Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.     

Expression of a mannose/fucose membrane lectin on human dendritic cells

Dendritic cells (CD) are the most efficient antigen presenting cells for T lymphocytes. CD1a+ CD14- CD with high antigen-presenting capacities can now be obtained easily from adherent peripheral blood monocytes by culture in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4 (Sallusto et al., J. Exp. Med. 1994. 179: 1109). Human macrophages express a membrane lectin, or sugar-specific receptor, which specifically mediates the binding and endocytosis of mannose- and fucose-terminated glycoproteins and is involved in the phagocytosis of pathogens. A similar lectin activity was sought on cultured human DC using flow cytometry and confocal microscopy to detect binding and internalization of fluoresceinated neoglycoproteins [bovine serum albumin (BSA) substituted with sugar residues]. Several neoglycoproteins, especially alpha-L-fucosyl-, alpha-D-mannosyl-, N,N'-di-acetyl-beta-chitobiosyl- and beta-D-glucosyl-BSA, were endocytosed by cultured human CD1a+ DC as well as by CD1a- CD14- cells which were also obtained in the culture. Fuc-BSA and Man-BSA had the same number of binding sites (1.7 x 10(6)/cell) on CD1a+ DC, and bound with an affinity constant close to 10(7) 1/mol. Inhibition experiments indicated that these two neoglycoproteins bound to the same membrane lectin. CD1a+ and CD1a- cells were both labeled by an antiserum specific for the human macrophage mannose receptor. The membrane lectin specific for mannose and fucose that is evidenced in these experiments on cultured DC may be similar to the macrophage membrane lectin or may share functional and structural properties with it.     

p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors

OBJECTIVES--(1) to evaluate regional cerebral blood flow (rCBF) with single photon emission computed tomography and 99mTc-hexamethylpropyleneamine oxime in patients with the idiopathic adult hydrocephalus syndrome (IAHS); (2) to examine regional cerebral blood flow (rCBF), gait, and psychometric functions before and after CSF removal (CSF tap test); (3) to assess abnormalities in subcortical white matter by MRI. METHODS--Thirty one patients fulfilling the criteria for IAHS (according to history and clinical and neuroradiological examination) were studied. Quantified gait measurements, psychometric testing, and rCBF before and after removal of CSF were obtained. Pressure of CSF and CSF outflow conductance were investigated with a constant pressure infusion method. Brain MRI was used to quantify the severity of white matter lesions and periventricular hyperintensities. In IAHS a widespread rCBF hypoperfusion pattern was depicted, with a caudal frontal and temporal grey matter and subcortical white matter reduction of rCBF as the dominant feature. Removal of CSF was not accompanied by a concomitant increase in rCBF. Significant white matter lesions were detected only in a minority of patients by MRI. An altered CSF hydrodynamic state with a higher CSF pressure and lower conductance was confirmed. IAHS is characterised by an abnormal CSF hydrodynamic state, associated with a widespread rCBF reduction with preference for subcortical white matter and frontal-temporal cortical regions. Furthermore in most patients MRI did not show white matter changes suggestive of a coexistent subcortical arteriosclerotic encephalopathy. At least in the idiopathic group of patients with AHS, measurements of rCBF before and after temporary relief of the CSF hydrodynamic disturbance will not provide additional information that would be helpful in the preoperative evaluation but is suggestive of a preserved autoregulation of rCBF.     

La?nnec, re-inventor of the stethoscope?

According to our common medical culture, some facts are simply unquestionable, for instance La?nnec invented the stethoscope. But was he the first one? On a recent trip to Egypt we visited the temple of Kom Ombo, built prior to the roman period and renowned as a medical care center. Today, the tourist is fascinated by the magnificent hieroglyphics on the well-preserved walls testifying to significant advances in various fields of medicine including ophthalmology and gynecology. We were particularly interested by the basreliefs presenting vivid drawings of some of the first medical instruments. We easily identified curettes, scissors, a balance, forceps for dental extraction, and a surgical saw, but were captivated by two other instruments. The first one looked a lot like what La?nnec invented around 1820. The second one was amazingly similar to the instrument we use everyday, with a distal opening and flexible tubes (woven papyrus?) leading to proximal ear pieces. Our Egyptian guide was formal: the stethoscope was invented in Egypt. The scientific impact of our observations leaves something to be desired, but did make us think about the huge gap between the advancement of medical knowledge in ancient Egypt and La?nnec's (re)-invention. Exposed to a similar gap in history, what would our documents stored on CD and video tapes have to say to future touring doctors?     

Is pancreatectomy with resection of the retro-pancreatic vessels for cancer justified?

Collagenase-1 (C1) is the predominant matrix metalloproteinase present in newly formed microvessels and serves as a marker of neovascularization. The expression of the oncofetal fragment of fibronectin (Fn-f) was found to be increased during angiogenesis. In the present study, we investigated the relationship between the expression of collagenase-1 and the oncofetal fragment of fibronectin in newly formed microvessels as markers of tumor angiogenesis. In aggressive skin tumors (i.e., morpheaform and recurrent basal cell carcinomas) and squamous cell carcinomas, neovascularization was associated with a marked increase in the number of C1-positive and Fn-f-positive microvessels. At the beginning of elongation, microvessels begin to produce C1 but lose their ability to express type IV collagen and FVIII-related antigen. Later, this endothelium produces both Fn-f and C1. As maturation of microvessels occurs, C1-containing endothelium fails to express Fn-f but begins to produce a type IV collagen-containing basement membrane and FVIII-related antigen. These studies show that there is a selective expression of both Fn-f and collagenase by immature endothelial cells. C1 production begins at early stages of blood vessel formation and continues throughout angiogenesis. In contrast, Fn-f expression is limited to later stages of vasculogenesis, indicating that these proteins are reliable markers of angiogenesis.     

Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.