center analysis, assessing adherence to treatment protocols and surgical adverse events as quality indicators in abdominal and thoracic pediatric solid tumor surgery. RESULTS: Forty-eight patients, enrolled in a research-associated treatment protocol, underwent 51 cancer-oriented surgical procedures. All the protocols contain precise technical criteria, indications, and instructions for tumor surgery. Overall, compliance with such items was very high, with 997/1,035 items (95 %) meeting protocol requirements. There was no surgical mortality. Twenty-one patients (43 %) had one or more complications, for a total of 34 complications (66 % of procedures). Overall, 85 % of complications were grade 1 or 2 according to Clavien-Dindo classification requiring observation or minor medical treatment. Case-sample and outcome/effectiveness data were comparable to published series. Overall, our data suggest that even with the modest caseload of a pSSCC within a Swiss tertiary academic hospital, compliance with international standards can be very high, and the incidence of adverse events can be kept minimal. CONCLUSION: Open and objective data sharing, and discussion between pSSCCs, will ultimately benefit our patient populations. Our study is an initial step towards the enhancement of critical self-review and quality-of-care measurements in this setting.

Determinants of brain cell metabolic phenotypes and energy substrate utilization unraveled with a modeling approach.

Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands.