Evidence for widespread changes in the structure, composition, and fire regimes of western North American forests.

Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.

How Much Greater is Obstetric Intervention in Women with Medical Disorders in Pregnancy When Compared to the General Population?

Introduction The purpose of this study was to compare obstetric and neonatal outcomes between women attending a specialised maternal medicine service and the general obstetric population. Methods Women attending from January 2011 to December 2016 were identified from the clinic database. Medical diagnosis, demographics, obstetric and neonatal outcomes were compared with data from hospital annual report 2014. Results 1873 women were compared with 8632 women who delivered at the hospital in 2014. Delivery before 34 weeks [82 (4.5%) vs 189 (2.2%)], induction of labour [761 (40.6%) vs 2664 (30.9%)] and delivery by Caesarean Section (CS) [664 (35%) vs 2479 (29%)] were higher p<0.001; but elective CS [334 (18%) vs 1425 (17%), p=0.18] did not differ between the two groups. Neonatal outcomes were similar. Conclusion Premature delivery, induction of labour and CS rates are higher in women with medical disorders in pregnancy. Encouragingly, 77% of women attempting vaginal birth in this group were successful.

Neutralization of ASC improves sperm motility in men with spinal cord injury.

STUDY QUESTION: Does neutralization of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) improve sperm motility in men with spinal cord injury (SCI)? SUMMARY ANSWER: Neutralization of ASC improves sperm motility in men with SCI. WHAT IS KNOWN ALREADY: Semen of men with SCI contains normal sperm concentrations but abnormally low sperm motility. Inflammatory cytokines, activated via the inflammasome complex, are contributory. A key component of the inflammasome is ASC. STUDY DESIGN, SIZE, DURATION: This prospective study included semen samples collected from 32 men with SCI. PARTICIPANTS/MATERIALS, SETTING, METHODS: At a major university medical center, untreated semen was compared with semen treated with anti-ASC polyclonal antibody. Semen treated with IgG was used as a control. MAIN RESULTS AND THE ROLE OF CHANCE: Addition of anti-ASC polyclonal antibody to semen significantly increased mean sperm motility from 11.5% (95% CI, 6.3-16.7) to 18.3% (95% CI, 11.8-24.8). Improvements were most pronounced in the subgroup whose starting motility ranged between 6 and 40%. In this subgroup, the mean sperm motility improved from 13.3% (95% CI, 9.3-17.3) to 23.9% (95% CI, 14.7-23.0). Sperm motility did not improve after treatment with IgG. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the small sample size as this is a rare population. WIDER IMPLICATIONS OF THE FINDINGS: Blockade of the inflammasome via treatment with anti-ASC improved sperm motility in men with SCI. In doing so, this treatment significantly increased their total motile sperm count. This is the first study to demonstrate that interference with the inflammasome improves sperm motility in men with SCI. This treatment has potential as a therapeutic intervention. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Craig H. Neilsen Foundation, Grant # 224598, the University of Miami Miller School of Medicine and the Miami Project to Cure Paralysis, Miami, FL, USA. R.W.K. and J.P.d.R.V. hold a patent for the treatment of inflammation after central nervous system injury using antibodies against inflammasome proteins. The other authors have no conflicts of interest to declare.

An awareness and prevalence study of Irish cold-water athletes and external auditory canal exostoses.

OBJECTIVE: This study aimed to determine the awareness, otological symptoms and prevalence of external auditory canal exostoses in Irish cold-water athletes. METHOD: An online and in person cross-sectional survey was undertaken with Irish cold-water athletes to explore athletes' awareness, known prevalence of external auditory canal exostoses and attitudes towards preventive measures. RESULTS: Of the 926 participants surveyed, 67.5 per cent were aware of external auditory canal exostoses. Triathletes reported the lowest awareness (39.9 per cent) among water athletes. A total of 9.7 per cent (n = 90) had previously been diagnosed with external auditory canal exostoses and 46.7 per cent (n = 42) were non-surfers. Ear symptoms were reported in 76 per cent of athletes. Otoscopic examinations showed that 23.7 per cent had external auditory canal exostoses, 3.6 per cent of whom were aware of their diagnosis. CONCLUSION: The majority of Irish surfing athletes are aware of external auditory canal exostoses. There is less awareness with regard to Ireland's newly emerging sports such as open water swimming and triathlons. Over 90 per cent of athletes surveyed had no idea they had external auditory canal exostoses, which highlights the need to increase public awareness.

Inappropriate colonoscopic surveillance of hyperplastic polyps.

Colonoscopic surveillance of hyperplastic polyps alone is controversial and may be inappropriate. The colonoscopy surveillance register at a university teaching hospital was audited to determine the extent of such hyperplastic polyp surveillance. The surveillance endoscopy records were reviewed, those patients with hyperplastic polyps were identified, their clinical records were examined and contact was made with each patient. Of the 483 patients undergoing surveillance for colonic polyps 113 (23%) had hyperplastic polyps alone on last colonoscopy. 104 patients remained after exclusion of those under appropriate surveillance. 87 of the 104 patients (84%) were successfully contacted. 37 patients (8%) were under appropriate colonoscopic surveillance for a significant family history of colorectal carcinoma. 50 (10%) patients with hyperplastic polyps alone and no other clinical indication for colonoscopic surveillance were booked for follow up colonoscopy. This represents not only a budgetary but more importantly a clinical opportunity cost the removal of which could liberate valuable colonoscopy time for more appropriate indications.

Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.

Astrocytes produce interferon that enhances the expression of H-2 antigens on a subpopulation of brain cells.

Using primary culture methods, we show that purified astrocytes from embryonic mouse or rat central nervous system (CNS) can be induced to produce interferon (IFN) activity when pretreated with a standard IFN-superinducing regimen of polyribonucleotide, cycloheximide, and actinomycin D, whereas IFN activity was not inducible in neuronal cultures derived from mouse CNS. Astrocyte IFN displays inductive, kinetic, physicochemical, and antigenic properties similar to those of IFN-alpha/beta, but is dissimilar to lymphocyte IFN (IFN-gamma). Treatment of pure astrocytic cultures or astrocytes cultured with neurons with astrocyte IFN or IFN-alpha/beta induced a dramatic increase in the expression of H-2 antigens on a subpopulation of astrocytes. Neither neurons nor oligodendroglia expressed detectable levels of H-2 antigens when exposed to astrocyte IFN, IFN-alpha/beta, or to IFN-beta. Injection of astrocyte IFN or IFN-alpha/beta directly into brains of newborn mice indicated that H-2 antigens were also induced in vivo. None of the IFNs (astrocyte, alpha/beta, or beta) tested induced Ia antigens on CNS cells in vitro or in vivo. Since H-2 antigens have a critical role in immune responses, astrocyte IFN may initiate and participate in immune reactions that contribute to immunoprotective and immunopathological responses in the CNS.

Neural differentiation, NCAM-mediated adhesion, and gap junctional communication in neuroectoderm. A study in vitro.

We studied the development of NCAM and gap junctional communication, and their mutual relationship in chick neuroectoderm in vitro. Expression of NCAM, as detected by monoclonal and polyclonal antibodies, and development of junctional communication, as detected by extensive cell-to-cell transfer of 400-500-D fluorescent tracers, occurred in cultures from stage-2 embryos onward. Both expressions presumably required primary induction. The differentiating cells formed discrete fields of expression on the second to third day in culture, with the NCAM fields coinciding with the junctional communication fields delineated by the tracers. Other neural differentiations developed in the following order: tetanus toxin receptors, neurofilament protein, and neurite outgrowth. Chronic treatment with antibody Fab fragments against NCAM interfered with the development of communication, suggesting that NCAM-mediated adhesion promotes formation of cell-to-cell channels. Temperature-sensitive mutant Rous sarcoma virus blocked (reversibly) communication and the subsequent development of neurofilament protein and neurites, but expression of NCAM continued.

Apoptotic and anti-apoptotic mechanisms following spinal cord injury.

A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that inhibit cell death pathways. In the present study, we examined caspase and IAP expression in spinal cords of rats subjected to moderate traumatic injury. Within 6 h after injury, caspase-8 and-9 (2 initiators of apoptosis) were predominantly present in gray matter neurons within the lesion epicenter. By 3 days following spinal cord injury (SCI), caspase-8 and-9 immunoreactivity was localized to gray and white matter cells, and by 7 days following SCI, both upstream caspases were expressed in cells within white matter or within foamy macrophages in gray matter. Caspase-3, an effector caspase, was evident in a few fragmented cells in gray matter at 24 h following injury and then localized to white matter in later stages. Thus, distinct patterns of caspase expression can be found in the spinal cord following injury. XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the cord. Immunoblots of spinal cord extracts revealed that the processed forms of caspases-8 and-9 and cleavage of PARP are present as early as 6 h following trauma. The expression of caspases corresponded with the detection of cleavage of XIAP into 2 fragments following injury. cIAP-1 and cIAP-2 expression remained constant during early periods following SCI but demonstrated alterations by 7 days following SCI. Our data are consistent with the idea that XIAP may have a protective role within the spinal cord, and that alteration in cleavage of XIAP may regulate cell death following SCI.

Apoptotic and antiapoptotic mechanisms after traumatic brain injury.

Caspase and inhibitor of apoptosis (IAP) expression was examined in rats subjected to moderate traumatic brain injury (TBI) using a parasagittal fluid-percussion brain insult (1.7 to 2.2 atm). Within 1 hour after injury, caspase-8 and -9, two initiators of apoptosis, were predominantly expressed in superficial cortical areas adjacent to the impact site and in the thalamus. Caspase-3, an effector caspase, was evident at 6 hours throughout the traumatized cerebral cortex and hippocampus. Moreover, the authors observed that XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the brain. Colocalization of XIAP-immunolabled cells with cell-specific markers indicated that XIAP is expressed within neurons and a subpopulation of oligodendrocytes. Immunoblots of brain extracts revealed that the processed forms of caspase-8, -9, and -3 are present as early as 1 hour after trauma. The appearance of activated caspases corresponded with the detection of cleavage of XIAP into fragments after injury and a concomitant increase in the levels of cIAP-1 and cIAP-2 in the traumatized hemispheres. The current data are consistent with the hypotheses that caspases in both the extrinsic and intrinsic apoptotic pathways are activated after moderate TBI and that IAPs may have a protective role within the brain with alterations in levels and cleavage of IAPs that contribute to cell death in this setting.

Resistance and susceptibility of neural cells to lysis by cytotoxic lymphocytes and by cytolytic granules.

The susceptibility of neural cells to immune-mediated lysis by alloantigen-specific cytotoxic lymphocytes is important in understanding cell-mediated immune responses during rejection of transplanted neural tissues and in inflammatory responses of the central (CNS) and peripheral (PNS) nervous systems. In this study, we used 51Cr-release and granzyme A assays to examine whether primary cultures of astrocytes and CNS and PNS neurons could serve as targets for alloantigen-specific CTLs and granule-mediated lysis. The level of astrocyte killing by alloantigen-specific CTLs correlated with expression of the class I gene products of the major histocompatibility complex. Astrocytes cultured for 1-2 weeks did not express class I MHC antigens and were not susceptible to lysis by activated alloantigen-specific CTLs. Lengthening the astrocyte culture period to 3 weeks resulted in class I MHC antigen expression on the astrocyte surface and alloantigen-specific lysis. Astrocytes of all ages tested were susceptible to lysis by isolated cytolytic lymphocyte granules. PNS neurons of various ages tested also served as targets for CTLs and were lysed by isolated granules. In contrast, CNS neurons did not express class I MHC antigens and were highly resistant to killing by CTLs and lymphocyte granules. CNS neurons and astrocytes did not trigger specific granzyme A secretion from effector cells. In the presence of leucoagglutinin, CTLs-specific recognition of target cells is bypassed, and virtually any cell, regardless of its antigens, is killed nonspecifically. Although leucoagglutinin-treated CNS neurons and astrocytes triggered increased granzyme A secretion from effector cells, only astrocytes were lysed in an antigen-nonspecific manner, whereas CNS neurons remained strikingly resistant. These results suggest differences in the susceptibility of PNS and CNS neurons to T cell-mediated lysis. CNS neurons appear to possess protective mechanisms that render them refractory to CTL-mediated lysis and granule-mediated lysis, whereas PNS neurons and astrocytes are far more susceptible to both types of immune attack.

Differentiation of an immortalized CNS neuronal cell line decreases their susceptibility to cytotoxic T cell lysis in vitro.

RN33B cells are a temperature-sensitive neuronal cell line derived from rat E12 medullary raphe nucleus (Whittemore and White (1993) Brain Research 615, 27-40). Undifferentiated RN33B cells express class I but not class II antigens of the major histocompatibility complex (MHC), and intercellular adhesion molecule-1 (ICAM-1), a ligand for lymphocyte function associated antigen-1 (LFA-1), expressed on cytotoxic T lymphocytes (CTLs). Treatment of undifferentiated RN33B cells with interferon-gamma (IFN-gamma) upregulated both class I MHC and ICAM-1. After neuronal differentiation, expression of class I MHC antigens or ICAM-1 was undetected, even after IFN-gamma treatment. The neuronally differentiated RN33B cells were also markedly less susceptible to lysis by alloantigen-specific CTLs. These data suggest that intrinsic to the differentiation of CNS neurons is a mechanism to escape CTL-mediated cell lysis.

Pregnancies complicated by retained placenta: sex ratio and relation to pre-eclampsia.

Pre-eclampsia and placenta accreta have opposite histological features of placentation. This study set out to test the hypotheses that the sex ratios in these two pregnancy complications are opposite and that these conditions are mutually exclusive. A population-based database covering all deliveries in South Australia between 1986 and 1995 and the hospital-based obstetric database of the Adelaide Women's and Children's Hospital, covering 8549 births between 1993 and 1995, were used to ascertain the sex ratios in singleton pregnancies and the sex ratios in those pregnancies in which there was retained placenta, hypertension in pregnancy, or pre-eclampsia. The likelihood of independence of occurrence or mutual exclusivity of retained placenta and hypertension in pregnancy or pre-eclampsia were also examined. The male:female sex ratio in the South Australian population was 1.077. In pregnancies with hypertension in pregnancy it was 1.165 (P<0.001) and in pregnancies with retained placenta it was 0.883 (P<0.0001). There was a trend to an increased sex ratio in pre-eclamptic pregnancy (1.248 in primigravid and 1.092 in multigravid women) but there was insufficient power to detect significance (P=0.207 and 0.470, respectively). Neither hypertension in pregnancy nor pre-eclampsia were mutually exclusive of placenta accreta: hypertensive disorders of pregnancy and placenta accreta occurred independently of each other. Our findings suggest that sex-linked antigens are unlikely to influence maternofetal interactions consistently to give rise to one but not the other pregnancy complication.

Regulation and selective expression of Ly-6A/E, a lymphocyte activation molecule, in the central nervous system.

The Ly-6 locus encodes a group of cell surface molecules found predominantly on lymphoid cells in the mouse. These proteins share several structural and functional characteristics with Thy-1, a molecule expressed in both lymphoid and neuronal tissue. Utilizing anti-Ly-6A/E monoclonal antibodies, the present results demonstrate in situ expression of these molecules in brain tissue. The findings also indicated that these molecules are not expressed during embryonic or neonatal stages of development. Moreover, although Ly-6b haplotype mice exhibited staining primary associated with vascular elements throughout the brain, Ly-6a mice exhibited staining predominantly associated with white matter limited to the hippocampal and midbrain regions. Although cultured glial and neuronal cells expressed marginally detectable levels of Ly-6A/E, the majority of GFAP+ cells in these cultures expressed high levels of Ly-6A/E following incubation with cytokines including rIFN-gamma. In addition, northern blot analysis of RNA from enriched astrocytic cultures corroborated the induction of Ly-6A/E expression. These findings have therefore established that Ly-6 is amongst those groups of genes expressed in both brain and lymphoid tissues.

Intestinal lactase, sucrase and alkaline phosphatase in relation to age, sex and site of intestinal biopsy in 477 Irish subjects.

Small intestinal lactase, sucrase and alkaline phosphatase activities were measured in histologically normal peroral intestinal biopsies from 477 individuals. Enzyme activities varied with age, sex, site of biopsy, and were lowest in post-weaning children and highest in young adults. Lactase activity does not decrease with advancing age.

Intestinal lactase, sucrase, and alkaline phosphatase in 373 patients with coeliac disease.

Lactase, sucrase, and alkaline phosphatase activities were measured in 833 peroral small intestinal biopsies from 373 patients with coeliac disease. Enzyme activities decreased with increasing degrees of mucosal damage. Enzyme activities in mucosae of patients with coeliac disease in remission were lower than in control groups matched for age, sex, and site of biopsy. Enzyme activities were measured in 81 patients when the mucosa was severely damaged and later when considerable improvement had occurred. Lactase activity remained low in 13% of patients under the age of 18 and in 33% of those over 18 years. Sucrase activity usually improved with histological recovery, but alkaline phosphatase activity tended to remain depressed in patients in whom lactase activity failed to improve.

Perioperative immune modulation.

BACKGROUND: The effects of operative trauma on systemic immunity were studied. The relative effects of skin incision and of breaching the peritoneum were determined. In addition, the role of the antiendotoxic agent taurolidine in preventing postoperative immune suppression was assessed. METHODS: Systemic immune responsiveness was measured as the delayed-type hypersensitivity (DTH) response to 2-4 dinitro l-fluorobenzene (DNFB) with an in vivo rat model. The effect of both laparotomy and taurolidine on the hepatic Kupffer cell population was determined by immunohistochemistry. RESULTS: This study confirmed that cellular immunity is significantly depressed after laparotomy (15.5%; range, 2.5%-24.0%) compared with unoperated controls (26.77%; range, 9.2%-38.0%). Opening the peritoneum appeared to be a critical factor in inducing this immunosuppression, in which animals undergoing a similar midline incision without opening of the peritoneum displayed minimal alteration in their DTH response (20.5%; range, 0.85%-41.5%). In addition, intraperitoneal administration of taurolidine in the perioperative period prevented this decrease in postoperative DTH response. Kupffer cell numbers were increased after intraperitoneal administration of taurolidine, compared with animals treated with intraperitoneal saline solution or unoperated controls. CONCLUSIONS: These findings confirm the presence of an operatively induced decrease in immune responsiveness and suggest that entering the peritoneum is an important factor in the induction of this effect. In addition, administration of taurolidine acts to prevent the impact of laparotomy on DTH response, possibly by preventing perioperative portal endotoxemia.

Impairment of human lymphocyte function by bile salts.

Since there appears to be an association between depressed lymphocyte function and liver disease, the effect of bile salts on lymphocyte function was determined in vitro. Peripheral lymphocytes from normal volunteers were incubated with varying concentrations of three bile salts (chenodeoxycholate, deoxycholate, or ursodeoxycholate) and stimulated by the mitogens phytohemagglutinin or concanavalin. The three bile salt concentrations used in these experiments were 75, 100, and 250, mumol/L, which are similar to serum levels found in various types of liver disease. Blast transformation, as measured by tritiated thymidine incorporation, was significantly depressed by all three bile salts at all concentrations and with both mitogens. Suppression increased with the higher bile salt concentrations. However, ursodeoxycholate suppressed lymphocyte function significantly less than did either chenodeoxycholate or deoxycholate. These data suggest that elevated serum bile levels associated with liver disease may contribute to immunosuppression and that ursodeoxycholate, an epimer of chenodeoxycholate that is used for gallstone dissolution, depresses lymphocyte function significantly less than does chenodeoxycholate.

Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats.

The aim of this study was to determine whether hypoxic-ischemia from asphyxial cardiac arrest activates brain caspases-1 and -3, and the anti-apoptotic protein, XIAP. Asphyxial cardiac arrest in rats was used to induce hypoxic-ischemia. A pan-caspase inhibitor (zVAD) was given in the treatment group. At 72 h after reperfusion, caspase-3 and XIAP expression were present in multiple vulnerable brain regions, whereas caspase-1 was predominantly found in the CA1 hippocampus. zVAD significantly reduced expression of caspases and XIAP and the number of ischemic neurons in the CA1 hippocampus while neurological deficit scores were improved. We conclude that hypoxic-ischemia increases caspases-1 and-3, and XIAP expression. Treatment with zVAD significantly decreases caspase and XIAP expression in these brain regions and improves neurological outcome.