The role of adipokines in the rapid antidepressant effects of ketamine.

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines-adiponectin, resistin and leptin-as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg-1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine's antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine's anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor.

Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). 11C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls. Twenty-three of the 44 patients had a follow-up 11C-(R)-rolipram PET scan ~8 weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment naïve. 11C-(R)-rolipram binding was measured using arterial sampling to correct for individual differences in radioligand metabolism. We found in unmedicated MDD patients widespread, ~20% reductions in 11C-(R)-rolipram binding compared with controls (P=0.001). SSRI treatment significantly increased rolipram binding (12%, P<0.001), with significantly greater increases observed in older patients (P<0.001). Rolipram binding did not correlate with severity of baseline symptoms, and increased rolipram binding during treatment did not correlate with symptom improvement. In brief, consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. The lack of correlation between PDE4 binding and depressive symptoms could reflect the heterogeneity of the disease and/or the heterogeneity of the target, given that PDE4 has four subtypes. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.

Immune reconstitution inflammatory syndrome in HIV infection: taking the bad with the good.

In this review, we will describe the immunopathogies of immune reconstitution inflammatory syndrome, IRIS. IRIS occurs in a small subset of HIV patient, initiating combination antiretroviral therapy (ART), where immune reconstitution becomes dysregulated, resulting in an overly robust antigen-specific inflammatory reaction. We will discuss IRIS in terms of the associated coinfections: mycobacteria, cryptococci, and viruses.

The meaning of participation for children in Malawi: insights from children and caregivers.

BACKGROUND: Global rates of childhood disability are high and are estimated through tools that focus on impairment, functioning and activity. The International Classification of Functioning, Disability and Health has promoted a framework to define disability more broadly and to include participation. New outcome measures have now been created to assess participation of children with disabilities for use in research and clinical practice. In order to use these in other cultural contexts, the validity of concepts and tools developed should be evaluated prior to use. We aim to create a tool that would be relevant and valid to the cultural context of Malawi, but to do so, we first need to understand what participation means to children in Malawi. AIM: The aim of this study is to explore what participation means for children (including those with and without disability) in rural Northern Malawi. METHODS: We used semi-structured interviews, focus group discussions, participatory action research and direct observations. Sixty-four participants were involved including children (8-18 years) with (14) and without disabilities (17), carers of children with (8) and without (6) disabilities, community members (14) and professionals/healthcare workers (5). Data analysis was carried out using the 'framework' approach. RESULTS: Activities reported by children, carers and community members fell within seven main themes or areas of participation. These include contribution to family life (chores and work), social activities (communicating and being with others), social activities (unstructured play), structured and organized activities, activities of daily living, education and schooling and entertainment (listening to and watching media). CONCLUSIONS: This study provides concepts and ideas that may be utilized in developing a suitable measure of participation of children with disabilities for rural African settings. Many of the most important activities for all children relate to family and day-to-day social life.

Baseline vitamin B12 and folate levels do not predict improvement in depression after a single infusion of ketamine.

INTRODUCTION: Deficiencies in both vitamin B12 and folate have been associated with depression. Recently, higher baseline vitamin B12 levels were observed in individuals with bipolar depression who responded to the antidepressant ketamine at 7 days post-infusion. This study sought to -replicate this result by correlating peripheral vitamin levels with ketamine's antidepressant efficacy in bipolar depression and major depressive disorder (MDD). METHODS: Baseline vitamin B12 and folate levels were obtained in 49 inpatients with treatment-resistant MDD and 34 inpatients with treatment-resistant bipolar depression currently experiencing a major depressive episode. All subjects received a single intravenous ketamine infusion. Post-hoc Pearson correlations were performed between baseline vitamin B12 and folate levels, as well as antidepressant response assessed by percent change in Hamilton Depression Rating Scale (HDRS) scores from baseline to 230 min, 1 day, and 7 days post-infusion. RESULTS: No significant correlation was observed between baseline vitamin B12 or folate and percent change in HDRS for any of the 3 time points in either MDD or bipolar depression. DISCUSSION: Ketamine's antidepressant efficacy may occur independently of baseline peripheral vitamin levels.

Effect of thoracic epidural anaesthesia on splanchnic blood flow.

BACKGROUND: Thoracic epidural anaesthesia (TEA) is used widely in colorectal surgery. However, there is increasing concern that epidurals are associated with postoperative hypotension, mediating a potential reduction in splanchnic flow. The aim was to review the literature on the effects of TEA on splanchnic blood flow. METHODS: PubMed and Cochrane databases were searched. Search terms used were: English language, 'thoracic epidural splanchnic flow', 'thoracic epidural gut blood flow', 'thoracic epidural intestinal blood flow' and 'thoracic epidural colonic blood flow'. Abstracts were reviewed by two independent researchers and irrelevant studies excluded. The full text of the remaining articles was then retrieved. RESULTS: Twenty-two abstracts were reviewed and three excluded. Nineteen papers were reviewed in full and seven irrelevant articles excluded. Five human studies investigated the effects of TEA on splanchnic flow. Two studies measured splanchnic flow directly and found an epidural-mediated fall in flow, unresponsive to intravenous fluids and requiring vasopressors or inotropes to restore baseline flow. The remaining three studies had inconsistent findings and haemodynamic stability was maintained. The seven animal studies identified were heterogeneous in both methodology and findings. Three suggested a protective role for thoracic epidurals in septic shock and pancreatitis. CONCLUSION: These findings are inconsistent; however, the two studies that investigated the effects of vasoconstrictors on splanchnic blood flow directly both found a significant epidural-mediated reduction in splanchnic blood flow that was unresponsive to fluid therapy.

Maintenance of genomic methylation requires a SWI2/SNF2-like protein.

Altering cytosine methylation by genetic means leads to a variety of developmental defects in mice, plants and fungi. Deregulation of cytosine methylation also has a role in human carcinogenesis. In some cases, these defects have been tied to the inheritance of epigenetic alterations (such as chromatin imprints and DNA methylation patterns) that do not involve changes in DNA sequence. Using a forward genetic screen, we identified a gene (DDM1, decrease in DNA methylation) from the flowering plant Arabidopsis thaliana required to maintain normal cytosine methylation patterns. Additional ddm1 alleles (som4, 5, 6, 7, 8) were isolated in a selection for mutations that relieved transgene silencing (E.J.R., unpublished data). Loss of DDM1 function causes a 70% reduction of genomic cytosine methylation, with most of the immediate hypomethylation occurring in repeated sequences. In contrast, many low-copy sequences initially retain their methylation in ddm1 homozygotes, but lose methylation over time as the mutants are propagated through multiple generations by self-pollination. The progressive effect of ddm1 mutations on low-copy sequence methylation suggests that ddm1 mutations compromise the efficiency of methylation of newly incorporated cytosines after DNA replication. In parallel with the slow decay of methylation during inbreeding, ddm1 mutants accumulate heritable alterations (mutations or stable epialleles) at dispersed sites in the genome that lead to morphological abnormalities. Here we report that DDM1 encodes a SWI2/SNF2-like protein, implicating chromatin remodelling as an important process for maintenance of DNA methylation and genome integrity.

Use of tobramycin-impregnated antibiotic beads in frontal sinus osteomyelitis.

OBJECTIVE: Osteomyelitis of the frontal bone is a rare but devastating complication of frontal sinusitis. Treatment involves aggressive surgery to remove all sequestra in combination with long-term antibiotic therapy. However, systemic antibiotics may struggle to penetrate any remaining infection in devascularised areas, and the morbidity associated with surgical resection of some areas of the skull base is too high. In contrast, locally implanted antibiotics provide a reliable, high concentration of treatment to these areas while also minimising potential systemic side effects. The clinical application of tobramycin beads has primarily been used in orthopaedics as an adjunct to the treatment of tibial osteomyelitis or prosthetic joint infection. CASE REPORT: To the best of the authors' knowledge, the two cases discussed here represent the first use of tobramycin antibiotic beads in frontal sinus osteomyelitis secondary to chronic rhinosinusitis. CONCLUSION: These cases show promising use of tobramycin beads in recalcitrant frontal osteomyelitis.

Interactions between males guppies facilitates the transmission of the monogenean ectoparasite Gyrodactylus turnbulli.

In a previous study we found that female guppies shoaled more than males and that there was greater transmission of the ectoparasite Gyrodactylus turnbulli between females. Here, to test for a possible sex bias in parasite transmission, we conducted a similar experiment on single sex shoals of male and female guppies, observing host behaviour before and after the introduction of an infected shoal mate. The initial parasite burden was considerably lower in the present experiment (30 worms versus >100 worms previously) and we used a different stock of ornamental guppies (Green Cobra variety versus a Tuxedo hybrid previously). Contrary to our previous finding, males aggregated significantly more than females. Males performed 'sigmoid' displays towards each other, a courtship behaviour that is more generally directed towards females. Due to the high rate of male-male interactions, parasite transmission was 10 times higher between males than between females. Furthermore, shoaling intensity was highest for the most parasitised fish indicating that these infected fish were not avoided by non-parasitised conspecifics. These studies show that certain social behaviours including shoaling and courtship displays, appear to facilitate the transmission of gyrodactylid parasites.

Salivary secretions from the honeybee mite, Varroa destructor: effects on insect haemocytes and preliminary biochemical characterization.

INTRODUCTION: The ectoparasitic honey bee mite Varroa destructor feeds on the haemolymph of the honey bee, Apis mellifera, through a single puncture wound that does not heal but remains open for several days. It was hypothesized that factors in the varroa saliva are responsible for this aberrant wound healing. METHODS: An in vitro procedure was developed for collecting salivary gland secretions from V. destructor. Mites were incubated on balls of cotton wool soaked in a tissue culture medium (TC-100), and then induced to spit by topical application of an ethanolic pilocarpine solution. RESULTS: Elution of secretions from balls of cotton wool, followed by electrophoretic analysis by SDS-PAGE and electroblotting indicated the presence of at least 15 distinct protein bands, with molecular weights ranging from 130 kDa to <17 kDa. Serial titration of V. destructor salivary secretions in TC-100 followed by an 18-h incubation with haemocytes from the caterpillar, Lacanobia oleracea, indicated that the secretions damage the haemocytes and suppresses their ability to extend pseudopods and form aggregates. CONCLUSION: We suggest that these secretions facilitate the ability of V. destructor to feed repeatedly off their bee hosts by suppressing haemocyte-mediated wound healing and plugging responses in the host.

Bulk glasses and ultrahard nanoceramics based on alumina and rare-earth oxides.

Although often regarded as a network-former in conventional silicate glasses, Al(2)O(3) alone cannot be obtained as a bulk glass. Until now, glasses comprising continuously linked [AlO(x)] polyhedra have been prepared in only a few systems under very fast cooling conditions, which limits their dimensions to a few millimetres. Yet it is desirable to prepare bulk, or monolithic, alumina-rich glasses, with the prospect of superior mechanical, chemical and optical properties. Here we report a novel process for preparing very-high-alumina glasses and nanoscale glass-ceramics. Fully dense bulk articles in net shape are obtained through viscous sintering of glass microbeads. Additional heat treatment of the consolidated glasses leads to fully crystallized transparent glass-converted nanoceramics with a hardness similar to that of alumina. This method avoids the impracticably high applied pressures (more than 1 GPa) that have been required in most cases to prepare nanocrystalline ceramics by sintering, owing to the concurrent nature of densification and grain growth under pressureless conditions. The reported techniques can be extended to form glasses and nanoceramics in other oxide systems that do not include a conventional glass-forming component.

Excluding medical and haematological conditions as a cause of bruising in suspected non-accidental injury.

A mistaken diagnosis of child abuse can occur in a number of medical conditions, many of which can be readily diagnosed by experienced paediatricians. Bleeding disorders offer a greater challenge, especially when court proceedings may demand their exclusion. Some of these disorders are rare but more prevalent in areas which have a high incidence of consanguinity. We advocate two stages of laboratory investigations but the limitations of some of these tests and their inability to exclude a bleeding disorder with absolute certainty should be recognised. However, if personal and family histories are absent and both first-stage and second-stage investigations are normal, it is highly unlikely that a bleeding disorder will be missed.

How does climate variability affect water quality dynamics in Canada's oil sands region?

In Canada's oil sands region, classic boreal hydrology (i.e., winter low flow followed by peaks during spring freshet and then summer flow recession) combined with erosion of both natural and anthropogenically-exposed bitumen results in seasonal and inter-annual variability in stream water chemistry. Using data collected from all seasons over three years (2012-2015), we investigated the mechanisms driving spatial and temporal change in the concentration of 26 water quality parameters for six rivers draining Canada's oil sands region. Mantel tests showed a strong spatial aggregation of climatic drivers (average daily precipitation, accumulated precipitation, snow water equivalent) associated with west versus east discharge patterns. Wavelet analysis highlighted unique watershed attributes, in particular the importance of developed area in lowering responsiveness to seasonal precipitation. Concentrations of most chemical parameters (20 of 23) showed distinct temporal patterns that were correlated with seasonal changes in hydrology which, in turn, were related to changes in weather. Comparison of concentrations observed in this study with those reported in the scientific literature for the same watersheds showed 81% of comparisons differed significantly. This was likely due to the short duration of previous field campaigns and thus the sampling of a very narrow window of the annual streamflow regime.

Arabidopsis thaliana DNA methylation mutants.

Three DNA hypomethylation mutants of the flowering plant Arabidopsis thaliana were isolated by screening mutagenized populations for plants containing centromeric repetitive DNA arrays susceptible to digestion by a restriction endonuclease that was sensitive to methylated cytosines. The mutations are recessive, and at least two are alleles of a single locus, designated DDM1 (for decrease in DNA methylation). Amounts of 5-methylcytosine were reduced over 70 percent in ddm1 mutants. Despite this reduction in DNA methylation levels, ddm1 mutants developed normally and exhibited no striking morphological phenotypes. However, the ddm1 mutations are associated with a segregation distortion phenotype. The ddm1 mutations were used to demonstrate that de novo DNA methylation in vivo is slow.

How to Investigate the Origins of Novelty: Insights Gained from Genetic, Behavioral, and Fitness Perspectives.

Biologists are drawn to the most extraordinary adaptations in the natural world, often referred to as evolutionary novelties, yet rarely do we understand the microevolutionary context underlying the origins of novel traits, behaviors, or ecological niches. Here we discuss insights gained into the origins of novelty from a research program spanning biological levels of organization from genotype to fitness in Caribbean pupfishes. We focus on a case study of the origins of novel trophic specialists on San Salvador Island, Bahamas and place this radiation in the context of other rapid radiations. We highlight questions that can be addressed about the origins of novelty at different biological levels, such as measuring the isolation of novel phenotypes on the fitness landscape, locating the spatial and temporal origins of adaptive variation contributing to novelty, detecting dysfunctional gene regulation due to adaptive divergence, and connecting behaviors with novel traits. Evolutionary novelties are rare, almost by definition, and we conclude that integrative case studies can provide insights into this rarity relative to the dynamics of adaptation to more common ecological niches and repeated parallel speciation, such as the relative isolation of novel phenotypes on fitness landscapes and the transient availability of ecological, genetic, and behavioral opportunities.

Como Investigar as Origens da Novidade: Ideias Obtidas a Partir de Perspectivas da Genética, do Comportamento e de Fitness (How to Investigate the Origins of Novelty: Insights Gained from Genetic, Behavioral, and Fitness Perspectives) Biólogos são atraídos pelas adaptações mais extraordinárias do mundo natural, muitas vezes chamdas de novidades evolutivas, mas raramente entendemos o contexto microevolutivo subjacente às origens de novas características, novos comportamentos ou nichos ecológicos. Aqui discutimos ideias obtidas sobre as origens da novidade evolutiva a partir de um programa de pesquisa abrangendo níveis biológicos de organização de genótipo para fitness em pupas do Caribe. Nós nos concentramos em um estudo de caso sobre as origens de novos especialistas tróficos na ilha de São Salvador, Bahamas, e colocamos essa radiação no contexto de outras radiações rápidas. Destacamos questões que podem ser abordadas sobre as origens da novidade evolutiva em diferentes níveis biológicos, como medir o isolamento de novos fenótipos no cenário adaptativo, localizando as origens espaciais e temporais da variação adaptativa que contribuem para a novidade evolutiva, detectando a regulação gênica disfuncional devido à divergência adaptativa, e conectando comportamentos com novas características. As novidades evolutivas são raras, quase por definição, e concluímos que estudos de caso integrativos podem fornecer ideias sobre essa raridade em relação à dinâmica de adaptação a nichos ecológicos mais comuns e especiação paralela repetitiva, como o relativo isolamento de novos fenótipos em cenários adaptativos e a disponibilidade transitória de oportunidades ecológicas, genéticas, e comportamentais. Translated to Portuguese by G. Sobral (gabisobral@gmail.com).

DNA methylation in eukaryotes.

Recent advances have expanded our understanding of the processes underlying the establishment, maintenance, and elaboration of DNA methylation patterns in eukaryotes. The functional significance of DNA methylation is sought in a comparison of results on a variety of epigenetic phenomena in different eukaryotes. The recent development of DNA methylation mutants in mice, Neurospora, and Arabadopsis will allow traditional genetic dissection to be applied to long-standing problems regarding the function and regulation of eukaryotic DNA methylation. Although methylation appears to be important for maintenance of different epigenetic states, the mechanism that establishes these states is likely to involve additional processes.

Effect of species variation and processing on phenolic composition and in vitro antioxidant activity of aqueous extracts of Cyclopia spp. (Honeybush Tea).

The in vitro antioxidant activity of aqueous extracts prepared from four Cyclopia spp. (unfermented and fermented) was assessed using radical (ABTS *+) scavenging, ferric ion reduction, and inhibition of Fe2+-induced microsomal lipid peroxidation as criteria. Aqueous extracts of unfermented and fermented Aspalathus linearis (rooibos) and Camellia sinensis teas (green, oolong, and black) were included as reference samples. Qualitative and quantitative differences in phenolic composition were demonstrated for the Cyclopia spp. The xanthone glycoside, a.k.a. mangiferin, was the major monomeric polyphenol present in the Cyclopia extracts, with both unfermented and fermented C. genistoides extracts containing the highest quantities. Fermentation resulted in a significant reduction in extract yields and their total polyphenolic and individual polyphenol contents. Unfermented plant material should preferentially be used for preparation of extracts, as fermentation significantly ( P < 0.05) lowered antioxidant activity of all species, except in the case of C. genistoides, where the ability to inhibit lipid peroxidation was not affected. Unfermented plant material also retained the highest concentration of mangiferin. Overall, extracts of unfermented Cyclopia were either of similar or lower antioxidant activity as compared to the other teas. However, the presence of high levels of mangiferin merits the use of Cyclopia spp. and, in particular, C. genistoides, as an alternative herbal tea and potential dietary supplement.

Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child's seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as "effective" versus those rated "ineffective". Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as "effective", with no clear differences between extracts perceived as "effective" and "ineffective". Contrary to family's expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

Author Correction: Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.