Knockout studies reveal an important role of <i>plasmodium</i> lipoic acid protein ligase a1 for asexual blood stage parasite survival

Lipoic acid (LA) is a dithiol-containing cofactor that is essential for the function of a-keto acid dehydrogenase complexes. LA acts as a reversible acyl group acceptor and 'swinging arm' during acyl-coenzyme A formation. The cofactor is post-translationally attached to the acyl-transferase subunits of the multienzyme complexes through the action of octanoyl (lipoyl): &lt;i&gt;N&lt;/i&gt;-octanoyl (lipoyl) transferase (LipB) or lipoic acid protein ligases (LplA). Remarkably, apicomplexan parasites possess LA biosynthesis as well as scavenging pathways and the two pathways are distributed between mitochondrion and a vestigial organelle, the apicoplast. The apicoplast-specific LipB is dispensable for parasite growth due to functional redundancy of the parasite's lipoic acid/octanoic acid ligases/transferases. In this study, we show that &lt;i&gt;LplA1&lt;/i&gt; plays a pivotal role during the development of the erythrocytic stages of the malaria parasite. Gene disruptions in the human malaria parasite &lt;i&gt;P.falciparum&lt;/i&gt; consistently were unsuccessful while in the rodent malaria model parasite &lt;i&gt;P. berghei&lt;/i&gt; the &lt;i&gt;LplA1&lt;/i&gt; gene locus was targeted by knock-in and knockout constructs. However, the &lt;i&gt;LplA1&lt;/i&gt; &lt;sup&gt;(-)&lt;/sup&gt; mutant could not be cloned suggesting a critical role of LplA1 for asexual parasite growth &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. These experimental genetics data suggest that lipoylation during expansion in red blood cells largely occurs through salvage from the host erythrocytes and subsequent ligation of LA to the target proteins of the malaria parasite

How doctors record breaking bad news in ovarian cancer

Revealing the diagnosis of cancer to patients is a key event in their cancer journey. At present, there are no minimal legal recommendations for documenting such consultations. We reviewed the Hospital records of 359 patients with epithelial ovarian cancer in the Mersey Area between 1992 and 1994. We identified the following factors: age, hospital, postcode, surgeon, stage of disease and survival. These were compared to information recorded at the time of the interview such as person present, descriptive words used, prognosis, further treatment and emotional response. In 11.6%, there was no information recorded in the notes. The diagnosis was recorded in 304 (94.7%), prognosis in 66 (20.6%) and collusion with relatives in 33 (10.3%). A total of 42 separate words/phrases were identified relating to diagnosis; cancer was recorded in 60 (19.6%). Collusion was three times as common in the patients over 65 years (17.9 vs 5.7%, P=0.001). There was a reduction in the number of diagnostic words recorded in the patients over 65 years (90.3 vs 98.3%, P=0.002) and by type of surgeon (P=0.001). Information was often poorly recorded in the notes. We have shown that the quality of information varies according to patient age, surgeon and specialty

Reliability of an injury scoring system for horses

<p>Abstract</p> <p>Background</p> <p>The risk of injuries is of major concern when keeping horses in groups and there is a need for a system to record external injuries in a standardised and simple way. The objective of this study, therefore, was to develop and validate a system for injury recording in horses and to test its reliability and feasibility under field conditions.</p> <p>Methods</p> <p>Injuries were classified into five categories according to severity. The scoring system was tested for intra- and inter-observer agreement as well as agreement with a 'golden standard' (diagnosis established by a veterinarian). The scoring was done by 43 agricultural students who classified 40 photographs presented to them twice in a random order, 10 days apart. Attribute agreement analysis was performed using Kendall's coefficient of concordance (Kendall's <it>W</it>), Kendall's correlation coefficient (Kendall's τ) and Fleiss' kappa. The system was also tested on a sample of 100 horses kept in groups where injury location was recorded as well.</p> <p>Results</p> <p>Intra-observer agreement showed Kendall's <it>W </it>ranging from 0.94 to 0.99 and 86% of observers had kappa values above 0.66 (substantial agreement). Inter-observer agreement had an overall Kendall's <it>W </it>of 0.91 and the mean kappa value was 0.59 (moderate). Agreement for all observers versus the 'golden standard' had Kendall's τ of 0.88 and the mean kappa value was 0.66 (substantial). The system was easy to use for trained persons under field conditions. Injuries of the more serious categories were not found in the field trial.</p> <p>Conclusion</p> <p>The proposed injury scoring system is easy to learn and use also for people without a veterinary education, it shows high reliability, and it is clinically useful. The injury scoring system could be a valuable tool in future clinical and epidemiological studies.</p

Exploratory analysis of obsessive compulsive symptom dimensions in children and adolescents: a Prospective follow-up study

BACKGROUND: Recent statistical approaches based on factor analysis of obsessive compulsive (OC) symptoms in adult patients have identified dimensions that seem more effective in symptom-based taxonomies and appear to be more stable over time. Although a phenotypic continuum from childhood to adulthood has been hypothesized, no factor analytic studies have been performed in juvenile patients, and the stability of OC dimensions in children and adolescents has not been assessed. METHODS: This study was designed to perform an exploratory factor analysis of OC symptoms in a sample of children and adolescents with OC disorder (OCD) and to investigate the course of factors over time (mean follow-up period: four years). RESULTS: We report for the first time that four symptom dimensions, remarkably similar to those previously described in adults, underlined the heterogeneity of OC symptoms in children and adolescents. Moreover, after follow-up, the symptom dimensions identified remained essentially unmodified. The changes observed concerned the intensity of dimensions rather than shifts from one dimension to another. CONCLUSION: These findings reinforce the hypothesis of a phenotypic continuum of OC symptoms from childhood to adulthood. They also strengthen the interest for investigating the clinical, neurobiological and genetic heterogeneity of OCD using a dimension-based approach

Generalized cerebral atrophy seen on MRI in a naturally exposed animal model for creutzfeldt-jakob disease

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance imaging has been used in the diagnosis of human prion diseases such as sCJD and vCJD, but patients are scanned only when clinical signs appear, often at the late stage of disease. This study attempts to answer the questions "Could MRI detect prion diseases before clinical symptoms appear?, and if so, with what confidence?"</p> <p>Methods</p> <p>Scrapie, the prion disease of sheep, was chosen for the study because sheep can fit into a human sized MRI scanner (and there were no large animal MRI scanners at the time of this study), and because the USDA had, at the time of the study, a sizeable sample of scrapie exposed sheep, which we were able to use for this purpose. 111 genetically susceptible sheep that were naturally exposed to scrapie were used in this study.</p> <p>Results</p> <p>Our MRI findings revealed no clear, consistent hyperintense or hypointense signal changes in the brain on either clinically affected or asymptomatic positive animals on any sequence. However, in all 37 PrP^Scpositive sheep (28 asymptomatic and 9 symptomatic), there was a greater ventricle to cerebrum area ratio on MRI compared to 74 PrP^Scnegative sheep from the scrapie exposed flock and 6 control sheep from certified scrapie free flocks as defined by immunohistochemistry (IHC).</p> <p>Conclusions</p> <p>Our findings indicate that MRI imaging can detect diffuse cerebral atrophy in asymptomatic and symptomatic sheep infected with scrapie. Nine of these 37 positive sheep, including 2 one-year old animals, were PrP^Scpositive only in lymph tissues but PrP^Scnegative in the brain. This suggests either 1) that the cerebral atrophy/neuronal loss is not directly related to the accumulation of PrP^Scwithin the brain or 2) that the amount of PrP^Scin the brain is below the detectable limits of the utilized immunohistochemistry assay. The significance of these findings remains to be confirmed in human subjects with CJD.</p

Luminescence Dating in Fluvial Settings: Overcoming the Challenge of Partial Bleaching

Optically stimulated luminescence (OSL) dating is a versatile technique that utilises the two most ubiquitous minerals on Earth (quartz or K-feldspar) for constraining the timing of sediment deposition. It has provided accurate ages in agreement with independent age control in many fluvial settings, but is often characterised by partial bleaching of individual grains. Partial bleaching can occur where sunlight exposure is limited and so only a portion of the grains in the sample was exposed to sunlight prior to burial, especially in sediment-laden, turbulent or deep water columns. OSL analysis on multiple grains can provide accurate ages for partially bleached sediments where the OSL signal intensity is dominated by a single brighter grain, but will overestimate the age where the OSL signal intensity is equally as bright (often typical of K-feldspar) or as dim (sometimes typical of quartz). In such settings, it is important to identify partial bleaching and the minimum dose population, preferably by analysing single grains, and applying the appropriate statistical age model to the dose population obtained for each sample. To determine accurate OSL ages using these age models, it is important to quantify the amount of scatter (or overdispersion) in the well-bleached part of the partially bleached dose distribution, which can vary between sediment samples depending upon the bedrock sources and transport histories of grains. Here, we discuss how the effects of partial bleaching can be easily identified and overcome to determine accurate ages. This discussion will therefore focus entirely on the burial dose determination for OSL dating, rather than the dose-rate, as only the burial doses are impacted by the effects of partial bleaching

Evaluation of skin dose associated with different frequencies of bolus applications in post-mastectomy three-dimensional conformal radiotherapy

<p>Abstract</p> <p>Background</p> <p>The study aimed to calculate chest-wall skin dose associated with different frequencies of bolus applications in post-mastectomy three-dimensional conformal radiotherapy (3D-CRT) and to provide detailed information in the selection of an appropriate bolus regimen in this clinical setting.</p> <p>Methods</p> <p>CT-Simulation scans of 22 post-mastectomy patients were used. Chest wall for clinical target volume (CTV) and a volume including 2-mm surface thickness of the chest wall for skin structures were delineated. Precise PLAN 2.11 treatment planning system (TPS) was used for 3D-CRT planning. 50 Gy in 25 fractions were prescribed using tangential fields and 6-MV photons. Six different frequencies of bolus applications (0, 5, 10, 15, 20, and 25) were administered. Cumulative dose-volume histograms were generated for each bolus regimen. The minimum, maximum and mean skin doses associated with the bolus regimens were compared. To test the accuracy of TPS dose calculations, experimental measurements were performed using EBT gafchromic films.</p> <p>Results</p> <p>The mean, minimum and maximum skin doses were significantly increased with increasing days of bolus applications (p < 0.001). The minimum skin doses for 0, 5, 10, 15, 20, and 25 days of bolus applications were 73.0% ± 2.0%, 78.2% ± 2.0%, 83.3% ± 1.7%, 88.3% ± 1.6%, 92.2% ± 1.7%, and 93.8% ± 1.8%, respectively. The minimum skin dose increments between 20 and 25 (1.6% ± 1.0%), and 15 and 20 (4.0% ± 1.0%) days of bolus applications were significantly lower than the dose increments between 0 and 5 (5.2% ± 0.6%), 5 and 10 (5.1% ± 0.8%), and 10 and 15 (4.9% ± 0.8%) days of bolus applications (p < 0.001). The maximum skin doses for 0, 5, 10, 15, 20, and 25 days of bolus applications were 110.1% ± 1.1%, 110.3% ± 1.1%, 110.5% ± 1.2%, 110.8% ± 1.3%, 111.2% ± 1.5%, and 112.2% ± 1.7%, respectively. The maximum skin dose increments between 20 and 25 (1.0% ± 0.6%), and 15 and 20 (0.4% ± 0.3%) days of bolus applications were significantly higher than the dose increments between 0 and 5 (0.2% ± 0.2%), 5 and 10 (0.2% ± 0.2%), and 10 and 15 (0.2% ± 0.2%) days of bolus applications (p ≤ 0.003). The TPS overestimated the near-surface dose 10.8% at 2-mm below the skin surface.</p> <p>Conclusion</p> <p>In post-mastectomy 3D-CRT, using a 1-cm thick bolus in up to 15 of the total 25 fractions increased minimum skin doses with a tolerable increase in maximum doses.</p

Temporal Trends in Vertebral Size and Shape from Medieval to Modern-Day

Human lumbar vertebrae support the weight of the upper body. Loads lifted and carried by the upper extremities cause significant loading stress to the vertebral bodies. It is well established that trauma-induced vertebral fractures are common especially among elderly people. The aim of this study was to investigate the morphological factors that could have affected the prevalence of trauma-related vertebral fractures from medieval times to the present day. To determine if morphological differences existed in the size and shape of the vertebral body between medieval times and the present day, the vertebral body size and shape was measured from the 4th lumbar vertebra using magnetic resonance imaging (MRI) and standard osteometric calipers. The modern samples consisted of modern Finns and the medieval samples were from archaeological collections in Sweden and Britain. The results show that the shape and size of the 4th lumbar vertebra has changed significantly from medieval times in a way that markedly affects the biomechanical characteristics of the lumbar vertebral column. These changes may have influenced the incidence of trauma- induced spinal fractures in modern populations