Out of Their Depth? Isolated Deep Populations of the Cosmopolitan Coral Desmophyllum dianthus May Be Highly Vulnerable to Environmental Change

Deep sea scleractinian corals will be particularly vulnerable to the effects of climate change, facing loss of up to 70% of their habitat as the Aragonite Saturation Horizon (below which corals are unable to form calcium carbonate skeletons) rises. Persistence of deep sea scleractinian corals will therefore rely on the ability of larvae to disperse to, and colonise, suitable shallow-water habitat. We used DNA sequence data of the internal transcribed spacer (ITS), the mitochondrial ribosomal subunit (16S) and mitochondrial control region (MtC) to determine levels of gene flow both within and among populations of the deep sea coral Desmophyllum dianthus in SE Australia, New Zealand and Chile to assess the ability of corals to disperse into different regions and habitats. We found significant genetic subdivision among the three widely separated geographic regions consistent with isolation and limited contemporary gene flow. Furthermore, corals from different depth strata (shallow <600 m, mid 1000–1500 m, deep >1500 m) even on the same or nearby seamounts were strongly differentiated, indicating limited vertical larval dispersal. Genetic differentiation with depth is consistent with the stratification of the Subantarctic Mode Water, Antarctic Intermediate Water, the Circumpolar Deep and North Pacific Deep Waters in the Southern Ocean, and we propose that coral larvae will be retained within, and rarely migrate among, these water masses. The apparent absence of vertical larval dispersal suggests deep populations of D. dianthus are unlikely to colonise shallow water as the aragonite saturation horizon rises and deep waters become uninhabitable. Similarly, assumptions that deep populations will act as refuges for shallow populations that are impacted by activities such as fishing or mining are also unlikely to hold true. Clearly future environmental management strategies must consider both regional and depth-related isolation of deep-sea coral populations

Rapid Transient Production in Plants by Replicating and Non-Replicating Vectors Yields High Quality Functional Anti-HIV Antibody

Background: The capacity of plants and plant cells to produce large amounts of recombinant protein has been well established. Due to advantages in terms of speed and yield, attention has recently turned towards the use of transient expression systems, including viral vectors, to produce proteins of pharmaceutical interest in plants. However, the effects of such high level expression from viral vectors and concomitant effects on host cells may affect the quality of the recombinant product. Methodology/Principal Findings: To assess the quality of antibodies transiently expressed to high levels in plants, we have expressed and characterised the human anti-HIV monoclonal antibody, 2G12, using both replicating and non-replicating systems based on deleted versions of Cowpea mosaic virus (CPMV) RNA-2. The highest yield (approximately 100 mg/kg wet weight leaf tissue) of affinity purified 2G12 was obtained when the non-replicating CPMV-HT system was used and the antibody was retained in the endoplasmic reticulum (ER). Glycan analysis by mass-spectrometry showed that the glycosylation pattern was determined exclusively by whether the antibody was retained in the ER and did not depend on whether a replicating or non-replicating system was used. Characterisation of the binding and neutralisation properties of all the purified 2G12 variants from plants showed that these were generally similar to those of the Chinese hamster ovary (CHO) cell-produced 2G12. Conclusions: Overall, the results demonstrate that replicating and non-replicating CPMV-based vectors are able to direct the production of a recombinant IgG similar in activity to the CHO-produced control. Thus, a complex recombinant protein was produced with no apparent effect on its biochemical properties using either high-level expression or viral replication. The speed with which a recombinant pharmaceutical with excellent biochemical characteristics can be produced transiently in plants makes CPMV-based expression vectors an attractive option for biopharmaceutical development and production

Primary spinal cord tumors of childhood: effects of clinical presentation, radiographic features, and pathology on survival

To determine the relationship between clinical presentation, radiographic features, pathology, and treatment on overall survival of newly diagnosed pediatric primary spinal cord tumors (PSCT). Retrospective analysis of all previously healthy children with newly diagnosed PSCT at a single institution from 1995 to present was performed. Twenty-five pediatric patients (15 boys, average 7.9 years) were diagnosed with PSCT. Presenting symptoms ranged from 0.25 to 60 months (average 7.8 months). Symptom duration was significantly shorter for high grade tumors (average 1.65 months) than low grade tumors (average 11.2 months) (P = 0.05). MRI revealed tumor (8 cervical, 17 thoracic, 7 lumbar, 7 sacral) volumes of 98–94,080 mm3 (average 19,474 mm3). Homogeneous gadolinium enhancement on MRI correlated with lower grade pathology (P = 0.003). There was no correlation between tumor grade and volume (P = 0.63) or edema (P = 0.36) by MRI analysis. Median survival was 53 months and was dependent on tumor grade (P = 0.05) and gross total resection (P = 0.01) but not on gender (P = 0.49), age of presentation (P = 0.82), duration of presenting symptoms (P = 0.33), or adjuvant therapies (P = 0.17). Stratified Kaplan–Meier analysis confirmed the association between degree of resection and survival after controlling for tumor grade (P = 0.01). MRI homogeneous gadolinium enhancement patterns may be helpful in distinguishing low grade from high grade spinal cord malignancies. While tumor grade and gross total resection rather than duration of symptoms correlated with survival in our series, greater than one-third of patients had reported symptoms greater than 6 months duration prior to diagnosis

Highly Pathogenic Avian Influenza Virus H5N1 Infection in a Long-Distance Migrant Shorebird under Migratory and Non-Migratory States

Corticosterone regulates physiological changes preparing wild birds for migration. It also modulates the immune system and may lead to increased susceptibility to infection, with implications for the spread of pathogens, including highly pathogenic avian influenza virus (HPAIV) H5N1. The red knot (Calidris canutus islandica) displays migratory changes in captivity and was used as a model to assess the effect of high plasma concentration of corticosterone on HPAIV H5N1 infection. We inoculated knots during pre-migration (N = 6), fueling (N = 5), migration (N = 9) and post-migration periods (N = 6). Knots from all groups shed similar viral titers for up to 5 days post-inoculation (dpi), peaking at 1 to 3 dpi. Lesions of acute encephalitis, associated with virus replication in neurons, were seen in 1 to 2 knots per group, leading to neurological disease and death at 5 to 11 dpi. Therefore, the risk of HPAIV H5N1 infection in wild birds and of potential transmission between wild birds and poultry may be similar at different times of the year, irrespective of wild birds' migratory status. However, in knots inoculated during the migration period, viral shedding levels positively correlated with pre-inoculation plasma concentration of corticosterone. Of these, knots that did not become productively infected had lower plasma concentration of corticosterone. Conversely, elevated plasma concentration of corticosterone did not result in an increased probability to develop clinical disease. These results suggest that birds with elevated plasma concentration of corticosterone at the time of migration (ready to migrate) may be more susceptible to acquisition of infection and shed higher viral titers—before the onset of clinical disease—than birds with low concentration of corticosterone (not ready for take-off). Yet, they may not be more prone to the development of clinical disease. Therefore, assuming no effect of sub-clinical infection on the likelihood of migratory take-off, this may favor the spread of HPAIV H5N1 by migratory birds over long distances

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Consensus statement on abusive head trauma in infants and young children

Abusive head trauma (AHT) is the leading cause of fatal head injuries in children younger than 2 years. A multidisciplinary team bases this diagnosis on history, physical examination, imaging and laboratory findings. Because the etiology of the injury is multifactorial (shaking, shaking and impact, impact, etc.) the current best and inclusive term is AHT. There is no controversy concerning the medical validity of the existence of AHT, with multiple components including subdural hematoma, intracranial and spinal changes, complex retinal hemorrhages, and rib and other fractures that are inconsistent with the provided mechanism of trauma. The workup must exclude medical diseases that can mimic AHT. However, the courtroom has become a forum for speculative theories that cannot be reconciled with generally accepted medical literature. There is no reliable medical evidence that the following processes are causative in the constellation of injuries of AHT: cerebral sinovenous thrombosis, hypoxic-ischemic injury, lumbar puncture or dysphagic choking/vomiting. There is no substantiation, at a time remote from birth, that an asymptomatic birth-related subdural hemorrhage can result in rebleeding and sudden collapse. Further, a diagnosis of AHT is a medical conclusion, not a legal determination of the intent of the perpetrator or a diagnosis of murder. We hope that this consensus document reduces confusion by recommending to judges and jurors the tools necessary to distinguish genuine evidence-based opinions of the relevant medical community from legal arguments or etiological speculations that are unwarranted by the clinical findings, medical evidence and evidence-based literature