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Almost any warm-blooded creature can be an intermediate host for Toxoplasma gondii . However, sexual reproduction of T . gondii occurs only in felids, wherein fertilisation of haploid macrogametes by haploid microgametes, results in diploid zygotes, around which a protective wall develops, forming unsporulated oocysts. Unsporulated oocysts are shed in the faeces of cats and meiosis gives rise to haploid sporozoites within the oocysts. These, now infectious, sporulated oocysts contaminate the environment as a source of infection for people and their livestock. RNA-Seq analysis of cat enteric stages of T . gondii uncovered genes expressed uniquely in microgametes and macrogametes. A CRISPR/Cas9 strategy was used to create a T . gondii strain that exhibits defective fertilisation, decreased fecundity and generates oocysts that fail to produce sporozoites. Inoculation of cats with this engineered parasite strain totally prevented oocyst excretion following infection with wild-type T . gondii , demonstrating that this mutant is an attenuated, live, transmission-blocking vaccine.

Background The apicomplexan parasite Toxoplasma gondii is cosmopolitan in nature, largely as a result of its highly flexible life cycle. Felids are its only definitive hosts and a wide range of mammals and birds serve as intermediate hosts. The latent bradyzoite stage is orally infectious in all warm-blooded vertebrates and establishes chronic, transmissible infections. When bradyzoites are ingested by felids, they transform into merozoites in enterocytes and expand asexually as part of their coccidian life cycle. In all other intermediate hosts, however, bradyzoites differentiate exclusively to tachyzoites, and disseminate extraintestinally to many cell types. Both merozoites and tachyzoites undergo rapid asexual population expansion, yet possess different effector fates with respect to the cells and tissues they develop in and the subsequent stages they differentiate into. Results To determine whether merozoites utilize distinct suites of genes to attach, invade, and replicate within feline enterocytes, we performed comparative transcriptional profiling on purified tachyzoites and merozoites. We used high-throughput RNA-Seq to compare the merozoite and tachyzoite transcriptomes. 8323 genes were annotated with sequence reads across the two asexually replicating stages of the parasite life cycle. Metabolism was similar between the two replicating stages. However, significant stage-specific expression differences were measured, with 312 transcripts exclusive to merozoites versus 453 exclusive to tachyzoites. Genes coding for 177 predicted secreted proteins and 64 membrane- associated proteins were annotated as merozoite-specific. The vast majority of known dense-granule ( GRA ), microneme ( MIC ), and rhoptry ( ROP ) genes were not expressed in merozoites. In contrast, a large set of surface proteins (SRS) was expressed exclusively in merozoites. Conclusions The distinct expression profiles of merozoites and tachyzoites reveal significant additional complexity within the T. gondii life cycle, demonstrating that merozoites are distinct asexual dividing stages which are uniquely adapted to their niche and biological purpose.

A new archiacanthocephalan in the family Gigantorhynchidae, Intraproboscis sanghae n. gen., n. sp. is described from females collected from the African black-bellied pangolin Phataginus tetradactyla Linn. (Manidae) in the Central African Republic. A dichotomous key to the genera of Gigantorhynchidae is provided. The specimens presented are distinct from those of the genus Gigantorhynchus Hamann, 1892 that have only 1 or 2 circles of hooks (crowns) at the apical end of the proboscis and are found in South American mammals, except for Gigantorhynchus pesteri Tadros, 1966 from baboons in Rhodesia (Zimbabwe), Africa (Amin, 2013). They superficially resemble those of the other gigantorhynchid genus Mediorhynchus Van Cleave, 1916, especially in the organization of the truncate-cone proboscis and the position of the receptacle. Species of Mediorhynchus are bird parasites. The new genus, Intraproboscis, now the third genus in Gigantorhynchidae; however, is distinguished from Mediorhynchus by having a simple proboscis receptacle that is completely suspended within the proboscis, the passage of the retractor muscles through the receptacle into the body cavity posteriorly, absence of neck, and presence of a parareceptacle structure (first finding in the Archiacanthocephala) and a uterine vesicle; among other features, including the differential dorsoventral thickness of the body wall. The receptacle in Mediorhynchus is complex, with many accessory muscles and retractor muscles passing into the body cavity dorsally and ventrally. Our specimens reached 180 mm in length and the proboscis had 34–36 rows of 6–7 ventrally lamellated, rooted hooks each anteriorly, and 15–17 spinelike hooks each posteriorly. Micropores extended into the anterior and posterior proboscis and energy dispersive x-ray analysis (EDXA) of anterior hooks showed high levels of calcium and phosphorus but negligible traces of sulfur. Spinelike hooks in the posterior proboscis had lower levels of Ca and P and slightly higher levels of S. Molecular and phylogenetic analyses based on the 18S rDNA gene placed I. sanghae in a clade with the archiacanthocephalans Mediorhynchus, Moniliformis, Macracanthorhynchus, Oncicola, and Oligacanthorhynchus.

Over the last decade, South American camelids (SAC) have gained increasing popularity in Switzerland. They are used for several purposes such as fiber and meat production, as companion or guard animals and for trekking activities. The purpose of this study was to investigate the frequency and reasons for pregnancy loss and perinatal death in SAC herds. Within the scope of this study, early embryonic losses could not be identified, as pregnancy examinations by ultrasonography are not performed routinely. Aborted and stillborn fetuses were collected, necropsied and analyzed for infectious abortifacients. A nationwide survey among breeders was carried out. During a 1.5-year period, only eight cases of aborted or stillborn alpaca and llama (out of a population of 6550 animals) were reported by the breeders, and their causes were subsequently analyzed. In half of the cases, Coxiella burnetii was identified in the fetoplacental material. Abortions and stillbirths were reported to be rare in Swiss herds. As a conclusion, recording of embryonic losses through ultrasound training of veterinarians should be impaired and breeders motivated to have abortions and perinatal mortality examined. Special focus should be laid on C. burnetii due to its zoonotic risk.

p38 Mitogen-activated protein (MAP) kinase is involved in the apoptosis of nucleated cells. Although platelets are anucleated cells, apoptotic proteins have been shown to regulate platelet lifespan. However, the involvement of p38 MAP kinase in platelet apoptosis is not yet clearly defined. Therefore, we investigated the role of p38 MAP kinase in apoptosis induced by a mimetic of BH3-only proteins, ABT-737, and in apoptosis-like events induced by such strong platelet agonists as thrombin in combination with convulxin (Thr/Cvx), both of which result in p38 MAP kinase phosphorylation and activation. A p38 inhibitor (SB202190) inhibited the apoptotic events induced by ABT-737 but did not influence those induced by Thr/Cvx. The inhibitor also reduced the phosphorylation of cytosolic phospholipase A2 (cPLA2), an established p38 substrate, induced by ABT-737 or Thr/Cvx. ABT-737, but not Thr/Cvx, induced the caspase 3-dependent cleavage and inactivation of cPLA2. Thus, p38 MAPK promotes ABT-737-induced apoptosis by inhibiting the cPLA2/arachidonate pathway. We also show that arachidonic acid (AA) itself and in combination with Thr/Cvx or ABT-737 at low concentrations prevented apoptotic events, whereas at high concentrations it enhanced such events. Our data support the hypothesis that the p38 MAPK-triggered arachidonate pathway serves as a defense mechanism against apoptosis under physiological conditions.

ObjectiveTranscranial sonography (TCS) shows characteristic hyperechogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD). Although this feature is well established, sufficient observer reliability and diagnostic accuracy are prerequisites for advancements of this method.MethodsThe authors investigated both aspects in a cross-sectional study with four blinded TCS raters in 22 PD patients and 10 healthy controls.ResultsAs expected, the authors found significant bilateral SN hyperechogenicity in PD patients. Quantitative computerised SN planimetry had a substantial intra- (intraclass correlation coefficient (ICC) 0.97 and 0.93 respectively for both hemispheres) and inter-rater reliability (ICC 0.84 and 0.89), while visual semiquantitative echogenicity grading of the SN revealed a moderate intrarater (weighted kappa 0.80 ipsilateral and 0.74 contralateral) and slight (0.33) to fair (0.51) inter-rater reliability only. Diagnostic accuracy measured as the area under the curve of receiver-operating characteristics plots was highest in TCS of the SN opposite the clinically most affected body side (planimetry 0.821, echogenicity grading 0.792) with a hyperechogenic area of 0.24 cm2 as the optimum cut-off value for the differentiation between PD and controls (sensitivity 79%, specificity 81%).ConclusionsThe data demonstrate that the observer variability of SN planimetry is low in the hands of experienced investigators. This approach also offers adequate diagnostic accuracy. The authors conclude that reliable SN TCS data on PD can be achieved in clinical routine and multicentre trials when standardised analysis protocols and certain quality criteria of brain parenchyma sonography are met.

Background: Clopidogrel is a potent drug for prevention of adverse effects during and after coronary intervention. Increasing experience indicates that a significant proportion of patients do not respond adequately to clopidogrel. Because failure of antiplatelet therapy can have severe consequences, there is need for a reliable assay to quantify the effectiveness of clopidogrel treatment. Methods: Of 24 healthy volunteers admitted to the study, 18 were treated for 1 week with clopidogrel (300-mg loading dose and 75-mg maintenance dose), and 6 with placebo. Platelet function was monitored by 2 assays, based on flow cytometry and enzyme immunoassay, that measure the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) and by aggregometry, flow cytometry of P-selectin, and the platelet function analyzer at baseline, on days 1–5, and on day 9 of treatment. Results: Aggregometry and VASP phosphorylation revealed a loss of platelet response to ADP within 12 h after clopidogrel intake. The phosphorylation status of VASP correlated with the inhibition of platelet aggregation. In contrast, neither P-selectin expression nor PFA-100 closure time was a clear indicator of clopidogrel effects on platelets. Conclusions: VASP phosphorylation assays are reliable for quantifying clopidogrel effects. Because the VASP assay directly measures the function of the clopidogrel target, the P2Y12 receptor, the assay is selective for clopidogrel effects rather than effects of other platelet inhibitors commonly in use.

Aim To investigate the influence of psychological well-being on academic success in school and to test for interaction effects of socioeconomic status (SES) and subjective well-being (SWB) on academic success. Subject and methods The analyzed data set contained information on 508 boys and girls in the sixth grade. The study had a cross-sectional design. The KIDSCREEN-27 questionnaire, an instrument for assessment of health-related quality of life in children and adolescents, which contains scales such as “Psychological well-being” and “School environment”, was used in this study. The combined average grade (CAG) in German and mathematics served as the indicator of academic success. The statistical analyses were using multiple linear regressions. Results Our analysis revealed an unexpected negative effect of psychological well-being on the CAG, but also an indirect positive effect, which was detected on the School Environment scale. The two effects more or less cancelled each other out overall. No interaction with socioeconomic status could be detected. Conclusion The results of the present study are inconsistent and are only partly in conformity with the findings of previous empirical research on this topic, which rarely reported both negative and positive effects of well-being on academic success.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome and an important differential diagnosis of parkinson’s disease (PD). The clinical diagnosis of PSP relies on characteristic symptoms. There is evidence of clinical subgroups within the entity of PSP interfering with making the firm diagnosis. It was the aim of the study to clarify the differences between phenotypical subtypes of PSP and PD focusing on transcallosal inhibition (TI). A systematic chart review of 67 patients supposed to have probable PSP was done in a standardized diagnostic work-up. As only complete data sets were included into further analysis, 26 PSP patients (mean age 68.6 ± 7.1 years) could be evaluated and subdivided into Richardson’s syndrome (RS) ( n  = 15) or PSP of parkinsonian type (PSP-P) ( n  = 11). Fifteen PD patients served as controls. TI was evaluated by investigation of the ipsilateral silent period (iSP) with transcranial magnetic stimulation (TMS). Cognition was assessed by the Addenbrooke′s cognitive examination (ACE-R). TMS revealed a significantly more severe affection of TI in RS patients as compared to PSP-P and PD patients who showed similar neurophysiological findings. 47 % of RS patient displayed an iSP loss, whereas PSP-P and PD did not. There was a significant correlation between iSP latency and ACE-R (Spearman’s coefficient −0.369, P  = 0.010). In conclusion, RS patients—contrary to PSP-P and PD patients—had pathological TI at least in one hemisphere indicating more severe involvement of transcallosally projecting output neurons in RS.

Transcranial sonography (TCS) shows an increased echogenic area of the substantia nigra (SN) in patients with Parkinson disease (PD). It has been increasingly used in the diagnosis of PD and its differentiation from atypical parkinsonian syndromes. Here, we studied the diagnostic accuracy of SN TCS in Italian patients. In this blinded cross-sectional study (NOBIS study), two expert neuro-sonologists performed TCS in 25 PD patients and 29 age- and sex-matched controls. The study participants were completely hidden to the TCS investigators using large drapery. One month later, the SN TCS recordings were re-read by the initial investigator, and cross-read by the second reader. Diagnostic accuracy was estimated on the first reading, intra-reader reliability on re-reading, and inter-reader reliability on cross-readings. The mean SN echogenic area was larger in the patients (0.24 cm 2 ) than in the controls (0.15 cm 2 ; Mann–Whitney test, p  < 0.001). SN measures did not differ between right and left, or between ipsilateral and contralateral to the clinically more affected side. There was no correlation between SN echogenicity and PD severity or duration. High intra-reader (concordance correlation coefficient 0.93) and inter-reader (0.98) agreement of SN measurements was found. The diagnostic accuracy for the detection of PD was high (area under receiver-operating characteristic curve 0.91; 95% CI 0.83–1.00) with an optimum cut-off value for SN echogenic area of 0.18 cm 2 with the device used here (specificity 0.83–0.90; sensitivity 0.72–0.92). This study supports the use of SN TCS in the diagnostic workup of PD if performed by trained readers.