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Withaferin A (WA) exhibits cancer chemopreventive efficacy in preclinical models representative of two different subtypes of breast cancer. However, the mechanism(s) underlying breast cancer chemoprevention by WA is not fully elucidated. We performed RNA-seq analyses using a non-tumorigenic mammary epithelial cell line (MCF-10A) and human breast cancer cells (BCC) belonging to the luminal-type (MCF-7), HER2-enriched (SK-BR-3), and basal-like subtype (MDA-MB-231) to identify novel cancer-selective mechanistic targets of WA. The WA-regulated transcriptome was strikingly different between MCF-10A versus BCC. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of genes associated with cellular senescence in WA-treated BCC. Consequently, the number of senescence-associated β-galactosidase positive cells was decreased significantly in WA-treated BCC but not in the MCF-10A cells. WA treatment caused upregulation of senescence marker p21 more robustly in BCC than in MCF-10A. Breast cancer prevention by WA in rats was also associated with upregulation of p21 protein expression. The Reactome pathway analyses indicated upregulation of genes associated with cellular response to stress/external stimuli in WA-treated BCC but not in MCF-10A. Two proteins represented in these pathways (HSPA6 and NRF2) were further investigated. While HSPA6 was dispensable for WA-mediated apoptosis and autophagy or inhibition of cell migration, the NRF2 knockout cells were more resistant to apoptosis resulting from WA treatment than control cells. Finally, expression of some glycolysis-related proteins was decreased by WA treatment both in vitro and in vivo. In summary, this study provides novel insights into cancer-selective pathways affected by WA that may contribute to its chemopreventive efficacy in breast cancer.

A 69‐year‐old woman presented to the emergency department with central dull chest pain. Electrocardiography revealed Q waves and ST elevation in the inferior leads and cardiac troponin I was elevated at 1506 ng/L (normal range

CEDNIK (CErebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome is a neuroichthyotic syndrome characterized by a constellation of clinical features including severe developmental retardation, microcephaly, and facial dysmorphism. Here, we report the first case of CEDNIK syndrome from India presenting with characteristic clinical features and harboring a novel mutation of SNAP29 gene.

Climate warming is expected to positively alter upward and poleward treelines which are controlled by low temperature and a short growing season. Despite the importance of treelines as a bioassay of climate change, a global field assessment and posterior forecasting of tree growth at annual scales is lacking. Using annually resolved tree-ring data located across Eurasia and the Americas, we quantified and modeled the relationship between temperature and radial growth at treeline during the 20th century. We then tested whether this temperature–growth association will remain stable during the 21st century using a forward model under two climate scenarios (RCP 4.5 and 8.5). During the 20th century, growth enhancements were common in most sites, and temperature and growth showed positive trends. Interestingly, the relationship between temperature and growth trends was contingent on tree age suggesting biogeographic patterns in treeline growth are contingent on local factors besides climate warming. Simulations forecast temperature–growth decoupling during the 21st century. The growing season at treeline is projected to lengthen and growth rates would increase and become less dependent on temperature rise. These forecasts illustrate how growth may decouple from climate warming in cold regions and near the margins of tree existence. Such projected temperature–growth decoupling could impact ecosystem processes in mountain and polar biomes, with feedbacks on climate warming. climate warming, forest limit, growth model, mountain ecosystems, tree rings acceptedVersion

Background: Patient anxiety is an often overlooked complication of pleural diagnostic and therapeutic procedures. Listening to music is effective in reducing patient anxiety in some endoscopy procedures but has not yet been evaluated in pleural procedures. Aim: To evaluate the benefits of music therapy during pleural procedures on a patient's anxiety, perceived pain and satisfaction with the procedure. Methods: Consecutive patients undergoing therapeutic pleural procedures were randomised to music and control groups. Participants in the music group listened to self‐selected music using ear‐bud headphones for the duration of the procedure. State anxiety was assessed before and after the procedure using the State Trait Anxiety Inventory. Physiological parameters were also measured. Results: Sixty patients were included in the study. In the music group, a reduction in state anxiety scores were observed post‐procedure (34 ± 11 vs 48 ± 13, P < 0.001), while no change was observed in the control group (40 ± 11 vs 42 ± 11, P = 0.51). Participants in the music group had reductions in heart rate (87 ± 17 vs 95 ± 15, P = 0.04), systolic (121 ± 13 vs 130 ± 16, P = 0.02) and diastolic blood pressure (72 ± 8 vs 78 ± 9, P = 0.01) post procedure compared to the pre‐procedures values. A similar change was not detected in the control group: heart rate (86 ± 17 vs 85 ± 15, P = 0.73), systolic (133 ± 21 vs 134 ± 20, P = 0.83) and diastolic blood pressure (77 ± 9 vs 79 ± 10, P = 0.30). There was no difference in patient pain scores (P = 0.8), willingness to undergo the procedure again (P= 0.27), satisfaction with the performance of the pleural procedure (P = 0.20) and duration of the procedure (P = 0.68) between the music and control groups. Conclusions: Listening to music appears to be beneficial in reducing anxiety in patients undergoing pleural procedures.

AIM:There are limited population-based data on global development and adaptive behaviour in children with early-onset epilepsy. The aims of this study were: (1) to identify the prevalence of deficits in global development and adaptive behaviour experienced by children with early-onset epilepsy; (2) to identify factors associated with such deficits; and (3) to compare the relationship between measures of neurodevelopment in the group with epilepsy to a group without epilepsy who had other neurological or neurodevelopmental difficulties. METHOD:The Sussex Early Epilepsy and Neurobehaviour study is a prospective, community-based study involving children (1-7y) with epilepsy. We undertook comprehensive psychological assessment with participants, including measures of global development and adaptive behaviour. We compared the children with epilepsy with a sex, age, and developmentally-matched group of children without epilepsy who had neurodevelopmental or neurological difficulties using correlation matrices. RESULTS:Forty-eight children (91% of the eligible population) with epilepsy underwent assessment. Seventy-one per cent of children displayed delayed global development (

Accurate diagnosis of a distinct epilepsy syndrome is based on well-defined electroclinical features that differentiate separate nosological entities. In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations posing a diagnostic challenge. This heterogeneity has been documented in several cases presenting with eyelid myoclonia with or without absences (EMA) diagnosed either as Jeavons syndrome (JS) variants or as genetic generalised epilepsies defined by the presence of this unique clinical entity. The hallmark of JS is the triad: (1) eyelid myoclonia with or without absences, (2) eye closure-induced paroxysms, and (3) photosensitivity. The presence of massive myoclonus, intellectual disability, or slowing of the EEG background are not typical features of the syndrome and may cause delay in making the correct diagnosis. Adding to the variability of clinical features, we describe two female paediatric patients with probable genetic epilepsy who presented with EMA but demonstrated clear atypical features, such as prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment. We also note the presence of interictal and ictal posterior discharges during eyelid myoclonia in one, supporting similar previous observations leading to consideration of EMA as an occipital cortex-initiated seizure activity. [Published with video sequences on www.epilepticdisorders.com].

The aim of this study was to evaluate the incidence of long-term oxygen therapy (LTOT)-related adverse outcomes in our health service. LTOT patients retrospectively recruited had their medical records reviewed for the period of 1 January 2014 to 30 June 2018. Burns, physical injuries, any falls attributable to LTOT requiring admission were the outcomes measured. Of 291 patients, four patients required admission due to LTOT-related adverse events where three admissions were related to falls secondary to tripping over oxygen tubing.

We report on preliminary observations on performing lung ultrasound (LUS) in patients admitted to hospital with an exacerbation of chronic obstructive pulmonary disease (COPD). We found that LUS had high specificity and moderate sensitivity in identifying patients with elevated B-type natriuretic peptide. Thus, we hypothesise that LUS may have utility in screening COPD patients with an exacerbation to identify the sub-group with elevated natriuretic peptides and are at risk of increased cardiovascular mortality. The use of LUS in patients with acute and chronic respiratory disorders is increasing and its role in COPD patients is an interesting subject for future research.

Preventive and therapeutic efficiencies of dietary sulforaphane (SFN) against human prostate cancer have been demonstrated in vivo, but the underlying mechanism(s) by which this occurs is poorly understood. Here, we show that the prostate cancer stem cell (pCSC)-like traits, such as accelerated activity of aldehyde dehydrogenase 1 (ALDH1), enrichment of CD49f+ fraction, and sphere forming efficiency, are attenuated by SFN treatment. Interestingly, the expression of c-Myc, an oncogenic transcription factor that is frequently deregulated in prostate cancer cells, was markedly suppressed by SFN both in vitro and in vivo. This is biologically relevant, because the lessening of pCSC-like phenotypes mediated by SFN was attenuated when c-Myc was overexpressed. Naturally occurring thio, sulfinyl, and sulfonyl analogs of SFN were also effective in causing suppression of c-Myc protein level. However, basal glycolysis, a basic metabolic pathway that can also be promoted by c-Myc overexpression, was not largely suppressed by SFN, implying that, in addition to c-Myc, there might be another SFN-sensitive cellular factor, which is not directly involved in basal glycolysis, but cooperates with c-Myc to sustain pCSC-like phenotypes. Our study suggests that oncogenic c-Myc is a target of SFN to prevent and eliminate the onset of human prostate cancer. J. Cell. Biochem. 117: 2482-2495, 2016. © 2016 Wiley Periodicals, Inc.

A Glivenko–Cantelli theorem is a fundamental result in statistics. It says that an empirical distribution function uniformly approximates the true distribution function for a sufficiently large sample size. We prove general Glivenko–Cantelli theorems for three types of sequences of random variables: delayed regenerative, delayed stationary and delayed exchangeable. In particular, our results hold for irreducible Harris recurrent Markov chains that admit a stationary probability distribution but are not necessarily in the stationary state. We also do not assume any mixing conditions on the Markov chain. This is useful in the application of Markov chain Monte Carlo methods. A key tool used is a generalized version of Polya's theorem on the convergence of distribution functions. Copyright © 2016 John Wiley & Sons, Ltd.

Objective:\ud To determine the prevalence of parent‐reported sleep problems in young children with epilepsy and their parents, and to compare findings with those in a non–epilepsy‐related neurodisability (neurodevelopmental/neurological difficulties) group.\ud \ud Method:\ud Parents of young children (1–7 years) with epilepsy (n = 48 [91% ascertainment]) completed the Child Sleep Habits Questionnaire (CSHQ). Parents (mothers and fathers) also completed the Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) in relation to their own functioning. The responses of parents of children with epilepsy were compared with parents of developmental‐, age‐, and gender‐matched children with nonepilepsy‐related neurodisability (n = 48).\ud \ud Results:\ud There was not a significant difference in the proportion of children with epilepsy and the children with neurodisability scoring in the at‐risk range on the CSHQ (81% vs. 71% respectively) (p = 0.232). 62% of mothers and 44% of fathers of children with epilepsy had ‘poor quality sleep’ on the PSQI; there was not a significant difference between mothers of children with epilepsy and those of children with neurodisability (p = 0.526) or IFS (p = 0.245) total scores. However, mothers of children with epilepsy had significantly more difficulties on the productivity subscale of the IFS (p = 0.004). There were no significant differences between fathers’ scores on either measure. In the epilepsy group, child behavioral problems (p = 0.001) were independently associated with child sleep difficulties and maternal mental health problems were associated with parental sleep difficulties (p = 0.04) and fatigue (p = 0.018).\ud \ud Significance:\ud Young children with epilepsy and their parents have a high rate of sleep difficulties. There is a need to develop effective interventions for this population, taking into consideration of the role of child behavioral problems and parental mental health difficulties.

The regulators of Mycobacterium tuberculosis DNA replication are largely unknown. Here, we demonstrate that in synchronously replicating M. tuberculosis, MtrA access to origin of replication (oriC) is enriched in the post-replication (D) period. The increased oriC binding results from elevated MtrA phosphorylation (MtrA~P) as evidenced by reduced expression of dnaN, dnaA and increased expression of select cell division targets. Overproduction of gain-of-function MtrAY102C advanced the MtrA oriC access to the C period, reduced dnaA and dnaN expression, interfered with replication synchrony and compromised cell division. Overproduction of wild-type (MtrA+) or phosphorylation-defective MtrAD56N did not promote oriC access in the C period, nor affected cell cycle progression. MtrA interacts with DnaA signaling a possibility that DnaA helps load MtrA on oriC. Therefore, oriC sequestration by MtrA~P in the D period may normally serve to prevent untimely initiations and that DnaA-MtrA interactions may facilitate regulated oriC replication. Finally, despite the near sequence identity of MtrA in M. smegmatis and M. tuberculosis, the M. smegmatis oriC is not MtrA-target. We conclude that M. tuberculosis oriC has evolved to be regulated by MtrA and that cell cycle progression in this organisms are governed, at least in part, by oscillations in the MtrA~P levels.

Aims To provide data on parent-reported features of developmental coordination disorder (DCD) and describe neurobehavioural comorbidity in children with epilepsy and DCD. Method Eighty-five (74% of those eligible) children (44 males, 41 females; age range 5–15y) with active childhood epilepsy (an epileptic seizure in the last year and/or currently taking antiepileptic drugs) in a population-based cohort underwent comprehensive multidisciplinary assessment. The DCD Questionnaire (DCD-Q) was completed by parents (n=69) of children with an IQ>34, of whom 56 did not have cerebral palsy (CP), and were considered for a diagnosis of DCD. Results Of those considered for a DCD diagnosis, 16 (29%) met DSM-IV-TR criteria whereas 34 (61%) scored in the at-risk range on the DCD-Q. The sensitivity of the DCD-Q was 100% (95% CI 76–100) and specificity was 55% (95% CI 39–70). Significant predictors of higher scores on the DCD-Q included the presence of autism spectrum disorder, CP, and early seizure onset. Increasing age and IQ were independently associated with higher DCD-Q scores. Intellectual disability, attention-deficit–hyperactivity disorder, academic underachievement, and specific memory problems were the most common neurobehavioural difficulties in those with both DCD and epilepsy. Interpretation Parent-reported symptoms of DCD are very common in childhood epilepsy. The DCD-Q has good sensitivity but lower specificity in this population.

SummaryObjective To provide population-based data on the performance of school-aged children with epilepsy on measures of academic achievement and factors associated with this performance after controlling for IQ. Methods Eighty-five (74%) of 115 children with “active” epilepsy (experienced a seizure in the past year and/or on antiepileptic drugs [AEDs]) underwent psychological assessment including measures of IQ, aspects of working memory and processing speed. Sixty-five of the 85 were able to complete subtests on the Wide Range Achievement Test–Fourth Edition (WRAT-4). Paired sample t-tests were conducted to compare subtest scores. Factors associated with academic performance after controlling for IQ were examined using linear regression. Results Seventy-two percent of the children, who could complete subtests on the WRAT-4, displayed “low achievement” (1 standard deviation [SD] below test mean) and 42% displayed “underachievement” (1 SD below assessed IQ) on at least one of the four WRAT-4 subtests. The mean scores on the Math Computation subtest and Sentence Comprehension subtest were significantly lower than scores on the Word Reading (p