Assessing the drivers shaping global patterns of urban vegetation landscape structure.

Vegetation is one of the main resources involve in ecosystem functioning and providing ecosystem services in urban areas. Little is known on the landscape structure patterns of vegetation existing in urban areas at the global scale and the drivers of these patterns. We studied the landscape structure of one hundred cities around the globe, and their relation to demography (population), socioeconomic factors (GDP, Gini Index), climate factors (temperature and rain) and topographic characteristics (altitude, variation in altitude). The data revealed that the best descriptors of landscape structure were amount, fragmentation and spatial distribution of vegetation. Populated cities tend to have less, more fragmented, less connected vegetation with a centre of the city with low vegetation cover. Results also provided insights on the influence of socioeconomics at a global scale, as landscape structure was more fragmented in areas that are economically unequal and coming from emergent economies. This study shows the effects of the social system and climate on urban landscape patterns that gives useful insights for the distribution in the provision of ecosystem services in urban areas and therefore the maintenance of human well-being. This information can support local and global policy and planning which is committing our cities to provide accessible and inclusive green space for all urban inhabitants.

On moving targets and magic bullets: Can the UK lead the way with responsible data linkage for health research?

PURPOSE: To provide an overview of essential elements of good governance of data linkage for health-related research, to consider lessons learned so far and to examine key factors currently impeding the delivery of good governance in this area. Given the considerable hurdles which must be overcome and the changing landscape of health research and data linkage, a principled, proportionate, risk-based approach to governance is advocated. DISCUSSION: In light of the considerable value of data linkage to health and well-being, the United Kingdom aspires to design and deliver good governance in health-related research. A string of projects have been asking: what does good governance look like in data linkage for health research? It is argued here that considerable progress can and must be made in order to develop the UK's contribution to future health and wealth economies, particularly in light of mis-start initiatives such as care.data in NHS England. Discussion centres around lessons learned from previous successful health research initiatives, identifying those governance mechanisms which are essential to achieving good governance. CONCLUSION: This article suggests that a crucial element in any step-increase of research capability will be the adoption of adaptive governance models. These must recognise a range of approaches to delivering safe and effective data linkage, while remaining responsive to public and research user expectations and needs as these shift and change with time and experience. The targets are multiple and constantly moving. There is not--nor should we seek--a single magic bullet in delivering good governance in health research.

Paclitaxel and carboplatin adjuvant therapy alone or with radiotherapy for resected nonsmall cell lung carcinoma: a feasibility study of the Minnie Pearl Cancer Research Network.

BACKGROUND: The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer). METHODS: One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m(2) intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy. RESULTS: Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3-4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free. CONCLUSIONS: Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted.

Comparison of a T cell clone and of T cells from a TCR transgenic mouse: TCR transgenic T cells specific for self-antigen are atypical.

It has been widely assumed that T cells from TCR-transgenic (Tg) mice better represent the behavior of T cells from normal mice than do in vitro cultures of T cell clones. We have found that autoreactive T cells arising in the presumably more physiological environment of the BDC-2.5 TCR-Tg mouse, despite being apparently "naive" in surface phenotype, are highly activated functionally and do not resemble CD4(+) T cells from a spontaneously diabetic nonobese diabetic (NOD) mouse or the NOD-derived, diabetogenic CD4(+) T cell clone of origin, BDC-2.5. Our results suggest that autoreactive T cells cloned from the spontaneously diabetic NOD mouse more closely resemble effector T cells arising during the natural disease process.

Subsets of macrophages and dendritic cells in nonobese diabetic mouse pancreatic inflammatory infiltrates: correlation with the development of diabetes.

Islet-specific T cells are essential in the development of type I diabetes. The role of non-lymphoid cells is relatively unclear, although infiltration of dendritic cells and macrophages is the first sign of islet autoimmunity in diabetes-prone nonobese diabetic (NOD) mice. BDC2.5 is one of the autoreactive T cell clones isolated from NOD mice. Transfer of BDC2.5 T cells into young NOD mice accelerates diabetes development, whereas transgenic expression of the BDC2.5 T cell receptor on NOD T cells (BDC2.5 TCR-Tg NOD) markedly reduces diabetes development. We show that, although the same antigen-specificity is involved, both models differ significantly in insulitis. BDC2.5 TCR-Tg NOD mice develop an extensive, but non-aggressive, peri-insulitis by 3 weeks of age. In these large peri-islet infiltrates, resembling secondary lymphoid tissue, BM8+ macrophages (Mphi) are virtually absent. In contrast, BDC2.5 T cell clone transfer results in an aggressive insulitis with small infiltrates, but relatively large numbers of BM8 Mphi. Infiltration of BM8+ Mphi therefore correlates with islet destruction. This is, however, not observed for all Mphi; Monts-4+ Mphi follow a reverse pattern and are present in higher numbers in BDC2.5 TCR-Tg than in transferred mice. ER-MP23+ Mphi are reduced in both transferred and transgenic mice compared with wild-type NOD. Thus, this study underlines and extends previous data suggesting that Mphi are implicated in both early and late phases in diabetes development. Furthermore, our data imply that subsets of non-lymphoid cells have different roles in diabetes development. It is, therefore, important to recognize this heterogeneity when interpreting both in vivo and in vitro studies concerning non-lymphoid cells in diabetes.

Stress-induced neuroendocrine modulation of viral pathogenesis and immunity.

Physical restraint (RST) was used to examine the interactions among the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the immune response to infection. In these studies, mice were infected with either herpes simplex virus (HSV) or influenza A/PR8 virus so that the impact of neuroendocrine activation could be assessed on disease pathophysiology and anti-viral immunity. RST suppressed lymphadenopathy in draining lymph nodes, reduced mononuclear cellular infiltration in the lungs, and suppressed virus-specific cytokine and cytolytic T-cell responses. Blockade of type II glucocorticoid receptors (by RU486) restored cellularity and cytokine responses to both organs in restraint-stressed, infected mice. Thus, the HPA axis modulated cell trafficking and T-cell cytokine responses. However, RU486 treatment failed to restore cytolytic T-cell responses. Blockade of beta-adrenergic receptors (by nadolol), in combination with RU486 treatment, fully restored cytolytic T-cell responses, suggesting that catecholamines were involved in suppressing the virus-specific CD8+ cytolytic T-cell response. RST also modulated the local development or expression of antibody-secreting cells (ASC) in the lungs draining lymph nodes, and spleen following infection of restrained mice. RST significantly suppressed the number of virus-specific ASC (IgM, IgG and subclasses IgG1 and IgG2a) in the lungs, mediastinal (MLN) lymph nodes and spleen, while it enhanced the responses in the superficial cervical (SCV) lymph nodes. This observation of differential modulation of ASC responses in the MLN and SCV lymph nodes supports the concept of tissue-specific immunoregulation in response to stress.

Black box radiation gauges and analyzers: dream or reality?

This paper describes our attempts to make radiation gauges and analyzers operate in more of a 'black box' manner-being more independent of or at least more insensitive to changes in such things as sample composition and position. Our overall approach relies heavily on Monte Carlo simulation and that is discussed first in relation to radiation gauge and analyzer design and usage. Then the principles and applications of radiation gauges and analyzers including the Measurement Chi-Square and Monte Carlo Library Least-Squares, respectively, are treated. Finally, future work in this area is discussed.

Neuroendocrine regulation of cytokine production during experimental influenza viral infection: effects of restraint stress-induced elevation in endogenous corticosterone.

A murine model of influenza viral infection was used to examine the neuroendocrine regulation of cytokine production. Restraint stress (RST) was used to activate the hypothalamic-pituitary-adrenal axis and elevate corticosterone (CORT) levels in influenza A/Puerto Rico/8/34 (PR8) virus-infected C57BL/6 mice. The type II glucocorticoid receptor antagonist RU486 was used to specifically examine the modulation of PR8 virus-specific cytokine responses by CORT. RST suppressed the PR8 virus- specific production of Th1-type (IL-2 and IFN-gamma) and Th2-type IL-10) cytokines by cells from the regional lymph nodes and spleens. In addition, IL-6 production by splenocytes was inhibited by RST; however, IL-6 production by cells from the regional lymph nodes was enhanced. Treatment of mice with RU486 prevented the effects of RST, suggesting that the RST-induced alterations in cytokine responses were mediated by CORT. Furthermore, CORT was shown to inhibit the PR8 virus-specific production of both Thl-type and Th2-type cytokines in vitro at doses corresponding to the physiologic range of free plasma CORT following hypothalamic-pituitary-adrenal axis activation.

Synthesis and characterization of indolicidin, a tryptophan-rich antimicrobial peptide from bovine neutrophils.

Indolicidin, a novel tryptophan-rich microbicidal tridecapeptide amide isolated originally from granules of bovine neutrophils, has been prepared by optimized manual and automated protocols of stepwise solid-phase synthesis with N alpha-9-fluorenylmethyloxycarbonyl (Fmoc) amino acid derivatives. Both standard polystyrene (PS) and polyethylene glycol-polystyrene (PEG-PS) graft supports were used in combination with handles that provide C-terminal peptide amides: 5-(4-Fmoc-aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) or 5-(9-Fmoc-aminoxanthen-2-oxy)valeric acid (XAL). Final deprotection/cleavage was carried out with reagent K, trifluoroacetic acid-phenol-water-thioanisole-1,2-ethanedithiol (82.5:5:5:5:2.5), or reagent B, trifluoroacetic acid-phenol-water-tri(isopropyl)silane (88:5:5:2), and related cocktails. Initial purities as high as 93% were obtained immediately following cleavage. In the largest-scale synthesis carried out, 0.8 g of HPLC-purified indolicidin (> 99% pure) was obtained, representing a 39% overall yield based on C-terminal Arg(Pmc) anchored to PAL-PS-resin. The main synthetic product, and some by-products, were characterized by analytical high-performance liquid chromatography (HPLC), sequencing, and fast atom bombardment mass spectrometry (FABMS). The antimicrobial potencies of natural and synthetic indolicidin, as determined by in vitro antibacterial and antifungal assays, were identical. Further, the reactivities of natural and synthetic peptides with anti-indolicidin antibody were indistinguishable.

Psychoneuroimmunology: stress effects on pathogenesis and immunity during infection.

The mammalian response to stress involves the release of soluble products from the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Cells of the immune system respond to many of the hormones, neurotransmitters, and neuropeptides through specific receptors. The function of the immune system is critical in the mammalian response to infectious disease. A growing body of evidence identifies stress as a cofactor in infectious disease susceptibility and outcomes. It has been suggested that effects of stress on the immune system may mediate the relationship between stress and infectious disease. This article reviews recent psychoneuroimmunology literature exploring the effects of stress on the pathogenesis of, and immune response to, infectious disease in mammals.

Mechanisms of stress-induced modulation of viral pathogenesis and immunity.

A murine model of herpes simplex virus (HSV) infection was used to examine the roles of catecholamines and corticosterone in the restraint stress-induced suppression of viral immunity. Treatment of C57BL/6 mice with RU486, a glucocorticoid receptor antagonist, reversed the stress-induced diminution of cellularity in response to local HSV infection. Treatment of mice with both nadolol, a peripherally acting beta-adrenergic antagonist, and RU486 completely reversed the restraint stress-induced suppression of HSV-specific CTL activation. These findings demonstrate that both corticosterone and catecholamine-mediated mechanisms are operative in the stress-induced suppression of anti-viral cellular immunity.

Ophthalmological and other toxicities related to cytosine arabinoside and total body irradiation as preparative regimen for bone marrow transplantation.

Cytosine arabinoside, 3 g/m2, every 12 h for 6 days, followed by fractionated total body irradiation, 200 cGy twice daily for 3 days, was administered to 39 adult patients undergoing bone marrow transplantation. Allogeneic transplant patients received cyclosporin and methotrexate for prophylaxis of graft-versus-host disease. There were 21 autologous transplants (16 with acute leukemia, four with an advanced stage of chronic myelocytic leukemia, and one with lymphoma) and 18 allogeneic transplants (14 with acute leukemia, two with an advanced stage of chronic myelocytic leukemia and two with myelodysplastic syndrome). Toxicities were compared between the two groups. There was a significantly greater degree and duration of mucositis and a greater frequency of radiation-type retinopathy developing in the allogeneic group, predominantly in those having had radiation for prophylaxis or treatment of central nervous system leukemia. Seven of 11 acute leukemic patients who received autologous transplants in remission survive. Two of seven acute leukemias who received allogeneic transplants while in remission survive. Although the increased morbidity, retinitis and mucositis, observed in the allogeneic group indicates that this regimen when combined with methotrexate and cyclosporin is too toxic, the results in autologous transplantation in acute leukemia in remission are encouraging.

Acute effects of alcohol on photic evoked potentials of rats: lateral geniculate nucleus and reticular formation.

This study examined the effects of ethanol on photic evoked potentials recorded from the dorsal lateral geniculate nucleus (LGN) and midbrain reticular formation (MRF) of chronically implanted albino rats. Animals were given intraperitoneal injections of saline, or of 0.5, 1.0, 1.5 or 2.5 g ethanol/kg body weight on separate days. Evoked potentials were recorded at 5, 20, 40 and 60 min following injection. An early positive component recorded from each structure was depressed in amplitude by only the 2.5 g/kg alcohol dose, while the succeeding negative component was depressed by both the 1.5 and 2.5 g/kg doses. Latencies of both early components in each structure were increased by the 1.5 and 2.5 g/kg alcohol doses. Alcohol doses of 1.0-2.5 g/kg depressed the amplitude of a later positive component in the LGN (latency of 78 msec), but latency was not altered. In contrast, a late positive component in the MRF (latency of 150 msec) was both decreased in amplitude and increased in latency by only the 2.5 g/kg dose. These results on subcortical structures are discussed in relation to alcohol's effects on cortical evoked potentials.

Therapeutic leukapheresis in hairy cell leukemia.

Therapeutic leukapheresis was performed on three patients, and plasmapheresis on two patients with far-advanced hairy cell leukemia. Two of the three patients who were treated with leukapheresis had many hairy cells in their peripheral blood, while the other had relatively few. In each patient, dramatic clinical and hematologic improvements were observed that have sustained for more than 23, 10, and 26 months, respectively. Plasmapheresis of similar intensity failed to show any appreciable therapeutic effects on two other patients with similar clinical and hematologic findings. We believe that the favorable therapeutic effects of leukapheresis are due to the removal of factors capable of inhibiting normal hematopoiesis. This factor(s) is present in the cells that were removed by leukapheresis. The exact nature of this factor(s) or the cells that produce this factor(s) remains to be identified.

Levamisole inhibition of microsomal lipid peroxidation as related to its sulfhydryl metabolite dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimadazolidine.

Levamisole was previously shown to protect rat liver microsomes from lipid peroxidation induced by ADP-Fe and either NADPH, ascorbate, or X irradiation. The present experiments provide information about the mechanism of protection. Incubation of levamisole with a microsomal system containing ADP-Fe and NADPH resulted in protection of sulfhydryl groups, whereas reaction of levamisole with ascorbate (nonenzymatic system) indicated generation of a sulfhydryl metabolite. Production of a sulfhydryl metabolite of levamisole, dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimidazolidine (OMPI), in either the enzymatic or nonenzymatic system was demonstrated by gas chromatography-mass spectrometry. While levamisole acts as an antioxidant at concentrations of 1.0 and 2.0 mM, OMPI had an enigmatic effect on microsomal lipid peroxidation induced enzymatically or nonenzymatically. OMPI exhibited a biphasic effect: at concentrations below 25 microM a prooxidant effect was observed, and at concentrations exceeding 50 microM an antioxidant effect was observed. The data suggest that the inhibition of microsomal lipid peroxidation by levamisole is due to the generation of a sulfhydryl metabolite and that the active intermediate is probably OMPI.

Assessment of renal function following irradiation of the intact spleen for Hodgkin disease.

Twenty-three patients with clinical Stage IA-IIIB Hodgkin disease underwent extended-field radiotherapy, including the intact spleen. In 17 of those patients, there was little evidence of renal dysfunction resulting from partial irradiation of the left kidney, which is inherent in such treatment. While isotopic images revealed an anatomic defect in the upper pole of the left kidney in one-third of the patients, dynamic studies showed that this anatomic alteration was not accompanied by any demonstrable dysfunction. Consistently normal serum BUN and creatinine levels in all patients tended to affirm that conclusion.

Circadian variations in concentrations of plasma thyroxine and triiodothyronine in man.

The plasma concentrations of thyroxine (T4), triiodothyronine (T3), and total protein (Pr) were measured at 2-h intervals in 8 male subjects during two 24-h periods. Plasma T4 and T3 levels varied significantly during the day. T4 values were highest at 0900 hours and thereafter declined rapidly reaching lowest levels at 1500-1700 hours (mean decrement, 13.2% of 0.00-hour value). Plasma T3 was highest at 0900 hours and lowest at 1700-1900 hours (mean decrement, 16.7% of 0900-hour value). Fluctuations observed in Pr were not significant. Variations in plasma T4 and T3 appeared concordant with respect to time, since no significant variation was detected in T3:T4 plasma concentration ratios. In view of previous studies that have demonstrated circadian variations in the binding of thyroid hormones by plasma proteins, it is suggested that the observed temporal variations in plasma concentrations of T3 and T4 reflect parallel changes in the capacity or affinity of specific plasma binding proteins of these iodothyronines.