Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma low-density lipoprotein (LDL) cholesterol concentrations and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but most remain unrecognised and those diagnosed remain inadequately treated. To bridge this gap in coronary prevention the FH Australasia Network has developed a model of care for FH. An executive summary of the model of care is presented, with a commentary on its recommendations and the key role of the clinical biochemistry laboratory.
Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca2+ sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor.
In high-income countries, depression is prevalent in HIV patients and is associated with lower medication adherence and clinical outcomes. Emerging evidence from low-income countries supports similar relationships. Yet little research has validated rapid depression screening tools integrated into routine HIV clinical care.
Using qualitative methods, we adapted the Patient Health Questionnaire-9 (PHQ-9) depression screening instrument for use with Cameroonian patients. We then conducted a cross-sectional validity study comparing an interviewer-administered PHQ-9 to the reference standard Composite International Diagnostic Interview in 400 patients on antiretroviral therapy attending a regional HIV treatment center in Bamenda, Cameroon.
The prevalence of major depressive disorder (MDD) in the past month was 3% (n=11 cases). Using a standard cutoff score of ≥10 as a positive depression screen, the PHQ-9 had estimated sensitivity of 27% (95% confidence interval: 6–61%) and specificity of 94% (91–96%), corresponding to positive and negative likelihood ratios of 4.5 and 0.8. There was little evidence of variation in specificity by gender, number of HIV symptoms, or result of a dementia screen.
The low prevalence of MDD yielded very imprecise sensitivity estimates. Although the PHQ-9 was developed as a self-administered tool, we assessed an interviewer-administered version due to the literacy level of the target population.
The PHQ-9 demonstrated high specificity but apparently low sensitivity for detecting MDD in this sample of HIV patients in Cameroon. Formative work to define the performance of proven screening tools in new settings remains important as research on mental health expands in low-income countries.
HIV; depression; validation study; screening instruments; Africa
Hypoxia is a characteristic feature of solid tumors and occurs very early in
neoplastic development. Hypoxia transforms cell physiology in multiple ways,
with profound changes in cell metabolism, cell growth, susceptibility to
apoptosis, induction of angiogenesis, and increased motility. Over the past 20
years, our lab has determined that hypoxia also induces genetic instability. We
have conducted a large series of experiments revealing that this instability
occurs through the alteration of DNA repair pathways, including nucleotide
excision repair, DNA mismatch repair, and homology dependent repair. Our work
suggests that hypoxia, as a key component of solid tumors, can drive cancer
progression through its impact on genomic integrity. However, the acquired
changes in DNA repair that are induced by hypoxia may also render hypoxic cancer
cells vulnerable to tailored strategies designed to exploit these changes.
DNA repair; hypoxia; homologous recombination; mismatch repair; BRCA1; MLH1; silencing; epigenetics; microRNAs
In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, β-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.
Multi-scale modeling plays an important role in understanding the structure and biological functionalities of large biomolecular complexes. In this paper, we present an efficient computational framework to construct multi-scale models from atomic resolution data in the Protein Data Bank (PDB), which is accelerated by multi-core CPU and programmable Graphics Processing Units (GPU). A multi-level summation of Gaus-sian kernel functions is employed to generate implicit models for biomolecules. The coefficients in the summation are designed as functions of the structure indices, which specify the structures at a certain level and enable a local resolution control on the biomolecular surface. A method called neighboring search is adopted to locate the grid points close to the expected biomolecular surface, and reduce the number of grids to be analyzed. For a specific grid point, a KD-tree or bounding volume hierarchy is applied to search for the atoms contributing to its density computation, and faraway atoms are ignored due to the decay of Gaussian kernel functions. In addition to density map construction, three modes are also employed and compared during mesh generation and quality improvement to generate high quality tetrahedral meshes: CPU sequential, multi-core CPU parallel and GPU parallel. We have applied our algorithm to several large proteins and obtained good results.
efficient computation; multi-scale modeling; biomolecular complex * mesh generation; multi-core CPU; GPU
Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen – Jasminum gilgianum, an Oleaceae species native to Papua New Guinea – induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non-canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN-193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME’s mechanism of action will help determine this compound’s pharmacological utility.
Tomatoes are a principal dietary source of carotenoids and flavonoids, both of which are highly beneficial for human health1,2. Overexpression of genes encoding biosynthetic enzymes or transcription factors have resulted in tomatoes with improved carotenoid or flavonoid content, but never with both3–7. We attempted to increase tomato fruit nutritional value by suppressing an endogenous photomorphogenesis regulatory gene, DET1, using fruit-specific promoters combined with RNA interference (RNAi) technology. Molecular analysis indicated that DET1 transcripts were indeed specifically degraded in transgenic fruits. Both carotenoid and flavonoid contents were increased significantly, whereas other parameters of fruit quality were largely unchanged. These results demonstrate that manipulation of a plant regulatory gene can simultaneously influence the production of several phytonutrients generated from independent biosynthetic pathways, and provide a novel example of the use of organ-specific gene silencing to improve the nutritional value of plant-derived products.
Human studies and animal experiments present a complex and often contradictory picture of the acute impact of marijuana on emotions. The few human studies specifically examining changes in negative affect find either increases or reductions following delta-9-tetrahydrocannabinol (THC) administration. In a 2 × 2, instructional set (told THC vs. told no THC) by drug administration (smoked marijuana with 2.8% THC vs. placebo) between-subjects design, we examined the pharmacologic effect of marijuana on physiological and subjective stimulation, subjective intoxication, and self-reported negative and positive affect with 114 weekly marijuana smokers. Individuals were first tested under a baseline/no smoking condition and again under experimental condition. Relative to placebo, THC significantly increased arousal and confusion/bewilderment. However, the direction of effect on anxiety varied depending on instructional set: Anxiety increased after THC for those told placebo but decreased among other participants. Furthermore, marijuana users who expected more impairment from marijuana displayed more anxiety after smoking active marijuana, whereas those who did not expect the impairment became less anxious after marijuana. Both pharmacologic and stimulus expectancy main effects significantly increased positive affect. Frequent marijuana users were less anxious after smoking as compared to less frequent smokers. These findings show that expectancy instructions and pharmacology play independent roles in effects of marijuana on negative affect. Further studies examining how other individual difference factors impact marijuana's effects on mood are needed.
marijuana; anxiety; affect; expectancy; subjective effects
Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Müller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways.
Mutations in the human CRB1 gene lead to one of the most severe forms of retinal dystrophies, called Leber congenital amaurosis. Here, we report that ablation of CRB1 and the second family member CRB2 are crucial for proper retinal development. These mice display severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. The thickening of the retina is due to increased cell proliferation during late retinal development leading to an increased number of late-born retinal cells. We describe in these CRB1 Leber congenital amaurosis mouse models the molecular and cellular events involving CRB proteins during the development of the retina.
Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls.
This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: ‘low’ (prevalence <1%), ‘medium’ (1–5%) and ‘high’ (>5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6–4.6) and had lower income (t = −4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in ‘high’ and ‘medium’ endemicity kebeles were less likely than people in ‘low’ endemicity areas to ‘ever’ have owned shoes (OR = 0.5, 95% CI = 0.4–0.7).
Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis.
Podoconiosis is a neglected tropical disease that results in swelling of the lower legs and feet. It is common among barefoot individuals within defined areas due to the geochemical characteristics of the soil in these areas. Presence of podoconiosis and its huge burden among the affected people in north Ethiopia has previously been documented. Moreover, difference in the occurrence of the disease by area and among individuals had been observed. In the present study, we investigated individual factors for the occurrence of podoconiosis, by comparing individuals with podoconiosis and without podoconiosis that live in three areas with varying disease prevalence. We found that individuals with the disease, particularly women, were less educated, with lower income and less likely to be married, compared to healthy individuals. Moreover, more than one individual was found in most of the affected households. Podoconiosis-affected individuals started wearing shoes at later ages than healthy individuals, and their feet were observed to be more cracked and dirty. There is a recent increase in shoe-wearing among all study subjects. We concluded that intervention efforts should focus to address late age shoe-wearing and inequalities in education, income and marriage, between podoconiosis affected individuals, and particularly among female patients. In addition, the presence of more than one patient per household helps for targeted case identification for intervention.
The chemokine Interferon gamma-induced protein 10 (IP-10) and human leukocyte antigen (HLA) are widely used indicators of glial activation and neuroinflammation and are up-regulated in many brain disorders. These inflammatory mediators have been widely studied in rodent models of brain disorders, but less work has been undertaken using human brain cells. In this study we investigate the regulation of HLA and IP-10, as well as other cytokines and chemokines, in microglia, astrocytes, pericytes, and meningeal fibroblasts derived from biopsy and autopsy adult human brain, using immunocytochemistry and a Cytometric Bead Array. Interferonγ (IFNγ) increased microglial HLA expression, but contrary to data in rodents, the anti-inflammatory cytokine transforming growth factor β1 (TGFβ1) did not inhibit this increase in HLA, nor did TGFβ1 affect basal microglial HLA expression or IFNγ-induced astrocytic HLA expression. In contrast, IFNγ-induced and basal microglial HLA expression, but not IFNγ-induced astrocytic HLA expression, were strongly inhibited by macrophage colony stimulating factor (M-CSF). IFNγ also strongly induced HLA expression in pericytes and meningeal fibroblasts, which do not basally express HLA, and this induction was completely blocked by TGFβ1, but not affected by M-CSF. In contrast, TGFβ1 did not block the IFNγ-induced increase in IP-10 in pericytes and meningeal fibroblasts. These results show that IFNγ, TGFβ1 and M-CSF have species- and cell type-specific effects on human brain cells that may have implications for their roles in adult human brain inflammation.
Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous “entourage” compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.
Papillary thyroid cancer (PTC) recurrence risk is difficult to predict. No current risk classification system incorporates BRAF mutational status. Here, we assess the incremental value of BRAF mutational status in predicting PTC recurrence relative to existing recurrence risk algorithms.
Serial data were collected for a historical cohort having undergone total thyroidectomy for PTC over a five-year period. Corresponding BRAFV600E testing was performed and Cox proportional hazard regression modeling, with and without BRAF status, was used to evaluate existing recurrence risk algorithms.
The five-year cumulative PTC recurrence incidence within our 356 patient cohort was 15%. 205 (81%) of associated archived specimens were successfully genotyped and 110 (54%) harbored the BRAFV600E mutation. The five-year cumulative recurrence incidence among BRAFV600E patients was 20%, versus 8% among BRAF wild type. BRAFV600E was significantly associated with time to recurrence when added to the following algorithms: AMES (HR 2.43 [1.08–5.49]), MACIS category (HR 2.46 [1.09–5.54]), AJCC-TNM (HR 2.51 [1.11, 5.66]), and ATA recurrence-risk category (HR 2.44 [1.08–5.50]), and model discrimination improved (incremental c-index range 0.046–0.109).
Addition of BRAF mutational status to established risk algorithms improves discrimination of recurrence risk in patients undergoing total thyroidectomy for PTC.
Oxidative stress has been implicated in Down syndrome (DS) pathology. This study compares DS individuals and controls on their urinary levels of allantoin and 2,3-dinor-iPF2α-III; these biomarkers have been previously validated in a clinical model of oxidative stress. Urine samples were collected from 48 individuals with DS and 130 controls. Biomarkers were assayed by ultra-performance liquid chromatography-tandem mass spectrometry, normalized by urinary creatinine concentration. After adjusting for age and gender, mean allantoin levels were lower among DS individuals versus controls (p = 0.04). The adjusted mean levels of 2,3-dinor-iPF2α-III were similar in DS individuals and controls (p = 0.7). Our results do not support the hypothesis that DS individuals have chronic systemic oxidative stress.
Down syndrome; biomarker; urine; tandem mass spectrometry
Over the past two decades, colleges and universities have seen a large increase in the number of students referred to the administration for alcohol policies violations. However, a substantial portion of mandated students may not require extensive treatment. Stepped care may maximize treatment efficiency and greatly reduce the demands on campus alcohol programs.
Participants in the study (N = 598) were college students mandated to attend an alcohol program following a campus-based alcohol citation. All participants received Step 1: a 15-minute Brief Advice session that included the provision of a booklet containing advice to reduce drinking. Participants were assessed six weeks after receiving the Brief Advice, and those who continued to exhibit risky alcohol use (n = 405) were randomized to Step 2, a 60–90 minute brief motivational intervention (BMI) (n = 211) or an assessment-only control (n = 194). Follow-up assessments were conducted 3, 6, and 9 months after Step 2.
Results indicated that the participants who received a BMI significantly reduced the number of alcohol-related problems compared to those who received assessment-only, despite no significant group differences in alcohol use. In addition, low risk drinkers (n = 102; who reported low alcohol use and related harms at 6-week follow-up and were not randomized to stepped care) showed a stable alcohol use pattern throughout the follow-up period, indicating they required no additional intervention.
Stepped care is an efficient and cost-effective method to reduce harms associated with alcohol use by mandated students.
Carotid endarterectomy (CEA) is a common surgical procedure. Its efficacy in the prevention of stroke has been proven by multiple clinical trials including North American Symptomatic Carotid Endarterectomy Trial and Asymptomatic Carotid Atherosclerosis Study. Currently, there is a wide variability in the technique of this operation. This study was performed to determine the variability of CEA at the University of Kentucky Medical Center with a focus on cost and short-term outcome. We reviewed the charts of a consecutive series of 349 patients undergoing CEA at our institution. We analyzed the variability in shunt used across surgeons, intraoperative variables, cost, and outcome. Data on 374 procedures on 349 patients who underwent CEA showed shunt utilization varied significantly by surgeon from 3 to 94%. Patch utilization also varied significantly by surgeon. Two in-hospital deaths occurred in the shunt group (1.3%) and none in the no-shunt group. Shunt placement was associated with 1 hour 24 minutes increase in operative time from 2 hours 3 minutes in the no-shunt group to 3 hours 27 minutes in the shunt group (t test, p < 0.01). Shunt placement was associated with a 1.74-day increase in length of stay, from 2.97 days in the no-shunt group to 4.71 days in the shunt group. There was no significant difference in the cost of procedure in these two groups: no-shunt $11,510 ± $3,977, shunt group $11,479 ± $4,030. This study showed no significant difference in cost or outcome between various techniques.
carotid endarterectomy; stroke; stenosis; shunt; patch; cost analysis; outcomes; mortality; morbidity
Two of the most agriculturally important cereal crop plants are wheat (Triticum aestivum) and rice (Oryza sativa). Rice has been shown to produce a number of diterpenoid natural products as phytoalexins and/or allelochemicals – specifically, labdane-related diterpenoids, whose biosynthesis proceeds via formation of an eponymous labdadienyl/copalyl diphosphate (CPP) intermediate (e.g., the ent-CPP of gibberellin phytohormone biosynthesis). Similar to rice, wheat encodes a number of CPP synthases (CPS), and the three CPS characterized to date (TaCPS1,2,&3) all have been suggested to produce ent-CPP. However, several of the downstream diterpene synthases will only react with CPP intermediate of normal or syn, but not ent, stereochemistry, as described in the accompanying report. Investigation of additional CPS did not resolve this issue, as the only other functional synthase (TaCPS4) also produced ent-CPP. Chiral product characterization of all the TaCPS then revealed that TaCPS2 uniquely produces normal, rather than ent-, CPP; thus, providing a suitable substrate source for the downstream diterpene synthases. Notably, TaCPS2 is most homologous to the similarly stereochemically differentiated syn-CPP synthase from rice (OsCPS4), while the non-inducible TaCPS3 and TaCPS4 cluster with the rice OsCPS1 required for gibberellin phytohormone biosynthesis, as well as with a barley (Hordeum vulgare) CPS (HvCPS1) that also is characterized here as similarly producing ent-CPP. These results suggest that diversification of labdane-related diterpenoid metabolism beyond the ancestral gibberellins occurred early in cereal evolution, and included the type of stereochemical variation demonstrated here.
Oryza sativa; Triticum aestivum; Hordeum vulgare; copalyl diphosphate synthase
In forensic genetics mitochondrial DNA (mtDNA) is usually analyzed by direct Sanger-type sequencing (STS). This method is known to be laborious and sometimes prone to human error. Alternative methods have been proposed that lead to faster results. Among these are methods that involve mass-spectrometry resulting in base composition profiles that are, by definition, less informative than the full nucleotide sequence. Here, we applied a highly automated electrospray ionization mass spectrometry (ESI-MS) system (PLEX-ID) to an mtDNA population study to compare its performance with respect to throughput and concordance to STS. We found that the loss of information power was relatively low compared to the gain in speed and analytical standardization. The detection of point and length heteroplasmy turned out to be roughly comparable between the technologies with some individual differences related to the processes. We confirm that ESI-MS provides a valuable platform for analyzing mtDNA variation that can also be applied in the forensic context.
Mass spectrometry; Sanger-type sequencing; Mitochondrial DNA; Point heteroplasmy; Length heteroplasmy
Objectives To describe the presentation, work-up, and management of patients with metastatic renal cell carcinoma (RCC) to the sinonasal cavity and skull base, and to describe our current treatment algorithm of endoscopic surgical resection followed by radiation therapy.
Design Retrospective review of two recent cases from our institution over a 1-year period, with a relevant review of the literature.
Setting A large regional tertiary care facility.
Participants Consecutive cases of RCC with metastases to the sinonasal cavity presenting to our institution.
Main Outcome Measures Preoperative and postoperative sinonasal outcome test (SNOT)-22 scores, duration of hospital stay, complications, and local disease control
Results Patients in this series underwent preoperative embolization followed by endoscopic resection without complication. Postoperatively they were treated with radiation therapy. They experienced improvement in their SNOT-22 scores and are currently free of local disease.
Conclusion Metastatic RCC to the sinonasal cavity can be safely treated with preoperative embolization followed by endoscopic surgical resection and radiation therapy, which can result in improvement in sinonasal quality of life and is a potential adjunct for local control of disease.
renal cell carcinoma; quality of life; embolization; epistaxis; nasal obstruction
•Incidence is modelled using HMIS data in Namibia.•Assembled data include parasitological and clinical diagnosed case. The clinical cases are adjusted using slide positivity rates at each facility.•Denominator catchment population adjusted for probability for seeking treatment when sick with fever.•Bayesian spatio-temporal model was implemented at facility level, adjusting for missing data using INLA.•Spatio-temporal monthly maps of incidence are produced and a mean prediction for 2009 for Namibia.
As malaria transmission declines, it becomes increasingly important to monitor changes in malaria incidence rather than prevalence. Here, a spatio-temporal model was used to identify constituencies with high malaria incidence to guide malaria control. Malaria cases were assembled across all age groups along with several environmental covariates. A Bayesian conditional-autoregressive model was used to model the spatial and temporal variation of incidence after adjusting for test positivity rates and health facility utilisation. Of the 144,744 malaria cases recorded in Namibia in 2009, 134,851 were suspected and 9893 were parasitologically confirmed. The mean annual incidence based on the Bayesian model predictions was 13 cases per 1000 population with the highest incidence predicted for constituencies bordering Angola and Zambia. The smoothed maps of incidence highlight trends in disease incidence. For Namibia, the 2009 maps provide a baseline for monitoring the targets of pre-elimination.
ACD, active case detection; CAR, conditional auto-regressive; CPO, conditional predictive ordinate; DIC, deviance information criterion; ESRI, Environmental System Research Institute; EVI, enhanced vegetation index; GF, Gaussian field; GIS, geographic information system; GMRF, Gaussian markov random field; GPS, global positioning system; GRUMP, Global Rural and Urban Mapping Project; HMIS, Health Management Information System; INLA, Integrated Nested Laplace Approximation; JAXA, Japan Aerospace Exploration Agency; MAUP, Modifiable Areal Unit Problem; MCMC, Markov Chain Monte Carlo; MODIS, MODerate-resolution Imaging Spectro-radiometer; MoHSS, Ministry of Health and Social Services; NASA, National Aeronautics and Space Administration; NVBDCP, National Vector-Borne and Disease Control Programme; PCD, passive case detection; PHS, public health sector; RDT, Rapid Diagnostic Test; SPA, Service Provision Assessments; TRMM, Tropical Rainfall Measuring Mission; TSI, temperature suitability index; WHO, World Health Organisation; ZIP, Zero-Inflated Poisson; Namibia; Malaria; Spatio-temporal; Conditional-autoregressive
Wheat (Triticum aestivum) and rice (Oryza sativa) are two of the most agriculturally important cereal crop plants. Rice is known to produce numerous diterpenoid natural products that serve as phytoalexins and/or allelochemicals. Specifically, these are labdane-related diterpenoids, derived from a characteristic labdadienyl/copalyl diphosphate (CPP), whose biosynthetic relationship to gibberellin biosynthesis is evident from the relevant expanded and functionally diverse family of ent-kaurene synthase-like (KSL) genes found in rice (OsKSL). Here we report biochemical characterization of a similarly expansive family of KSL from wheat (the TaKSLs). In particular, beyond ent-kaurene synthases (KS), wheat also contains several biochemically diversified KSLs. These react either with the ent-CPP intermediate common to gibberellin biosynthesis or with the normal stereoisomer of CPP that also is found in wheat (as demonstrated by the accompanying description of wheat CPP synthases). Comparison with a barley (Hordeum vulgare) KS indicates conservation of monocot KS, with early and continued expansion and functional diversification of KSLs in at least the small grain cereals. In addition, some of the TaKSLs that utilize normal CPP also will react with syn-CPP, echoing previous findings with the OsKSL family, with such enzymatic promiscuity/plasticity providing insight into the continuing evolution of diterpenoid metabolism in the cereal crop plant family, as well as more generally, which is discussed here.
ent-kaurene synthase; phytoalexin; phytoanticipin; allelochemicals; natural products biosynthesis; plant defense
A One Health approach considers the role of changing environments with regard to infectious and chronic disease risks affecting humans and nonhuman animals. Recent disease emergence events have lent support to a One Health approach. In 2010, the Stone Mountain Working Group on One Health Proof of Concept assembled and evaluated the evidence regarding proof of concept of the One Health approach to disease prediction and control. Aspects examined included the feasibility of integrating human, animal, and environmental health and whether such integration could improve disease prediction and control efforts. They found evidence to support each of these concepts but also identified the need for greater incorporation of environmental and ecosystem factors into disease assessments and interventions. The findings of the Working Group argue for larger controlled studies to evaluate the comparative effectiveness of the One Health approach.
One Health; proof of concept; zoonoses; comparative effectiveness research; veterinary medicine; public health; animal health; human health; environmental health; interprofessional relations