Zygomycoses caused by fungi of the mucorales order (mucormycoses) are emerging                    fungal diseases with a high fatality rate. The most important risk factors                    include neutropenia or functional neutropenia, diabetic ketoacidosis, iron                    overload, major trauma, prolonged use of corticosteroids, illicit intravenous                    drug (ID) use, neonatal prematurity, malnourishment, and maybe a previous                    exposure to antifungal agents with no activity against zygomycetes, such as                    voriconazole and echinocandins.A high index of suspicion is crucial for the diagnosis, as prompt and appropriate                    management can considerably reduce morbidity and mortality. Suspicion index can                    be increased through recognition of the differential patterns of clinical                    presentation. In the non- haematological immunocompromised patients,                    mucormycosis can manifest in various clinical forms, depending on the underlying                    condition: mostly as rhino-orbital or rhino-cerebral in diabetes patients,                    pulmonary infection in patients with malignancy or solid organ transplantation,                    disseminated infection in iron overloaded or deferoxamine treated patients,                    cerebral - with no sinus involvement - in ID users, gastrointestinal in                    premature infants or malnourishment, and cutaneous after direct inoculation in                    immunocompetent individuals with trauma or burns.Treating a patient’s underlying medical condition and reducing                    immunosuppression are essential to therapy. Rapid correction of metabolic                    abnormalities is mandatory in cases such as uncontrolled diabetes, and                    corticosteroids or other immunosuppressive drugs should be discontinued where                    feasible. AmphotericinB or its newer and less toxic lipid formulations are the                    drugs of choice regarding antifungal chemotherapy, while extensive surgical                    debridement is essential to reduce infected and necrotic tissue. A high number                    of cases could be prevented through measures including diabetes control                    programmes and proper pre- and post-surgical hygiene. The term ‘Zygomycosis’ refers to a group of rare infections caused by                hyaline filamentous fungi belonging to the class of Zygomycetes. This class is                subdivided in two orders, Mucorales and Entomophthorales, both involved in human                    disease.1Rhizopus, Mucor, Lichtheimia                (formerly known as Absidia corymbifera or                    Mycocladus), Rhizomucor,                    Apophysomyces, Saksenaea, and                    Cunninghamella.1Mucorales are saprobiotic organisms ubiquitous in nature; some members of this order                are weak plant parasites or plant pathogens and opportunistic pathogens for                    man.For Mucorales the portals of entry in the human body are the respiratory tract                through inhalation of fungal spores, the skin and less frequently the gut. They grow                rapidly and produce wide hyaline, aseptate or poorly septated ribbon-like hyphae in                tissues. They invade blood vessels and cause thrombosis and necrosis of the infected                tissues. Disease in humans is limited to severely immunocompromised individuals,                those with diabetic ketoacidosis, or those with burns or trauma. Infection usually                progresses rapidly and the case fatality rate is very high. Depending on the                underlying condition and the portal of entry they can cause rhinocerebral,                pulmonary, cutaneous, gastrointestinal or even disseminated infection.1Conidiobolus and                    Basidiobolus. They affect mainly immunocompetent individuals,                are prevalent in the tropics and do not disseminate.Human infections caused by Entomophthorales, which are mainly insect pathogens,                constitute a completely different clinical entity (entomopfthoramycoses). Genera                involved in human disease are The most important risk factors for mucormycosis include prolonged neutropenia,                diabetic ketoacidosis, iron overload and major trauma. Other important predisposing                factors of mucormycosis include prolonged use of corticosteroids, illicit                intravenous drug use, neonatal prematurity, malnourishment and broad-spectrum                antimicrobial agents, as well as antifungal agents with no activity against                zygomycetes, such as voriconazole and caspofungin.The recent years, mucormycosis incidence is seemingly increasing, particularly in                patients with haematological malignancies or haematopoietic stem cell                transplantation, at least in western countries.Diabetes mellitus as a predisposing factor has been reported in                        36–88% of all mucormycosis cases.26neutrophils are chemotactically attracted to the hyphae,they attach andspread on the hyphae and finally,using their oxidative cytotoxic system, neutrophils damage and                                    kill the fungal elements without accompanying phagocytosis.In the normal host protection from mucormycosis is provided by macrophages.                        They prevent the initiation of infection by phagocytosis and oxidative                        killing of the fungal spores. In case infection is established, neutrophils                        are activated and play a pivotal role in fungal killing. Activation happens                        in four phases: In diabetes, each of the four phases of neutrophil activation is                            impaired.29The most common clinical presentation of mucormycosis in patients with                        diabetes mellitus is sinus disease 66%).6%.6 Diab30Disease in diabetics can also present as pulmonary mucormycosis, a clinical                        presentation more common in neutropenic patients with malignancies or                            HSCT.6The epidemiology in diabetic patients is variable. Roden et al.The overall mortality of diabetic patients with mucormycosis who undergo                        treatment is approximately 44%, and this is lower compared to other                        immunocompromising conditions.37Besides diabetic ketoacidosis, chronic metabolic acidosis due to other                        causes, such as chronic renal failure with uremia,Many microorganisms require iron to grow, and conditions of iron excess have                        been known to predispose to infection with certain bacteria.43et                            al,48Therapy with DFO, an iron chelator used for the treatment of iron and/or                        aluminum overload in dialysis patients, was found paradoxically to be a risk                        factor for angioinvasive mucormycosis.Rhizopus spp. In a                        study reviewing a series of five cases of invasive mucormycosis among 263                        allogeneic bone marrow transplant recipients,Besides DFO, iron overload per se, either transfusional or due to                        dyserythropoiesis has also been recognized as a risk factor for                            mucormycosis.Patients with diabetic ketoacidosis have elevated levels of available serum                        iron, likely due to the release of iron from binding proteins in the                        presence of low pH. Iron is then internalized by the zygomycetes with the                        help of copper oxidase (Cu-oxidase) and the high affinity iron permease                        rFTR1. Therefore, the increased susceptibility of patients with diabetic                        ketoacidosis to mucormycosis is likely due, at least in part, to an                        elevation in available serum iron during diabetic ketoacidosis following                        proton-mediated dissociation of iron from transferrin.43The most common presentation of mucormycosis in patients receiving DFO                        appears to be the disseminated form (44%) and is associated with                        high mortality, reaching 80%.47In contrast to DFO, two other iron chelators, deferiprone and deferasirox, do                        not supply iron to the fungus. This could be either because of their                        different structures and smaller size, rendering them inaccessible to fungal                        iron uptake systems, or because they share higher affinity constants for                            iron.43The incidence of mucormycosis in transplant recipients, including both                        hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT)                        patients has increased. Although global surveys of the incidence of                        mucormycosis are still lacking, data from individual countries and                        institutions show that mucormycosis in SOT is rare, but seems to be a                        concern because of the high mortality rate.The estimated incidence ranges from 0.4–16%.Mycocladus (Lichtheimia)                            corymbifer as causative pathogen appeared to be                        associated with a higher risk for dissemination in SOT with pulmonary                        mucormycosis in one study.55The lung seems to be the most common site of infection in SOT recipients with                            mucormycosis.In a matched case-controlled studyMucormycosis in HIV/AIDS patients is very rare. Antinori et al.57Recently, human immunodeficiency virus (HIV) infection has been recognized as                        a risk factor for mucormycosis, but most cases in HIV-infected patients are                        also associated with intravenous drug abuse.Endocarditis as well as the rhinocerebral form can also occur. Merchant et                            al.Mucormycosis in the HIV+ can also present in the kidneys, the skin,                        the gastrointestinal tract, the respiratory tract, or may be                            disseminated.1Corticosteroid therapy is another primary risk factor that enhances a                        patient’s susceptibility to mucormycosis by causing either defects                        in macrophages and neutrophils or steroid-induced diabetes.1Corticosteroids have a wide range of complex immunosuppressive effects,                        mainly by affecting cellular immunity, and increase host susceptibility to                        invasive fungal infections.34Of the few cases of mucormycosis in patients with lupus erythematosus (SLE)                        reported in English language literature78Mucormycosis in other autoimmune diseases are scarce, but in cases such as in                        Wegener’s granulomatosis it may mimic disease relapse and remain                            underdiagnosed.94A considerable proportion of patients with mucormycosis have no apparent                        immune deficiency.Infection usually occurs through direct inoculation. It can be very invasive                        locally, penetrating the cutaneous and subcutaneous tissues into the                        adjacent fat, muscle, fascia and bone. In rare cases it can even disseminate                        to deep organs. Road traffic accidents, crush injuries, but also minor                        traumas such as those caused by plant thorns or insect bites, can lead to                        traumatic implantation of contaminated soil and subsequent mucormycosis.                        Major burn injury is another well described cause of cutaneous mucormycosis.                        An increased risk for developing mucormycosis in burn patients is the                        development of a condition called “burned stressed                        pseudodiabetes”, which is marked by hyperglycemia and                            glycosuria.97In a new PubMed search from 2008 – 2010, we found 27 additional cases                        of cutaneous mucormycosis occurring in non immunocompromised hosts.Pseudomonas, Aspergillus,                            Histoplasma etc. Biopsy specimens for histology and                        cultures are necessary to establish diagnosis.The clinical presentation is variable. The clinical signs initially are non                        specific, consisting of erythema and induration. Eventually the lesions may                        form blisters, pustules, or necrotic ulcerations. Cotton wool-like material                        may also be observed on the margins of the wound. The lesions may mimic                        pyoderma gangrenosum, bacterial synergistic gangrene or infections produced                        by Rhizopus spp. (the majority),                            Lichtheimia corymbifera , Apohysomyces elegans,                            Mucor spp., Cunninghamella                            bertholetiae and Saksenaea vasiformis. In the                        cases reported after 2008 the cultured species were R.                            arrhizus in 3 cases,Lichtheimia spp.in 5,A. elegans in 4,S. vasiformis in 3,Rhizomucor                            variabilis in 7.Rhizomucor, in contrast to other                        mucorales can cause large but slowly progressing opportunistic infections of                        the skin in immune-competent individuals. These fungi seem to have an                        increasing incidence in farmers from China.Strains involved are usually The prognosis of mucormycosis in the immunocompetent is better than that in                        other patient groups but mortality remains high depending on the site,                        extension of infection and time of initiation of antifungal therapy.                        Iatrogenic cutaneous mucormycosis could easily be prevented with proper                        preoperative preparation and postoperative dressing of the surgical                        sites.The clinical diagnosis of mucormycosis among non haematological immunocompromised                patients is notoriously difficult because of the similarity with aspergillosis or                other mycoses caused by filamentous fungi. Diagnosis is usually delayed, as the                majority of the physicians are not so much familiar with the disease. The leading                signs and symptoms of mucormycosis are presented in When clinical presentation may suggest mucormycosis, imaging techniques are helpful,                but cultures and histopathology are required for confirmation.In case of rhinocerebral involvement, CT and particularly MRI are helpful in enabling                an early detection of orbital, sinus, meningeal, bone, and cerebral lesions as well                as intracranial vascular occlusion even before clinical signs develop. In pulmonary                mucormycosis, lung biopsies  should be performed,                depending on the radiological findings obtained by CT scans. CT guided percutaneous                lung biopsy has been found highly efficient to early differentiate aspergillosis                from mucormycosis in haematological patients. Whatever the initial clinical site                involved, a sinus and chest CT are mandatory in addition to brain imaging. This is                of major importance for the indicated therapeutic approach.112The laboratory diagnosis of mucormycosis is challenging and requires expertise and                proper sampling. Proper clinical samples include scrapings and aspirates from                sinuses, nasal discharges, BAL, needle biopsies from pulmonary lesions, skin                scrapings from cutaneous lesions and biopsy tissues. Zygomycetes are almost never                isolated from blood and very rarely isolated from cultures of cerebrospinal fluid,                sputum, urine or faeces, or swabs of infected areas.113The significance of the isolates grown in cultures may be doubtful, especially when                grown from samples of non sterile sites, as they are commonly encountered as                contaminants. Histopathologic evidence of fungal invasion of tissue is required to                confirm clinical or radiological diagnosis and/or reliability of culture.Aspergillus spp. Histopathologic sections occasionally show                folded, twisted, and compressed hyphae, which may be mistaken for septated hyphae.                Sporangia, the reproductive hyphal structures that contain spores, are seen rarely                in tissue in patients infected with zygomycetes. These hyphae are poorly stained                with PAS and Gram stains but are very well seen by H&E, GMS, or                Periodic-acid Schiff stain. Hyphae may be observed within necrotic tissue and signs                of angioinvasion and infarction; neutrophilic infiltrates or granuloma formation may                be present in patients who are not granulocytopenic or with more chronic infection,                    respectively.114The direct microscopic examination of biopsy material in                10%–20% KOH and/or calcofluor-white wet mount shows                characteristic broad (6–15 μm in diameter), thin walled, mostly                aseptate, ribbon-like hyaline hyphae with almost right –angle branching at                irregular intervals. In tissue, Zygomycetes hyphae can be distinguished from the                regularly septated hyphae of more common opportunistic molds such as                    A. elegans. If all other media fail, sterile                bread without preservatives in a test tube may recover zygomycetes from clinical                samples, since these fungi are commonly associated with bread.Identification of zygomycetes at the genus and species levels requires culture                studies, because all members of this group are morphologically similar in tissue.                Poor recovery of Zygomycetes may reflect limited septation of the hyphae, making the                fungi more liable to damage resulting from tissue excessive grinding. Samples should                be kept at room temperature until culture plating, as these fungi may not survive                refrigerator temperatures, and excessive grinding should be avoided. The zygomycetes                can be easily grown on conventional media like SDA with antibiotics, at temperatures                25° C to 37°C, without cycloheximide as this substance is inhibitory                to most of them except There are no reliable serologic or skin tests for mucormycosis and the recently                introduced antigen tests for Aspergillus  and other fungal species                (b-D-glucan) do not detect Zygomycetes because of the limited amount of                galactomannan and glucan in their cell walls.116When cultures are negative, molecular identification of zygomycetes from fresh frozen                or paraffin embedded tissue can help to confirm diagnosis and identify the fungus to                the genus and species level. Different techniques have been reported: DNA probes                targeting the ribosomal 18S subunit, ITS1 sequencing after PCR with pan-fungal                primers, 18S-targeted semi-nested PCR and real-time PCR targeting cytochrome b                    gene.Sequencing of PCR products leads to a presumptive identification of the Zygomycetes,                which provides some guidance in selecting antifungal therapy that would not have                been available using histopathology alone. Molecular typing is most useful for                characterizing zygomycete epidemiology in the setting of a cluster of nosocomial                cases, outbreaks, or pseudo-outbreaks, in order to rule out clonal spread or a                common infecting source.The prognosis of patients with zygomycosis due to Mucorales without treatment is very                poor approaching 100%, depending on the underlying condition and form of                    mucormycosis.124The therapeutic approach to mucormycosis is multimodal, with an equally important                three-point strategy that includes (a) antifungal therapy, (b) surgical debridement                and (c) correction of the underlying condition predisposing the patient to the                disease. Moreover, management of co-morbid factors and adjunctive treatments may                improve host response.Because of the relative rarity of mucormycosis, prospective, comparative studies of                antifungal agents and strategies have not been conducted. Therefore, the management                of mucormycosis is so far based on the results of case series and case reports,                animal model studies and in vitro susceptibility data.The most frequently used antifungal agents to treat mucormycosis are listed in Amphotericin B has the most significant in-vitro activity against Zygomycetes and has                been successfully used to treat mucormycosis for many years. Amphotericin B                deoxycholate (d-AmB) is the only antifungal agent that has been approved by the US                Food and Drug Administration for primary treatment of mucormycosis. However, this                formulation has significant toxicity. The newer lipid formulations of amphotericin B                that include liposomal AmB (L-AmB), AmB lipid complex (ABLC), and AmB colloidal                dispersion (ABCD) are less nephrotoxic and have almost completely replaced                amphotericin B deoxycholate in the recent years. It seems reasonable to recommend                either L-AmB or ABLC as first-line treatment for mucormycosis.129Of the azoles only posaconazole has in vitro activity against Zygomycetes and has                been shown to be active as salvage therapy.Rhizomucor and                    LichtheimiaZygomycetes are resistant to caspofungin and 5-flucytosine in vitro.There is some evidence that combination of amphotericin B with caspofungin may be                active, but these results are preliminary.139Certain Mucorales species have however variable susceptibilities to amphotericin,                with MICs ranging from <1 to 100 μg/ml and treatment may be                unsuccessful. Moreover, the drug may not reach the target because of tissue                infarction and thrombosis.141Another option for the treatment of mucormycosis is the adjunctive use of                iron-chelators deferasirox and deferiprone. A clinical trial is currently underway,                testing the combination of deferasirox with liposomal amphotericin B.Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage                colony-stimulating factor (GM-CSF), G-CSF and GM-CSF are routinely given to                neutropenic patients with mucormycosis or another invasive fungal disease. These two                cytokines have also be used in a limited number of cases of mucormycosis in                non-neutropenic patients as adjunctive treatment with favorable outcomes.143Treating a patient’s underlying medical condition and reducing                immunosuppression are essential to therapy. Rapid correction of metabolic                abnormalities is mandatory in uncontrolled diabetes. Corticosteroids should be                discontinued, if feasible, and other immunosuppressive drugs should be tapered as                much as possible.Diabetics may have a more favourable outcome than non-diabetics. An overall survival                rate of 60–77% for rhino-orbito-cerebral mucormycosis has been                reported in diabetics, versus 20–34% in non-diabetics.146Despite the progress in the treatment of mucormycosis, many problems are yet unsolved                and the mortality of the disease is still high.Depending on the underlying condition of immunocompromised non- haematological                patients, mucormycosis can manifest in various clinical forms: mostly as                rhino-orbital or rhino-cerebral in diabetes patients, pulmonary infection in                patients with malignancy or solid organ transplantation, disseminated infection in                iron overloaded or deferoxamine treated patients, cerebral - with no sinus                involvement - in ID users, gastrointestinal in premature infants, and cutaneous                after direct inoculation in the immunocompetent.Although there are many unresolved issues concerning the epidemiology, diagnosis and                treatment of mucormycosis, advances have been made. Knowledge of the differential                patterns of clinical presentation can raise the suspicion index for these rare but                highly lethal infections. This is very important since prompt and appropriate                management can reduce mortality and morbidity considerably.


Across the planet, high-intensity farming has transformed native vegetation into monocultures, decreasing biodiversity on a landscape scale. Yet landscape-scale changes to biodiversity and community structure often emerge from processes operating at local scales. One common process that can explain changes in biodiversity and community structure is the creation of abrupt habitat edges, which, in turn, generate edge effects. Such effects, while incredibly common, can be highly variable across space and time; however, we currently lack a general analytical framework that can adequately capture such spatio-temporal variability. We extend previous approaches for estimating edge effects to a non-linear mixed modeling framework that captures such spatio-temporal heterogeneity and apply it to understand how agricultural land-uses alter wildlife communities. We trapped small mammals along a conservation-agriculture land-use interface extending 375 m into sugarcane plantations and conservation land-uses at three sites during dry and wet seasons in Swaziland, Africa. Sugarcane plantations had significant reductions in species richness and heterogeneity, and showed an increase in community similarity, suggesting a more homogenized small mammal community. Furthermore, our modeling framework identified strong variation in edge effects on communities across sites and seasons. Using small mammals as an indicator, intensive agricultural practices appear to create high-density communities of generalist species while isolating interior species in less than 225 m. These results illustrate how agricultural land-use can reduce diversity across the landscape and that effects can be masked or magnified, depending on local conditions. Taken together, our results emphasize the need to create or retain natural habitat features in agricultural mosaics. Saccharum spp.) production With human population growth as its catalyst, agricultural production has become the dominant land-use on the planet, responsible for altering and endangering wildlife communities on a massive scale Within agricultural landscapes, native wildlife communities often utilize isolated patches of intact native vegetation interspersed throughout the croplands. One conservation concern about this landscape configuration is that conditions created at the interface (edge) of agricultural lands are likely to alter wildlife communities within natural areas, favoring generalists at the expense of specialists While edge effects are incredibly common and are generally thought to help explain large-scale patterns in species distribution and community structure Our objectives were to: 1) evaluate changes in community structure between and across conservation and agriculture land-uses prevalent in much of south-eastern Africa, using eastern Swaziland as a model; and 2) extend existing non-linear models for edge effects Acacia savannah, broadleaved woodland, and riverine forest de facto conservation areas, or lands managed for wildlife conservation, wildlife viewing, and sustainable grazing We conducted our research in the lowveld of Swaziland between the northern Drakensburg Escarpment and the Lubombo Mountains . The lowWe conducted our research on three sites--Hlane-Mbuluzi, Crookes, and Nisela Farms--where conservation lands directly adjoined large-scale sugarcane plantations. Hlane-Mbuluzi included lands administered by Hlane Royal National Park, Mbuluzi Game Reserve, Tongaat-Hulett Sugar (Tabankulu Estate), and Royal Swazi Sugar Corporation (Simunye and Mhlume Estates). Conservation lands  at Hlane-Mbuluzi were managed explicitly for wildlife conservation. Hlane-Mbuluzi did not allow cattle grazing and conducted land management activities such as prescribed burning. Adjacent sugarcane was irrigated and had both dirt and graveled access roads and 3 m high fence separating conservation lands and sugarcane restricting movements of medium- to large-sized mammals We used ground-truthed aerial photographs, Landsat images and GIS , to identify the conservation-agriculture edge and generate sampling locations. We randomly (without replacement) generated 4 locations along the edges of each of the three study sites. In an effort to ensure spatial independence among locations, we did not allow random points to be placed within 300 m of another location, which is greater than the home range of the most widespread Muridae rodent in Swaziland th and continued until January 6, 2009. We trapped site in the same order during each season.We surveyed each site once per season . During each sampling period, we trapped we trapped all traplines on a transect over four consecutive nights Mus minutoides were given ear punches .We baited traps with a combination of oats and peanut butter, opened our traps in the morning and checked them each morning for four subsequent days. For each captured individual, we recorded species, age, sex, and reproductive condition Crocidura spp. and Suncus spp.) were collected and deposited in the Durban Natural Science Museum (South Africa) for identification. We also collected voucher specimens of each rodent species from each site and deposited them in the collections of the Durban Natural Science Museum. All capture protocols and data collection followed guidelines outlined by the American Society of Mammalogists All captured species of shrews  estimates from each trapline (by site and season) Changes in community structure are not easy to encapsulate; therefore, we examined a set of complementary metrics, which included estimating dissimilarity of sampling units and measures of species richness and heterogeneity S; the number of species within a site), and a metric of heterogeneity using an inverse Simpson index  at each trapline, on each transect S and D we fitted generalized-linear mixed models. Each metric was modeled as a function of land-use, season and site, with transect as random effect using IBM SPSS Statistics (v.20). We examined the F statistics, degrees of freedom (DF) and p-value of each parameter to determine its importance in explaining variation in the metric.To further understand how small mammal communities changed across competing land-uses we estimated species richness , on the overall response . The random coefficients logistic model was defined as:t2 is the random effect of transect t, N∼, on the distance effect.where γS and βS, and αD for both seasons) as the model with the lowest Akaike’s Information Criterion corrected for small sample size (AICc). We graphically displayed the predicted fit and 95% CI of the best models (best linear unbiased predictors) along with the estimates for each transect  across the land-uses for each season.We fit models to the data with SAS 9.2  using the PROC NLMIXED for fitting non-linear mixed models. We defined the best fitting and most parsimonious model for each set of models . Our study areas received approximately 19% and 81% of the rainfall recorded during the dry and wet trapping seasons respectively . Over the duration of the study we captured 1,613 unique individuals representing 10 species . All of Multi-dimensional scaling helped elucidate patterns graphically with distinct groupings formed by each land-use type; stress levels were acceptable , and land-uses , with greater species richness and heterogeneity in the wet season and in conservation areas .Measures of on areas . HoweverS and D during both seasons  and a single herbivore  We examined small mammal communities across agricultural-conservation interfaces in southern Africa and found considerable variation in measures of diversity between land-uses, seasons and patterns of change across the land-use interface. Sugarcane plantations showed significant reductions in species richness and heterogeneity, and greater similarity in community composition when compared with conservation areas. The sugarcane land-use was dominated by a homogenized community of three species: two generalist species with omnivorous diets , were generally limited to conservation areas and more common during the wet season  showed a similar pattern of increasing towards the edge (from the sugarcane), and tending to plateau within 200 m into the conservation areas . HoweverBy extending Ewers and Didham’s In our study, sugarcane plantations contained no unique small mammal species and diversity decreased with distance into the sugarcane. Additionally, we did not observe an increase in species diversity at the conservation-sugarcane edge. The extensive sugarcane plantations that abut conservation areas throughout Swaziland and in many other parts of south-eastern Africa appeared to have no measurable positive effect on small mammal diversity.Globally, the vast areas of the earth’s surface dedicated to agriculture are increasingly farmed using high-intensity practices Conservation efforts cannot be focused solely on isolated areas of pristine or intact vegetation. Broader approaches which view conservation in natural areas in conjunction with agricultural development are necessary to promote conservation within the agricultural mosaic landscape. Agricultural landscapes can be managed for mosaics of different patches that maximize cover and connectivity and retain natural habitat features, all of which help mitigate stressors on wildlife communities Although our research does not directly address these problems, the extension of Ewers and Didham’s (2006) methodology for examining edge effects will allow researchers and managers to more clearly identify local differences in edge effects across their study sites. Researchers can use this information to focus on investigations of the mechanisms driving community diversity on fine scales, while managers can use this methodology to identifying areas and characteristics associated with high diversity and areas in need of management or restoration.


COPD is a complex inflammatory airway disease characterized by airflow limitation that is not fully reversible. The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood. Current treatments have limited efficacy in COPD and there is a clear need for new therapies that can prevent the induction and progression of COPD. Animal modeling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies.in vivo models that recapitulate many of the features of COPD.To develop preclinical Mice were exposed to cigarette smoke (CS) for up to 6 months and the hallmarks of COPD investigated. In some experiments, CS-exposed mice were infected with influenza A virus  to mimic acute exacerbations of COPD (AECOPD).We have developed preclinical murine models of COPD that replicate key clinical traits observed in human disease, including BAL and lung inflammation, induction of various cytokines/chemokines/proteases, increased oxidative stress, goblet cell hyperplasia, emphysema and lung function deterioration. These models have identified novel pathways that control leukocyte accumulation and lung damage. When modeling systemic comorbidities of COPD, we found that mice exposed to CS had reduced body weight, fat mass, hind limb skeletal muscles mass, grip strength and aerobic endurance. CS altered the mRNA expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-I, atrogin-1 and IL-6. Moreover, the levels of neuropeptide Y were reduced in CS-exposed mice. Compared to CS or influenza alone, mice exposed to CS and then influenza had more BAL inflammation, lung virus titres, altered profiles of key cytokines, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BAL. CS exposure caused temporary weight loss and when smoking ceased after viral infection, CS and influenza mice regained significantly less weight than CS alone mice.in vivo models of COPD, we have identified key mediators which initiate and drive COPD. Understanding the neuromolecular and systemic processes that lead to loss of body weight in smokers may provide novel intervention points for improving cessation therapy and may also contribute to understanding wasting syndromes in smoking-related lung diseases. With respect to exacerbations of COPD, it is clear that CS exposure worsens the host response to influenza virus.Using these preclinical


Community acupuncture is a recent innovation in acupuncture service delivery that provides low-cost treatments in group-based settings. Recent data suggests improved access to acupuncture through the community acupuncture model. However, there is a paucity of research on quality of care provided at community acupuncture clinics. The aim of this study was to assess patients’ perspectives on the quality of care received through community acupuncture clinics.A cross-sectional survey of 478 patients at two community acupuncture clinics in Portland, Oregon collected patient demographics, reasons for use, and satisfaction with treatment. In an open-ended survey question, respondents were invited to share additional comments about their experiences with community acupuncture. Qualitative analysis of open-ended survey responses was conducted using a grounded theory approach and Donabedian’s triad framework on quality of care .Qualitative analysis of written comments identified two primary themes that elucidate patients’ perspectives on quality of care: (1) comparing community acupuncture to other healthcare delivery models, and (2) patients engaging in their own health care. Patients perceive the care they receive through community acupuncture as high quality compared to conventional medicine and to individual acupuncture treatment. Patients identify unique aspects of receiving quality care through community acupuncture including: structures that facilitate access; processes that make treatments more comfortable and effective; and holistic outcomes including physical improvements, enhanced quality of life, and empowerment.The group setting, community-based locations, and low cost of this model potentially reduce access barriers for those who might not otherwise consider acupuncture. These themes provide insight into patient values and experiences unique to community acupuncture, and are discussed here in the context of quality of care.


Glioblastoma multiforme (GBM) is one of the most deadly diseases that affect humans, and it is characterized by high resistance to chemotherapy and radiotherapy. Its median survival is only fourteen months, and this dramatic prognosis has stilled without changes during the last two decades; consequently GBM remains as an unsolved clinical problem. Therefore, alternative diagnostic and therapeutic approaches are needed for gliomas. Nanoparticles represent an innovative tool in research and therapies in GBM due to their capacity of self-assembly, small size, increased stability, biocompatibility, tumor-specific targeting using antibodies or ligands, encapsulation and delivery of antineoplastic drugs, and increasing the contact surface between cells and nanomaterials. The active targeting of nanoparticles through conjugation with cell surface markers could enhance the efficacy of nanoparticles for delivering several agents into the tumoral area while significantly reducing toxicity in living systems. Nanoparticles can exploit some biological pathways to achieve specific delivery to cellular and intracellular targets, including transport across the blood-brain barrier, which many anticancer drugs cannot bypass. This review addresses the advancements of nanoparticles in drug delivery, imaging, diagnosis, and therapy in gliomas. The mechanisms of action, potential effects, and therapeutic results of these systems and their future applications in GBM are discussed. Cancer is the most common cause of death in many countries. Central nervous system (CNS) tumors are an important cause of morbidity and mortality worldwide. It was estimated that 22,340 new cases of primary malignant brain and CNS tumors were diagnosed in the United States in 2011. Approximately 3,000 of them were new cases in childhood whereas about half of all CNS tumors were malignant in adults  fluoropropyl) homocysteine have been used for the PET imaging of tumors, but L- and D-S-(3-[18F] fluoropropyl)homocysteine biodegradation products generate a high background signal in the tissues 3+ is the contrast agent mainly used in magnetic resonance imaging. However, it is known that high levels of gadolinium in vivo cause toxicity; therefore it requires the metal to be complexed by strong organic chelators. Gadolinium III (Gd III) is a highly paramagnetic complex with seven unpaired electrons, which have a strong impact on the relaxation of influenced water protons. Advances in colloidal nanocrystal synthesis have led to the development of ultrasmall crystals of gadolinium oxide (US-Gd2O3), with 2-3 nm in diameter, the smallest and the densest of all Gd-containing nanoparticles. Each nanocrystal can generate signal contrast of several orders of magnitude higher than a gadolinium chelate. Currently, US-Gd2O3 has been successfully used to label glioma cells GL-261 from localization and visualization in vivo using MRI. Because very high amounts of Gd are efficiently internalized and retained into the cells, it has been possible to detect the bright in T1-weighted MRI images [Gadolinium [Gd imaging is able to track materials with extremely short T(2)*-weighted and very fast signal decay , 55. Witd tumors –59. A hid tumors .Besides PET and MRI, fluorophores have been used in imaging applications. However, their use has been limited by poor quantum yield, poor tissue penetration of the excitatory light, and excessive tissue autofluorescence. The use of inorganic fluorescent particles that offer a high quantum yield is frequently limited due in part to the toxicity of the particles.Metal nanoshells and quantum dots are complexes that have shown good resolution in glioma imaging. Metal nanoshells are composed of a silica core surrounded by a thin metal shell or ultrathin coating of silver or gold . These n4), which are nanocrystalline infrared-to-visible upconversion phosphors, ytterbium (Yb), and erbium (Er) codoped NaYF4. These nanoparticles could be complexed with human serum albumin to originate water-dispersible nanoparticles, which could act as promising upconverting fluorescence labels when they are conjugated with cyclic arginine-glycine-aspartic acid (cRGD) sequence, specifically targeting both human glioblastoma cell lines and melanoma cells overexpressing αvβ3 integrin receptors. These characteristics offer an appropriate tool for targeted imaging of focal diseases [Other nanoparticles which are now under extensive research are nanoshell conjugates of luminescent rare-earth-doped sodium ytterium fluoride  are based on semiconductor compounds consisting of a cadmium-based core surrounded by an inert layer of metallic shell , 71. Sim2++ and gelatin. Compared with bare CdHgTe QDs, the photostability of this compact complex nanostructure is remarkably improved. The fluorescence of CdHgTe/gelatin nanospheres was much more resistant to the interference from certain endogenous biomolecules such as human serum albumin, transferrin, and hemoglobin [Near-infrared QDs composed of Cd(NO3)2, Hg(NO3)2, NaHTe , and a thiol group as stabilizer in gelatin solution are newly emerged as inorganic fluorescent probes. They provide several advantages over organic fluorophores for biological imaging, including broad excitation spectra coupled with narrow, tunable emission spectra and high resistance to photobleaching . Lately,moglobin .in vivo studies have shown that the CdHgTe/gelatin nanospheres are immediately distributed to all over the vessels by blood circulation after injection. A network of blood vessels could be distinguished in fluorescence images, and the dynamic changes of nanospheres in the superficial vessels were clearly observed [in situ, real time monitoring of drug release and therapy studies in the near future.In glioma cell cultures, nanospheres were small enough to be taken up by cells, and the fluorescence of QDs was not quenched inside the cells. Moreover, no morphological change of the cells was observed, indicating that the nanospheres were biocompatible. Some observed . AlthougIn Despite considerable advancements in therapy of malignant gliomas in the last years, treatment outcomes are mostly unsatisfactory. A promising way to bypass these impairments and to elicit the specific delivering of drugs to treat tumors within the CNS is the employment of biodegradable polymeric NPs, which can be loaded with different chemotherapeutic drugs to induce selective toxicity, and additionally, modulate cellular and humoral immune responses when looking for a specific immune response against tumoral cells . A wide In vitro and in vivo experiments have indicated that the activity of a range of drugs or their active metabolites may be enhanced by their encapsulation in liposomes [Liposomes are concentric bilayered vesicles surrounded by a phospholipid membrane. They are related to micelles which are generally composed by hydrophilic and hydrophobic regions. The amphiphilic nature of liposomes, their facility of surface modification, and a good biocompatibility profile make them an appealing solution for increasing the circulating half-life of proteins and peptides. They may contain hydrophilic compounds, which remain encapsulated in the aqueous interior, which may escape encapsulation through diffusion out of the phospholipid membrane. Liposomes can be designed to adhere to cellular membranes to deliver a drug payload or simply transfer drugs through endocytosis –86. In viposomes –89.in vitro using transwell membrane were significantly increased, and the cell viability of U87 MG glioma cells after crossing the BBB was significantly decreased by ANG-NP-paclitaxel [Paclitaxel is a chemotherapeutic that inhibits cell division through promotion of the assembly and stabilization of microtubules. Unfortunately, paclitaxel is highly hydrophobic, and its absorption across the BBB is also poor. To overcome this limitation, paclitaxel has been conjugated to liposomes . Recentlclitaxel . Additioclitaxel . The PEGclitaxel .β (NFκβ), and Notch [In vitro studies proved that the cytotoxicity of these nanoconjugates would be result of a pro-apoptotic effect against rat C6 glioma cell line in a dose-dependent manner [Curcumin is a polyphenolic compound derived from the Indian spice turmeric. It has been shown to exert antitumor effects in many different cancer cell lines and animal models either by proapoptotic, antiangiogenic, anti-inflammatory, immunomodulatory, and antimitogenic effects –95. Somend Notch , 97. Thend Notch , 99. Limnd Notch . Also, ct manner .Celecoxib, a cyclo-oxygenase- (COX-) 2 inhibitor, has been reported to mediate growth inhibitory effects and to induce apoptosis in various cancer cell lines . CelecoxAlthough doxorubicin (DOX) has not been used as treatment in brain tumors, because it has poor distribution and limited penetration, it is one of the most likely candidates for CNS chemotherapy . Here, wIn vivo results exhibited good correlation of glioma targeting of the CTx-modified liposomes, with the CTx as the targeting ligand [Nanoconjugates coupled with liposomes could be a new treatment of gliomas, because they increase both the uptake of and specificity to glioma cells. The chlorotoxin (CTx) is a scorpion-derived peptide, which binds with high specificity to glioma cell surface as a specific chloride channel and matrix metalloproteinase-2 blocker. It was firstly applied to establish the CTx-modified doxorubicin- (DOX-)loaded liposome delivery system for targeting brain glioma and improving the anticancer efficacy. Recently, it has been developed in BALB/c mice-bearing U87 tumor xenografts, a novel liposome system with a uniform distribution, high encapsulation efficiency, and adequate loading capacity of both fluorescent probe and DOX. The biodistribution of DOX-loaded liposomes by body imaging and antiglioma pharmacodynamics were studied finding that CTx-modified liposomes were drastically accumulated in subcutaneous and intracranial tumors, showing higher tumor growth inhibition and lower blood toxicity in the armpit tumor model. g ligand .in vitro [in vivo systemic administration increases the accumulation of Lf-PCLs in the brain [In order to increase the uptake of these nanoparticles, specific ligands were coupled to the distal ends of the PEG chains to increase their uptake through receptor-mediated targeting while maintaining PEG stability. The membrane transferrin receptor (Tr) mediated endocytosis or internalization of the complex of transferrin bound iron, and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors , 109. Stin vitro , 111. Onhe brain . These sNanocrystals are aggregates of molecules that can be combined into a crystalline form of the drug surrounded by a thin coating of surfactant. They have extensive uses in materials research, chemical engineering, and as quantum dots for biological imaging; there is no carrier material as in polymeric nanoparticles –114. NanSome nanocrystals have shown to inhibit the proliferation in different cancer cells lines . Silver in vitro. In the glioma-bearing rat model, AgNPs combined with MNPH enhance Bax (Bcl-2–associated X protein) expression in cancer cells, which was correlated with cell apoptosis induction. The mechanism of thermosensitization by AgNPs might be related to the release of Ag+ cation from the silver nanostructures inside cells. Ag+ cation has the ability to capture electrons and thus functions as an oxidative agent [The combination of AgNPs with magnetic nanoparticles hyperthermia (MNPH) treatment has been used as treatment in glioma model. AgNPs had significant effect on enhancing thermoinduced killing ve agent , 122.2S nanoparticles that increase physical and chemical stability [+ released from nanocrystals, which were predominantly endocytosed, and partly adhered to the membrane surface [Based on thermodynamic constraints, metallic Ag cores have been modified with (in)organic ligands allowing the synthesis of protein-conjugated Agtability . Recentl surface . Even wh surface , 78.Self-assembling sheets of atoms arranged in tubes are defined as nanotubes. They may be organic or inorganic in composition and can be produced as single- or multiwalled structures. They have large internal volumes, and the external surface can be easily functionalized. While they are potentially promising for pharmaceutical applications, human tolerance of these compounds remains unknown, toxicity reports are conflicting, and extensive researches regarding the biocompatibility and toxicity of nanotubes are needed . Carbon in vitro, demonstrating the ability of BV2 cells to more efficiently internalize MWCNTs as compared to glioma cells without any significant signs of cytotoxicity. They were able to visualize ingestion of MWCNTs into MG, cytotoxicity, and loading capacity of MWCNTs under normal culture conditions, suggesting that MWCNTs could be used as a novel, nontoxic, and biodegradable nanovehicles for targeted therapy in brain tumors.As in nanovectors, CNTs have the advantage of providing a versatile, biodegradable, and nonimmunogenic delivery alternative to viral vectors for molecular therapy or immunotherapy as direct delivery of antigens to antigen presenting cells (APCs) or microglia in the central nervous system . Kateb eOn the other hand, this group also analyzed the internalization of these nanotubes in an intracranial glioma model and characterized some changes in tumor cytokine production following intratumoral injection of MWCNTs in GL261 murine glioma model. Authors demonstrated that MWCNTs were preferentially detected in tumor macrophages (MPs), and to a lesser extent in MG. In addition to MG and MP, a small fraction of glioma cells, which are not typically capable of phagocytosis, also became positive for MWCNTs; FACS and quantitative RT-PCR were performed to analyze the inflammatory response and cytokine profile. A transient influx of MP was seen in both normal brain and GL261 gliomas in response to MWCNTs; whereas no significant change in cytokine expression was noted in normal group . They coCeramic nanoparticles are typically composed of inorganic compounds such as silica or alumina. Originally used with silica-based materials , this apDendrimers are polymer-based macromolecules formed from monomeric or oligomeric units, such that each layer of branching units doubles or triples the number of peripheral groups. These structures are considered as one of the most promising polymer architectures in biomedical applications in recent years , 136. Supolyfect consists of dendrimer molecules radiating from a central core. Amino groups at the terminal ends of the dendrimer branches are positively charged at physiological pH, therefore interacting with the negatively charged phosphate groups of nucleic acids [The avoid area within dendrimer and the extent of its branching, the size control, and its facility of modification and preparation offer great potential for drug delivery. Generally, they have a symmetrical structure, with the potential to create an isolated “active site” core area through chemical functionalization. The modification of the degree of branching may allow for encapsulation of a molecule within this structure . For insic acids . Howeverin vitro BBB model and their distribution into vascular human glioma tumor spheroids were also studied. Glycosylated dendrimers were found to be endocytosed in significantly higher amounts than nonglucosylated dendrimers by the cell lines mentioned above. These MTX-loaded dendrimers were also able to kill even MTX-resistant cells highlighting their ability to overcome MTX resistance. In addition, the amount of MTX transported across BBB was three to five times more after loading in the dendrimers. Glycosylation further increased the cumulative permeation of dendrimers across BBB and hence increased the amount of MTX available across it. These results shown that glucosamine not only can be used as an effective ligand for targeting glial tumors but also enhanced their permeability across BBB [Drug carriers such as dendrimers have been used for therapeutic purposes in the treatment of gliomas. These nanomaterials were conjugated to D-glucosamine as the ligand for enhancing their permeability across BBB and tumor targeting. The efficacy of methotrexate- (MTX-)loaded dendrimers was established against U87 MG and U343 MGa cells. Permeability of rhodamine-labeled dendrimers and MTX-loaded dendrimers across an ross BBB .Furthermore, the poly(amidoamine) (PAMAM) dendrimer was employed as a carrier to codeliver antisense-miR-21 oligonucleotide (as-miR-21) and 5-fluorouracil (5-FU) to achieve delivery of as-miR-21 to human glioblastoma cells and enhance the cytotoxicity of 5-FU antisense therapy. PAMAM could be simultaneously loaded with 5-FU and as-miR-21, forming a complex smaller than 100 nm in diameter. Both the chemotherapeutant and as-miR-21 could be efficiently introduced into tumor cells. The codelivery of as-miR-21 significantly improved the cytotoxicity of 5-FU and dramatically increased the apoptosis of U251 cells, while the migration ability of the tumor cells was decreased. These results suggest that the codelivery system may have important clinical applications in the treatment of miR-21-overexpressing glioblastoma .Tumor-specific targeting using achievements of nanotechnology is a mainstay of increasing efficacy of antitumor drugs. One of the most significant advances in tumor-targeted therapy is the surface modification of nanoparticles with monoclonal antibodies (mAbs) alone or in combination with antineoplastic drugs in cancer therapy . Anotherβ-l-malic acid) (PMLA) polymer, natural product of Physarum polycephalum [in vitro and in vivo, nonimmunogenicity, biodegradability, stability in the bloodstream, and easy cellular uptake [In order to improve direct tumor targeting and to avoid the damage of nontumor cells Fujita et al.  synthesicephalum  that is r uptake –152. Alsr uptake , 154 andr uptake , 156 pro10B conjugated with anti-EGFR antibodies by ZZ-His provides a selective delivery system into glioma cells, and this was confirmed by inductively coupled plasma-atomic emission spectrometry (ICP-AES) both in vitro and in vivo [Another interesting approach is the use of immunoliposomes, which are antibodies conjugated to the liposomes using the antibody motif of protein A (ZZ) as an adaptor. Feng et al.  used the in vivo .Solid lipid nanoparticles are lipid-based submicron colloidal carriers. They were initially designed in the early 1990s as a pharmaceutical alternative to liposomes and emulsions. In general, they are more stable than liposomes in biological systems due to their relatively rigid core consisting of hydrophobic lipids that are solid at room and body temperatures, surrounded by a monolayer of phospholipids . These aα. Thereby, anti-EGFR/BCNU-CASLNs could have a potential use in anticancer chemotherapy for clinical application [Recently, Kuo and Liang used innovative catanionic solid lipid nanoparticles (CASLNs) prepared in microemulsions carrying carmustine (BCNU) (BCNU-CASLNs) that were grafted with antiepithelial growth factor receptor (EGFR) (anti-EGFR/BCNU-CASLNs) and applied to inhibit the propagation of human brain malignant glioblastomas cells due to gliomas normally express certain types of growth factor receptor. The catanionic surfactants (1 Mm) yielded the smallest particle size of BCNUCASLNs and the largest entrapment efficiency of BCNU with a moderate toxicity to human brain-microvascular endothelial cell and a tolerable expression of TNF-lication .These nanoparticles could be loaded with others types of chemotherapeutics such as doxorubicin (DOX). The use of CASLNs loaded with DOX and grafted with antiepithelial growth factor receptor (EGFR) (anti-EGFR/DOX-CASLNs) suppressed the propagation of malignant U87MG cells. At 1 mM concentrations of these catanionic surfactants conjugated with hexadecyltrimethylammonium bromide and sodium anionic sodium dodecylsulfate, CASLNs entrapped the largest quantity of DOX, concluding that catanionic surfactants at 1 mM and 100% of cacao butter (CB) could be satisfactory conditions for preparing anti-EGFR/DOX-CASLNs to inhibit proliferation of malignant U87MG cells, and the grafted anti-EGFR could substantially enhance the delivery efficiency of DOX to U87MG cells .Above all, these nanoparticles are not used yet in clinical trials against glioblastoma or others types of brain tumors, but this innovative approach can be an effective delivery system with high targeting efficacy against brain tumors due to the great capacity to deliver chemotherapeutic agents and to reduce toxicity.In While it is important to achieve an increased uptake of functional targeting nanoparticles by GBM cells, it is also important to consider the biodistribution of the nanoparticles in blood circulation and liver accumulation, highlighting the importance of controlling ligand loading in order to achieve optimal performance for therapeutic and imaging applications for multivalent nanoparticle-based systems . Nowadays, several research groups are actively trying to combine a variety of functions into NPs as platforms for targeting different immune and tumoral cells and to develop diverse strategies to modulate specific treatments. A major effort toward successful NP-based therapeutics will be needed to avoid extensive and nonspecific immunostimulatory or immunosuppressive reactions to the nanomaterials, once they have been administered into the body, in order to find a right balance between any remaining potential damage and the health and quality of life of patients. This implies the future development of new or adapted methods appropriate to assess new medicinal tools involving NPs. Although many questions still require extensive investigation, the available data suggest that a variety of NPs can be engineered to become part of the next generation of immunomodulatory platforms and treatments .Nanoparticles exploit biological pathways to achieve payload delivery to cellular and intracellular targets, including transport across the BBB. The central nervous system is protected by this barrier which maintains its homeostasis. However, many potential drugs for the treatment of diseases of the central nervous system (CNS) cannot reach the brain in high concentrations. This physical barrier limits the brain uptake of the vast majority of neurotherapeutics and neuroimaging contrast agents , 17. OneStudies on the biological composition, administrations, and adverse events of new nanomaterials suited for biomedical applications are important for therapeutic drug delivery and the development of innovative and better treatments . FurtherThe use of nanoparticles could be a good option in diagnosis and treatment of gliomas. Studies suggest that a variety of NPs can be engineered to become part of the next generation of agents delivery and specific treatment on gliomas. The use of a biocompatible system of NPs, conjugates should reduce the toxicity and side effects of systemic drugs administration and therefore improve the quality of life in cancer patients. However, several studies conducted largely on mice have shown undesired side effects such as inflammatory response including substantial lung neutrophil influx and mortality at high doses. In addition, NPs may feasibly represent a useful imaging tool to diagnosis and followup; also, it to be used to assess/monitor efficacy of antiangiogenic or other antitumour treatments, thus improving the clinical management of brain tumours. Nevertheless, additional research is required in multifunctional NPs based drug delivery systems to overcome the problems and understand how nanoparticles interact with biological systems and the environment for effective therapy.


The ongoing global decline in vulture populations raises major conservation concerns, but little is known about the factors that mediate scavenger habitat use, in particular the importance of abundance of live prey versus prey mortality. We test this using data from the Serengeti-Mara ecosystem in East Africa. The two hypotheses that prey abundance or prey mortality are the main drivers of vulture habitat use provide alternative predictions. If vultures select areas based only on prey abundance, we expect tracked vultures to remain close to herds of migratory wildebeest regardless of season. However, if vultures select areas where mortality rates are greatest then we expect vultures to select the driest regions, where animals are more likely to die of starvation, and to be attracted to migratory wildebeest only during the dry season when wildebeest mortality is greatest. We used data from GSM-GPS transmitters to assess the relationship between three vulture species and migratory wildebeest in the Mara-Serengeti ecosystem. Results indicate that vultures preferentially cluster around migratory herds only during the dry season, when herds experience their highest mortality. Additionally during the wet season, Ruppell’s and Lappet-faced vultures select relatively dry areas, based on Normalized Difference Vegetation Index, whereas White-backed vultures preferred wetter areas during the wet season. Differences in habitat use among species may mediate coexistence in this scavenger guild. In general, our results suggest that prey abundance is not the primary driver of avian scavenger habitat use. The apparent reliance of vultures on non-migratory ungulates during the wet season has important conservation implications for vultures in light of on-going declines in non-migratory ungulate species and use of poisons in unprotected areas. The study of animal ecology has focused on herbivores, predators and parasites, and has largely overlooked scavengers Connochaetes taurinus) represent the highest abundance of live ungulate prey in the Mara-Serengeti ecosystem of East Africa. The region has a distinct and steep rainfall gradient with considerable asynchrony in rainfall patterns across the area Vultures (Accipiridae and Cathartidae) are the only obligate vertebrate scavengers Historic studies on vultures involving marked individuals and radio telemetry suggested that vultures followed herds of migratory ungulates. However results were limited by small sample sizes, limited re-sightings, and the short duration of telemetry devices used Torgos tracheliotos), White-backed (Gyps africanus) and Ruppell’s vultures (Gyps rueppellii) are not well understood Gpys species, in particular, is difficult to explain given the similarity in their feeding and social behavior Three species of vultures make up the bulk of the avian scavenger guild in the region. Given their dependence on a common resource, the mechanisms that enable coexistence of Lappet-faced , Kenya and was covered under research permit number NCST/5/002/R/448 issued by the National Council for Science and Technology in Kenya. We are indebted to the Narok County Council and the staff of the Masai Mara National Reserve, in particular the wardens Mr. Sindiyo and Mr. Minis for their assistance and permission to conduct vulture research in the reserve. Vultures were trapped using nooses, set up as grids or in a line, along and on top of carcasses Processing captured birds took approximately 30 minutes; the birds’ eyes were covered to reduce stress and a handler restrained both feet and head. The majority of birds captured in this study were adults, but several sub-adults and one fledgling Lappet-faced Vulture also were tagged and tracked. Age was determined based on plumage and coloration following Mundy et al. (1992). Units were attached as backpacks using 11-mm Teflon ribbon  following procedures similar to other vulture studies East Africa has high wildlife densities and few human-mediated sources of carrion, making it an ideal study system in which to investigate natural scavenger behaviors. The Mara-Serengeti ecosystem is unique because it maintains one of the few ungulate migrations remaining in the world Equus burchelli), and 250,000 Thomson’s and Grant’s gazelle (Eudorcas thomsonii and Nanger granti) moving between Serengeti National Park, Tanzania, and Masai Mara National Reserve, Kenya, each year. As a result, this ecosystem is arguably one of the most important areas for scavengers in Africa, supporting high densities of vultures of many species The Mara-Serengeti ecosystem has the largest ungulate migration in the world, with 1.3 million Western white-bearded wildebeest, 180,000 Burchell’s zebra  were deployed. Fourteen transmitters were deployed from May to August 2009, 21 from April to October 2010, and 3 in March 2011. These deployments include three re-deployments that occurred after units were recovered from dead birds Analyses were focused on mid-day locations  when vultures are most likely to be foraging. Nest sites were established for each individual based on consistent use of an area within a 50 m radius across several months with at least 50 locations in the area. For nests within Masai Mara National Reserve, nest sites were confirmed by spotting the tagged bird on the nest. Days when birds were on the nest during a mid-day point were removed from analysis. To increase independence, a single point was used for each day, which was calculated as the centroid of three mid-day points using ArcGIS 9.3 . Data for which these three points were not available in a given day were excluded.To assess the relationship with ungulate abundance, we related vulture movement to migratory ungulate movement based on 75% kernel polygons representing the distribution of migratory wildebeest from movement data collected over a five-year study for four separate seasons  http://lpdaac.usgs.gov/get_data maintained by the NASA Land Processes Distributed Archive Center (LP DAAC), USGS/Earth Resources Observation and Science (EROS) Center, Sioux Falls, South Dakota in January 2012. These data provide 16-day composites of vegetation indices at 250-meter spatial resolution. High NDVI values can be indicative of either high tree cover or high grass cover. Thus, data points were also related to tree cover using data from Guan et al. Normalized Difference Vegetation Index (NDVI) is a reliable measure of greenness or wetness and is linked to rainfall and forage availability, and thus mortality, for many ungulate species We used a linear mixed-effects model to assess patterns of vulture habitat use. To determine habitat selectivity in relation to wildebeest, values were averaged across month to reduce issues of pseudo-replication. Two models were run – one for wildebeest and one for NDVI. For both models, the dependent variable was calculated as the real values minus the randomly generated values of either proximity to wildebeest or NDVI. Therefore, values near zero suggest the distribution of vulture movement is no different from random, while negative values suggest vultures are close to wildebeest (or in relatively dry areas) and positive values suggest vultures are far from wildebeest (or in relatively wet areas). Models included season , species , and breeding status of the individual (used nest or did not use nest) as fixed factors with unit id as a random factor to account for differences between individuals using lme4 package Data included in the analysis came from 39 vultures tracked for an average of 149 days from which sufficient data were collected . Twenty-Gyps species, in particular, frequented a number of areas beyond the Mara-Serengeti ecosystem including both Tsavo National Parks in Kenya and Northern Kenya (Kobus kob) occurs All three species showed a significant preference for being closer to wildebeest herds only in the dry season . In addirn Kenya . One RupVultures being near migratory wildebeest herds, in relation to NDVI, was significantly affected by season, species, and breeding status . White-bCarcass availability is mediated by both prey abundance and prey mortality. In our study area, vulture habitat use is not driven by abundance of live ungulates. Despite the fact that migratory wildebeest herds consistently represent the greatest prey abundance in this landscape, vultures selectively associate with them only during the dry season. Vultures showed limited preference for being near migratory herds, with overlap between vultures and wildebeest migratory herds being limited to less than 30%, contrary to previous studies Our study suggests that prey mortality may be a more important driver of vulture habitat use than prey abundance. As predicted, vultures showed greater use of migratory herds during the dry season, when migratory-herd mortality is high Seasonal shifts in ranging behavior, particularly wider ranging of White-backed vultures during the wet than dry season, is consistent with movement studies in Southern Africa Gyps vultures, likely due to differences in wing-loading and use of small as well as large carrion sources Differences in habitat use among these three species may enable coexistence. Lappet-faced vultures showed less selection for migratory wildebeest than Gyps species, particularly during periods of reduced food availability as occurs during the wet season.White-backed vultures selected relatively green areas during the wet season, unlike Lappet-faced and Ruppell’s vultures, suggesting that different factors may drive wet-season habitat use in this species. Reasons for this remain unclear. White-backed vultures may use slightly different foraging strategies than the other two species, perhaps with closer dependence on prey abundance, as evidenced by their higher selectivity to be near migratory herds. This difference in large-scale habitat use may be critical for the coexistence in the two Poisoning of carrion resources, typically done by pastoralists to kill predators, is believed to be the primary threat to vultures at our study site . Nevertheless, declines in food availability have led to rapid declines in vulture populations elsewhere Gyps vultures in East Africa. The rapid declines in these species that are now underway, coupled with difficulties in assessing population status of wide-ranging vertebrates, suggest that such monitoring should continue Concentrations of vultures around migratory herds during the dry season may offer a significant opportunity for monitoring vulture populations. Because all vultures used in this study frequented the wildebeest herds throughout the dry season, roadside counts done in this area during this period may give the most accurate and cost-effective account of the population status of


Acute liver failure as life threatening condition comprises a difficult diagnostic situation to evaluate potential outcomes and therapeutic options. Thus, prognostic indicators are urgently needed for evaluation of progression of liver injury, clinical outcome, prognosis, and for therapeutic response. Recently, circulating microRNA, in particular miR-122, was described as a potential biomarker of acute liver injury after intoxication of mice. Circulating microRNA (miRNA) molecules are very stable and RNase-resistant due to protein aggregation and vesicle enclosure. Since miRNA species are known to be associated with chronic liver damage or with liver cancer, circulating miRNA patterns are suggested to serve also as reporters for progression of acute liver failure. miRNA profiling analyses using PCR arrays or next generation sequencing, may achieve identification of miRNA species that are linked to the rapid progression of acute liver injury, to the outcome of liver failure, or to the therapeutic response. Therefore, circulating miRNAs are promising, non-invasive biomarkers of future diagnostic approaches. However, normalisation of circulating miRNA levels is essential and further standardisation of miRNA quantification assays is needed. Acute liver failure is a life-threatening liver disease characterized by a rapid and fulminant loss of liver function. Common causes of acute liver failure are viral hepatitis infection, mainly hepatitis A and B, and drug-induced liver intoxication  are short noncoding, endogenous RNAs that regulate posttranscriptional gene expression by either RNA interference or inhibition of translational initiation and elongation Bartel, . TherefoIn addition to the cellular function of miRNA in posttranscriptional gene repression, recent data collect evidence that miRNA also occur in extracellular compartments   is also a valuable method to detect the pattern of circulating miRNAs followed by PCR quantification to validate data on a wide cohort of patients Figure .Although miR-122, miR-192, miR-21, and miR-34a are shown by most reports to be increased after experimental or human liver injury Table . It is wIn addition, the accuracy of extracellular miRNA quantification highly depends on normalisation using an appropriate reference RNA. Thus, Xu et al. identified increased levels of circulating miR-122 and mir-92a as putative markers of chronic HBV infection after normalisation to endogenous miR-181 values, whereas Ji et al. observed decreasing levels of both miRNA after normalisation using snU6-RNA (Ji et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Brain repair involves a compendium of natural mechanisms that are activated following stroke. From a therapeutic viewpoint, reparative therapies that encourage cerebral plasticity are needed. In the last years, it has been demonstrated that modulatory treatments for brain repair such as trophic factor- and stem cell-based therapies can promote neurogenesis, gliogenesis, oligodendrogenesis, synaptogenesis and angiogenesis, all of which having a beneficial impact on infarct volume, cell death and, finally, and most importantly, on the functional recovery. However, even when promising results have been obtained in a wide range of experimental animal models and conditions these preliminary results have not yet demonstrated their clinical efficacy. Here, we focus on brain repair modulatory treatments for ischaemic stroke, that use trophic factors, drugs with trophic effects and stem cell therapy. Important and still unanswered questions for translational research ranging from experimental animal models to recent and ongoing clinical trials are reviewed here. Brain repair after ischaemic strokeTrophic factor-based therapies– Experimental animal models– Trophic factors– Clinical studiesStem cell therapies– Experimental animal models– Clinical studiesLast commentsProtective therapies that focused on saving just the neural cells instead of protecting all the components of the neurovascular unit have consistently failed . Rather We should first consider that protection and repair mechanisms are activated and work together from the very beginning of cerebral ischaemia . The accSynchronized events after damage may allow initial deleterious signals to transition into beneficial effects and recovery . During Trophic factors, stem cell therapy and rehabilitation have all been shown to exert potential therapeutic effects by modulating brain repair- associated mechanisms . In expeThe discovery of nerve growth factor (NGF) in the 1950s by Levi-Montalcini and Hamburger  opened a, the administration of other factors, like basic fibroblast growth factor (bFGF), has been shown to promote neurogenesis in both intact and ischaemic brain [The reported number of biological modulatory molecules that mediate in brain repair is high and ever-growing. Besides NGF, which has been reported to improve cholinergic function, stimulate axonal growth, cerebral perfusion and neurogenesis by stimulating proliferation through tyrosine kinase receptor signalling , 17, theic brain . Indeed,ic brain . While hic brain , it is iic brain . In thisic brain .How can brain repair be modulated by the action of factors like BDNF? Although still unclear, white matter glial cells have been reported to play a key role in protecting and promoting the regeneration of nerve fibres by producing BDNF itself . Also, pIt bears mentioning that trophic factors not only enhance single processes like neurogenesis, but they also exert pleiotropic effects on other biological pathways such as vascular function, immune cell function or cell death. In this sense, it was recently reported that the preserved neuronal loss and reduced number of TUNEL-positive cells after intranasal administration of BDNF might also be due to modulation of local inflammation by this factor, which would reduce tumour necrosis factor-α (TNF-α) levels and augment those of interleukin (IL)-10 .However, in addition to all of this pleiotropic interplay, the activity of most of these factors within the brain under ischaemic conditions is not clear. After the hypoxic insult, many hypoxia-response genes such as HIF-1alpha are upregulated, triggering downstream changes in other interacting genes such as vascular endothelial growth factor (VEGF), which is the key gene for the angiogenesis induced in penumbral regions of the brain. This angiogenesis is known to depend on several factors including VEGF, VEGFR2, Angiopoietins 1 and 2 and its Tie2 receptors . In a reAnother process that is modulated by brain repair therapies is myelin formation. Again, we emphasize the importance of connections between elements of the different pathways involved in brain repair after ischaemia. Recent publications have suggested connections within signal transduction pathways between elements such as Lingo-1 and epidermal growth factor . Given tOther possible treatment approaches are blood-mobilizing drugs like erythropoietin (EPO) –42 or Gr, like CDP-choline, which have been attributed with a protective role [On the other hand, some other drugs with trophic effectsive role , 47, havive role . Experimive role . Anotherive role . Indeed,ive role , 52.Some of the trophic factors mentioned above, including bFGF, EPO and G-CSF, have been tested in controlled human clinical trials . UnfortuIn the case of EPO, the results are also inconclusive. While an initial small-size proof of concept trial performed in acute stroke patients reported an improvement in stroke outcome at 1 month and significantly smaller lesion size in the treated group than in controls without relevant side effects , a large, specifically CDP-choline and Cerebrolysin, have also been tested in clinical trials. A meta-analysis of pooled data collected from several small phase III trials, concluded that CDP-choline was reported to be safe and present a certain efficacy. In patients with moderate to severe ischaemic stroke, oral CDP-choline for 6 weeks increased the global odds of recovery at 3 months by 33% compared with the placebo [Based on their pre-clinical results, other drugs with trophic effects placebo  and this placebo . A syste placebo , a large placebo , 66. ThuIn summary, to date there is insufficient knowledge of efficacy of trophic factors in ischaemic stroke based on clinical trials, and the publication of the results of the AXIS-II trial should give more information. On the other hand, research on drugs with trophic effects has demonstrated the safety of CDP-choline and of Cerebrolysin, and suggests some efficacy in acute ischaemic stroke.ex-vivo experiments, trophic interactions between MSCs and ischaemic brain have led to increased production of trophic factors including BDNF, VEGF or HGF (hepatocyte growth factor) [in vitro before their application. Under this perspective, stem cells genetically modified to overexpress specific trophic factors might enhance neuronal differentiation and survival [i.e. FGF-2) in comparison with ‘wild type’-MSC transplantation [As well as immune-modulation and substitution of damaged areas under certain conditions , 67, the factor)  and it i factor) , 71. Fur factor) . This resurvival ; in addiantation .Four major aspects will be reviewed below, concerning: (i) stem cell sources; (ii) the type of cell transplant, based on cell source; (iii) the time of administration or therapeutic window; and finally, (iv) the most suitable administration route for its clinical translation.Looking at the wide range of stem cell sources, cerebral ischaemia can be treated using different types of cells from different origins see . EnhanceIn experimental animal models, neural stem cell (NSC) administration has been shown to enhance axonal sprouting and transport, dendritic activity and the expression of neurogenesis, gliogenesis and neurotrophic support-associated genes –81. WhilIn vivo, bioactive molecules secreted by MSCs provide a regenerative microenvironment that enhances a self-regulated regenerative response. This regenerative microenvironment (trophic activity) mediates tissue repair and regeneration under ischaemia conditions [Meanwhile, bone marrow-derived MSC  also holnditions .As was previously mentioned, endothelial cell regeneration and neovascularization after tissue ischaemia are subjects of interest nowadays in the context of brain repair and it has been reported that repair can be enhanced by the administration of endothelial progenitor cells (EPCs), the positive effects of which have been observed in long-term neurobehavioural tests , 94.Lastly, another ethically unproblematic source of cells with great potential are inducible pluripotent stem cells (iPS). First described by the Yamanaka group , this kiIndependently of the above-mentioned cell sources, an important practical issue is the type of transplant: autologous , allogenic (same species) or xenogenic (another species). To prevent rejection, autologous administration can be considered the best option. A limitation of this approach in a clinical situation is that it would only allow treatment several weeks after the stroke, as this is the time needed for the cultivation and expansion of cells from the donor . HoweverTo emphasize results from a clinical perspective, the route of administration for stem cells is still a major concern. There are several possible options which have been tested in experimental animals including intrastriatal, intraventricular, intravenous , intracaTaking into consideration that in patients acute stroke is usually considered a ‘time is life’ condition, the time of transplant is critical, and, for now, there is no clear concordance between animal models and humans. It has been described that the blood-brain barrier is open continuously for several weeks after ischaemia , indicatGlobally and in contrast to results from experimental animal models , clinicaWith regards to MSCs, some studies have reported that they can be safely transplanted into the brain of patients with excellent tolerance and without complications . Also syCurrently, there are open clinical trials using MSCs in ischaemic stroke. Phase I and phase II studies exist for BMMCs and results will be obtained soon. Other studies are evaluating the feasibility and tolerance of the intravenous injection of autologous MSCs in phase II and another 2 clinical trials in phase I/II are evaluating the intravenous injection of allogenic MSCs As has been discussed above, multiple subtypes of stem cell therapies have been developed in recent years for the treatment of cerebral ischaemia. However, large and well-designed trials are needed to identify the best options for their transfer to the clinical setting . In 2007In our opinion, as suggested in a recent review by our group , and basIn cerebral ischaemia, protection and brain repair mechanisms are activated and orchestrated as a continuum once the disease process is initiated. Both trophic factors and stem cell therapy have been shown to modulate genetic and molecular programs underlying neuronal cell survival and axonal connectivity, angiogenesis, oligodendrogenesis and modulation of inflammation. Both therapeutic approaches have consistently shown exciting results in experimental animal models but their efficacy in patients has not yet been confirmed. Although not entirely understood, recent data have demonstrated paracrine interactions between stem cells and trophic factors, and this could suggest a multi-modal strategy for brain repair. Experimental research in the coming years will be focused on combining both approaches. At the same time, protocolizing the clinical context, dose, times and routes of administration will help design more effective clinical trials.