Influenza transmission in a cohort of households with children: 2010-2011

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Disturbed families or families disturbed: a reconsideration.

BACKGROUND: The relationship between anorexia nervosa (AN) and family disturbance has been a subject of debate since its first description. What began as a clear view of the pathologically disturbed family causing AN has become ever more complex over the decades. OBJECTIVE: The aim of this review is to explore the literature to examine the changes and evolution of clinical opinion around family dysfunction and AN over the last 20 years. METHODS: A narrative review of heterogeneous studies in peer-reviewed publications sourced from the major databases, including PubMed and ScienceDirect, to illuminate the topic of family distress and AN by highlighting the conflicting and complementary ways it has been studied. RESULTS: This review has highlighted the complexity of the relationship between anorectic sufferers and their families. It has explored the literature about parental burden, emotions and cognitive mechanisms together with parental attitudes about weight and shape. It is clear that there is no consistent psycho-social pathology in families which has been shown to be causative. However, over the last twenty years, research has highlighted the distress and family dysfunction caused by having to look after an anoretic child with poor mentalisation skills, insecure attachment and emotion dysregulation. CONCLUSION: The area has become clearer over the last 20 years; research suggests a bi-directional relationship between AN and family dysfunction, with difficult dynamics becoming entrenched within the family. This is best addressed, the consensus suggests, by specialist family therapy and carer skills interventions. Longitudinal research is needed to definitively answer the question with rigorous scientific certainty. EMB RATING: Level V. LEVEL OF EVIDENCE: Level I: Evidence obtained from: at least one properly designed randomized controlled trials; systematic reviews and meta-analyses; experimental studies. Level II: Evidence obtained from well-designed controlled trials without randomization. Level III: Evidence obtained from well-designed cohort or case-control analytic studies. Level IV: Evidence obtained from with multiple time series analysis such as case studies. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level V: Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees

Fetal in vivo continuous cardiovascular function during chronic hypoxia.

Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean P(aO2) levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Δ: 4.8 ± 1.6 vs. 0.5 ± 1.4 μmol l(-1), P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase-derived reactive oxygen species.This work was supported by the British Heart Foundation.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/JP27109

Focal epilepsy in SCN1A-mutation carrying patients: is there a role for epilepsy surgery?

Variants in the gene SCN1A are a common genetic cause for a wide range of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome. Focal onset seizures and structural lesions can be present in these patients and the question arises whether epilepsy surgery should be considered. We report eight patients (mean age 13y 11mo [SD 8y 1mo], range 3–26y; four females, four males) with SCN1A variants, who underwent epilepsy surgery. Outcomes were variable and seemed to be directly related to the patient’s anatomo‐electroclinical epilepsy phenotype. Patients with Dravet syndrome had unfavourable outcomes, whilst patients with focal epilepsy, proven to arise from a single structural lesion, had good results. We conclude that the value of epilepsy surgery in patients with an SCN1A variant rests on two issues: understanding whether the variant is pathogenic and the patient’s anatomo‐electroclinical phenotype. Careful evaluation of epilepsy phenotype integrated with understanding the significance of genetic variants is essential in determining a patient’s suitability for epilepsy surgery. Patients with focal onset epilepsy may benefit from epilepsy surgery, whereas those with Dravet syndrome do not

Top down tandem mass spectrometric analysis of a chemically modified rough-type lipopolysaccharide vaccine candidate

Recent advances in lipopolysaccharide (LPS) biology have led to its use in drug discovery pipelines, including vaccine and vaccine adjuvant discovery. Desirable characteristics for LPS vaccine candidates include both the ability to produce a specific antibody titer in patients and a minimal host inflammatory response directed by the innate immune system. However, in-depth chemical characterization of most LPS extracts has not been performed; hence, biological activities of these extracts are unpredictable. Additionally, the most widely adopted workflow for LPS structure elucidation includes nonspecific chemical decomposition steps before analyses, making structures inferred and not necessarily biologically relevant. In this work, several different mass spectrometry workflows that have not been previously explored were employed to show proof-of-principle for top down LPS primary structure elucidation, specifically for a rough-type mutant(J5) E.coli-derived LPS component of a vaccine candidate. First, ion mobility filtered precursor ions were subjected to collision induced dissociation (CID) to define differences in native J5 LPS v. chemically detoxified J5 LPS (dLPS). Next, ultra-high mass resolving power, accurate mass spectrometry was employed for unequivocal precursor and product ion empirical formulae generation. Finally, MS 3 analyses in an ion trap instrument showed that previous knowledge about dissociation of LPS components can be used to reconstruct and sequence LPS in a top down fashion. A structural rationale is also explained for differential inflammatory dose-response curves, in vitro, when HEK-Blue hTLR4 cells were administered increasing concentrations of native J5 LPS v. dLPS, which will be useful in future drug discovery efforts

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Why Moral Expertise Needs Moral Theory

Discussions of the nature or possibility of moral expertise have largely proceeded in atheoretical terms, with little attention paid to whether moral expertise depends on theoretical knowledge of morality. Here I argue that moral expertise is more theory-dependent than is commonly recognized: Moral expertise consists, at least in part, in knowledge of the correct or best moral theory, and second, that knowledge of moral theory is essential to moral experts dispensing expert counsel to non-experts. Moral experts would not be moral experts absent knowledge of moral theory, nor could they play the testimonial role we would expect them to play in moral inquiry and deliberation absent such knowledg

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation