Scatter plots show the quantification of Gb3 load in CD77 stains of skin punch biopsy specimens from the lower leg of patients with Fabry disease (FD) stratified for enzyme replacement therapy (ERT).

<p>Male and female FD patients without ERT did not differ from patients on ERT. Number of subjects from left to right: n = 16; n = 17, n = 18, n = 35). Abbreviations: ERT = enzyme replacement therapy; F = female; Gb3 = globotriaosylceramide 3; M = male; n.s. = not significant; ROI: investigated region of interest on skin punch biopsy specimens. *p<0.05.</p

Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease

<div><p>Background</p><p>The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.</p><p>Methods</p><p>At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.</p><p>Results</p><p>We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.</p><p>Conclusions</p><p>Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.</p></div

Demographics.

<p>Demographics.</p

Scatter plots illustrate quantification of Gb3 load in CD77 stains of skin punch biopsy specimens from the lower leg of patients with Fabry disease (FD) of classical and non-classical phenotype stratified for gender.

<p>Skin Gb3 load is higher in male and female FD patients with classical phenotype compared to respective healthy controls. Patients with non-classical phenotype do not differ from controls and only one patient out of seven exceeded the threshold of >0.05% ROI Gb3 deposition in distal skin. Number of subjects from left to right: n = 32, n = 2, n = 5, n = 39, n = 5, n = 10, n = 11. Abbreviations: Co = controls; F = female; Gb3 = globotriaosylceramide 3; M = male; ROI: investigated region of interest on skin punch biopsy specimens; SFN = small fiber neuropathy. *p<0.05, **p<0.01.</p

Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium–glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data—crystallising the key findings, from safety to efficacy—and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease

Single nucleotide polymorphisms (SNPs) that were nominal significantly different in frequency between patients and controls.

<p>Data are adjusted for age and sex.</p

Characteristics of patient population.

<p>Characteristics of patient population.</p

Representative photomicrograph of skin punch biopsy samples from the lower leg of patients with Fabry disease and healthy controls are shown using double immunofluorescence stains.

<p>Globotriaosylceramide 3 (Gb3) deposition is shown in cutaneous sweat glands, blood vessels, and dermal cells. Ten-μm skin sections were immunoreacted with an antibody against the pan-axonal marker protein-gene product 9.5 (PGP 9.5; Ultraclone, UK, 1:800) to visualize nerve fibers; with an antibody agains factor VIII (von Willebrand factor, vWF; Dako, USA, 1:200) to show endothelium of blood vessels; with an antibody against the CD77 antigen (i.e. Gb3; BD Pharmingen, Heidelberg, Germany, 1:100) to visualize Gb3 deposits. Nuclei were visualized using 4,6-diamidin-2-phenylindol (DAPI; Boehringer, Mannheim). Dermal sweat glands of a Fabry patient (A) and a healthy control (D) are densely innervated (arrows pointing at PGP9.5 immunoreactive nerve fibers). In the sweat gland tubules of the Fabry patient dense Gb3 deposits are seen (arrows) while no such deposits are found in the healthy control (E). C) and F) show the respective merged photomicrographs. Dermal vessels of a Fabry patient (G) and a healthy control (J) are determined by the endothelial vWF (arrows). The vessel wall of the Fabry patient contains Gb3 deposits (H; arrows), while no such deposits are seen in the vessel walls of the healthy control (K). I) and L) show the respective merged photomicrographs. Dermal cells are determined by nuclear staining in skin of a Fabry patient (M, arrows). Intracellular Gb3 deposits are found in some (N, arrow) but not all (O, arrow head) dermal cells. Bar = 50 μm.</p

Receiver operating characteristic (ROC) curve is shown for distal skin Gb3 load in male FD patients compared to healthy controls.

<p>The relative frequency of ‘‘true positive” values on the y-axis (i.e., sensitivity) is plotted against the relative frequency of ‘‘true negative” values on the x-axis (i.e., 1-sensitivity). Note that the highest sensitivity (59%) and specificity (100%) for FD was found with the cut-off value set at 0.05. Abbreviations: AUC = area under the curve; CI = confidence interval; F = female; Gb3 = globotriaosylceramide 3; M = male; ROI: investigated region of interest on skin punch biopsy specimens; SE = standard error.</p

Scatter plot of annual progression rate of myocardial fibrosis versus the alterations in geometry.

<p>On the x-axis values of the sphericity index (SI, parameter for geometry) and on the y-axis the annual progression of late enhancement (LE, parameter for fibrosis) is displayed. The size of the red dots represents the systolic blood pressure (SBP) at baseline. The vertical line indicates the pathological value of the SI. Note the appearance of high SI in combination with elevated SBP and high progression rate. EDV; End-diastolic volume.</p