Transformation starts at the periphery of networks where pushback is less.

Complex systems ranging from societies to ecological communities and power grids may be viewed as networks of connected elements. Such systems can go through critical transitions driven by an avalanche of contagious change. Here we ask, where in a complex network such a systemic shift is most likely to start. Intuitively, a central node seems the most likely source of such change. Indeed, topological studies suggest that central nodes can be the Achilles heel for attacks. We argue that the opposite is true for the class of networks in which all nodes tend to follow the state of their neighbors, a category we call two-way pull networks. In this case, a well-connected central node is an unlikely starting point of a systemic shift due to the buffering effect of connected neighbors. As a result, change is most likely to cascade through the network if it spreads first among relatively poorly connected nodes in the periphery. The probability of such initial spread is highest when the perturbation starts from intermediately connected nodes at the periphery, or more specifically, nodes with intermediate degree and relatively low closeness centrality. Our finding is consistent with empirical observations on social innovation, and may be relevant to topics as different as the sources of originality of art, collapse of financial and ecological networks and the onset of psychiatric disorders.

Five fundamental ways in which complex food webs may spiral out of control.

Theory suggests that increasingly long, negative feedback loops of many interacting species may destabilize food webs as complexity increases. Less attention has, however, been paid to the specific ways in which these 'delayed negative feedbacks' may affect the response of complex ecosystems to global environmental change. Here, we describe five fundamental ways in which these feedbacks might pave the way for abrupt, large-scale transitions and species losses. By combining topological and bioenergetic models, we then proceed by showing that the likelihood of such transitions increases with the number of interacting species and/or when the combined effects of stabilizing network patterns approach the minimum required for stable coexistence. Our findings thus shift the question from the classical question of what makes complex, unaltered ecosystems stable to whether the effects of, known and unknown, stabilizing food-web patterns are sufficient to prevent abrupt, large-scale transitions under global environmental change.

Linking human impacts to community processes in terrestrial and freshwater ecosystems.

Human impacts such as habitat loss, climate change and biological invasions are radically altering biodiversity, with greater effects projected into the future. Evidence suggests human impacts may differ substantially between terrestrial and freshwater ecosystems, but the reasons for these differences are poorly understood. We propose an integrative approach to explain these differences by linking impacts to four fundamental processes that structure communities: dispersal, speciation, species-level selection and ecological drift. Our goal is to provide process-based insights into why human impacts, and responses to impacts, may differ across ecosystem types using a mechanistic, eco-evolutionary comparative framework. To enable these insights, we review and synthesise (i) how the four processes influence diversity and dynamics in terrestrial versus freshwater communities, specifically whether the relative importance of each process differs among ecosystems, and (ii) the pathways by which human impacts can produce divergent responses across ecosystems, due to differences in the strength of processes among ecosystems we identify. Finally, we highlight research gaps and next steps, and discuss how this approach can provide new insights for conservation. By focusing on the processes that shape diversity in communities, we aim to mechanistically link human impacts to ongoing and future changes in ecosystems.

Foreseeing the future of mutualistic communities beyond collapse.

Changing conditions may lead to sudden shifts in the state of ecosystems when critical thresholds are passed. Some well-studied drivers of such transitions lead to predictable outcomes such as a turbid lake or a degraded landscape. Many ecosystems are, however, complex systems of many interacting species. While detecting upcoming transitions in such systems is challenging, predicting what comes after a critical transition is terra incognita altogether. The problem is that complex ecosystems may shift to many different, alternative states. Whether an impending transition has minor, positive or catastrophic effects is thus unclear. Some systems may, however, behave more predictably than others. The dynamics of mutualistic communities can be expected to be relatively simple, because delayed negative feedbacks leading to oscillatory or other complex dynamics are weak. Here, we address the question of whether this relative simplicity allows us to foresee a community's future state. As a case study, we use a model of a bipartite mutualistic network and show that a network's post-transition state is indicated by the way in which a system recovers from minor disturbances. Similar results obtained with a unipartite model of facilitation suggest that our results are of relevance to a wide range of mutualistic systems.

Finding the direction of lowest resilience in multivariate complex systems.

The dynamics of complex systems, such as ecosystems, financial markets and the human brain, emerge from the interactions of numerous components. We often lack the knowledge to build reliable models for the behaviour of such network systems. This makes it difficult to predict potential instabilities. We show that one could use the natural fluctuations in multivariate time series to reveal network regions with particularly slow dynamics. The multidimensional slowness points to the direction of minimal resilience, in the sense that simultaneous perturbations on this set of nodes will take longest to recover. We compare an autocorrelation-based method with a variance-based method for different time-series lengths, data resolution and different noise regimes. We show that the autocorrelation-based method is less robust for short time series or time series with a low resolution but more robust for varying noise levels. This novel approach may help to identify unstable regions of multivariate systems or to distinguish safe from unsafe perturbations.

Divergent effects of AKI to CKD models on inflammation and fibrosis.

Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with 99mTc-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 ( HMGB1), and colony stimulating factor-1 ( CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.

Cryopreservation of saltwater crocodile (Crocodylus porosus) spermatozoa.

The aim of the present study was to develop a protocol for the successful cryopreservation of Saltwater crocodile spermatozoa. Sperm cells were frozen above liquid nitrogen vapour in phosphate-buffered saline (PBS) containing either 0.3M trehalose, 0.3M raffinose or 0.3M sucrose and compared with glycerol (0.3-2.7M). Although the highest levels of mean post-thaw motility were observed following cryopreservation in 0.3M trehalose (7.6%) and 0.3M sucrose (7.3%), plasma membrane integrity (PI) was best following cryopreservation in 2.7M glycerol (52.5%). A pilot study then assessed the cytotoxicity of glycerol and sucrose prior to cryopreservation and revealed no loss of survival when spermatozoa were diluted in 0.68M glycerol or 0.2-0.3M sucrose once cryoprotectants were washed out with PBS or Biggers, Whitten and Whittingham medium containing sperm capacitation agents (BWWCAP). A final study refined the combined use of permeating (0.68 or 1.35M glycerol) and non-permeating (0.2 or 0.3M sucrose) cryoprotectants. Spermatozoa were cryopreserved in liquid nitrogen vapour at rates of approximately -21°Cmin-1 (fast freeze) or -6.0°Cmin-1 (slow freeze). Post-thaw survival was highest with a combination of 0.2M sucrose and 0.68M glycerol and when these cryoprotectants were washed out with BWWCAP, regardless of whether spermatozoa were frozen using a fast (motility 14.2±4.7%; PI 20.7±2.0%) or slow (motility 12.0±2.7%; PI 22±4%) cryopreservation rate.

The sudden collapse of pollinator communities.

Declines in pollinator populations may harm biodiversity and agricultural productivity. Little attention has, however, been paid to the systemic response of mutualistic communities to global environmental change. Using a modelling approach and merging network theory with theory on critical transitions, we show that the scale and nature of critical transitions is likely to be influenced by the architecture of mutualistic networks. Specifically, we show that pollinator populations may collapse suddenly once drivers of pollinator decline reach a critical point. A high connectance and/or nestedness of the mutualistic network increases the capacity of pollinator populations to persist under harsh conditions. However, once a tipping point is reached, pollinator populations collapse simultaneously. Recovering from this single community-wide collapse requires a relatively large improvement of conditions. These findings may have large implications for our view on the sustainability of pollinator communities and the services they provide.

Dissolution of composition B detonation residuals.

Composition B (Comp B) detonation residuals pose environmental concern to the U.S. Army because hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a constituent, has contaminated groundwater near training ranges. To mimic their dissolution on surface soils, we dripped water at 0.51 ml/h onto individual Comp B particles (0.1-2.0 mg) collected from the detonation of 81-mm mortars. Analyses of the effluent indicate thatthe RDX and 2,4,6-trinitrotoluene (TNT) in Comp B do not dissolve independently. Rather, the relatively slow dissolution of RDX controls dissolution of the particle as a whole by limiting the exposed area of TNT. Two dissolution models, a published steady-flow model and a drop-impingement model developed here, provide good agreementwith the data using RDX parameters for time scaling. They predict dissolution times of 6-600 rainfall days for 0.01-100 mg Comp B particles exposed to 0.55 cm/h rainfall rate. These models should bracket the flow regimes for dissolution of detonation residuals on soils, but they require additional data to validate them across the range of particle sizes and rainfall rates of interest.

Comparison of stress induced by manual restraint and immobilisation in the estuarine crocodile, Crocodylus porosus.

This study compared the stress induced in captive estuarine crocodiles, Crocodylus porosus, by two different handling methods: manual restraint (noosing with ropes) and immobilization by electro-stunning. To stun, a short charge (approx. 6 s) at 110 V was delivered to the back of the necks of C. porosus using a custom-built device, which immobilized the animals for 5-10 min. Immobilized and restrained animals were measured and sexed, and the condition of the skin assessed. Blood samples were taken from some animals immediately after restraint or immobilization. Other animals were returned to their pens to recover for periods of 30 min, 1, 4, 12, 24 or 48 hours after which they were stunned and blood samples taken. Individual animals (mean body length 1.96 m, N=99) were bled only once. Haematocrit and haemoglobin concentrations were measured and plasma samples were analysed for corticosterone, glucose and lactate levels. Following restraint, there were significant increases in haematocrit, haemoglobin, glucose, lactate and corticosterone concentrations in C. porosus. For restrained animals, recovery to baseline levels occurred after approximately 8 hours. The stress response of stunned animals was significantly reduced compared to manually captured and restrained crocodiles. Both groups showed a significant increase in haematocrit, haemoglobin concentration and lactate levels, however the magnitude of change was significantly reduced, and recovery was faster in stunned animals. No increase in either glucose or corticosterone levels occurred with immobilisation. The results imply that immobilization by electro-stunning is much less stressful.

Paget's disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis.

A 1974 survey of Paget's disease of bone in 31 UK towns identified a cluster of six Lancashire former cotton mill towns with the highest prevalence rates of the disease and noted a link with the cotton industry. The two highest-prevalence towns are situated on estuaries and are jointly the smallest of the six by the size of their former cotton industry. The two lowest-prevalence towns of the six are highest above sea level and jointly the largest by the size of their former cotton industry. This pattern suggests a waterborne agent. A 1993 repeat survey of 10 of the 31 towns identified a general decline in prevalence, greatest in the three cotton towns included from the six in the earlier survey, further suggesting a link to the cotton industry. Cotton mills and bleach/dyeworks produced a large volume of wastewater that was commonly discharged into adjacent waterways. Wastewater contained process chemicals and imported organisms and pesticides carried in cotton bales. The process chemicals and imported organisms could be discounted as a probable factor in Paget's disease; however, pesticides could not be discounted. Lancashire cotton came predominantly from the American cotton belt. From 1917 to 1945, calcium arsenate pesticide was used intensively to combat the boll weevil and was imported to Lancashire in cotton bales. The calcium arsenate era is consistent with the high-prevalence findings in 1974 and the decline in 1993, allowing for time lags. Geochemical arsenate is widespread in the environment and may account for geographic variations in Paget's prevalence, although data are inadequate for correlation studies. Noncytotoxic doses of arsenic affect all the steroid receptors and some signal transduction pathways, which may lead to dysfunctional osteoclast signaling and differentiation. Human cells are more susceptible than animal cells to arsenic, based on studies of nonbone cells. It is speculative that arsenic may be a factor in the abnormal variation in prevalence rates in Lancashire. It is not a general theory of Paget's disease.

HuR binds a cyclic nucleotide-dependent, stabilizing domain in the 3' untranslated region of Na(+)/glucose cotransporter (SGLT1) mRNA.

Differentiation-dependent expression of the Na(+)/glucose cotransporter (SGLT1) is accompanied by a large, cAMP-dependent increase in stability of its mRNA. Stabilization is mediated by protein binding to a critical uridine-rich element (URE) in its 3' untranslated region. In the present study, we demonstrate that HuR, an RNA binding protein of the embryonic lethal abnormal vision family, binds the SGLT1 URE. HuR binding was increased after elevation of intracellular cAMP levels and was dependent on protein phosphorylation. This interaction was prevented by a substitution mutation previously shown to block cAMP-dependent reporter message stabilization. These results implicate HuR as a key mediator of cAMP-dependent SGLT1 mRNA stabilization.

Standardized Mini-Mental State Examination. Use and interpretation.

OBJECTIVE: To review administration of the Standardized Mini-Mental State Examination (SMMSE) for dementia and depression and to evaluate how well it interprets older people's cognitive function. QUALITY OF EVIDENCE: Literature from January 1990 to December 1999 was searched via MEDLINE using the MeSH headings Alzheimer Disease, Vascular Dementia, Lewy Bodies, and Depression. Several studies have described the reliability and validity of the SMMSE. MAIN MESSAGE: The SMMSE, a standardized approach to scoring and interpreting older people's cognitive function, provides a global score of cognitive ability that correlates with daily function. Careful interpretation of results of the SMMSE, together with history and physical assessment, can assist in differential diagnosis of cognitive impairment resulting from Alzheimer's disease, vascular dementia, dementia with Lewy bodies, or depression. Repeated measurements can be used to assess change over time and response to treatment. CONCLUSION: The SMMSE is a valuable tool for family doctors who are often the first medical professionals to identify changes in patients' cognitive function. The SMMSE requires little time to complete and is a key component of a comprehensive dementia workup. Determining whether a patient has dementia is important because there are now effective medications that are most beneficial if started early.

The Zarit Burden Interview: a new short version and screening version.

PURPOSE: The purpose of the study was to develop a short and a screening version of the Zarit Burden Interview (ZBI) that would be suitable across diagnostic groups of cognitively impaired older adults, and that could be used for cross-sectional, longitudinal, and intervention studies. DESIGN AND METHODS: We used data from 413 caregivers of cognitively impaired older adults referred to a memory clinic. We collected information on caregiver burden with the 22-item ZBI, and information about dependence in activities of daily living (ADLs) and the frequency of problem behaviors among care recipients. We used factor analysis and item-total correlations to reduce the number of items while taking into consideration diagnosis and change scores. RESULTS: We produced a 12-item version (short) and a 4-item version (screening) of the ZBI. Correlations between the short and the full version ranged from 0.92 to 0.97, and from 0.83 to 0.93 for the screening version. Correlations between the three versions and ADL and problem behaviors were similar. We further investigated the behavior of the short version with a two-way analysis of variance and found that it produced identical results to the full version. IMPLICATIONS: The short and screening versions of the ZBI produced results comparable to those of the full version. Reducing the number of items did not affect the properties of the ZBI, and it may lead to easier administration of the instrument.

Dual incorporation of photoaffinity ligands on dopamine transporters implicates proximity of labeled domains.

We have recently developed novel high-affinity blockers for the dopamine transporter (DAT) by carrying out structure-activity studies of GBR 12909 molecule piperidine analogs. To investigate the molecular basis of binding of these compounds in comparison to known sites of action of GBR 12909, cocaine, and benztropine analogs, we developed a piperidine-based photoaffinity label [(125)I]4-[2-(diphenylmethoxy)ethyl]-1-[(4-azido- 3-iodophenyl)methyl]-piperidine [(125)I]AD-96-129), and used proteolysis and epitope-specific immunoprecipitation to identify the protein domains that interact with the ligand. [(125)I]AD-96-129 became incorporated into two different regions of the DAT primary sequence, an N-terminal site containing transmembrane domains (TMs) 1 to 2, and a second site containing TMs 4 to 6. Both of these regions have been identified previously as sites involved in the binding of other DAT photoaffinity labels. However, in contrast to the previously characterized ligands that showed nearly complete specificity in their binding site incorporation, [(125)I]AD-96-129 became incorporated into both sites at comparable levels. These results suggest that the two domains may be in close three-dimensional proximity and contribute to binding of multiple uptake blockers. We also found that DATs labeled with [(125)I]AD-96-129 or other photoaffinity labels displayed distinctive sensitivities to proteolysis of a site in the second extracellular loop, with protease resistance related to the extent of ligand incorporation in the TM4 to 6 region. These differences in protease sensitivity may indicate the relative proximity of the ligands to the protease site or reflect antagonist-induced conformational changes in the loop related to transport inhibition.

Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label.

The dopamine transporter (DAT) has been implicated strongly in cocaine's reinforcing effects. Many derivatives of piperidine analogs of GBR 12909 have been developed and were found to be quite potent and selective for the DAT. In this regard, most of these derivatives were found to be much more selective for the DAT than conventional GBR compounds e.g. GBR 12909 when their selectivity was compared with the serotonin transporter (SERT). A brief structure-activity relationship (SAR) study has been carried out in the development of a novel photoaffinity ligand which illustrated the effect of the presence of a sterically bulky iodine atom next to the azido group in activity and selectivity for the DAT. This SAR study also led to the development of the compound 4 which is one of the most potent and selective blockers for the DAT known today. The photoaffinity ligand [125I]AD-96-129 was incorporated into the DAT molecule as was demonstrated by immunoprecipitation with serum 16 which is specific for DAT. This photolabeling was antagonized by DAT-specific blockers and was unaffected by specific SERT and norepinephrine transporter (NET) blockers indicating interaction of this novel ligand with the DAT.

Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus.

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

A cis-dominant cyclic nucleotide-dependent regulatory domain in the 3'-untranslated region of Na(+)/glucose cotransporter (SGLT1) mRNA.

A 122 nt uridine-rich sequence (URE) in the Na(+)/glucose cotransporter (SGLT1) mRNA 3'-untranslated region is critical for cAMP-dependent message stabilization. Its function was investigated in LLC-PK(1) cells stably expressing beta-globin reporter transcripts. Insertion of the SGLT1 URE downstream from an unrelated destabilizing sequence, the c-fos ARE, evoked cAMP-dependent message stabilization. Stabilization was blocked by a substitution mutation within the SLGT1 URE. These observations indicate that the SGLT1 URE is sufficient to transmit cAMP-dependent, cis-dominant mRNA stabilization in the presence of appropriate trans-acting factors and appears to function independently of the nature of the destabilizing domain.

Receipt of preventive health care services by lesbians.

BACKGROUND: We measured receipt of age-appropriate preventive health services by lesbians and assessed whether provider and individual characteristics, including disclosure of sexual orientation, are independently associated with receipt of these services. METHODS: A questionnaire was printed in a national biweekly gay, lesbian, and bisexual news magazine, and self-identified lesbians living in all U. S. states (N =6935) responded to the survey. Main outcome variables were receipt of a Pap smear within the preceding 1 and 2 years and, for women aged > or= 50, receipt of a mammogram within the past 1 and 2 years. RESULTS: Fifty-four percent had Pap smears within 1 year and 71% within 2 years, with increasing rates among older and more educated respondents. Seventy percent of respondents aged > or = 50 had a mammogram in the past year, and 83% within 2 years; rates did not vary significantly controlling for education. Sixty percent had disclosed their sexual orientation to their regular health care provider. Controlling for patient and provider characteristics, disclosure was independently associated with receipt of Pap smears, but not mammograms. CONCLUSIONS: It is important for providers to identify their lesbian patients' unmet needs for preventive health care. Additionally, it is important for providers to provide complete and appropriate preventive health care for their lesbian patients. Further research is needed to determine why lesbians are not receiving Pap smears at the recommended rate and whether this disparity is reflective of aspects of cervical cancer screening or indicates a more general problem with access to health care including receipt of preventive services.

Sevoflurane-N2O versus propofol/isoflurane-N2O during elective surgery using the laryngeal mask airway in adults.

STUDY OBJECTIVES: To compare a sevoflurane-nitrous oxide (N2O) general anesthetic technique with a standard technique of propofol for induction, and isoflurane-N2O for maintenance. DESIGN: Prospective, randomized study. SETTING: University-affiliated tertiary-care hospital. PATIENTS: 62 adults undergoing elective surgery using the laryngeal mask airway (LMA). INTERVENTIONS: Patients received either the standard technique of propofol for induction and isoflurane-N2O for maintenance (controls) or sevoflurane-N2O for both induction and maintenance of general anesthesia. MEASUREMENTS: Induction and emergence times, heart rate, blood pressure, oxygen saturation, and end-tidal carbon dioxide were recorded. MAIN RESULTS: Time to loss of consciousness was faster after propofol (mean +/- SEM: 51 +/- 3 sec) than after sevoflurane-N2O (85 +/- 10 sec; p < 0.05). Ready for surgery times, were however, similar between groups (10 +/- 1 vs. 11 +/- 1 min, respectively). All patients in the control group had apnea after LMA insertion compared with 4 patients in the sevoflurane-N2O group (p < 0.05). Heart rate was lower 5 and 10 minutes after LMA insertion in the sevoflurane-N2O group (69 +/- 3 and 66 +/- 3 bpm) versus the control group (81 +/- 3 bpm and 74 +/- 3 bpm, p < 0.05). After cessation of anesthetic gases, there were no differences in time to LMA removal, eye opening, or exiting the operating room (OR) between the control group (7, 8, and 10 min) and sevoflurane-N2O groups (7, 8, and 12 min, respectively). The majority of patients in both groups (92% to 97%) rated their anesthetic experience as excellent or good. CONCLUSIONS: Sevoflurane-N2O and propofol provided comparable conditions for LMA insertion. Sevoflurane-N2O was not associated with a faster return of consciousness or faster time to exit the OR compared with isoflurane-N2O.