A new mib allele with a chromosomal deletion covering foxc1a exhibits anterior somite specification defect

mibnn2002, found from an allele screen, showed early segmentation defect and severe cell death phenotypes, which are different from previously known mib mutants. Despite distinct morphological phenotypes, the typical mib molecular phenotypes: her4 down-regulation, neurogenic phenotype and cold sensitive dlc expression pattern, still remained. The linkage analysis also indicated that mibnn2002 is a new mib allele. Failure of specification in anterior 7-10 somites is likely due to lack of foxc1a expression in mibnn2002 homozygotes. Somites and somite markers gradually appeared after 7-10 somite stage, suggesting that foxc1a is only essential for the formation of anterior 7-10 somites. Apoptosis began around 16-somite stage with p53 up-regulation. To find the possible links of mib, foxc1a and apoptosis, transcriptome analysis was employed. About 140 genes, including wnt3a, foxc1a and mib, were not detected in the homozygotes. Overexpression of foxc1a mRNA in mibnn2002 homozygotes partially rescued the anterior somite specification. In the process of characterizing mibnn2002 mutation, we integrated the scaffolds containing mib locus into chromosome 2 (or linkage group 2, LG2) based on synteny comparison and transcriptome results. Genomic PCR analysis further supported the conclusion and showed that mibnn2002 has a chromosomal deletion with the size of about 9.6 Mbp.published_or_final_versio

Coronary microvascular ischemia in hypertrophic cardiomyopathy - a pixel-wise quantitative cardiovascular magnetic resonance perfusion study.

BACKGROUND: Microvascular dysfunction in HCM has been associated with adverse clinical outcomes. Advances in quantitative cardiovascular magnetic resonance (CMR) perfusion imaging now allow myocardial blood flow to be quantified at the pixel level. We applied these techniques to investigate the spectrum of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and to explore its relationship with fibrosis and wall thickness. METHODS: CMR perfusion imaging was undertaken during adenosine-induced hyperemia and again at rest in 35 patients together with late gadolinium enhancement (LGE) imaging. Myocardial blood flow (MBF) was quantified on a pixel-by-pixel basis from CMR perfusion images using a Fermi-constrained deconvolution algorithm. Regions-of-interest (ROI) in hypoperfused and hyperemic myocardium were identified from the MBF pixel maps. The myocardium was also divided into 16 AHA segments. RESULTS: Resting MBF was significantly higher in the endocardium than in the epicardium (mean ± SD: 1.25 ± 0.35 ml/g/min versus 1.20 ± 0.35 ml/g/min, P < 0.001), a pattern that reversed with stress (2.00 ± 0.76 ml/g/min versus 2.36 ± 0.83 ml/g/min, P < 0.001). ROI analysis revealed 11 (31%) patients with stress MBF lower than resting values (1.05 ± 0.39 ml/g/min versus 1.22 ± 0.36 ml/g/min, P = 0.021). There was a significant negative association between hyperemic MBF and wall thickness (β = −0.047 ml/g/min per mm, 95% CI: −0.057 to −0.038, P < 0.001) and a significantly lower probability of fibrosis in a segment with increasing hyperemic MBF (odds ratio per ml/g/min: 0.086, 95% CI: 0.078 to 0.095, P = 0.003). CONCLUSIONS: Pixel-wise quantitative CMR perfusion imaging identifies a subgroup of patients with HCM that have localised severe microvascular dysfunction which may give rise to myocardial ischemia

A Technique for Obtaining True Approximations for kk-Center with Covering Constraints

There has been a recent surge of interest in incorporating fairness aspects into classical clustering problems. Two recently introduced variants of the $k$-Center problem in this spirit are Colorful $k$-Center, introduced by Bandyapadhyay, Inamdar, Pai, and Varadarajan, and lottery models, such as the Fair Robust $k$-Center problem introduced by Harris, Pensyl, Srinivasan, and Trinh. To address fairness aspects, these models, compared to traditional $k$-Center, include additional covering constraints. Prior approximation results for these models require to relax some of the normally hard constraints, like the number of centers to be opened or the involved covering constraints, and therefore, only obtain constant-factor pseudo-approximations. In this paper, we introduce a new approach to deal with such covering constraints that leads to (true) approximations, including a $4$-approximation for Colorful $k$-Center with constantly many colors---settling an open question raised by Bandyapadhyay, Inamdar, Pai, and Varadarajan---and a $4$-approximation for Fair Robust $k$-Center, for which the existence of a (true) constant-factor approximation was also open. We complement our results by showing that if one allows an unbounded number of colors, then Colorful $k$-Center admits no approximation algorithm with finite approximation guarantee, assuming that $\mathrm{P} \neq \mathrm{NP}$. Moreover, under the Exponential Time Hypothesis, the problem is inapproximable if the number of colors grows faster than logarithmic in the size of the ground set

Male age is associated with extra-pair paternity, but not with extra-pair mating behaviour

Extra-pair paternity is the result of copulation between a female and a male other than her social partner. In socially monogamous birds, old males are most likely to sire extra-pair offspring. The male manipulation and female choice hypotheses predict that age-specific male mating behaviour could explain this old-over-young male advantage. These hypotheses have been difficult to test because copulations and the individuals involved are hard to observe. Here, we studied the mating behaviour and pairing contexts of captive house sparrows, Passer domesticus. Our set-up mimicked the complex social environment experienced by wild house sparrows. We found that middle-aged males, which would be considered old in natural populations, gained most extra-pair paternity. However, both, female solicitation behaviour and subsequent extra-pair matings were not associated with male age. Further, copulations were more likely when solicited by females than when initiated by males (i.e. unsolicited copulations). Male initiated within-pair copulations were more common than male initiated extra-pair copulations. To conclude, our results did not support either hypothesis regarding age-specific male mating behaviour. Instead, female choice, independent of male age, governed copulation success, especially in an extra-pair context. Post-copulatory mechanisms might determine why older males sire more extra-pair offspring

Using haloperidol as an anti-emetic in palliative care: informing practice through evidence from cancer treatment and post-operative contexts

YesNausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlledtrials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity

The Role of Growth Retardation in Lasting Effects of Neonatal Dexamethasone Treatment on Hippocampal Synaptic Function

BACKGROUND: Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used to prevent or lessen the morbidity of chronic lung disease in preterm infants. However, evidence is now increasing that this clinical practice negatively affects somatic growth and may result in long-lasting neurodevelopmental deficits. We therefore hypothesized that supporting normal somatic growth may overcome the lasting adverse effects of neonatal DEX treatment on hippocampal function. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we developed a rat model using a schedule of tapering doses of DEX similar to that used in premature infants and examined whether the lasting influence of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance are correlated with the deficits in somatic growth. We confirmed that neonatal DEX treatment switched the direction of synaptic plasticity in hippocampal CA1 region, favoring low-frequency stimulation- and group I metabotropic glutamate receptor agonist (S)-3,5,-dihydroxyphenylglycine-induced long-term depression (LTD), and opposing the induction of long-term potentiation (LTP) by high-frequency stimulation in the adolescent period. The effects of DEX on LTP and LTD were correlated with an increase in the autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase II at threonine-286 and a decrease in the protein phosphatase 1 expression. Neonatal DEX treatment resulted in a disruption of memory retention subjected to object recognition task and passive avoidance learning. The adverse effects of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance of the animals from litters culled to 4 pups were significantly less than those for the 8-pup litters. However, there was no significant difference in maternal care between groups. CONCLUSION/SIGNIFICANCE: Our results demonstrate that growth retardation plays a crucial role in DEX-induced long-lasting influence of hippocampal function. Our findings suggest that therapeutic strategies designed to support normal development and somatic growth may exert beneficial effects to reduce lasting adverse effects following neonatal DEX treatment

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