Warming and acidification threaten glass sponge Aphrocallistes vastus pumping and reef formation.

The glass sponge Aphrocallistes vastus contributes to the formation of large reefs unique to the Northeast Pacific Ocean. These habitats have tremendous filtration capacity that facilitates flow of carbon between trophic levels. Their sensitivity and resilience to climate change, and thus persistence in the Anthropocene, is unknown. Here we show that ocean acidification and warming, alone and in combination have significant adverse effects on pumping capacity, contribute to irreversible tissue withdrawal, and weaken skeletal strength and stiffness of A. vastus. Within one month sponges exposed to warming (including combined treatment) ceased pumping (50-60%) and exhibited tissue withdrawal (10-25%). Thermal and acidification stress significantly reduced skeletal stiffness, and warming weakened it, potentially curtailing reef formation. Environmental data suggests conditions causing irreversible damage are possible in the field at +0.5 °C above current conditions, indicating that ongoing climate change is a serious and immediate threat to A. vastus, reef dependent communities, and potentially other glass sponges.

The effects of low and moderate doses of caffeine supplementation on upper and lower body maximal voluntary concentric and eccentric muscle force.

Despite the growing quantity of literature exploring the effect of caffeine on muscular strength, there is a dearth of data that directly explores differences in erogenicity between upper and lower body musculature and the dose-response effect. The present study sought to investigate the effects of low and moderate doses of caffeine on the maximal voluntary strength of the elbow flexors and knee extensors. Ten nonspecifically strength-trained, recreationally active participants (aged 21 ± 0.3 years) completed the study. Using a randomised, counterbalanced, and double-blind approach, isokinetic concentric and eccentric strength was measured at 60 and 180°/s following administration of a placebo, 3 mg·kg-1 body mass caffeine, and 6 mg·kg-1 body mass caffeine. There was no effect of caffeine on the maximal voluntary concentric and eccentric strength of the elbow flexors, or the eccentric strength of the knee extensors. Both 3 and 6 mg·kg-1 body mass caffeine caused a significant increase in peak concentric force of the knee extensors at 180°/s. No difference was apparent between the 2 concentrations. Only 6 mg·kg-1 body mass caused an increase in peak concentric force during repeated contractions. The results infer that the effective caffeine concentration to evoke improved muscle performance may be related to muscle mass and contraction type. The present work indicates that a relatively low dose of caffeine treatment may be effective for improving lower body muscular strength, but may have little benefit for the strength of major muscular groups of the upper body.

Development of an integrated electronic platform for patient self-report and management of adverse events during cancer treatment.

BACKGROUND: Significant adverse events (AE) during cancer therapy disrupt treatment and escalate to emergency admissions. Approaches to improve the timeliness and accuracy of AE reporting may improve safety and reduce health service costs. Reporting AE via patient reported outcomes (PROs), can improve clinician-patient communication and making data available to clinicians in 'real-time' using electronic PROs (ePROs) could potentially transform clinical practice by providing easily accessible records to guide treatment decisions. This manuscript describes the development of eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice) is a National Institute for Health Research-funded programme, a system for patients to self-report and manage AE online during and after cancer treatment. MATERIALS AND METHODS: A multidisciplinary team of IT experts, staff and patients developed using agile principles a secure web application interface (QStore) between an existing online questionnaire builder (QTool) displaying real-time ePRO data to clinicians in the electronic patient record at Leeds Teaching Hospitals NHS Trust. Hierarchical algorithms were developed corresponding to Common Terminology Criteria for Adverse Events grading using the QTool question dependency function. Patient advocates (N = 9), patients (N = 13), and staff (N = 19) usability tested the system reporting combinations of AE. RESULTS: The eRAPID system allows patients to report AE from home on PC, tablet or any web enabled device securely during treatment. The system generates immediate self-management advice for low or moderate AE and for severe AE advice to contact the hospital immediately. Clinicians can view patient AE data in the electronic patient record and receive email notifications when patients report severe AE. CONCLUSIONS: Evaluation of the system in a randomised controlled trial in breast, gynaecological and colorectal cancer patients undergoing systemic therapy is currently underway. To adapt eRAPID for different treatment groups, pilot studies are being undertaken with patients receiving pelvic radiotherapy and upper gastrointestinal surgery. ISRCTN88520246.

The effects of arousal on apical amplification and conscious state.

Neocortical pyramidal cells can integrate two classes of input separately and use one to modulate response to the other. Their tuft dendrites are electrotonically separated from basal dendrites and soma by the apical dendrite, and apical hyperpolarization-activated currents (Ih) further isolate subthreshold integration of tuft inputs. When apical depolarization exceeds a threshold, however, it can enhance response to the basal inputs that specify the cell's selective sensitivity. This process is referred to as apical amplification (AA). We review evidence suggesting that, by regulating Ih in the apical compartments, adrenergic arousal controls the coupling between apical and somatic integration zones thus modifying cognitive capabilities closely associated with consciousness. Evidence relating AA to schizophrenia, sleep, and anesthesia is reviewed, and we assess theories that emphasize the relevance of AA to consciousness. Implications for theories of neocortical computation that emphasize context-sensitive modulation are summarized. We conclude that the findings concerning AA and its regulation by arousal offer a new perspective on states of consciousness, the function and evolution of neocortex, and psychopathology. Many issues worthy of closer examination arise.

The neurobiology of infant maternal odor learning

Infant rats must learn to identify their mother’s diet-dependent odor. Once learned, maternal odor controls pups’ approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver.

The neurobiology of infant maternal odor learning.

Infant rats must learn to identify their mother's diet-dependent odor. Once learned, maternal odor controls pups' approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver.

Electrolytic lesions within central complex neuropils of the cockroach brain affect negotiation of barriers.

Animals must negotiate obstacles in their path in order to successfully function within natural environments. These actions require transitions from walking to other behaviors, many of which are more involved than simple reflexes. For these behaviors to be successful, insects must evaluate objects in their path and then use that information to change posture or re-direct leg movements. Some of this control may occur within a region of the brain known as the central complex (CC). We used discrete electrolytic lesions to examine the role of certain sub-regions of the CC in various obstacle negotiation behaviors. We found that cockroaches with lesions to the protocerebral bridge (PB) and ellipsoid body (EB) exhibit abnormalities in turning and dealing with shelf-like objects; whereas, individuals with lesions to the fan-shaped body (FB) and lateral accessory lobe (LAL), exhibit abnormalities of those behaviors as well as climbing over blocks and up walls to a horizontal plane. Abnormalities in block climbing include decreased success rate, changes in climbing strategy, and delayed response to the block. Increases in these abnormal behaviors were significant in individuals with lesions to the FB and LAL. Although turning abnormalities are present in individuals with lesions to the LAL, EB and the lateral region of the FB, there are some differences in how these deficits present. For instance, the turning deficits seen in individuals with lateral FB lesions only occurred when turning in the direction opposite to the side of the brain on which the lesion occurred. By contrast, individuals with lesions to the EB and LAL exhibited turning abnormalities in both directions. Lesions in the medial region of the FB did not result in directional turning deficits, but in abnormalities in block climbing.

Cost of fractures commonly associated with osteoporosis in a managed-care population.

OBJECTIVE: To examine direct costs of hip, vertebral, and non-hip non-vertebral (NHNV) fractures, and to estimate the rate of osteoporosis (OA) diagnosis and treatment in the fracture population. METHODS: Subjects ≥ 45 years with a new hip, vertebral, or NHNV fragility (closed) fracture between June 30, 2002 and June 30, 2006 were studied retrospectively. All-cause and fracture-specific medical costs were calculated from medical claims in the 12-month baseline and follow-up periods. Total healthcare costs included pharmacy and medical costs. Diagnosis for OA and OA treatment were identified in both the baseline and follow-up period from diagnosis codes on medical claims for OA, and from pharmacy claims for treatment. Analyses were performed separately for commercial (COM) and Medicare Advantage (MA) populations and stratified by fracture type. Generalized linear models were estimated for total follow-up healthcare cost. RESULTS: The study sample included 36,521 COM and 10,160 MA subjects. Hip fracture subjects had the highest follow-up medical costs in unadjusted and adjusted analyses (COM: mean $35,898; median $22,945; MA: mean $32,919; median $26,047). Follow-up costs were much higher than baseline costs. Fracture-related costs accounted for a large proportion of follow-up medical costs. Although rates of osteoporosis diagnosis and treatment increased from baseline to follow-up, the majority of both COM and MA subjects had no evidence of osteoporosis diagnosis or treatment in either period. CONCLUSIONS: Despite limitations of this study, including conventional generalizability issues, and sensitivity and specificity of claims-based diagnoses, results are consistent with other research and provide compelling results of substantial cost burden of fractures related to osteoporosis. Low rates of osteoporosis diagnosis and treatment among patients with costly fragility fractures underscore the opportunity for managed care organizations to initiate comprehensive disease management programs in osteoporosis.

Prevalence of Parkinson's disease-induced psychosis in a large U.S. managed care population.

Using 10 years' enrollment history, patients with non-drug-induced Parkinson's disease were identified, and the prevalence of Parkinson's disease-induced psychosis (PDP) was estimated using three different claims algorithms based on an expert working group criteria. The estimated prevalence of PDP ranged from 4 to 45/1,000 Parkinson's disease patients. PDP patients were just as likely to be male as female and were significantly older than Parkinson's disease patients without PDP. PDP patients more commonly had evidence of dementia and use of atypical antipsychotics. PDP occurs in up to 45,000 Parkinson's disease patients in the United States but represents a unique neuropsychiatric finding with important treatment implications.

Characterization of obstacle negotiation behaviors in the cockroach, Blaberus discoidalis.

Within natural environments, animals must be able to respond to a wide range of obstacles in their path. Such responses require sensory information to facilitate appropriate and effective motor behaviors. The objective of this study was to characterize sensors involved in the complex control of obstacle negotiation behaviors in the cockroach Blaberus discoidalis. Previous studies suggest that antennae are involved in obstacle detection and negotiation behaviors. During climbing attempts, cockroaches swing their front leg that then either successfully reaches the top of the block or misses. The success of these climbing attempts was dependent on their distance from the obstacle. Cockroaches with shortened antennae were closer to the obstacle prior to climbing than controls, suggesting that distance was related to antennal length. Removing the antennal flagellum resulted in delays in obstacle detection and changes in climbing strategy from targeted limb movements to less directed attempts. A more complex scenario - a shelf that the cockroach could either climb over or tunnel under - allowed us to further examine the role of sensory involvement in path selection. Ultimately, antennae contacting the top of the shelf led to climbing whereas contact on the underside led to tunneling However, in the light, cockroaches were biased toward tunnelling; a bias which was absent in the dark. Selective covering of visual structures suggested that this context was determined by the ocelli.

Risk of fracture in women treated with monthly oral ibandronate or weekly bisphosphonates: the eValuation of IBandronate Efficacy (VIBE) database fracture study.

The eValuation of IBandronate Efficacy (VIBE) head-to-head database fracture study compared fracture rates between patients treated with monthly ibandronate and weekly oral bisphosphonates (BPs). This large study included women >/=45 years old, newly prescribed monthly oral ibandronate or weekly oral alendronate or risedronate, and without malignancy or Paget's disease of bone. The primary analysis included patients who were adherent to treatment during the first 90 days after the index date. The risks of hip, nonvertebral, vertebral and any clinical fracture were compared using Cox proportional hazards models and adjusted for potential confounding factors. A secondary, "intent-to-treat" analysis included all patients who received at least one BP prescription. Sensitivity analyses based on the primary analysis compared patients receiving ibandronate with patients receiving weekly alendronate or risedronate separately, and explored the effect of excluding patients with potential confounding factors from the analysis. Further sensitivity analyses varied the requirement for adherence during the first 90 days after the index date. The primary analysis population included 7345 monthly ibandronate and 56,837 weekly BP patients. Fracture rates after the 12-month observational period were <2% and fracture risk was not significantly different between patients receiving monthly ibandronate or weekly BPs for hip, nonvertebral or any clinical fracture (adjusted relative risk: hip=1.06, p=0.84; nonvertebral=0.88, p=0.255; any clinical fracture=0.82, p=0.052). Ibandronate patients had a significantly lower risk of vertebral fracture than weekly BP patients (adjusted relative risk 0.36, 95% confidence interval 0.18-0.75, p=0.006). In the secondary, "intent-to-treat" analysis, relative risks of fracture were not significantly different between treatment groups for any fracture type. The results of the sensitivity analyses were generally consistent with the primary analysis. This retrospective cohort study found that patients treated with oral monthly ibandronate or weekly BPs (alendronate and risedronate) had similar, low risks of hip fracture, nonvertebral fracture and any clinical fracture. Ibandronate patients had a significantly lower relative risk of vertebral fracture than weekly BP patients; the clinical implications of these findings require further exploration and validation.

Calcineurin inhibition eliminates the normal inverted U curve, enhances acquisition and prolongs memory in a mammalian 3'-5'-cyclic AMP-dependent learning paradigm.

The role protein phosphatase 2B (calcineurin, CaN) plays in learning and memory has received a significant amount of attention due to its promotion of the dephosphorylation of 3'-5'-cyclic AMP response element binding protein (CREB). Researchers have ascertained that overexpression of CaN is associated with memory retention deficits [Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca(2+) dysregulation with brain aging. J Neurosci 21:4066-4073; Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39-49], while CaN inhibition enhances learning and memory [Gerdjikov TV, Beninger RJ (2005) Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats. Eur J Neurosci 22:697-705; Ikegami S, Inokuchi K (2000) Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction. Neuroscience 98:637-646]. The present study hypothesized that infusion of a CaN inhibitor (FK506) bilaterally into the olfactory bulbs of postnatal day 6 Sprague Dawley rat pups would prolong the duration of a conditioned odor preference and retard cyclic AMP response element binding protein dephosphorylation. A 2 mg/kg s.c. injection of isoproterenol (ISO, beta-adrenoceptor agonist) was paired with a 10 min exposure to peppermint and subsequently an infusion of FK506. Immunohistochemistry for phosphorylated 3'-5'-cyclic AMP response element binding protein (pCREB) revealed that unilateral infusion of FK506 resulted in an amplification of phosphorylated CREB in the olfactory bulb 40 min after training compared with saline-infused bulbs. Pups infused bilaterally with FK506 maintained a learned preference for peppermint 48, 72 and 96 h after training. CaN inhibition also modified the conventional inverted U curve obtained when ISO is used to replace stroking, as the unconditioned stimulus. When pups were infused with FK506, learning occurred with sub- and supra-optimal doses of ISO indicating that CaN overcomes non-optimal effects ISO may have on learning. We demonstrate that CaN inhibition can extend the duration of conditioned olfactory memory and may provide a target for memory prolongation that is superior to even phosphodiesterase inhibition observed in previous studies.

The comparative effectiveness of rosuvastatin vs. other statins in patients with an increased risk of failure to reach NCEP ATP III goal.

BACKGROUND: Previous studies have demonstrated that failure to reach National Cholesterol Education Program (NCEP) target low-density lipoprotein cholesterol (LDL-C) goal increases the risk of cardiovascular events. Ability to meet goal may be impacted by the choice of statin therapy. PURPOSE: This study compares rosuvastatin to other statin therapies among patients presenting with risk factors associated with failure to reach NCEP goal. METHODS: Retrospective analysis using medical and pharmacy claims linked to laboratory results from a national health plan encompassing private and MedicareAdvantage enrollees age > or = 18 years and newly treated with statins from 1 August 2003 to 28 February 2005. Predictors of failure to reach goal were statin treatment group, age, gender, NCEP risk level, per cent reduction required to attain goal and days from index to LDL-C measurement. RESULTS: Of 11,814 eligible patients, 9.6% were initiated on rosuvastatin, 54.2% atorvastatin, 17.9% simvastatin, 7.1% pravastatin, 2.0% fluvastatin and 9.3% lovastatin. Independent predictors of failure to reach goal included > or = 15% LDL-C reduction required to reach goal, and high and moderate NCEP risk status. In the subset of patients at higher risk of failure to reach goal, rosuvastatin demonstrated a significantly lower rate of failure to achieve goal than atorvastatin, simvastatin, pravastatin, fluvastatin or lovastatin. CONCLUSIONS: Real-world factors associated with high risk of failure to reach goal may be used in identifying patients more likely to succeed on rosuvastatin compared with other statins. Low-risk patients needing < 15% LDL-C reduction would be suitable candidates for initiation of most other statins, specifically simvastatin, which has recently become available in the generic form.

Color polymorphism and genetic structure in the sea star Pisaster ochraceus.

The sea star Pisaster ochraceus is one of the more striking species on the rocky shores of the Northeast Pacific, in part due to the dramatic color polymorphism of the adults. Along the open Pacific coast, Pisaster populations are 6%-28% orange, with a small percentage of brilliant purple stars and a large percentage of reddish-brown to dull purple ones. However, populations in the San Juan Island Archipelago (Washington, USA) and the southern Strait of Georgia (British Columbia, Canada) are almost entirely brilliant purple. The factors that maintain the color polymorphism, and those that contribute to among-site variation in color frequencies, remain unknown. We examined the relationships between color frequencies and several ecological and morphological variables, and conducted a large-scale phylogeographic survey of Pisaster populations. We found very low population genetic structure, suggesting that gene flow is high and geographic variation in color frequencies is not a vestige of Pleistocene glacial refugia. Color frequencies are also unrelated to adult size and to the frequency of injury within a population. However, there are suggestive relationships between color frequency and diet, and with areas of potentially low salinity. We propose that, although the color polymorphism may have an underlying genetic component, the regional-scale variation in color frequency is ecologically controlled.

Disruption of sitting balance after stroke: influence of spoken output.

OBJECTIVES: To identify the extent of dual task interference between cognitive and motor tasks, (cognitive motor interference (CMI)) in sitting balance during recovery from stroke; to compare CMI in sitting balance between stroke and non-stroke groups; and to record any changes to CMI during sitting that correlate with functional recovery. METHOD: 36 patients from stroke rehabilitation settings in three NHS trusts. Healthy control group: 21 older volunteers. Measures of seated postural sway were taken in unsupported sitting positions, alone, or concurrently with either a repetitive utterance task or an oral word category generation task. Outcome measures were variability of sway area, path length of sway, and the number of valid words generated. RESULTS: Stroke patients were generally less stable than controls during unsupported sitting tasks. They showed greater sway during repetitive speech compared with quiet sitting, but did not show increased instability to posture between repetitive speech and word category generation. When compared with controls, stroke patients experienced greater dual task interferences during repetitive utterance but not during word generation. Sway during repetitive speech was negatively correlated with concurrent function on the Barthel ADL index. CONCLUSIONS: The stroke patients showed postural instability and poor word generation skills. The results of this study show that the effort of verbal utterances alone was sufficient to disturb postural control early after stroke, and the extent of this instability correlated with concomitant Barthel ADL function.

Potentiation and prolongation of long-term odor memory in neonate rats using a phosphodiesterase inhibitor.

Cyclic AMP has been shown to have a critical role in learning and memory in invertebrates. Here we use the rat pup odor preference learning model in which odor acts as a conditioned stimulus and beta-adrenoceptor stimulation acts as an unconditioned stimulus to test the role of cyclic AMP in an associative mammalian paradigm. A phosphodiesterase inhibitor that prevents cyclic AMP breakdown (cilomilast) makes a low, learning-ineffective dose of a beta-adrenoceptor agonist (isoproterenol, 1mg/kg) an effective unconditioned stimulus in pup odor preference learning. A dose of the phosphodiesterase inhibitor (cilomilast, 1 mg/kg) that induces learning with a weak unconditioned stimulus interferes with learning using a normally optimal unconditioned stimulus (isoproterenol, 2 mg/kg). Cilomilast (3 mg/kg) paired with peppermint odor during learning, prolonged memory at least four times longer than without the drug (24 h vs. 96 h). These data demonstrate a causal role for cyclic AMP in the acquisition and duration of odor preference learning in the rat pup.

Anticoagulation therapy in patients with chronic atrial fibrillation: a retrospective claims data analysis.

OBJECTIVES: This study assessed the risk of thrombo embolic events and bleeding complications among atrial fibrillation patients. METHODS: A cohort of patients with chronic non-valvular atrial fibrillation were identified from medical claims (diagnosis codes 427.31 and 427.32). Subjects were identified from 1 January 1998-31 December 2000 and were continuously enrolled for 6 months prior to the first occurring atrial fibrillation medical claim. Cox proportional hazards analysis with time varying covariates was used for the event analysis. RESULTS: Of 6764 subjects retained for analysis, 3541 (52.4%) were exposed to warfarin. Adjusting for baseline characteristics, warfarin exposure was associated with lower likelihood of an arterial thromboembolic event compared to no exposure (HR: 0.710, CI: 0.540-0.934). No benefit was found in the use of warfarin in the prevention of intracranial events (HR: 1.119, CI: 0.929-1.349). Use of warfarin increased the risk of minor bleeding events (HR: 3.600, CI: 2.537-5.109), and all bleeding events (HR: 1.502, CI: 1.289-1.749). CONCLUSIONS: The risk of arterial thromboembolic events was associated with warfarin exposure as expected. An increase in the risk of minor and total bleeding events among patients treated with warfarin was observed. The results of this study suggest that there may be a gap between the clinical trial and coagulation clinic performance of warfarin in reducing the risk of thromboembolic events versus what is achievable in general practice.

Telomerase inhibitors--oligonucleotide phosphoramidates as potential therapeutic agents.

We have designed, synthesized, and evaluated using physical, chemical and biochemical assays various oligonucleotide N3'-->P5' phosphoramidates, as potential telomerase inhibitors. Among the prepared compounds were 2'-deoxy, 2'-hydroxy, 2'-methoxy, 2'-ribo-fluoro, and 2'-arabino-fluoro oligonucleotide phosphoramidates, as well as novel N3'-->P5' thio-phosphoramidates. The compounds demonstrated sequence specific and dose dependent activity with IC50 values in the sub-nM to pM concentration range.

Infusion of the metabotropic receptor agonist, DCG-IV, into the main olfactory bulb induces olfactory preference learning in rat pups.

DCG-IV, a type 2 metabotropic glutamate receptor (mGluR2) agonist, was infused into the main olfactory bulb of 1-week-old pups exposed to peppermint odor. A preference for peppermint was demonstrated 24 h later. The data support the proposal that disinhibition at dendrodendritic synapses between granule cells and mitral cells is a critical component of olfactory memory formation in the rat pup olfactory bulb as well as in the accessory olfactory bulb of adult rodents.