Localized amyloidosis of the uterine cervix

Summary Localized amyloidosis of the uterine cervix was found in a 56-year-old woman. The firm enlarged cervix showed massive tumorous amyloid deposition. In the amyloid deposits there were foci of ossification and calcification. An infiltrate of multinucleated giant cells, histiocytes, lymphocytes, and plasma cells was seen adjacent to the amyloid deposits. Immunohistochemically, the amyloid reacted with antisera against A-lambda, amyloid protein of immunoglobulin lambda light chain origin. This indicated that the amyloid protein was of immunoglobulin origin in this rare case of localized amyloidosis of the uterine cervix.     

High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carpal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-5.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.     

Down-regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin-1 receptor antagonist

An inflammatory response was induced in C57BL/6 mice using silver nitrate. Co-administration of a recombinant mouse interleukin-1 receptor antagonist (rmIL-1ra) significantly reduced the magnitude of hepatic induction of the mRNA specifying the serum amyloid A (A-SAA) isoforms A-SAA1 and A-SAA2 for up to 24 h. In relative terms, the amount by which the induction of serum A-SAA protein levels could be countered by the antagonist was less, probably reflecting extrahepatic A-SAA synthesis that is regulated independently of IL-1. Induction of hepatic serum amyloid P component (SAP) mRNA and other acute-phase reactant (APR) mRNA were all partially blocked by rmIL-1ra for up to 24 h, indicating that induction of these APR mRNA involves both IL-1 and additional factors acting independently of IL-1. Hepatic mRNA levels of the negative APR apolipoprotein A-I (apo A-I) and serum albumin were down-regulated by silver nitrate treatment; rmIL-1ra partially restored serum albumin mRNA levels but not those of apo A-I. The IL-1ra-mediated reduction in inflammation-induced hepatic mRNA and serum protein concentrations of A-SAA and SAP (the precursors of the main protein components of amyloid deposits in secondary amyloidosis) was, however, not sufficient to prevent or delay early amyloid deposition in the silver nitrate/amyloid enhancing factor model of accelerated amyloidosis. The rmIL-1ra may be a useful component in future therapies to control inflammation and secondary amyloidosis; in addition, it will be a useful tool for the detailed analysis of the IL-1-driven aspects of inflammation per se.     

Cross talk between the extracellular matrix and the immune system in the context of endocrine pancreatic islet transplantation. A review article

This review aims to highlight the importance of the bidirectional influence of the extracellular matrix (ECM) and immune cells in the context of type 1 diabetes mellitus (T1DM) and endocrine pancreatic islet transplantation. We introduced the main classes of molecules and proteins constituting the ECM as well as cells and cytokines of the immune system with the aim to further examine their roles in T1DM and islet transplantation. Integrins expressed by immune cells and their functions are detailed. Finally, this article reviews the roles of the ECM and the immune system in islet transplantation as well as ECM-related cytokines and their influence on the ECM and immune cells.     

Heparan sulfate proteoglycan expression in the regenerating zebrafish fin

Background

Heparan sulfate proteoglycan (HSPG) expression is found in many animal tissues and regulates growth factor signaling such as of Fibroblast growth factors (Fgf), Wingless/Int (Wnt) and Hedgehog (HH). Glypicans, which are GPI (glycosylphosphatidylinositol)-anchored proteins, and transmembrane-anchored syndecans represent two major HSPG protein families whose involvement in development and disease has been demonstrated. Their participation in regenerative processes both of the central nervous system and of regenerating limbs is well documented. However, whether HSPG are expressed in regenerating zebrafish fins, is currently unknown.

Results

Here, we carried out a systematic screen of glypican and syndecan mRNA expression in regenerating zebrafish fins during the outgrowth phase. We find that 8 of the 10 zebrafish glypicans and the three known zebrafish syndecans show specific expression at 3 days post amputation. Expression is found in different domains of the regenerate, including the distal and lateral basal layers of the wound epidermis, the distal most blastema and more proximal blastema regions.

Conclusions

HSPG expression is prevalent in regenerating zebrafish fins. Further research is needed to delineate the function of glypican and syndecan action during zebrafish fin regeneration.

     

Matrix metalloproteinase family polymorphisms and the risk of aortic aneurysmal diseases: A systematic review and meta‐analysis

It has been suggested that matrix metalloproteinase (MMP) polymorphisms are associated with the pathogenesis of aortic aneurysmal diseases. In this study, we conducted a systematic review with an update meta‐analysis to investigate the relationship between MMP family polymorphisms and aortic aneurysmal diseases. We systematically reviewed 24 polymorphisms in 8 MMP genes related to the risk of abdominal aortic aneurysm (AAA), thoracic AA or thoracic aortic dissection (TAD). A total of 19 case‐control studies with 15 highly studied MMP polymorphisms were included in our meta‐analysis. Our results suggested that MMP2rs243865, MMP3rs3025058, MMP13rs2252070 polymorphisms were significantly associated with AAA risk, MMP2rs11643630, MMP8rs11225395 polymorphisms were correlated with TAD risk, and MMP9rs3918242 under the dominant model could increase AAA risk in hospital‐based subgroup. No associations with aortic aneurysmal diseases were identified for other polymorphisms assessed in our meta‐analysis. In summary, some studied MMP polymorphisms associated with the risk of aortic aneurysmal diseases are potential predictive biomarkers for the clinical application. Moreover, other MMP polymorphisms with limited studies but relevant to aortic aneurysmal formation and progression need further prospective and large investigations to confirm results.     

Arterial stiffness,the brain and cognition: A systematic review

BackgroundArterial stiffness is a known predictor of cardiovascular disease, and has also been associated with markers of cerebral small vessel disease as well as poor cognitive function and cognitive decline. The consistency of these associations and their relationship to each other are unclear.MethodWe conducted a systematic review of the evidence associating arterial stiffness with cognitive function and cognitive decline, and with makers of cerebral small vessel disease, specifically lacunar infarcts and white matter hyperintensities.ResultsThirteen cross-sectional studies examining arterial stiffness and white matter hyperintensities or lacunar infarctions reported a positive association between increased arterial stiffness and radiological findings of cerebral small vessel disease. Two longitudinal studies examining the relationship between arterial stiffness and white matter hyperintensities found increased pulse wave velocity to be an independent predictor of white matter hyperintensity volume. Fifteen cross-sectional and seven longitudinal studies examining arterial stiffness and cognition were identified. Fourteen of the fifteen cross-sectional studies associated increased arterial stiffness with lower cognitive function, and six of the seven longitudinal studies found arterial stiffness to be predictive of cognitive decline.ConclusionArterial stiffness is associated with cerebral small vessel disease and decreased cognitive function. However methodological limitations such as differing covariates between studies and an over-reliance on the MMSE to measure cognition are a concern across much of the literature.     

Inflammation and frailty in the elderly: A systematic review and meta-analysis

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n = 3232 frail, n = 11,483 pre-frail and n = 8522 robust, and 563 pre-frail + robust; 3 longitudinal studies n = 3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD = 1.00, 95%CI: 0.40–1.61) and 8568 pre-frail (SMD = 0.33, 95%CI: 0.04–0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n = 1057; SMD = 1.12, 95%CI: 0.27–2.13) and pre-frailty (n = 4467; SMD = 0.56, 95%CI: 0.00–1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n = 2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR = 1.06, 95%CI: 0.78–1.44,) and IL-6 (OR = 1.19, 95%CI: 0.87–1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed.     

Arterial stiffness and brain integrity: A review of MRI findings

BackgroundGiven the increasing incidence of vascular diseases and dementia, a better understanding of the cerebrovascular changes induced by arterial stiffness is important for early identification of white and gray matter abnormalities that might antedate the appearance of clinical cognitive symptoms. Here, we review the evidence from neuroimaging demonstrating the impact of arterial stiffness on the aging brain.MethodThis review presents findings from recent studies examining the association between arterial stiffness, cognitive function, cerebral hypoperfusion, and markers of neuronal fiber integrity using a variety of MRI techniques.ResultsOverall, changes associated with arterial stiffness indicates that the corpus callosum, the internal capsule and the corona radiata may be the most vulnerable regions to microvascular damage. In addition, the microstructural integrity of these regions appears to be associated with cognitive performance. Changes in gray matter structure have also been found to be associated with arterial stiffness and are present as early as the 5th decade. Moreover, low cerebral perfusion has been associated with arterial stiffness as well as lower cognitive performance in age-sensitive tasks such as executive function.ConclusionConsidering the established relationship between arterial stiffness, brain and cognition, this review highlights the need for future studies of brain structure and function in aging to implement measurements of arterial stiffness in parallel with quantitative imaging.     

Age-related alterations in the lacrimal gland of adult albino rat: A light and electron microscopic study

BackgroundAge related changes in the lacrimal gland are associated with alterations in the structural organization and functional response in the gland of diverse mammalian species. Dry eye syndrome is one of the most common ocular problems in the world especially in old age. It results when the lacrimal gland fails to secrete proteins and fluid in sufficient quantity or appropriate composition.Aim of the workThe present study is designed to demonstrate the influence of aging on the structure of the lacrimal gland of albino rat and to provide a morphological basis to explain the pathogenesis of the dry eye syndrome with ageing. It also aims to carry out a comparative analysis of age-dependent changes in male and female rats and to address how the lacrimal gland ages in each sex.Material and MethodsEighty albino rats were used in this study. The animals were divided into two age groups, young adult and senile. Tear secretion was measured using a modified Schirmer test. Corneal impression cytology of the anesthetized rats was done. The glands were subjected to gross morphologic examination, microscopic examination using H&E, PAS, Masson's trichrome and Giemsa stains. Electron microscopic examination was done in addition to quantitative histomorphometric estimations included acinar density, ductal count and mast cell count.ResultsLight microscopic examination of the lacimal glands of the senile rats revealed different pathological changes. These included acinar, ductal as well as stromal changes. Electron microscope examination of the lacrimal gland of the senile group showed a decrease in the electron dense secretory vesicles, mitochondrial swelling and lipofuscin-like inclusions were frequently seen in the cytoplasm of acinar cells in senile rats.ConclusionThe structural changes in the lacrimal glands of senile rats were associated with reduction in tear secretion as well as alterations in corneal epithelium. Gender difference in lacrimal gland structure was recorded.     

Corticoreticular pathway in the human brain: diffusion tensor tractography study

LINGO-1 (leucine rich repeat and Ig domain containing Nogo receptor interacting protein-1) is a central nervous system transmembrane protein which simultaneously interacts with the Nogo-66 receptor and p75^NTR or TROY on neurons to form a receptor complex responsible for myelin-mediated neurite outgrowth inhibition. On oligodendroglial cells, LINGO-1 interacts with p75^NTR to constitutively inhibit multiple aspects of oligodendrocyte differentiation. Recently, LINGO-1 was identified as an in vivo interacting partner of the amyloid precursor protein (APP) and, correspondingly, cellular LINGO-1 expression was found to augment the release of the Abeta peptide, the potential causative agent of Alzheimer's disease. In addition, the recombinant LINGO-1 ectodomain has been shown to self-interact in solution and after crystallisation. Here, we have used deletional mutagenesis to identify the regions on LINGO-1 that are involved in homo- and heterotypic interactions. We have found that the N-terminal region containing the leucine-rich repeats along with the transmembrane and cytoplasmic domains of LINGO-1 are not required for self-interaction or interaction with APP.     

Macrophage-mediated extracellular matrix remodeling controls host Staphylococcus aureus susceptibility in the skin

1. Download : Download high-res image (281KB)
2. Download : Download full-size image

     

Living with the enemy: from protein-misfolding pathologies we know,to those we want to know

Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer’s and Parkinson’s diseases, respectively.     

Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease

Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease.     

A link between sICAM-1, ACE and parietal blood flow in the aging brain

A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE (p = 0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio (p < 0.0001). Higher concentrations of sICAM-1 (>893 ng/L) and ACE (>5.22 μg/L) were exclusively associated with lower parietal blood flow (p < 0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.     

Use of near-infrared spectroscopy in the investigation of brain activation during cognitive aging: A systematic review of an emerging area of research

The cognitive neuroscience of aging is a growing and stimulating research area. The development of neuroimaging techniques in the past two decades has considerably increased our understanding of the brain mechanisms that might underlie cognitive performance and resulting changes due to normal aging. Beside traditional metabolic neuroimaging techniques, such as Positron Emission Tomography and functional Magnetic Resonance Imaging, near infrared spectroscopy (NIRS), an optical imaging technique allowing to monitor real-time cerebral blood oxygenation, has gained recent interest in this field. The aim of the present review paper, after briefly presenting the NIRS technique, is to review and to summarize the recent results of neuroimaging studies using this technique in the field of cognitive aging. The reviewed literature shows that, despite low spatial resolution and cerebral depth penetration, this technique provides consistent findings on the reduced hemodynamic activity as a function of chronological age, mainly in the prefrontal cortex. Important moderators of brain hemodynamics, such as cognitive load, subjects’ characteristics and experimental conditions, for which the NIRS technique is sensitive, are discussed. Strengths and weaknesses of functional NIRS in the field of cognitive aging are presented and finally, novel perspectives of research are proposed.     

Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients

Interleukin (IL)-1β, IL-6, epidermal growth factor (EGF), and transforming growth factor-α (TGF-α) were measured for the first time in the brain (caudate nucleus, putamen and cerebral cortex) from control and parkinsonian patients by highly sensitive sandwich enzyme immunoassays. The concentrations of IL-1β, IL-6, EGF, and TGF-α in the dopaminergic, striatal regions were significantly higher in parkinsonian patients than those in controls, whereas those in the cerebral cortex did not show significant differences between parkinsonian and control subjects. Since these cytokines and growth factors may play important roles as neurotrophic factors in the brain, the present results suggest that they may be produced as compensatory responses in the nigrostriatal dopaminergic regions in Parkinson's disease, and may be related, at least in part, to the process of neurodegeneration in Parkinson's disease.     

Menopause and aging: Changes in the immune system—A review

Background

The higher risk of women developing autoimmune diseases suggests that immune system is mediated by sex steroids.

Objective

To review the effects of aging and menopause in immune system.

Methods

A systematic review of in vitro, animal and human studies involving aging and menopause and immune system was carried out. An electronic search based on Internet search engines, MEDLINE (1966–June 2010) and the Cochrane Controlled Clinical Trials Register was done.

Results

After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable. The concept of immunosenescence reflects changes in both cellular and serological immune responses throughout the process of generating specific response to foreign antigens. This may be related with a higher incidence of infectious and chronic diseases. After menopause, there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increase in response of the immune blood cells to these cytokines, a decrease in CD4 T and B lymphocytes and a decrease in the cytotoxic activity of NK cells. Additionally, IL-6 is a key factor in bone resorption and also seems to be associated with other diseases more common after menopause such as diabetes, atherosclerosis and cardiovascular disease.

Conclusions

Most of the studies suggested that in addition to age, in postmenopausal women, changes of the immune system have been attributed to estrogen deprivation. Furthermore, recent studies point out changes in immune response related to use or cessation of hormone replacement at menopause.