Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

<p>Background: Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.</p> <p>Methods: The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.</p> <p>Results: No growth defect under low and elevated oxygen tension, no up-or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.</p&gt

How to pass the false-belief task before your fourth birthday.

The experimental record of the last three decades shows that children under 4 years old fail all sorts of variations on the standard false-belief task, whereas more recent studies have revealed that infants are able to pass nonverbal versions of the task. We argue that these paradoxical results are an artifact of the type of false-belief tasks that have been used to test infants and children: Nonverbal designs allow infants to keep track of a protagonist's perspective over a course of events, whereas verbal designs tend to disrupt the perspective-tracking process in various ways, which makes it too hard for younger children to demonstrate their capacity for perspective tracking. We report three experiments that confirm this hypothesis by showing that 3-year-olds can pass a suitably streamlined version of the verbal false-belief task. We conclude that young children can pass the verbal false-belief task provided that they are allowed to keep track of the protagonist's perspective without too much disruption

Children's suggestibility in relation to their understanding about sources of knowledge

In the experiments reported here, children chose either to maintain their initial belief about an object's identity or to accept the experimenter's contradicting suggestion. Both 3– to 4–year–olds and 4– to 5–year–olds were good at accepting the suggestion only when the experimenter was better informed than they were (implicit source monitoring). They were less accurate at recalling both their own and the experimenter's information access (explicit recall of experience), though they performed well above chance. Children were least accurate at reporting whether their final belief was based on what they were told or on what they experienced directly (explicit source monitoring). Contrasting results emerged when children decided between contradictory suggestions from two differentially informed adults: Three– to 4–year–olds were more accurate at reporting the knowledge source of the adult they believed than at deciding which suggestion was reliable. Decision making in this observation task may require reflective understanding akin to that required for explicit source judgments when the child participates in the task

Lymphoproliferative disorders in non-AIDS associated Kaposi's sarcoma

The association of the non-AIDS-related, classic fonn of Kaposi's sarcoma (KS) with secondary malignancies, especially Iymphoproliferative disorders, has frequently been noted. However, in endemic: African-type KS, such an association has been reported only rarely. A review of 62 non-AIDS-related cases of KS treated and followed up at Johannesburg General Hospital between 1980 and 1992 revealed 8 patients (13%)'in whom KS was associated with malignant Iymphoproliferative disorders. The prevalence of secondary Iymphoproliferative disorders was not significantly different among patients with classic KS (3/15; 20%) when compared with those who had African KS (4/47; 8%). In both forms of KS subtle disturbances of immunity have been described which may play a role in the pathogenesis of secondary Iymphoproliferative disorders, although the factors responsible and the pathogenetic mechanisms involved in malignant lymphoid transfonnation in these patients have not been fully elucidated

What children know about the source of their knowledge without reporting it as the source

We argue that, amongst 3- to 5- year-olds, failure to report the source of knowledge recently acquired in answer to “How do you know…?” is due to a specific failure to make a causal inference, in line with source monitoring theory but not fuzzy trace theory. In three Experiments, children (N = 37; 30; 59) identified a hidden toy by seeing, feeling, or by being told, having had two modes of access on each trial, one informative (e.g. seeing a toy identified by colour) and the other uninformative (e.g. being told the toy’s colour by the Experimenter who had only felt it). Children who answered the know question wrongly nevertheless reported accurately who saw and who felt the toy, and what the well-informed player had said. They also realised when the Experimenter’s uninformative access implied their own knowledge was unreliable, suggesting precocious working understanding of knowledge sources

Comparison of routes for achieving parenteral access with a focus on the management of patients with Ebola virus disease.

Dehydration is an important cause of death in patients with Ebola virus disease (EVD). Parenteral fluids are often required in patients with fluid requirements in excess of their oral intake. The peripheral intravenous route is the most commonly used method of parenteral access, but inserting and maintaining an intravenous line can be challenging in the context of EVD. Therefore it is important to consider the advantages and disadvantages of different routes for achieving parenteral access (e.g. intravenous, intraosseous, subcutaneous and intraperitoneal). To compare the reliability, ease of use and speed of insertion of different parenteral access methods. We ran the search on 17 November 2014. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R), Embase Classic + Embase (OvidSP), CINAHL (EBSCOhost), clinicaltrials.gov and screened reference lists. Randomised controlled trials comparing different parenteral routes for the infusion of fluids or medication. Two review authors examined the titles and abstracts of records obtained by searching the electronic databases to determine eligibility. Two review authors extracted data from the included trials and assessed the risk of bias. Outcome measures of interest were success of insertion; time required for insertion; number of insertion attempts; number of dislodgements; time period with functional access; local site reactions; clinicians' perception of ease of administration; needlestick injury to healthcare workers; patients' discomfort; and mortality. For trials involving the administration of fluids we also collected data on the volume of fluid infused, changes in serum electrolytes and markers of renal function. We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach for the following outcomes: success of insertion, time required for insertion, number of dislodgements, volume of fluid infused and needlestick injuries. We included 17 trials involving 885 participants. Parenteral access was used to infuse fluids in 11 trials and medications in six trials. None of the trials involved patients with EVD. Intravenous and intraosseous access was compared in four trials; intravenous and subcutaneous access in 11; peripheral intravenous and intraperitoneal access in one; saphenous vein cutdown and intraosseous access in one; and intraperitoneal with subcutaneous access in one. All of the trials assessing the intravenous method involved peripheral intravenous access.We judged few trials to be at low risk of bias for any of the assessed domains.Compared to the intraosseous group, patients in the intravenous group were more likely to experience an insertion failure (risk ratio (RR) 3.89, 95% confidence interval (CI) 2.39 to 6.33; n = 242; GRADE rating: low). We did not pool data for time to insertion but estimates from the trials suggest that inserting intravenous access takes longer (GRADE rating: moderate). Clinicians judged the intravenous route to be easier to insert (RR 0.15, 95% CI 0.04 to 0.61; n = 182). A larger volume of fluids was infused via the intravenous route (GRADE rating: moderate). There was no evidence of a difference between the two routes for any other outcomes, including adverse events.Compared to the subcutaneous group, patients in the intravenous group were more likely to experience an insertion failure (RR 14.79, 95% CI 2.87 to 76.08; n = 238; GRADE rating: moderate) and dislodgement of the device (RR 3.78, 95% CI 1.16 to 12.34; n = 67; GRADE rating: low). Clinicians also judged the intravenous route as being more difficult to insert and patients were more likely to be agitated in the intravenous group. Patients in the intravenous group were more likely to develop a local infection and phlebitis, but were less likely to develop erythema, oedema or swelling than those in the subcutaneous group. A larger volume of fluids was infused into patients via the intravenous route. There was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine if the risk of insertion failure differed between the saphenous vein cutdown (SVC) and intraosseous method (RR 4.00, 95% CI 0.51 to 31.13; GRADE rating: low). Insertion using SVC took longer than the intraosseous method (MD 219.60 seconds, 95% CI 135.44 to 303.76; GRADE rating: moderate). There were no data and therefore there was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine the relative effects of intraperitoneal or central intravenous access relative to any other parenteral access method. There are several different ways of achieving parenteral access in patients who are unable meet their fluid requirements with oral intake alone. The quality of the evidence, as assessed using the GRADE criteria, is somewhat limited because of the lack of adequately powered trials at low risk of bias. However, we believe that there is sufficient evidence to draw the following conclusions: if peripheral intravenous access can be achieved easily, this allows infusion of larger volumes of fluid than other routes; but if this is not possible, the intraosseous and subcutaneous routes are viable alternatives. The subcutaneous route may be suitable for patients who are not severely dehydrated but in whom ongoing fluid losses cannot be met by oral intake.A film to accompany this review can be viewed here (http://youtu.be/ArVPzkf93ng)

Продукты ограниченного протеолиза: подходы к обнаружению и диагностические возможности в оценке тяжести патологии при эндогенной интоксикации

ПРОДУКТЫ ОГРАНИЧЕННОГО ПРОТЕОЛИЗАПРОТЕИНАЗО-ИНГИБИТОРНАЯ СИСТЕМАОТРАВЛЕНИЕ /ДИАГН /ОСЛЭНДОГЕННАЯ ИНТОКСИКАЦИЯ /ДИАГН /ОСЛСРЕДНЕМОЛЕКУЛЯРНАЯ ПЕПТИДНАЯ ФРАКЦИЯПАТОЛОГИЧЕСКИЕ ПРОЦЕССЫЛАБОРАТОРНЫЕ МЕТОДЫ И ПРОЦЕДУРЫБЕЛКОВО-ПЕПТИДНЫЕ КОМПОНЕНТ