New approaches in detection and treatment of familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that clinically leads to increased low density lipoprotein-cholesterol (LDL-C) levels. As a consequence, FH patients are at high risk for cardiovascular disease (CVD). Mutations are found in genes coding for the LDLR, apoB, and PCSK9, although FH cannot be ruled out in the absence of a mutation in one of these genes. It is pivotal to diagnose FH at an early age, since lipid lowering results in a decreased risk of cardiovascular complications especially if initiated early, but unfortunately FH is largely underdiagnosed. While a number of clinical criteria are available, identification of a pathogenic mutation in any of the three aforementioned genes is seen by many as a way to establish a definitive diagnosis of FH. It should be remembered that clinical treatment is based on LDL-C levels and not solely on presence or absence of genetic mutations as LDL-C is what drives risk. Traditionally, mutation detection has been done by means of dideoxy sequencing. However, novel molecular testing methods are gradually being introduced. These next generation sequencing-based methods are likely to be applied on broader scale once their efficacy and effect on cost are being established. Statins are the first-line therapy of choice for FH patients as they have been proven to reduce CVD risk across a range of conditions including hypercholesterolemia (though not specifically tested in FH). However, in a significant proportion of FH patients LDL-C goals are not met, despite the use of maximal statin doses and additional lipid-lowering therapies. This underlines the need for additional therapies, and inhibition of PCSK9 and CETP is among the most promising new therapeutic options. In this review, we aim to provide an overview of the latest information about the definition, diagnosis, screening, and current and novel therapies for F

The Leech Haemopis lateromaculata (Hirudinea: Haemopidae): Its North America Distribution and Additional Notes on Species Description

The geographic range of Haemopis lateromaculata Mathers 1963 (Hirudinea: Haemopidae) is extended across North America. Its distribution in the coastal region of Alaska and British Columbia suggests a coastal Pleistocene refugia separate from the populations in the lower United States and suggests that H. lateromaculata and the Eurasian H. sanguisuga Linnaeus 1758 are sister taxa. Support of the identification and geography is based on the anatomical positions of the reproductive organs in H. lateromaculata and H. marmorata Say 1824. The variations within these species are described, noting that no specific variation was confined to a geographical region

Predicting Forage Production from Pasture by use of the Delphi Technique

The objective of this study was to determine the effect of various pasture management techniques on the predicted yield of forage from pasture. Twelve researchers, extension and industry personnel in Atlantic Canada participated in the Delphi technique as well as the Conjoint analysis to arrive at estimates for the yield response expected from the use of single pasture management techniques and multiple combinations of the same. The results of the Delphi survey demonstrated that all of the pasture management techniques would increase the yield of forage, from seven percent up to forty-seven percent beyond the yield of unimproved, unmanaged pasture

Change in Water Activity and Fungal Counts of Maize-pigeon Pea Flour During Storage Utilizing Various Packaging Materials

AbstractMaize-pigeon pea fortified flour has been processed with the potential to address protein-malnutrition, especially among children. This combination is preferred since cereals lack amino acids, such as methionine, and legumes lack lysine. When mixed together, the amino acid concentrations can be complemented. However, stored maize is an excellent substrate for Aspergillus spp., especially under warm (20-300C) and humid conditions (70-900C). This study investigated the changes in water activity and fungal counts in maize-pigeon pea flour stored for up to 8 weeks using different packaging materials. Maize pigeon flour was processed at different concentrations of 90:10 to 70:30 from fermented, dried, and milled maize and blanched, dehulled, and milled pigeon pea seeds. The flour samples were packaged into four different packaging materials: low and high density polythene bags, as well as plastic and aluminum containers. These containers were stored under simulated tropical conditions of 28+20C and 83+2% relative humidity in an incubator. Water activity (aw) of the flours was determined and fungi were enumerated using Petrifilm. Initial (day 0) aw of samples ranged from 0.15 to 0.17; after 8 weeks, aw ranged from 0.20 to 0.32 in low density polyethene, while lower aw was recorded for samples stored in the plastic and aluminum containers. Initial fungal counts ranged from 1.69 to 2.31 log10 CFU/g which increased from a range of 2.45 to 2.78 log10 CFU/g after 8 weeks of storage, with higher counts in samples stored in low density polythene bags. These results indicate that aw and fungal counts of the flours increased slightly over time in the different packaging materials, but values appear to be within tolerable limits. Further research will evaluate the stability of amino acids, as well as the level of fungi and resulting aflatoxin production up to 11 months under the storage conditions, formulations, and packaging materials described above

Extending the use of GWAS data by combining data from different genetic platforms

BACKGROUND: In the past decade many Genome-wide Association Studies (GWAS) were performed that discovered new associations between single-nucleotide polymorphisms (SNPs) and various phenotypes. Imputation methods are widely used in GWAS. They facilitate the phenotype association with variants that are not directly genotyped. Imputation methods can also be used to combine and analyse data genotyped on different genotyping arrays. In this study we investigated the imputation quality and efficiency of two different approaches of combining GWAS data from different genotyping platforms. We investigated whether combining data from different platforms before the actual imputation performs better than combining the data from different platforms after imputation. METHODS: In total 979 unique individuals from the AMC-PAS cohort were genotyped on 3 different platforms. A total of 706 individuals were genotyped on the MetaboChip, a total of 757 individuals were genotyped on the 50K gene-centric Human CVD BeadChip, and a total of 955 individuals were genotyped on the HumanExome chip. A total of 397 individuals were genotyped on all 3 individual platforms. After pre-imputation quality control (QC), Minimac in combination with MaCH was used for the imputation of all samples with the 1,000 genomes reference panel. All imputed markers with an r2 value of <0.3 were excluded in our post-imputation QC. RESULTS: A total of 397 individuals were genotyped on all three platforms. All three datasets were carefully matched on strand, SNP ID and genomic coordinates. This resulted in a dataset of 979 unique individuals and a total of 258,925 unique markers. A total of 4,117,036 SNPs were available when imputation was performed before merging the three datasets. A total of 3,933,494 SNPs were available when imputation was done on the combined set. Our results suggest that imputation of individual datasets before merging performs slightly better than after combining the different datasets. CONCLUSIONS: Imputation of datasets genotyped by different platforms before merging generates more SNPs than imputation after putting the datasets together

Virulence Associated Gene 8 of Bordetella pertussis Enhances Contact System Activity by Inhibiting the Regulatory Function of Complement Regulator C1 Inhibitor.

Bordetella pertussis is a Gram-negative bacterium and the causative agent of whooping cough. Whooping cough is currently re-emerging worldwide and, therefore, still poses a continuous global health threat. B. pertussis expresses several virulence factors that play a role in evading the human immune response. One of these virulence factors is virulence associated gene 8 (Vag8). Vag8 is a complement evasion molecule that mediates its effects by binding to the complement regulator C1 inhibitor (C1-INH). This regulatory protein is a fluid phase serine protease that controls proenzyme activation and enzyme activity of not only the complement system but also the contact system. Activation of the contact system results in the generation of bradykinin, a pro-inflammatory peptide. Here, the activation of the contact system by B. pertussis was explored. We demonstrate that recombinant as well as endogenous Vag8 enhanced contact system activity by binding C1-INH and attenuating its inhibitory function. Moreover, we show that B. pertussis itself is able to activate the contact system. This activation was dependent on Vag8 production as a Vag8 knockout B. pertussis strain was unable to activate the contact system. These findings show a previously overlooked interaction between the contact system and the respiratory pathogen B. pertussis. Activation of the contact system by B. pertussis may contribute to its pathogenicity and virulence

Low‐Density Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific

Background: Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex‐specific differential effect of genetically increased low‐density lipoprotein cholesterol (LDL‐C) on cardiovascular disease (CVD) and other lipid‐associated diseases. Methods and Results: This is a 2‐sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80‐variant LDL‐C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex‐specific LDL‐C effects on lipids, carotid‐intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL‐C effect on CVD events was sex specific: per SD genetically increased LDL‐C, female participants had a higher LDL‐C increase but an attenuated CVD risk increase compared with male participants (LDL‐C: female participants 0.71 mmol/L, 95% CI, 0.70–0.72 and male participants 0.57 mmol/L, 95% CI, 0.56–0.59. P for interaction: 5.03×10−60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24–1.40 and male participants: OR, 1.52; 95% CI, 1.46–1.58. P for interaction: 9.88×10−5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL‐C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL‐C was also associated with an attenuated carotid‐intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex‐specific weighted genetic scores showed similar results. Conclusions: We found that genetically increased LDL‐C has a sex‐specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL‐C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL‐C targeted therapies for CVD management than female patients and warranting investigations into the sex‐specific relative contribution of risk factors for CVD

Response of a lithium fall to an inertially confined fusion microexplosion

One of the most difficult technology problems in an inertially confined fusion reactor is the survival of the structure from the repeated stresses caused by the microexplosion products. To mitigate the damage from the microexplosion products, a thick lithium fall can be circulated in front of the structure. This fall will absorb the short-ranged products and moderate and attenuate the neutrons. This paper discusses the response of the fall to the microexplosion products, and estimates the resulting loading and stresses in the first structural wall