Autism research is heavily skewed towards western high-income countries. Culturally appropriate screening and diagnostic instruments for autism are lacking in most low-and middle-income settings where the majority of the global autism population lives. To date, a clear overview of the possible cultural and contextual factors that may affect the process of identifying and diagnosing individuals with ASD is missing. This study aims to outline these factors by proposing a conceptual framework. A multidisciplinary review approach was applied to inform the development of the conceptual framework, combining a systematic review of the relevant autism research literature with a wider literature search spanning key texts in global mental health, cultural psychiatry, cross-cultural psychology and intellectual disability research. The resulting conceptual framework considers the identification, helpseeking and diagnostic process at four interrelated levels: i) the expression, ii) recognition, iii) interpretation and iv) reporting of autism symptoms, and describes the cultural and contextual factors associated with each of these levels, including cultural norms of typical and atypical behaviour, culture-specific approaches to parenting, mental health literacy, cultural beliefs, attitudes and stigma, as well as the affordability, availability, accessibility and acceptability of services. This framework, mapping out the cultural and contextual factors that can affect the identification, help-seeking and diagnosis of ASD, may function as a springboard for the development of culturally appropriate autism screening and diagnostic instruments, and inform future cross-cultural autism research directions. The framework also has relevance for clinicians and policy makers aiming to improve support for underserved autism populations worldwide. Lay summaryThe vast majority of autism research is conducted in western high-income settings. We therefore know relatively little of how culture and context can affect the identification, helpseeking and diagnosis of autism across the globe. This paper synthesises what is known from the autism research literature and a broader literature and maps out how culture and context may affect i) the expression, ii) recognition, iii) interpretation and iv) reporting of autism symptoms.

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Primary cultures and cell lines were established from suspensions of purified fat-storing cells isolated from the rat liver. When seeded at a suitable density, fat-storing cells in primary culture reached confluency in 3 to 4 days and could be transferred and established as cell lines for at least two passages. The typical morphological characteristics of fat-storing cells in vivo were retained in the cells during primary culture. Vitamin A fluorescence was still associated with lipid droplets of cells in culture up to and including the second passage. Investigation of the cytoskeletal structure by indirect immunofluorescence showed the presence of vimentin, actin and tubulin in the cells; no alpha-prekeratin was present. The presence of vimentin suggested a fibroblastic or possible myogenic origin for fat-storing cells. The presence of connective tissue components in fat-storing cells in culture was demonstrated by indirect immunofluorescence. Collagen Types I and IV and laminin were present intracellularly in small granules in fat-storing cells in primary culture and in the first passage. Cells in the fourth passage contained only collagen Type 1. Fibronectin was only aligned extracellularly along the cell membrane, which did not exclude an extracellular source. Rat liver fat-storing cells in culture show a high proliferating capacity. Cell multiplication during prolonged culture was associated with phenotypic transition to a more fibroblastic appearance and gradual disappearance of vitamin A. These results indicate that fat-storing cells may be among the cell types involved in pathological changes observed during development of liver fibrosis.

AimConduction of vasomotor responses may contribute to long‐term regulation of resistance artery function and structure. Most previous studies have addressed conduction of vasoactivity only during very brief stimulations. We developed a novel set‐up that allows the local pharmacological stimulation of arteries in vitro for extended periods of time and studied the conduction of vasomotor responses in rat mesenteric arteries under those conditions.MethodsThe new in vitro set‐up was based on the pressure myograph. The superfusion chamber was divided halfway along the vessel into two compartments, allowing an independent superfusion of the arterial segment in each compartment. Local and remote cumulative concentration‐response curves were obtained for a range of vasoactive agents. Additional experiments were performed with the gap junction inhibitor 18β‐glycyrrhetinic acid and in absence of the endothelium.ResultsPhenylephrine‐induced constriction and acetylcholine‐induced dilation were conducted over a measured distance up to 2.84 mm, and this conduction was maintained for 5 minutes. Conduction of acetylcholine‐induced dilation was inhibited by 18β‐glycyrrhetinic acid, and conduction of phenylephrine‐induced constriction was abolished in absence of the endothelium. Constriction in response to high K+ was not conducted. Absence of remote stimulation dampened the local response to phenylephrine.ConclusionThis study demonstrates maintained conduction of vasoactive responses to physiological agonists in rat mesenteric small arteries likely via gap junctions and endothelial cells, providing a possible mechanism for the sustained functional and structural control of arterial networks.

Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable progress in managing the progression of the disease, the development of effective therapies for heart failure (HF) remains challenging. Therefore, it is of great importance to understand the molecular mechanisms that maintain calcium level and contractility in homeostatic conditions. Here we identified a transcription factor ZEB2 that regulates the expression of numerous contractile and calcium-related genes. Zinc finger E-box-binding homeobox2 (ZEB2) is a transcription factor that plays a role during early fetal development and epithelial-to-mesenchymal transition (EMT); however, its function in the heart remains to be determined. Recently, we found that ZEB2 is upregulated in murine cardiomyocytes shortly after an ischemic event, but returns to baseline levels as the disease progresses. Gain- and loss-of-function genetic mouse models revealed the necessity and sufficiency of ZEB2 to maintain proper cardiac function after ischemic injury. We show that cardiomyocyte-specific ZEB2 overexpression (Zeb2 cTG) protected from ischemia-induced diastolic dysfunction and attenuated the structural remodeling of the heart. Moreover, RNA-sequencing of Zeb2 cTG hearts post-injury implicated ZEB2 in the regulation of numerous calcium-handling and contractile-related genes when compared to wildtype mice. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2A), thereby augmenting contractility. Improved cardiac function in ZEB2-overexpressing hearts correlated with higher expression of several sarcomeric proteins like myosin-binding protein C3 (MYBPC3), desmin (DES) and myosin regulatory light chain 2 (MYL2) further contributing to the observed protective phenotype. Furthermore, we observed a decrease in the activity of Ca2+-depended calcineurin/NFAT signaling, which is the main driver of pathological cardiac remodeling. Conversely to Zeb2 cTg mice, loss of ZEB2 from cardiomyocytes perturbed the expression of calcium- and contractile-related proteins and increased the activity of calcineurin/NFAT pathway, exacerbating cardiac dysfunction. Together, we show that ZEB2 is a central regulator of contractile and calcium-handling components, consequently mediating contractility in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in the regulation of calcium homeostasis in cardiomyocytes is a critical step towards the development of improved therapies for various forms of heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): DR. E. Dekker from Dutch Heart Foundation

Sinusoidal liver cells were isolated from the livers of 3-, 12-, 30-, and 36-month-old female BN/ BiRij rats by enzymatic digestion. The Kupffer cells in the sinusoidal cel suspensions were purified by centrifugal elutriation and kept in maintenance culture for periods of up to about 3 weeks. The viability and yield of Kupffer cells per gram of body weight did not change with the age of the donor rat. The ultrastructural, cytochemical, and functional characteristics of Kupffer cells as observed in perfusion-fixed liver were retained during several days of maintenance culture. The consistent observation of worm-like structures in cultured Kupffer cells indicated the reformation of the specific fuzzy coat of the cells during culture. Endogenous peroxidatic and acid phosphatase activities were evident in cultured Kupffer cells and showed the same localization as observed in perfusion-fixed liver. Kupffer cells in culture were able to endocytose colloidal carbon, latex particles (0.8 Mm), horseradish peroxidase, and endotoxin, indicating the reappearance of different types of specific membrane receptors. The ultrastructural appearance of Kupffer cells was not markedly influenced by the age of the donor rat. However, with increasing age, the lysosomes showed increasing amounts of electron dense lipid-like material and iron in the form of ferritin.No qualitative age-related changes in the enzymes tested or in the endocytic capacity of the Kupffer cells were observed. On the basis of these observations, maintenance cultures of purified Kupffer cells can be considered as a valuable model for studying Kupffer cell functions, also in relation to aging phenomena.

Obese patients undergoing surgery have a higher risk of cardiovascular complications due to an unidentified instability in blood pressure (BP) regulation. The sympathetic nervous system is a crucial BP regulator, acting through α‐ and β‐adrenoreceptors (ARs), and is influenced by anesthesia. Our study aimed to determine how obesity alters cardiovascular AR responsiveness in vivo, and how this is affected by anesthesia. Sixteen week old Male Zucker Obese rats (n=7) and lean littermates (n=7) underwent dual implantation surgery. A radiotelemeter in the abdominal aorta provided mean arterial pressure (MAP) and heart rate (HR), and a vascular access port in the femoral vein provided non‐invasive intravenous access. Animals were injected with incrementing doses of dobutamine (2‐120 µg/kg) or phenylephrine (1‐100µg/kg) to stimulate β‐ or α‐ARs respectively, under conscious and anesthetized (2% isoflurane) conditions. Obese animals displayed a reduced HR increase to β‐AR stimulation under conscious conditions (103±12 vs. 61±9 bpm; p<0.001 at 15µg/kg), which was lost during anesthesia (51±3 vs. 66±5 bpm; NS at 15µg/kg). α‐AR stimulation elicited greater increases in MAP in conscious obese rats (53±5 vs. 70±3 mmHg; p<0.01 at 8µg/kg), an effect that was exacerbated by anesthesia (41±5 vs. 69±4 mmHg; p<0.001 at 8µg/kg). Interstingly, obesity interacted with anesthesia, resulting in a significantly prolonged α‐AR‐mediated elevation in MAP compared to lean animals. Thus, both α‐AR and β‐AR dysfunction are observed in obesity, and are differently affected by anesthesia. The inability of obese patients to appropriately alleviate excess BP during anesthesia may cause undue pressures on the heart and contribute to their perioperative complications.

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