The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle

A multimodal image guiding system for Navigated Ultrasound Bronchoscopy (EBUS): A human feasibility study

Background Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is the endoscopic method of choice for confirming lung cancer metastasis to mediastinal lymph nodes. Precision is crucial for correct staging and clinical decision-making. Navigation and multimodal imaging can potentially improve EBUS-TBNA efficiency. Aims To demonstrate the feasibility of a multimodal image guiding system using electromagnetic navigation for ultrasound bronchoschopy in humans. Methods Four patients referred for lung cancer diagnosis and staging with EBUS-TBNA were enrolled in the study. Target lymph nodes were predefined from the preoperative computed tomography (CT) images. A prototype convex probe ultrasound bronchoscope with an attached sensor for position tracking was used for EBUS-TBNA. Electromagnetic tracking of the ultrasound bronchoscope and ultrasound images allowed fusion of preoperative CT and intraoperative ultrasound in the navigation software. Navigated EBUS-TBNA was used to guide target lymph node localization and sampling. Navigation system accuracy was calculated, measured by the deviation between lymph node position in ultrasound and CT in three planes. Procedure time, diagnostic yield and adverse events were recorded. Results Preoperative CT and real-time ultrasound images were successfully fused and displayed in the navigation software during the procedures. Overall navigation accuracy (11 measurements) was 10.0 ± 3.8 mm, maximum 17.6 mm, minimum 4.5 mm. An adequate sample was obtained in 6/6 (100%) of targeted lymph nodes. No adverse events were registered. Conclusions Electromagnetic navigated EBUS-TBNA was feasible, safe and easy in this human pilot study. The clinical usefulness was clearly demonstrated. Fusion of real-time ultrasound, preoperative CT and electromagnetic navigational bronchoscopy provided a controlled guiding to level of target, intraoperative overview and procedure documentation.publishedVersio

Allopregnanolone as a mediator of affective switching in reproductive mood disorders

RATIONALE: Reproductive mood disorders, including premenstrual dysphoria (PMD) and postpartum depression (PPD), are characterized by affective dysregulation that occurs during specific reproductive states. The occurrence of illness onset during changes in reproductive endocrine function has generated interest in the role of gonadal steroids in the pathophysiology of reproductive mood disorders, yet the mechanisms by which the changing hormone milieu triggers depression in susceptible women remain poorly understood. OBJECTIVES: This review focuses on one of the neurosteroid metabolites of progesterone – allopregnanolone (ALLO) – that acutely regulates neuronal function and may mediate affective dysregulation that occurs concomitant with changes in reproductive endocrine function. We describe the role of the ‘neuroactive’ steroids estradiol and progesterone in reproductive endocrine-related mood disorders to highlight the potential mechanisms by which ALLO might contribute to their pathophysiology. Finally, using existing data, we test the hypothesis that changes in ALLO levels may trigger affective dysregulation in susceptible women. RESULTS: Although there is no reliable evidence that basal ALLO levels distinguish those with PMD or PPD from those without, existing animal models suggest potential mechanisms by which specific reproductive states may unmask susceptibility to affective dysregulation. Consistent with these models, initially euthymic women with PMD and those with a history of PPD show a negative association between depressive symptoms and circulating ALLO levels following progesterone administration. CONCLUSIONS: Existing animal models and our own preliminary data suggest that ALLO may play an important role in the pathophysiology of reproductive mood disorders by triggering affective dysregulation in susceptible women