BackgroundIt is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1).MethodsWe investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition.Results[18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion.ConclusionsHuman TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

There are several significant differences in GFR and ECV between healthy men and women.

Clinical, cognitive, genetic and imaging data suggest increased severity in early-onset schizophrenia. Studying younger-onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene-environment interactions leading to the emergence of this debilitating disorder.

PET is an important functional imaging technique that can be used to investigate neurotransmitter receptors and transporters directly by mapping human brain function. PET is increasingly being used greatly to advance our understanding of the neurobiology and pathophysiology of schizophrenia. Methods: This review focuses on the use of PET tracers and kinetic modeling in identifying regional brain abnormalities and regions associated with cognitive functioning in schizophrenia. A variety of PET tracers have been used to identify brain abnormalities, including 11 C, 15 O-water, 18 F-fallypride, and L-3,4-dihydroxy-6-18 F-fluorophenylalanine ( 18 F-FDOPA). Results: Some studies have used compartmental modeling to determine tracer binding kinetics. The most consistent findings show a difference in the dopamine content in the prefrontal cortex, anterior cingulate gyrus, and hippocampus between healthy controls and patients with schizophrenia. Studies also show a higher density of D 2 receptors in the striatum and neural brain dysconnectivity. Conclusion: Future investigations integrating clinical, imaging, genetic, and cognitive aspects are warranted to gain a better understanding of the pathophysiology of this disorder.

Amyloid positron emission tomography (PET) imaging enables in vivo detection of brain Aβ deposition, one of the neuropathological hallmarks of Alzheimer’s disease. There is increasing evidence to support its clinical utility, with major studies showing that amyloid PET imaging improves diagnostic accuracy, increases diagnostic certainty and results in therapeutic changes. The Amyloid Imaging Taskforce has developed appropriate use criteria to guide clinicians by predefining certain scenarios where amyloid PET would be justified. This review provides a practical guide on how and when to use amyloid PET, based on the available research and our own experience. We discuss its three main appropriate indications and illustrate these with clinical cases. We stress the importance of a multidisciplinary approach when deciding who might benefit from amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in its interpretation.