Biomechanics and biorheology of red blood cells in sickle cell anemia

Sickle cell anemia (SCA) is an inherited blood disorder that causes painful crises due to vaso-occlusion of small blood vessels. The primary cause of the clinical phenotype of SCA is the intracellular polymerization of sickle hemoglobin resulting in sickling of red blood cells (RBCs) in deoxygenated conditions. In this review, we discuss the biomechanical and biorheological characteristics of sickle RBCs and sickle blood as well as their implications toward a better understanding of the pathophysiology and pathogenesis of SCA. Additionally, we highlight the adhesive heterogeneity of RBCs in SCA and their specific contribution to vaso-occlusive crisis.     

A genetic and spatial Bayesian analysis of mastitis resistance

A nationwide health card recording system for dairy cattle was introduced in Norway in 1975 (the Norwegian Cattle Health Services). The data base holds information on mastitis occurrences on an individual cow basis. A reduction in mastitis frequency across the population is desired, and for this purpose risk factors are investigated. In this paper a Bayesian proportional hazards model is used for modelling the time to first veterinary treatment of clinical mastitis, including both genetic and environmental covariates. Sire effects were modelled as shared random components, and veterinary district was included as an environmental effect with prior spatial smoothing. A non-informative smoothing prior was assumed for the baseline hazard, and Markov chain Monte Carlo methods (MCMC) were used for inference. We propose a new measure of quality for sires, in terms of their posterior probability of being among the, say 10% best sires. The probability is an easily interpretable measure that can be directly used to rank sires. Estimating these complex probabilities is straightforward in an MCMC setting. The results indicate considerable differences between sires with regards to their daughters disease resistance. A regional effect was also discovered with the lowest risk of disease in the south-eastern parts of Norway.     

Residue Glu83 plays a major role in negatively regulating α-synuclein amyloid formation

α-Synuclein (α-syn) amyloid filaments are the major ultrastructural component of pathological inclusions that define several neurodegenerative disorders, including Parkinson disease and other disorders that are collectively termed synucleinopathies. Since the aggregation of α-syn is associated with the etiology of these diseases, defining the molecular elements that influence this process may have important therapeutics implication. The deletions of major portions of the hydrophobic region of α-syn (Δ74-79 and Δ71-82) impair the ability to form amyloid. However, mutating residue E83 to an A restored the ability of these proteins to form amyloid. Additionally supporting an inhibitory role of residue E83 on amyloid formation, mutating this residue to an A enhanced amyloid formation in the presence of small molecule inhibitors, such as dopamine and EGCG. Our data, therefore, suggest that the presence and placement of the highly charged E83 residue plays a significant inhibitory role in α-syn amyloid formation and these findings provide important insights in the planning of therapeutic agents that may be capable of preventing α-syn amyloid formation.     

Risk of parasite transmission influences perceived vulnerability to disease and perceived danger of disease-relevant animals

Adaptationist view proposes that emotions were shaped by natural selection and their primary function is to protect humans against predators and/or disease threat. This study examined cross-cultural and inter-personal differences in behavioural immune system measured by disgust, fear and perceived danger in participants from high (Turkey) and low (Slovakia) pathogen prevalence areas. We found that behavioural immune system in Turkish participants was activated more than those of Slovakian participants when exposed to photographs depicting disease-relevant cues, but not when exposed to disease-irrelevant cues. However, participants from Slovakia, where human to human disease transmission is expected to be more prevalent than in Turkey, showed lower aversion in Germ Aversion subscale supporting hypersensitiveness of the behavioural immune system. Having animals at home was less frequent both in Turkey and in participants who perceived higher danger about disease relevant animals. Participants more vulnerable to diseases reported higher incidence of illness last year and considered perceived disease-relevant animals more dangerous than others. Females showed greater fear, disgust and danger about disease-relevant animals than males. Our results further support the finding that cultural and inter-personal differences in human personality are influenced by parasite threat.     

Diet and attrition in the Natufians

There is a high correlation between the rate of dental attrition and the physical consistency of the diet. Hypotheses concerning types of diet and methods of food preparation in prehistoric populations may therefore be tested by comparing attrition rates in the specimens under investigation with standards derived from groups of known dietary status. For such comparisons the age factor is of paramount importance, but difficult to assess accurately in fragmentary skeletal material. The use of attrition gradients rather than mean attrition scores provides an age independent method for comparison of attrition rates. When Natufian specimens from three different sites (Kebara, El Wad and Eynan) were compared by this method, significant differences in the gradient of attrition were found at one site, Kebara. The incidences of caries and periodontal disease were also lower at this site, and taken in conjunction with the low level of attrition were considered to relate to differences in the vegetable content of the diet between the individuals recovered from Kebara and those recovered from El Wad and Eynan.     

The pattern of involvement of appendicular degenerative joint disease

Patterns of degenerative joint disease are investigated in the shoulder, elbow, hip, and knee joints of the macerated remains of approximately 800 individuals from 20th century American and two prehistoric populations. Age is an important contributory factor in all joints, but its effects are seen most directly in the shoulder and hip. Patterns of right-left involvement also indicate the elbow is the most susceptible area to local factors. Multiple joint involvement is seen more often in females from contemporary populations but more often in males from archeological groups. No significant association is found between degenerative involvement and osteometric measurements, and cause of death is probably only incidentally associated with degenerative disease.     

Models for Trypanosoma evansi (surra), its control and economic impact on small-hold livestock owners in the Philippines

Simple demographic and infectious disease models of buffaloes and other domestic hosts for animal trypanosomosis (surra) caused by Trypanosoma evansi were developed. The animal models contained deterministic and stochastic elements and were linked to simulate the benefit of control regimes for surra in village domestic animal populations in Mindanao, Philippines. The impact of the disease on host fertility and mortality were key factors in determining the economic losses and net-benefit from the control regimes. If using a high (99%) efficacy drug in surra-moderate to high risk areas, then treating all animals twice each year yielded low prevalence in 2 years; targeted treatment of clinically sick animals, constantly monitored (monthly), required 75% fewer treatments but took longer to reach a low prevalence than treating all animals twice each year. At high drug efficacy both of these treatment strategies increased the benefit over untreated animals by 81%. If drug efficacy declined then the benefit obtained from twice yearly treatment of all animals declined rapidly compared with regular monitoring and targeting treatment to clinically sick animals. The current control regimen applied in the Philippines of annual sero-testing for surra and only treating sero-positive animals provided the lowest net-benefit of all the control options simulated and would not be regarded as effective control. The total net-benefit from effective surra control for a typical village in a moderate/high risk area was 7.9 million pesos per annum (US $158,000). The value added to buffaloes, cattle, horses, goats/sheep and pigs as a result of this control was US $88, $84, $151, $7, $114 per animal/year, respectively.     

State-dependency of host-seeking in Rhodnius prolixus: The post-ecdysis time

The source of blood of most haematophagous insects plays at the same time the double role of host and potential predator. Feeding behaviour should be triggered only when necessary and should be completed as quickly as possible. From an epidemiological point of view, this modulation has an impact on the feeding frequency of disease vectors and, as a consequence, on the transmission of parasites. At present, not many data are available on the influence of the physiological state on the motivation to feed, and mostly limited to a few mosquito species. We analyzed the host-seeking behaviour of Rhodnius prolixus as a function of the time elapsed since the ecdysis, by testing the response of larvae to a blood source, and long- (CO₂) and short-range (heat) orientation cues associated to their vertebrate hosts. Our experiments demonstrated that during the first days following the ecdysis insects do not respond to any stimuli. The ability to follow chemical and physical cues increases either gradually (heat) or step-wise (CO₂) with post-ecdysis time. A few insects started to feed on day 2, but only at day 7 following the ecdysis 50% of them took a blood meal, to reach the highest motivation to feed on day 10. The reasons for the “maturation period” in feeding behaviour of R. prolixus are discussed.     

Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella pneumophila

Legionella pneumophila is an aerobic, Gram-negative bacterium of the genus Legionella, which constitutes the major causative agent of Legionnaires’ disease. Recently a nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila was identified and termed Lp1NTPDase; it was found to be a structural and functional homolog of mammalian NTPDases catalyzing the hydrolysis of ATP to ADP and ADP to AMP. Its activity is believed to contribute to the virulence of Legionella pneumophila. Therefore Lp1NTPDase inhibitors are considered as novel antibacterial drugs. However, only weakly potent compounds are available so far. In the present study, a capillary electrophoresis (CE)-based enzyme assay for monitoring the Lp1NTPDase activity was established. The enzymatic reaction was performed in a test tube followed by separation of substrate and products by CE and subsequent quantification by UV analysis. After kinetic characterization of the enzyme, a series of 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinone derivatives structurally related to the anthraquinone dye Reactive Blue 2, a non-selective ecto-NTPDase inhibitor, was investigated for inhibitory activity on Lp1NTPDase using the CE-based enzyme assay. Derivatives bearing a large lipophilic substituent (e.g., fused aromatic rings) in the 4-position of the 1-amino-2-sulfoanthraquinone showed the highest inhibitory activity. Compounds with IC₅₀ values in the low micromolar range were identified. The most potent inhibitor was 1-amino-4-[phenanthrene-9-yl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (28, PSB-16131), with an IC₅₀-value of 4.24 μM. It represents the most potent Lp1NTPDase inhibitor described to date. These findings may serve as a starting point for further optimization. Lp1NTPDase inhibition provides a novel approach for the (immuno)therapy of Legionella infections.