Extended phenotypes on coral reefs: cryptic phenotypes modulate coral-vermetid interactions.

Phenotypic variation can lead to variation in the strength and outcome of species interactions. Variation in phenotypic traits can arise due to plastic responses to environmental stimuli, underlying genetic variation, or both, and may reflect differences in the focal organism or aspects of the extended phenotype (e.g., associated microbes). We used a reciprocal transplant experiment of Porites corals to evaluate the role of plasticity vs. heritable diversity on phenotypic traits and performance of corals that varied in their prior exposure to vermetid gastropods, an organism known to reduce coral growth and survival. We measured a suite of phenotypic traits associated with coral performance, many of which showed a plastic response to vermetid exposure. Vermetids decreased calcification of corals, increased microbial diversity, and shifted microbial composition. Most traits also showed a signature of previous exposure environment that persisted even when exposure was reversed: i.e., under the same conditions, corals naïve to vermetids had slower calcification rates, thicker tissues, higher Symbiodiniaceae densities, and different microbiomes than corals previously exposed to vermetids. We suggest the phenotypic differences are heritable, as reefs with and without vermetids were comprised of two different mitotypes, that revealed high, consistent genetic variation. Vermetids were only found on the fast-growing coral mitotype that was characterized by thin tissue, and that likely had a history of disturbance. As extended phenotypes can have community impacts, we suggest vermetid, in addition to microbes, are part of the extended community phenotype of these corals. Coral genotypes can establish different reef trajectories, with thin-tissue types more prone to disturbance and subsequent colonization by other species, like vermetids, which can further facilitate the degradation of coral reefs. The effects of the extended phenotype of species likely influence heterogeneity across landscapes as well as temporal differences in community composition.

ß-Cell and renal transplantation options for diabetes.

Despite major advances in structured education, insulin delivery and glucose monitoring, diabetes self-management remains an unremitting challenge. Insulin therapy is inextricably linked to risk of dangerous hypoglycaemia and sustained hyperglycaemia remains a leading cause of renal failure. This review sets out to demystify transplantation for diabetes multidisciplinary teams, facilitating consideration and incorporation within holistic overall person-centred management. Deceased and living donor kidney, whole pancreas and isolated islet transplant procedures, indications and potential benefits are described, in addition to outcomes within the integrated UK transplant programme.

Aerobic method for the synthesis of nearly size-monodisperse bismuth nanoparticles from a redox non-innocent precursor.

Herein, we report an aerobic synthesis method to produce bismuth nanoparticles (Bi NPs) with average diameters in the range 40-80 nm using commercially available bismuth triiodide (BiI3) as the starting material; the method uses only readily available chemicals and conventional laboratory equipment. Furthermore, size data from replicates of the synthesis under standard reaction conditions indicate that this method is highly reproducible in achieving Bi NP populations with low standard deviations in the mean diameters. We also investigated the mechanism of the reaction, which we determined results from the reduction of a soluble alkylammonium iodobismuthate precursor species formed in situ. Under appropriate concentration conditions of iodobismuthate anion, we demonstrate that burst nucleation of Bi NPs results from reduction of Bi3+ by the coordinated, redox non-innocent iodide ligands when a threshold temperature is exceeded. Finally, we demonstrate phase transfer and silica coating of the Bi NPs, which results in stable aqueous colloids with retention of size, morphology, and colloidal stability. The resultant, high atomic number, hydrophilic Bi NPs prepared using this synthesis method have potential for application in emerging x-ray contrast and x-ray therapeutic applications.

Vermetid gastropods modify physical and chemical conditions above coral-algal interactions.

Interaction modifications can arise when a third species alters the physical and chemical environment within which two other species interact. On coral reefs, corals and algae commonly interact amid a suite of other species that may modify their interaction. Massive Porites coral and algal turfs often are covered by mucus nets cast by the vermetid gastropod, Ceraesignum maximum. Previously, vermetid mucus nets have been shown to have deleterious effects on corals. Here, we hypothesized that vermetids not only have direct effects on coral, but they also change the local physical and chemical environment establishing the potential for interaction modifications by intensifying the effects of algae on corals. To test this, we examined the effect of vermetids on physical and chemical aspects of the environments. We quantified light penetration, water flow, diffusive boundary layer (DBL) thickness, and oxygen concentrations in the presence and absence of vermetid nets. Vermetid nets did not affect light levels. Because we observed reduced water flow and increased DBL thickness in the presence of nets, we also expected to observe high oxygen concentration over coral surfaces. Instead, we observed no difference in oxygen concentrations in the presence of mucus nets. To explain the lower than expected oxygen concentrations, we hypothesize that nets decreased photosynthesis and/or increased respiration of corals and algae and their associated microbiota. This is the first study to explore mechanisms underlying the deleterious effects of vermetids on corals, and shows that vermetid mucus nets may modify coral-algal interactions by intensifying physical and chemical conditions.

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes.

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.

Thrombotic Microangiopathy as a Cause of Chronic Kidney Transplant Dysfunction: Case Report Demonstrating Successful Treatment with Eculizumab.

Atypical hemolytic uremic syndrome is a rare disease associated with genetic or acquired defects in complement regulation which frequently leads to renal failure. Disease often recurs early after kidney transplantation, leading to a rapid irreversible loss of function. Extrarenal features, such as hemolysis and thrombocytopenia, may not always occur, and diagnosis is made by demonstrating the classic features of thrombotic microangiopathy on renal biopsy. Eculizumab, a terminal complement inhibitor, has been used successfully to treat fulminant early recurrent disease after transplantation. We describe a case of disease recurrence presenting in the second year after transplantation with a gradual decline in function and the first report of eculizumab treatment for chronic thrombotic microangiopathy in a transplanted kidney. The resultant diagnostic challenges and successful response to eculizumab in this setting are discussed.

Clinical, haematological, cytokine and acute phase protein changes during experimental Babesia gibsoni infection of beagle puppies.

Babesia gibsoni is a haemoprotozoan parasite of emerging global importance. The clinical presentation of babesial infections is diverse and the systemic inflammatory response induced by infection is considered to be a major feature of the pathophysiology of canine babesiosis. An experimental case-controlled longitudinal study was conducted to assess the clinical, haematological, cytokine and acute phase protein changes that occur during experimental B. gibsoni infection of beagle puppies. Infected dogs became transiently pyrexic and anaemic, intermittently neutropenic and transiently, but profoundly, thrombocytopenic, although this had no apparent adverse clinical effect. Experimental B. gibsoni infection also induced an acute phase response, characterised by a marked increase in the concentration of C-reactive protein, which was delayed in onset following infection but preceded the detection of peripheral parasitaemia. Experimental B. gibsoni infection was also associated with marked increases in the concentration of multiple cytokines which were also delayed in onset following infection and occurred subsequent to the detection of peripheral parasitaemia and the acute phase response. This study furthers our understanding of the immune response that occurs during babesial infections and the role that systemic inflammation plays in the pathophysiology of canine babesiosis.

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

Distinct miRNA expression in dorsal striatal subregions is associated with risk for addiction in rats.

Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that addiction/relapse vulnerability was associated with deficits in synaptic plasticity-associated gene expression in the dorsal striatum (DS). Notable was the strong reduction in expression for activity-regulated cytoskeleton-associated protein (Arc) considered a master regulator of synaptic plasticity. In the present study, we confirmed that Arc messenger RNA was significantly decreased in the DS, but importantly, we identified that this reduction was restricted to the dorsomedial (DMS) and not dorsolateral striatum (DLS). There is recent evidence of microRNA (miRNA)-associated posttranscriptional suppression of Arc and animal models of addiction have identified a key role for miRNA in the regulation of addiction-relevant genes. In further support of this link, we identified several differentially expressed miRNA with the potential to influence addiction-relevant plasticity genes, including Arc. A key study recently reported that miR-212 expression is protective against compulsive cocaine-seeking. Supporting this hypothesis, we found that miR-212 expression was significantly reduced in the DMS but not DLS of addiction-vulnerable animals. Together, our data provide strong evidence that miRNA promote ongoing plasticity deficits in the DS of addiction-vulnerable animals.

Longitudinal annoyance responses to a road traffic noise management strategy that reduced heavy vehicles at night.

A traffic management strategy was designed to reduce trucks using an urban corridor. The intervention had potential to affect night-time truck flows, but did not target truck traffic in the day, or vehicles other than trucks at any hour. A two-year long panel study measured the community's response to this intervention, using five repeated measurements of response. There were significant reductions in the panel's response to noise, both for night-time annoyance and for interference with activities. This was remarkable given that noise monitoring showed that the intervention produced no change in conventional traffic noise indicators. However, there were measureable changes in the number of articulated truck movements at night, and the benefit can be attributed to reduction in the number of noise events from heavy vehicles. The parallel tracking of changes in reported noise effects and the numbers of heavy vehicles in the night hours in this longitudinal study provides strong support to the notion that noise effects at night depend on the number of noise events experienced, not only on the overall level of traffic noise. The latter appear to be unresponsive indicators by which to assess the noise-effect benefit of heavy vehicle reduction strategies.

Perceptual constancy in auditory perception of distance to railway tracks.

Distance to a sound source can be accurately estimated solely from auditory information. With a sound source such as a train that is passing by at a relatively large distance, the most important auditory information for the listener for estimating its distance consists of the intensity of the sound, spectral changes in the sound caused by air absorption, and the motion-induced rate of change of intensity. However, these cues are relative because prior information/experience of the sound source-its source power, its spectrum and the typical speed at which it moves-is required for such distance estimates. This paper describes two listening experiments that allow investigation of further prior contextual information taken into account by listeners-viz., whether they are indoors or outdoors. Asked to estimate the distance to the track of a railway, it is shown that listeners assessing sounds heard inside the dwelling based their distance estimates on the expected train passby sound level outdoors rather than on the passby sound level actually experienced indoors. This form of perceptual constancy may have consequences for the assessment of annoyance caused by railway noise.

Glia determine the course of brain-derived neurotrophic factor-mediated dendritogenesis and provide a soluble inhibitory cue to dendritic growth in the brainstem.

Cardiorespiratory control neurons in the brainstem nucleus tractus solitarius (NTS) undergo dramatic expansion of dendritic arbors during the early postnatal period, when functional remodeling takes place within the NTS circuitry. However, the underlying molecular mechanisms of morphological maturation of NTS neurons are largely unknown. Our previous studies point to the neurotrophin brain-derived neurotrophic factor (BDNF), which is abundantly expressed by NTS-projecting primary sensory neurons, as a candidate mediator of NTS dendritogenesis. In the current study, we used neonatal rat NTS neurons in vitro to examine the role of BDNF in the dendritic development of neurochemically identified subpopulations of NTS neurons. In the presence of abundant glia, BDNF promoted NTS dendritic outgrowth and complexity, with the magnitude of the BDNF effect dependent on neuronal phenotype. Surprisingly, BDNF switched from promoting to inhibiting NTS dendritogenesis upon glia depletion. Moreover, glia depletion alone led to a significant increase in NTS dendritic outgrowth. Consistent with this result, astrocyte-conditioned medium (ACM), which promoted hippocampal dendritogenesis, inhibited dendritic growth of NTS neurons. The latter effect was abolished by heat-inactivation of ACM, pointing to a diffusible astrocyte-derived negative regulator of NTS dendritic growth. Together, these data demonstrate a role for BDNF in the postnatal development of NTS neurons, and reveal novel effects of glia on this process. Moreover, previously documented dramatic increases in NTS glial proliferation in victims of sudden infant death syndrome (SIDS) underscore the importance of our findings and the need to better understand the role of glia and their interactions with BDNF during NTS circuit maturation. Furthermore, while it has previously been demonstrated that the specific effects of BDNF on dendritic growth are context-dependent, the role of glia in this process is unknown. Thus, our data carry important implications for mechanisms of dendritogenesis likely beyond the NTS.

Severe systemic hypertension in a cat with pituitary-dependent hyperadrenocorticism.

A seven-year-old Burmese cat was presented with sudden onset blindness. On physical examination, the cat had bilateral retinal detachment and severe systemic hypertension. Further clinical investigations revealed pituitary-dependent hyperadrenocorticism. Antihypertensive therapy was discontinued when the hypertension resolved after bilateral adrenalectomy. Systolic blood pressure remained normal until 19 months post-operatively when systemic hypertension recurred and was attributed to chronic kidney disease. The cat was euthanased 47 months after initial presentation. A pituitary adenoma was identified at post-mortem examination. This case illustrates that systemic hypertension can occur secondary to hyperadrenocorticism in the cat.

Health effects of green tea catechins in overweight and obese men: a randomised controlled cross-over trial.

Regular consumption of green tea may be cardioprotective. In the present study we investigated the health effects of dietary supplementation with green tea catechins and the potential modifying effect of the catechol-O-methyltransferase (COMT) Val/Met genotype. Subjects (sedentary males, aged 40-69 years, with BMI ≥ 28 and ≤ 38 kg/m(2)) were randomly assigned to consume decaffeinated green tea extract (DGT; 530 mg containing about 400 mg total catechins/capsule, twice daily) and placebo in a complete cross-over design. Ambulatory blood pressure and biomarkers of metabolic function (cholesterol, TAG, glucose and insulin) were measured at weeks 0 and 6. Although a marked increase in the concentration of plasma epigallocatechin gallate (EGCG), urinary epigallocatechin (EGC) and urinary 4'-O-methyl EGC was found after DGT treatment, no effect on blood pressure or biomarkers of metabolic function was observed. However, a period × treatment interaction (P < 0·05) was detected for body-weight change. Despite a similar increase in estimated energy intake during intervention period 1, body weight decreased by 0·64 (sd 2·2) kg and increased by 0·53 (sd 1·9) kg in the DGT and placebo groups, respectively (P = 0·025), suggesting a protective effect of green tea catechins on weight gain. Additionally, the COMT Val/Met genotype influenced urinary accumulation of EGC and 4'-O-methyl EGC (P < 0·01). Mean concentrations were lower in individuals homozygous for the high-activity G-allele, possibly reflecting increased metabolic flux and a more rapid conversion to downstream metabolic species, compared with individuals carrying at least one copy of the low-activity A-allele. Additional studies are needed to confirm these findings and further explore the modifying effect of genotype.

Tooth pulp inflammation increases brain-derived neurotrophic factor expression in rodent trigeminal ganglion neurons.

Nociceptive pathways with first-order neurons located in the trigeminal ganglion (TG) provide sensory innervation to the head, and are responsible for a number of common chronic pain conditions, including migraines, temporomandibular disorders and trigeminal neuralgias. Many of those conditions are associated with inflammation. Yet, the mechanisms of chronic inflammatory pain remain poorly understood. Our previous studies show that the neurotrophin brain-derived neurotrophic factor (BDNF) is expressed by adult rat TG neurons, and released from cultured newborn rat TG neurons by electrical stimulation and calcitonin gene-related peptide (CGRP), a well-established mediator of trigeminal inflammatory pain. These data suggest that BDNF plays a role in activity-dependent plasticity at first-order trigeminal synapses, including functional changes that take place in trigeminal nociceptive pathways during chronic inflammation. The present study was designed to determine the effects of peripheral inflammation, using tooth pulp inflammation as a model, on regulation of BDNF expression in TG neurons of juvenile rats and mice. Cavities were prepared in right-side maxillary first and second molars of 4-week-old animals, and left open to oral microflora. BDNF expression in right TG was compared with contralateral TG of the same animal, and with right TG of sham-operated controls, 7 and 28 days after cavity preparation. Our ELISA data indicate that exposing the tooth pulp for 28 days, with confirmed inflammation, leads to a significant upregulation of BDNF in the TG ipsilateral to the affected teeth. Double-immunohistochemistry with antibodies against BDNF combined with one of nociceptor markers, CGRP or transient receptor potential vanilloid type 1 (TRPV1), revealed that BDNF is significantly upregulated in TRPV1-immunoreactive (IR) neurons in both rats and mice, and CGRP-IR neurons in mice, but not rats. Overall, the inflammation-induced upregulation of BDNF is stronger in mice compared to rats. Thus, mouse TG provides a suitable model to study molecular mechanisms of inflammation-dependent regulation of BDNF expression in vivo.

Prostate biopsy in Western Australia 1998-2004.

We reviewed the status of prostate cancer diagnosis in Western Australia (WA) with the aim of improving decision-making about PSA testing and prostate biopsy. Our patient cohort was 5145 men undergoing an initial biopsy for prostate cancer diagnosis in WA between 1998 and 2004. Transrectal ultrasound-guided biopsies were performed by one of 18 clinicians whereas all pathology was assessed by one urological pathologist. Cancer detection rates were 59% for initial biopsies and 32% for repeat biopsies. High-grade cancer (Gleason sum > or =7) accounted for 69 and 38% of tumours diagnosed on initial and repeat biopsy, respectively. The rates of cancer diagnosis and detection of high-grade tumours were both 1.6-fold higher in WA patients compared with those obtained at baseline screening of the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial of US men (P<0.001). These higher than expected rates of cancer detection and high histological grade indicate that urological practice in WA between 1998 and 2004 was significantly more conservative than US practice over this time period, probably leading to underdiagnosis of prostate cancer. Our findings may be relevant to other countries where urological practice differs from that in the United States.