BackgroundThe endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown.MethodsGenetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology.ResultsWe identified six individuals (5–33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7–2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability.ConclusionsA homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.

No abstract

No abstract

Osteomyelitis in the diabetic foot can be difficult to diagnose and has serious consequences. Although 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) was traditionally used in oncology, it is emerging as a useful method in inflammatory and infectious entities. In this chapter, original research articles, meta-analyses, and reviews on the performance of FDG PET in diagnosing osteomyelitis in the diabetic foot will be discussed. In addition, PET available data in comparison to different imaging methods, different analysis methods, and impact of other co-existing conditions such as hyperglycemia, and long-term antibiotic treatment on the performance of FDG PET will be reviewed. Studies published in the last two decades showed variable performance of FDG PET in the assessment of diabetic foot infection with a relatively high specificity (67-93%) but a wide range of sensitivity (29-100%). More recent studies showed better sensitivity, probably due to improved imaging technology and analysis methods and use of hybrid imaging with positron emission tomography/ computed tomography (PET/CT). FDG PET/CT has several advantages compared to other anatomical and functional imaging methods, including short acquisition time, high resolution, low radiation dose, and better tolerability. Further research is required to establish its role in the clinical practice.