Age-related microvascular degeneration in the human cerebral periventricular white matter

Clinical studies have identified white matter (WM) lesions as hyperintensive regions in the MRI images of elderly patients. Since a cerebrovascular origin was attributed to such lesions, the present analysis set out to define the microvascular histopathologic changes in the periventricular WM in the aged. Post-mortem samples of the frontal, parietal, and occipital periventricular WM of 40–90-year-old subjects were prepared for quantitative light and electron microscopy. Light microscopic examination revealed microvascular fibrohyalinosis as the most common type of microvascular damage in the elderly. Ultrastructural analysis identified the microvascular thickening as collagen deposits affecting the basement membrane. The vascular density did not correlate with the age. The basement membrane pathology significantly increased, while the number of intact microvessels gradually decreased, with advancing age in the frontal and occipital WM. Finally, peripheral atherosclerosis coincided with massive microvascular fibrosis, particularly in the frontal WM. Our results demonstrate an age-related microvascular degeneration in the periventricular WM, which may contribute to the development of WM lesions by hindering a sufficient supply of nutrients to the affected WM sites. Furthermore, the data accord with previous observations identifying the frontal lobe as the site at which WM vulnerability is most pronounced. Finally, atherosclerosis in large, peripheral vessels is considered to be a predictive marker of microvascular pathology in the WM.     

Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells

Antiinflammatory effects of glucocorticoids are critical to treatment of airway inflammation in such common disorders as asthma. There is considerable variation in responsiveness to glucocorticoid, and prolonged exposure can result in glucocorticoid resistance. We cloned LGL2, a glucocorticoid-inducible gene in fetal rat lung. We described the characterization of lgl2 as a nuclear transport protein, classified as importin 13 (IPO13), and demonstrated developmental regulation of IPO13 nucleocytoplasmic shuttling. We now report on the identification of the glucocorticoid receptor (GR) as a cargo substrate for IPO13. Binding of GR and IPO13 was demonstrated by GR-GST pulldown and coimmunoprecipitation. To investigate the role of IPO13 in modulating GR signaling in the lung, we studied IPO13-regulated GR transport in airway epithelial cells. Small interfering RNAs that inhibited IPO13 synthesis prevented nuclear translocation of GR. Silencing of IPO13 also abrogated the ability of cortisol to inhibit synthesis of the inflammatory cytokine IL-8 after stimulation with TNF-alpha. Our findings support a role for IPO13 in promoting nuclear occupancy of GR in a way that strongly potentiates the antiinflammatory effects of glucocorticoids. We speculate that variation in cellular levels of IPO13 and intracellular IPO13 shuttling rates may contribute to glucocorticoid resistance.     

Echocardiographic findings in patients with Williams-Beuren syndrome

BACKGROUND: Williams-Beuren syndrome is a multisystem developmental disorder caused by a microdeletion at chromosome 7q11.23. In its classic form it includes dysmorphic facial features, joint contractures, retardation of growth and mental development, gregarious personality, visuospatial cognitive deficits, hypercalcemia, primary or secondary hypertension and cardiovascular disorders. AIM: Clinical diagnosis of Williams-Beuren syndrome can be a challenge in young patients if none of the characteristic cardiovascular features, i.e. supravalvular aortic stenosis or pulmonary artery stenosis, are present. Our aim was to demonstrate the changes in cardiovascular lesions during the postnatal development of Williams-Beuren patients and to follow all cardiovascular findings beyond the most common ones. METHODS: The cardiovascular status of 29 patients with Williams-Beuren syndrome (mean age 12.8 years) was recorded in correlation with age. RESULTS: Cardiovascular diagnoses changed in the majority (72.4%) of patients. Interestingly, 44.8% of the patients had periods with no reported cardiovascular disease. Furthermore, 65.5% of the patients experienced periods when none of the typical cardiovascular lesions, i.e. diffuse or localized supravalvular aortic stenosis and/or pulmonary artery stenosis, were detected. Spontaneous regression and progression of both supravalvular aortic stenosis and pulmonary artery stenosis were observed. An unexpectedly high frequency (41%) of mitral valve disorders was found. CONCLUSIONS: Our study showed that temporary absence of and changes in cardiovascular findings are frequent in Williams-Beuren syndrome. These results could contribute to the refinement of diagnostic criteria and recommendations for cardiovascular follow-up of patients with this syndrome.     

Possible pathogenic nature of the recently discovered TT virus: does it play a role in autoimmune rheumatic diseases?

Pathogenesis of viral origin has long been suggested in autoimmune rheumatic diseases. Beside the well-defined virus induced transient or chronic rheumatic diseases often resembling systemic autoimmune disorders such as rheumatoid arthritis, viruses can contribute to disease pathogenesis by several different pathomechanisms. TT virus is a recently discovered virus of extremely high genetic diversity which commonly infects humans. Despite accumulated evidence on the biological characteristics of TTV, its pathogenicity is still in question; many consider TTV as a harmless endosymbiont. The recent paper overviews the biology of TT virus and investigates the hypothesis that TTV might have a causative role in human diseases with special attention to the possibility that TTV might trigger autoimmunity in rheumatic disorders.     

Human herpesvirus 6A decreases the susceptibility of macrophages to R5 variants of human immunodeficiency virus 1: possible role of RANTES and IL-8

Human herpesvirus 6 (HHV-6) frequently reactivates in human immunodeficiency virus 1 (HIV-1) infected patients, and is thought to be a cofactor in AIDS progression. Macrophages are targets and reservoirs of HIV-1 and HHV-6; hence, they have an important role in dissemination and pathogenesis of these viruses. The present study examined the effects of HHV-6 A variant on replication of R5 variants of HIV-1 in macrophages. For this purpose, HIV-1 replication was investigated in macrophages infected with HIV-1 alone or along with HHV-6A. Our results demonstrated that HHV-6A significantly suppressed HIV-1 replication in coinfected cultures. HHV-6A infection resulted in increased secretion of RANTES and IL-8. Experiments with exogenous RANTES and IL-8 revealed that these chemokines also significantly suppressed HIV-1 replication in infected macrophages. RANTES is able to induce desensitization and internalization of CCR5, the chemokine coreceptor of R5 variants. In addition, IL-8 receptor activation results in cross-desensitization and cross-internalization of CCR5. We found that CCR5 sensitivity and expression level is diminished in HHV-6A-infected macrophage cultures compared with uninfected cells. Taken together, our results indicate that HHV-6A infection decreases the susceptibility of macrophages to R5 variants of HIV-1 in which the HHV-6A induced RANTES and IL-8 may have importance.     

Investigation of monoclonal gammopathy of undetermined significance: a single-centre study

Summary The main characteristic of monoclonal gammopathies (MG) is the presence of an increased amount of both electrophoretically and immunologically homogeneous immunoglobulins (M component). According to the WHO classification, monoclonal gammopathies are classified among the non-Hodgkin's lymphomas as 'plasma cell dyscrasias'. The unknown behaviour state, so-called MGUS (monoclonal gammopathy of undetermined significance), is distinguished from the malignant diseases. We investigated the frequency and features of MG and MGUS by reviewing the serum immunochemistry protein analyses between 1998 and 2004. Among 18,642 analyses, MG was found in 1,983 cases (10.39%) derived from one or more samples of 416 patients. Case histories of 340 patients were analysed. A malignant lymphoproliferative disease was proved in 171 cases, while in 169 cases the behaviour of the gammopathy was unknown. In 65 cases, the disease was possibly not related to MG. Mean follow-up time of the 65 patients with MGUS was 42 (9-81) months. During the follow-up period seven patients progressed into a malignant lymphoproliferative disorder-- mean probability of the malignant transformation was 3.07%/year and it occurred more frequently in the presence of immunoglobulin A isotype. There was no correlation between the progression of the disease and other laboratory findings. Besides the analyses of MG-related diseases, we focus on the malignant transformation of MGUS and on the importance of regular clinical and laboratory control examinations.     

Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n?=?948/1,258), Hungary (n?=?262/65), Venezuela (n?=?112/190) and Pakistan (n?=?103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt-PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR?=?1.21; 95% Cl?=?1.04-1.40; P?=?0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR?=?1.23; 95% Cl?=?1.05-1.44; P?=?0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR?=?1.18; 95% Cl?=?1.12-1.25; P?相似文献   

Frequency of Genetic and Epigenetic Alterations of p14ARF and p16INK4A in Head and Neck Cancer in a Hungarian Population

Occurrence of genetic and epigenetic alterations affecting p14ARF and p16INK4A were investigated in tumour samples of 37 oral (OSCC) and 28 laryngeal squamous cell cancer (LSCC) patients, and compared to exfoliated buccal epithelial cells of 68 healthy controls. Presence of deletions and mutations/polymorphisms affecting exons were examined using sequencing. Methylation status of promoters was assessed by methylation-specific PCR. Chi-square and Fisher’s exact tests were used to compare frequency of events. Exon deletions were found in four controls, one OSCC and 22 LSCC patients; the latter significantly differed from controls (p?p?=?0.043 and p?=?0.001, respectively) compared to the control group. In summary, exon deletion may be important in LSCC, while promoter methylation was relatively frequent in both patient groups.     

Developmental shift in TcR-mediated rescue of thymocytes from glucocorticoid-induced apoptosis

Glucocorticoid hormone (GC) production by thymic epithelial cells influences TcR signalling in DP thymocytes and modifies their survival. In the present work, we focused on exploring details of GC effects on DP thymocyte apoptosis with or without parallel TcR activation in AND transgenic mice, carrying TcR specific for pigeon cytochrome C, in vivo. Here we show that the glucocorticoid receptor (GR) protein level was the lowest in DP thymocytes, and it was slightly down-regulated by GC analogue, anti-CD3, PCC and combined treatments as well. Exogenous GC analogue treatment or TcR stimulation alone lead to marked DP cell depletion, coupled with a significant increase of early apoptotic cell ratio (AnnexinV staining), marked abrogation of the mitochondrial function in DP cells (CMXRos staining), and significant decrease in the Bcl-2(high) DP thymocyte numbers, respectively. On the other hand, the simultaneous exposure to these two proapototic signals effectively reversed all the above-described changes. The parallel analysis of CD4 SP cell numbers, AnnexinV, CMXRos, Bcl-2 and GR stainings revealed, that the GR and TcR signals were not antagonistic on the mature thymocytes. These data provide experimental evidence in TcR transgenic mice, in vivo, that when TcR activation and GR signals are present simultaneously, they rescue double positive thymocytes from programmed cell death. The two separate signalling pathways merge in DP thymocytes at such important apoptosis regulating points as the Bcl-2 and GR, showing that their balanced interplay is essential in DP cell survival.