Proteome analysis of human substantia nigra in Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.</p> <p>Results</p> <p>The gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results.</p> <p>Conclusion</p> <p>Using an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than previously thought. The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease.</p

Effects of 1,25(OH)2D3 on compensatory renal growth in the growing rat

Effects of 1,25(OH)2D3 on compensatory renal growth in the growing rat. Renal compensatory growth after uninephrectomy (UNX) was examined in vitamin D replete male 100g Sprague-Dawley rats. Five days after UNX, the contralateral kidney wet weight increased by 25% with the kidney weight/body weight ratio reaching a plateau by day 7 after UNX. The early weight increase was primarily due to an increased cell number, as evaluated by a stereological technique in perfusion-fixed kidneys. Twenty pmol 1,25(OH)2D3 by daily s.c. injection increased time-averaged 1,25(OH)2D3 concentrations 3.3-fold and reduced the increment in the kidney weight of UNX pairfed rats compared to solvent UNX controls. The number of mitoses (whole kidney and different nephron segments) were significantly reduced by giving 1,25(OH)2D3 to UNX animals at different levels of food intake. The effect was also demonstrable in PTX animals on a constant infusion of exogenous PTH (100 ng/kg/hr 1,34 bPTH by osmotic minipump). The data suggest that changes of 1,25(OH)2D3 concentration within a physiologically relevant range modulate compensatory (and possibly basal) growth of the kidney

Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats

Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats.BackgroundCardiovascular death continues to be a major problem in renal failure. Structural abnormalities of the heart and the vasculature contribute to the increased cardiovascular risk. They are ameliorated by angiotensin-converting enzyme (ACE) inhibitors, but because of the nonspecifity of ACE inhibition, it is uncertain whether the beneficial effect is mediated by interfering with angiotensin II (Ang II) or by modulating other effector systems, for example, bradykinin.MethodsTo assess a potential role of bradykinin, subtotally nephrectomized Sprague-Dawley rats (SNX) received either the ACE inhibitor Ramipril (Rami, 0.2 mg/kg body weight p.o.), the specific B2 bradykinin receptor antagonist Hoe140 (0.2 mg/kg body weight, s.c.), or a combination of both, and were compared to sham-operated controls. To separately assess the effect of Ramipril on development and reversal of structural abnormalities, animals were either treated from the third day after SNX or from the fourth week after SNX onward (0.01 mg/kg body weight, p.o.).ResultsHeart and aorta were evaluated by morphometric and stereologic techniques. The weight of the perfused left ventricle, as an index of cardiac hypertrophy, was significantly higher in untreated SNX. While it was significantly lower in animals with early and late Ramipril treatment, the beneficial effect was completely antagonized by Hoe140. The wall-to-lumen ratio of intramyocardial arterioles was significantly higher in untreated SNX compared with controls, but failed to be modified by administration of either Ramipril or Hoe140. In the heart, the intercapillary distance was significantly higher in SNX, but it was not lowered by either early or late Ramipril or Hoe140 treatment. Treatment of SNX with Hoe140 alone, however, resulted in a marked further increase in intercapillary distance. The wall thickness of the aorta was significantly higher in SNX than in controls; early and late Ramipril treatment prevented such increase, and this effect was antagonized by Hoe140.ConclusionThese findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats

The CPLEAR Electromagnetic Calorimeter

A large-acceptance lead/gas sampling electromagnetic calorimeter (ECAL) was constructed for the CPLEAR experiment to detect photons from decays of $\pi^0$s with momentum $p_{\pi^0} \le 800$ MeV$/c$. The main purpose of the ECAL is to determine the decay vertex of neutral-kaon decays \ko \rightarrow \pi^0\pi^0 \rightarrow 4 \gamma and \ko \rightarrow \pi^0\pi^0\pi^0 \rightarrow 6 \gamma. This requires a position-sensitive photon detector with high spatial granularity in $r$-, $\varphi$-, and $z$-coordinates. The ECAL --- a barrel without end-caps located inside a magnetic field of 0.44 T --- consists of 18 identical concentric layers. Each layer of $1/3$ radiation length (X${_0}$) contains a converter plate followed by small cross-section high-gain tubes of 2640 mm active length which are sandwiched by passive pick-up strip plates. The ECAL, with a total of $6$ X${_0}$, has an energy resolution of $\sigma (E)/E \approx 13\% / \sqrt{E(\mathrm{GeV})}$ and a position resolution of 4.5 mm for the shower foot. The shower topology allows separation of electrons from pions. The design, construction, read-out electronics, and performance of the detector are described

Endometriosis and adenomyosis – a shared pathophysiology

The major authors of the last century described endometriosis as ectopic endometrial lesions occurring both in the uterus and in the peritoneal cavity, and the lesions were considered as variants of the same disease process. In the 1920s a theory had been put forward that, although severely and chronically challenged, resulted in the clear cut separation of the two entities. A new understanding of the disease process, however, enables to reunify these two disease entities and to integrate them into a new nosological concept. Circumstantial evidence suggests that endometriosis and adenomyosis share a similar pathophysiology and are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumata with the activation of the basal and general mechanism of “tissue injury and repair” (TIAR). This results in the local production of estrogens. With ongoing peristaltic activity, such sites will accumulate and the increasingly produced estrogens interfere via paracrine mode of action with the endocrine ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus, with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall, ensues. In most cases of endometriosis/adenomyosis, a causal event early in the reproductive period of life must be postulated leading to uterine hyperperistalsis. In late premenopausal adenomyosis such overt event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life may result in events that accumulate to the same extent of microtraumatizations. With the activation of the TIAR mechanism, followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principal the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of ‘tissue injury and repair’ (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary. It appears that many of the altered endometrial molecular markers described in the context of endometriosis are the consequence rather than the cause(s) of the disease