Children with severe obesity have greater risk of adverse health outcomes. The purpose of this study was to assess trends in the prevalence of morbid and severe obesity in Australian children between ...1985 and 2012.
Secondary analysis of four national Australian cross-sectional surveys of measured height/weight in 7-15 year olds: Australian Health and Fitness Survey 1985 (n = 8,486), National Nutrition Survey 1995 (n = 1,541), the National Children's Nutrition and Physical Activity Survey 2007 (n = 2,585) and the National Health Survey 2012 (n = 2,940). International Obesity Taskforce cut-point was used for morbid obesity (equivalent to a BMI ≥35kg/m2 at age 18 years). Severe obesity class 2 was defined as BMI ≥120% and <140% of the 95th percentile of the CDC 2000 growth charts or a BMI ≥35 and <40, and severe obesity class 3 as BMI ≥140% of the 95th percentile or a BMI ≥40.
Between 1985 and 2012 the prevalence of morbid obesity increased from 0.2% to 1.8%, class 2 severe obesity from 0.3% to 2.0%, and class 3 from 0.1% to 0.5%. Children with morbid obesity represented 11.3% of children with obesity in 1985 and increased to 22.5% in 2012 (P = 0.005). Children with severe obesity represented 19.3% of children with obesity in 1985 and increased to 32.0% in 2012 (P = 0.016). The greatest increase was observed between 1995 and 2007. The proportion of children who were classified as morbidly or severely obese was not significantly different between 2007 and 2012, nor was it significantly different between age and sex groups.
Prevalence of morbid and severe obesity among children is low, but has significantly increased between 1985 and 2012. In contrast to overweight and obese children, children with morbid obesity require tertiary intervention. Failure to treat these children will have significant implications for the individual child and community.
•Exposure to LTA can induce inflammatory changes in both microglia and neuronal cells.•LTA and Aβ synergise to promote microglial activation and activity of hippocampal neurons.•The flavonoid agent ...7,8,3-THF attenuates LTA-induced activation of BV2 microglial cells.
Toll-like receptor 2 (TLR2) is a primary sensor for pathogens, including those derived from gram-positive bacteria. It can also mediate the effects of endogenous inflammatory signals such as β-amyloid peptide (Aβ), thus promoting the microglial activation and subsequent neuronal dysfunction, characteristic of chronic neuroinflammatory conditions. More recently, a role for TLR2 has been proposed in the pathogenesis of disorders associated with acute inflammation, including anxiety and depression. The current study aims to characterise the acute effects of the TLR2 agonist lipoteichoic acid (LTA) on microglial activation and neuronal integrity, and to evaluate the influence of LTA exposure on sensitivity to the inflammation and neuronal dysfunction associated with Aβ. Using BV2 and N2a cells as an in vitro model, we highlight that acute exposure to LTA robustly promotes inflammatory cytokine and nitric oxide (NO) production in microglia but also in neurons, similar to that reported under longer-term and chronic inflammatory conditions. Moreover, we find that exposure to LTA can enhance sensitivity to subthreshold Aβ, promoting an ‘M1′-like phenotype in microglia and provoking dysregulation of neuronal activity in acute hippocampal slices. Anti-inflammatory agents, including mimetics of brain-derived neurotrophic factor (BDNF), have proven effective at alleviating chronic neuroinflammatory complications. We further examined the effects of 7,8,3-trihydroxyflavone (7,8,3-THF), a small-molecule TrkB agonist, on LTA-induced microglial activation. We report that 7,8,3-THF can significantly ameliorate interleukin (IL)-6 and NO production in LTA-stimulated BV2 cells. Taken together, our findings offer support for exploration of TLR2 as a potential target for therapeutic intervention into acute neuroinflammatory conditions. Moreover we propose that exposure to gram-positive bacterial pathogens may promote sensitivity to the inflammatory changes characteristic of the aged brain.
Abstract Alzheimer's disease (AD) is characterized by overproduction of Aβ derived from APP cleavage via β- and γ-secretase pathway. Recent evidence has linked altered cholesterol metabolism to AD ...pathogenesis. In this study, we show that AD brain had significant cholesterol retention and high β- and γ-secretase activities as compared to age-matched non-demented controls (ND). Over one-half of AD patients had an apoE4 allele but none of the ND. β- and γ-secretase activities were significantly stimulated in vitro by 40 and 80 μM cholesterol in AD and ND brains, respectively. Both secretase activities in AD brain were more sensitive to cholesterol (40 μM) than those of ND (80 μM). Filipin-stained cholesterol overlapped with BACE and Aβ in AD brain sections. Cholesterol (10–80 μM) added to N2a cultures significantly increased cellular cholesterol, β- and γ-secretase activities and Aβ secretion. Similarly, addition of cholesterol (20–80 μM) to cell lysates stimulated both in vitro secretase activities. Ergosterol slightly decreased β-secretase activity at 20–80 μM, but strongly inhibited γ-secretase activity at 40 μM. Cholesterol depletion reduced cellular cholesterol, β-secretase activity and Aβ secretion. Transcription factor profiling shows that several key nuclear receptors involving cholesterol metabolism were significantly altered in AD brain, including decreased LXR-β, PPAR and TR, and increased RXR. Treatment of N2a cells with LXR, RXR or PPAR agonists strongly stimulated cellular cholesterol efflux to HDL and reduced cellular cholesterol and β-/γ-secretase activities. This study provides direct evidence that cholesterol homeostasis is impaired in AD brain and suggests that altered levels or activities of nuclear receptors may contribute to cholesterol retention which likely enhances β- and γ-secretase activities and Aβ production in human brain.
Urea is the major nitrogen-containing product of protein metabolism, and the urea cycle is intrinsically linked to nitric oxide (NO) production via the common substrate L-arginine. Urea accumulates ...in the brain in neurodegenerative states, including Alzheimer’s and Huntington’s disease. Urea transporter B (UT-B, SLC14A1) is the primary transport protein for urea in the CNS, identified most abundantly in astrocytes. Moreover, enhanced expression of the
Slc14a1
gene has been reported under neurodegenerative conditions. While the role of UT-B in disease pathology remains unclear, UT-B-deficient mice display behavioural impairment coupled with urea accumulation, NO disruption and neuronal loss. Recognising the role of inflammation in neurodegenerative disease pathology, the current short study evaluates the role of UT-B in regulating inflammatory responses. Using the specific inhibitor UTB
inh
-14, we investigated the impact of UT-B inhibition on LPS-induced changes in BV2 microglia and N2a neuroblastoma cells. We found that UTB
inh
-14 significantly attenuated LPS-induced production of TNFα and IL-6 from BV2 cells, accompanied by reduced release of NO. While we observed a similar reduction in supernatant concentration of IL-6 from N2a cells, the LPS-stimulated NO release was further augmented by UTB
inh
-14. These changes were accompanied by a small, but significant downregulation in UT-B expression in both cell types following incubation with LPS, which was not restored by UTB
inh
-14. Taken together, the current evidence implicates UT-B in regulation of inflammatory responses in microglia and neuronal-like cells. Moreover, our findings offer support for the further investigation of UT-B as a novel therapeutic target for neuroinflammatory conditions.
Introduction
Sarcopenia is an independent predictor of poor post‐operative outcomes following major surgery. Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis ...(UC), which are chronic inflammatory conditions involving the gastrointestinal system. Evidence demonstrates that up to 60% of patients with IBD have sarcopenia. Despite advances in medical management, more than 15% of patients with UC and 80% with CD eventually require surgical intervention. The primary aim of the study was to assess the impact of sarcopenia on post‐operative anastomotic leak rates.
Methods
A retrospective cohort study of patients at Royal Perth Hospital who underwent major abdominal surgery for management of IBD between January 2010 and December 2020 was performed. Sarcopenia was assessed according to the skeletal muscle index at the level of the third lumbar vertebrae using the cut off 52.4 and 38.5 cm2/m2 for men and women, respectively.
Results
A total of 147 patients were included. The prevalence of sarcopenia within the study population was 36.1%. Patients with sarcopenia were significantly taller (P = 0.025) and were more likely to be on pre‐operative steroid medications (P = 0.045). There was no difference in the remaining baseline characteristics between sarcopenic and non‐sarcopenic patients. Patients with sarcopenia were more likely to develop a post‐operative anastomotic leak (OR:11.303, 95% CI, 1.53–83.51, P = 0.017), grade IV complications (OR:6.79, 95%CI:1.1–43.6, P = 0.044) and require total parenteral nutrition (TPN) (OR:3.212, 95% CI:1.3–8.1, P = 0.013).
Conclusions
Sarcopenia significantly increases the risk of major post‐operative complications for patients with IBD undergoing colorectal surgery.
A retrospective analysis of 147 patients with inflammatory bowel disease that underwent major abdominal surgery was performed. Patient CT scans were assessed for evidence of sarcopenia and outcomes were compared between sarcopenia and non‐sarcopenia patients. Sarcopenia patients were more likely to develop major post‐operative complications, anastomotic leak and require TPN.
The regulation of the serotonin transporter (SERT) by guanine nucleotide‐binding protein alpha (Gα) q was investigated using Gαq knockout mice. In the absence of Gαq, SERT‐mediated uptake of ...5‐hydroxytryptamine (5HT) was enhanced in midbrain and frontal cortex synaptosomes, but only in female mice. The mechanisms underlying this sexual dimorphism were investigated using quantitative western blot analysis revealing brain region‐specific differences. In the frontal cortex, SERT protein expression was decreased in male knockout mice, seemingly explaining the sex‐dependent variation in SERT activity. The differential expression of Gαi1 in female mice contributes to the sex differences in the midbrain. In fact, Gαi1 levels inversely correlate with 5HT uptake rates across both sexes and genotypes. Likely due to differential SERT regulation as well as sex differences in the expression of tryptophan hydroxylase 2, Gαq knockout mice also displayed sex‐ and genotype‐dependent alterations in total 5HT tissue levels as determined by high‐performance liquid chromatography. Gαq inhibitors, YM‐254890 and BIM‐46187, differentially affected SERT activity in both, synaptosomes and cultured cells. YM‐254890 treatment mimicked the effect of Gαq knockout in the frontal cortex. BIM‐46187, which promotes the nucleotide‐free form of Gα proteins, substantially inhibited 5HT uptake, prompting us to hypothesise that Gαq interacts with SERT similarly as with G‐protein‐coupled receptors and inhibits SERT activity by modulating transport‐associated conformational changes. Taken together, our findings reveal a novel mechanism of SERT regulation and impact our understanding of sex differences in diseases associated with dysregulation of serotonin transmission, such as depression and anxiety.
In this study, we show that the serotonin transporter (SERT) is sex specifically regulated by guanine nucleotide‐binding protein alpha (Gα)q. SERT‐mediated uptake of 5‐hydroxytryptamine (5HT) is enhanced in female Gαq knockout mice, which is correlated with differential Gαi1 expression in the midbrain, while in the frontal cortex the sexual dimorphism is caused by a down‐regulation of SERT expression in male mice. The effects of Gαq inhibitors, YM‐254890 and BIM‐46187, on SERT activity support the hypothesis that Gαq and Gαi, through direct interaction with SERT, inhibit 5HT uptake by modulating transport‐associated conformational changes.
Infective endocarditis (IE) is associated with significant morbidity and mortality. Non-adherence to IE guidelines and recommendations is frequent, and may adversely impact patient outcomes.
To ...assess the impact of non-adherence to components of existing IE guidelines and recommendations on a composite outcome consisting of any of the following: mortality, unplanned cardiac surgery, embolic event or relapse of positive blood culture within six months of diagnosis.
A single centre, retrospective cohort study.
Amongst 157 patients, there was inconsistent adherence to: initial diagnosis of an infective condition (87%), timely administration of antimicrobial therapy (82%), appropriateness of predominant antimicrobial regime (94%), appropriate management of the portal of entry (86%), multidisciplinary input (75%), end of antimicrobial therapy repeat echocardiography (60%) and adherence to indications for surgery (76%). Inpatient mortality was 12.1% (n = 19) and the composite adverse outcome occurred in 36 (22.9%) patients. In multivariate logistic regression analysis, infection of prosthetic device (adjusted odds ratio 95% confidence interval; 2.43 1.07–5.50) and non-adherence to surgical guidelines (aOR 3.67 1.60–8.47) were significantly associated with an adverse outcome.
Our data suggests that adherence to differing components of IE management guidelines and recommendations varies and that non-adherence to surgical aspects of guidelines has the biggest impact in determining outcomes.
There has been an evident decline in the number of subscriptions for traditional media while the digital forms of consumer‐centric media, specifically in the fashion area, including fashion blogs and ...social media, have ascended to unprecedented popularity for information‐seeking, especially with millennials. Despite the transformation of media consumption patterns, the literature has primarily focused on information givers' perspectives, while it has paid little attention to information seekers' standpoints. Utilizing thematic analysis of qualitative data collected from six focus groups, we found key motivations driving millennials to turn to digital fashion media for their information needs: search autonomy, virtual storage, instant gratification, visual inspiration, gratuitous information, and authenticity. This study provides insight into how to strategically respond to consumers' needs in the current digitalized media environment.
Résumé
Le nombre d'abonnements aux médias traditionnels a manifestement diminué, tandis que les formes numériques de médias axés sur le consommateur, en particulier dans le domaine de la mode, y compris les blogues sur la mode et les médias sociaux, sont devenues des outils d'information privilégiés, notamment auprès des milléniaux. Malgré la transformation observée dans les modes de consommation des médias, les auteurs des travaux antérieurs se sont surtout concentrés sur les points de vue des donneurs d'informations, et n'ont prêté qu'une attention limitée aux opinions des chercheurs d'information. En utilisant l'analyse thématique des données qualitatives recueillies auprès de six groupes de discussion, les auteurs de cette étude mettent en lumière les principales motivations qui poussent les milléniaux à recourir aux médias numériques pour leurs besoins en information. Il s'agit de l'autonomie en recherche, le stockage virtuel, la satisfaction immédiate, l'inspiration visuelle, la gratuité de l'information et l'authenticité. Les auteurs proposent des pistes pour répondre stratégiquement aux besoins des consommateurs dans l'environnement actuel des médias numériques.
Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many ...individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5–28, prevalence = 5.8–60.8; DS: incidence proportion = 2.2–6.5, prevalence = 1.2–6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6–9.2 years; LGS, 2–15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person‐years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.
Fully elucidating the burden that Lennox–Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This ...systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.
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