bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin and Insulin‐Like Growth Factor Resistance in Alcoholic Neurodegeneration
Authors: De La Monte Suzanne M. , Tong Ming , Cohen Ariel C. , Sheedy Donna , Harper Clive , Wands Jack R.
Published: July 2008

Background:  Chronic alcohol feeding of adult Long Evans rats causes major central nervous system abnormalities that link neuronal loss and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin‐like growth factor (IGF) signaling and increased oxidative stress.

Objectives:  We now characterize the integrity of insulin and IGF signaling mechanisms and assess molecular indices of neurodegeneration in the cerebellar vermis and anterior cingulate gyrus of human alcoholics.

Results:  Alcoholic cerebella had increased neuronal loss, gliosis, lipid peroxidation, and DNA damage relative to control. Quantitative RT‐PCR studies demonstrated reduced expression of insulin, insulin receptor and IGF‐II receptor in the anterior cingulate, and reduced expression of insulin, IGF‐I, and their corresponding receptors in the vermis. Competitive equilibrium binding assays revealed significantly reduced specific binding to the insulin, IGF‐I, and IGF‐II receptors in both the anterior cingulate and vermis of alcoholic brains. These effects of chronic alcohol abuse were associated with significantly reduced expression of choline acetyltransferase, which is needed for acetylcholine biosynthesis.

Conclusions:  The results suggest that alcoholic neurodegeneration in humans is associated with insulin and IGF resistance with attendant impairment of neuronal survival mechanisms and acetylcholine homeostasis.
Trazodone for Sleep Disturbance After Alcohol Detoxification: A Double‐Blind, Placebo‐Controlled Trial
Authors: Friedmann Peter D. , Rose Jennifer S. , Swift Robert , Stout Robert L. , Millman Richard P. , Stein Michael D.
Published: July 2008

Background:  Trazodone is a commonly prescribed off‐label for sleep disturbance in alcohol‐dependent patients, but its safety and efficacy for this indication is unknown.

Methods:  We conducted a randomized, double‐blind, placebo‐control trial of low‐dose trazodone (50 to 150 mg at bedtime) for 12 weeks among 173 alcohol detoxification patients who reported current sleep disturbance on a validated measure of sleep quality or during prior periods of abstinence. Primary outcomes were the proportion of days abstinent and drinks per drinking day over 6‐months; sleep quality was also assessed.

Results:  Urn randomization balanced baseline features among the 88 subjects who received trazodone and 85 who received placebo. The trazodone group experienced less improvement in the proportion of days abstinent during administration of study medication (mean change between baseline and 3 months: −0.12; 95% CI: −0.15 to −0.09), and an increase in the number of drinks per drinking day on cessation of the study medication (mean change between baseline and 6 months, 4.6; 95% CI: 2.1 to 7.1). Trazodone was associated with improved sleep quality during its administration (mean change on the Pittsburgh Sleep Quality Index between baseline and 3 months: −3.02; 95% CI: −3.38 to −2.67), but after it was stopped sleep quality equalized with placebo.

Conclusions:  Trazodone, despite a short‐term benefit on sleep quality, might impede improvements in alcohol consumption in the postdetoxification period and lead to increased drinking when stopped. Until further studies have established benefits and safety, routine initiation of trazodone for sleep disturbance cannot be recommended with confidence during the period after detoxification from alcoholism.
Implementation of buffy coat platelet component production: comparison to platelet‐rich plasma platelet production
Authors: Levin Elena , Culibrk Brankica , Gyöngyössy‐Issa Maria I. C. , Weiss Sandra , Scammell Kenneth , LeFresne Wanda , Jenkins Craig , Devine Dana V.
Published: July 2008

BACKGROUND: Buffy coat (BC) production of platelets (PLTs) has been successfully used in Europe for more than two decades. Currently, Canadian Blood Services is implementing the BC method. This article summarizes results of the validation testing performed to qualify the process of PLT production from whole blood and compares the quality of PLTs produced in routine production by either the PLT‐rich plasma method (PRP‐PCs) or the BC method (BC‐PCs).

STUDY DESIGN AND METHODS: Validation data included variables used for routine quality control (QC; pH, PLT count, volume, sterility, residual white blood cell count) as well as nonroutine testing of PLTs for PLT activation, metabolic changes during storage, and PLT responsiveness to hypotonic shock and the extent of shape change induced by adenosine 5′‐diphosphate. BC‐PCs were tested on Days 1 and 6. QC of production runs included the same routine tests performed on Day 6.

RESULTS: PLTs produced by the BC method during validation and pilot implementation met all Canadian Standards Association standards with respect to yield, volume, pH, and leukoreduction. Additional validation testing indicated a moderate level of PLT storage lesion development. In comparison to PRP‐PCs, in vitro variables of BC‐PCs, either pH in this study, or other markers compared to the literature were better, suggesting that BC‐PCs have less evidence of production‐related damage and improved PLT quality during storage.

CONCLUSIONS: PLT concentrates produced from whole blood by the BC method after an overnight hold have laboratory variables suggestive of a higher quality than those concentrates produced by the PRP method.
Incorporating Marginal Covariate Information in a Nonparametric Regression Model for a Sample ofR×CTables
Authors: Staniswalis Joan G.
Published: July 2008

SummaryNonparametric regression models are proposed in the framework of ecological inference for exploratory modeling of disease prevalence rates adjusted for variables, such as age, ethnicity/race, and socio‐economic status. Ecological inference is needed when a response variable and covariate are not available at the subject level because only summary statistics are available for the reporting unit, for example, in the form ofR×Ctables. In this article, only the marginal counts are assumed available in the sample ofR×Ccontingency tables for modeling the joint distribution of counts. A general form for the ecological regression model is proposed, whereby certain covariates are included as a varying coefficient regression model, whereas others are included as a functional linear model. The nonparametric regression curves are modeled as splines fit by penalized weighted least squares. A data‐driven selection of the smoothing parameter is proposed using the pointwise maximum squared bias computed from averaging kernels (explained byO'Sullivan, 1986,Statistical Science 1, 502–517). Analytic expressions for bias and variance are provided that could be used to study the rates of convergence of the estimators. Instead, this article focuses on demonstrating the utility of the estimators in a study of disparity in health outcomes by ethnicity/race.
Tea Polyphenols as Nutraceuticals
Authors: Sajilata M.G. , Bajaj Poonam R. , Singhal R.S.
Published: July 2008

ABSTRACT: The use of dietary ingredients is gaining much significance as a practical approach to the reduction of the risk of a number of diseases. Epidemiological evidence has linked the habitual consumption of tea with reduced risk of cardiovascular disorders and cancer. Polyphenols appear to play an important role in the potential health benefits associated with tea. With growing interests on the positive health attributes of tea, the present review covers relevant findings on many therapeutic properties of tea. Types of tea, the polyphenols, and their nutraceutical implications, as well as adverse effects and course of action together with bioavailability form the essence of coverage in this review.
Exercise and dialysis
Authors: JOHANSEN Kirsten L.
Published: July 2008

Fortunately, the literature on exercise among patients on hemodialysis has grown too broad to be included in a single review. The focus of this review is on interventional studies, with an emphasis on those studies that included a control group. The good news is that there is ample evidence that exercise can improve fitness (VO2 peak), physical functioning, and some cardiovascular risk factors in the dialysis population. However, there have been few comparative studies, and there is no consensus regarding the most beneficial regimen or the one most acceptable to large numbers of patients. A new set of recommendations from the American College of Sports Medicine and the American Heart Association for older individuals and individuals with chronic diseases is relevant for our patient population and can be used to guide exercise prescription until disease‐specific data are available to fill the gap.
Dialysis Disequilibrium Syndrome presenting as a focal neurological deficit
Authors: ATTUR Ravindra Prabhu , KANDAVAR Ramprasad , KADAVIGERE Rajagopal , BAIG Waqas Wahid
Published: July 2008

We report a patient suffering from chronic kidney disease who presented to us with severe pulmonary edema. His clinical, laboratory, and sonological parameters were suggestive of end‐stage renal disease. Hemodialysis was initiated, and after 48 hours (3 sessions of hemodialysis) he became drowsy and a neurological examination revealed left upper limb monoplegia with left facial palsy. Urgent computerized tomography scan of the brain revealed diffuse hypodensity in the cerebral white matter bilaterally, and brain magnetic resonance imaging showed diffuse hyperintensity in the cerebral white matter bilaterally, right internal capsule and external capsule on fluid attenuated inversion recovery and T2 sequences (hypointense on T1 sequence). He made a gradual but complete neurological recovery and was discharged 2 weeks later with normal neurological status. A repeat brain magnetic resonance imaging on follow‐up 6 weeks later revealed complete resolution of the white matter abnormalities.
Hepatitis B and C in dialysis units in Iran: Changing the epidemiology
Authors: ALAVIAN Seyed Moayed , BAGHERI‐LANKARANI Kamran , MAHDAVI‐MAZDEH Mitra , NOUROZI Shahram
Published: July 2008

Hepatitis B (HBV) and C (HCV) viruses are the most important infections transmitted by the parenteral route in patients receiving maintenance dialysis. The prevalence varies markedly from country to country. The aim of this study is to review the efficacy of the strategies to reduce the incidence of these infections and the trend of results in Iran. As a routine, all hemodialysis patients in Iran have biannual blood samples for assessment of serum HBSAg, HBS Abs, and HCV Abs. The data are collected in the Ministry of Health. For statistical analysis, prevalence, and incidence were calculated. There is an increasing prevalence/incidence of end‐stage renal disease (ESRD) in Iran, from 238/49.9 pmp in 2000 to 357/63.8 pmp in 2006. The prevalence of positive HBSAg and HCV Abs decreased from 3.8% and 14.4% in 1999 to 2.6% and 4.5% in 2006, respectively. Regarding the genotype distribution in Iran, no one was found with genotype 2. On the subject of decreasing HBV infection, our next strategy should be mandatory vaccination in dialysis centers and in the pre‐ESRD period. Concerning HCV infection prevention, 2 approaches may be recommended: the first is decrease of duration of the hemodialysis period by possible early transplantation of suitable patients. The next is a strictly enforced isolation policy for HCV‐positive patients, which may play a role in limiting HCV transmission in HD units, and universal precaution in dialysis units should be under constant close surveillance.
The renaissance of home hemodialysis: Where we are, why we got here, what is happening in the United States and elsewhere
Authors: BLAGG Christopher R.
Published: July 2008

Home hemodialysis has been around since 1964, but its use has declined over the years in most countries, this despite its advantages, particularly improved patient survival and quality of life and significant cost savings. Experience has shown that home hemodialysis can be performed successfully by many more patients than at present. Recently, with the demonstration of even better results with more frequent hemodialysis that is obviously best performed at home and with the development of new, more patient‐friendly machines, the use of home hemodialysis is beginning to increase again.
The advantages and disadvantages of home hemodialysis
Authors: MASTERSON Rosemary
Published: July 2008

In Australia, 12% of the hemodialysis population dialyze at home. Until recently, the majority of these patients dialyzed for similar hours to those in satellite dialysis. However, in the past 5 years there has been a new departure such that in many centers the concept of home hemodialysis is now synonymous with extended hours dialysis. Registry data supports the concept that increased frequency and duration of dialysis may result in improved patient survival and a reduction in cardiovascular risk profile. It is hoped, therefore, that the long recognized survival benefit observed in home hemodialysis patients may be further augmented by the swing to extended hours dialysis in this patient population. In addition to the physiological benefits of extended hours home dialysis, there are clear quality of life, social, and economic advantages associated with dialyzing at home. There are however a number of perceived disadvantages to home hemodialysis including the application and time commitment required for training, the potential for relationship strain or “burnout,” and reluctance to “hospitalize” the home. Overall, however, in this new era of extended hours dialysis, the advantages both physiological and lifestyle of home hemodialysis far outweigh the disadvantages.
Complications of home hemodialysis
Authors: HAWLEY Carmel M. , JEFFRIES Janine , NEARHOS Jane , VAN EPS Carolyn
Published: July 2008

Home hemodialysis is regaining popularity as a treatment choice for end‐stage kidney disease. This trend is fueled by numerous reports of better survival and improved quality of life with primarily home‐based more frequent and/or longer hours of hemodialysis. Home hemodialysis in the contemporary era is generally very safe. Advances in machine technology have reduced technical complications and longer and more frequent treatments have reduced the risk of hypotension and cardiovascular instability. A successful home hemodialysis program must focus on patient safety to prevent serious hemorrhage from needle dislodgement and enable an aseptic cannulation technique. In addition, vigilance in relation to machine maintenance procedures and attention to water quality are key skills that patients must acquire for optimal outcomes. The possibility of increased septic events with longer and more frequent hemodialysis regimens performed in the home, the long‐term psychosocial effects of home hemodialysis, and the best methods for maintaining compliance of patients in the long term are of particular contemporary interest.
A molecular study of pathways involved in the inhibition of cell proliferation in neuroblastoma B65 cells by the GSK‐3 inhibitors lithium and SB‐415286
Authors: Pizarro Javier G. , Folch Jaume , Esparza José Luis , Jordan J. , Pallàs Mercè , Camins Antoni
Published: July 2008

Pharmacological GSK‐3 inhibitors are potential drugs for the treatment of neurodegenerative diseases, cancer and diabetes. We examined the antiproliferative effects of two GSK‐3 inhibitors, lithium and SB‐415286, on B65 neuroblastoma cell line. Treatment of B65 cells with either drug administered separately caused a decrease in cell proliferation that was associated with G2/M cell cycle arrest. Cell‐cycle proteins such as cyclins D, E, A, cdk4 and cdk2 were up‐regulated. Since lithium and SB‐415286‐induced G2/M arrest we studied changes in the expression of proteins involved in this phase, specifically cyclin B, cdc2 and the phosphorylated form of this protein (tyr15‐cdc2). Both drugs increased the expression of tyr15‐cdc2, thus inhibiting mitosis. On the other hand, SB‐415286 increased the expression of SIRT2, involved in the regulation of proliferation. Moreover, cell‐cycle arrest mediated by SB‐415286 was accompanied by apoptosis that was not prevented by 100 μM of zVAD‐fmk (benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethylketone), a pan‐caspase inhibitor. Likewise, GSK‐3 inhibitors did not affect the mitochondrial release of apoptosis inducing factor (AIF). We conclude that inhibitors of GSK‐3 induced cell‐cycle arrest, mediated by the phosphorylation of cdc2 and, in the case of SB‐415286, SIRT2 expression, which induced apoptosis in a caspase‐independent manner.
Combined R‐α–lipoic acid and acetyl‐L‐carnitine exerts efficient preventative effects in a cellular model of Parkinson’s disease
Authors: Zhang Hongyu , Jia Haiqun , Liu Jianghai , Ao Ni , Yan Bing , Shen Weili , Wang Xuemin , Li Xin , Luo Cheng , Liu Jiankang
Published: July 2008

Mitochondrial dysfunction and oxidative damage are highly involved in the pathogenesis of Parkinson’s disease (PD). Some mitochondrial antioxidants/nutrients that can improve mitochondrial function and/or attenuate oxidative damage have been implicated in PD therapy. However, few studies have evaluated the preventative effects of a combination of mitochondrial antioxidants/nutrients against PD, and even fewer have sought to optimize the doses of the combined agents. The present study examined the preventative effects of two mitochondrial antioxidant/nutrients, R‐α–lipoic acid (LA) and acetyl‐L‐carnitine (ALC), in a chronic rotenone‐induced cellular model of PD. We demonstrated that 4‐week pretreatment with LA and/or ALC effectively protected SK‐N‐MC human neuroblastoma cells against rotenone‐induced mitochondrial dysfunction, oxidative damage and accumulation of α‐synuclein and ubiquitin. Most notably, we found that when combined, LA and ALC worked at 100–1000‐fold lower concentrations than they did individually. We also found that pretreatment with combined LA and ALC increased mitochondrial biogenesis and decreased production of reactive oxygen species through the up‐regulation of the peroxisome proliferator‐activated receptor‐γ coactivator 1α as a possible underlying mechanism. This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.
Lysophosphatidylcholine up‐regulates human endothelial nitric oxide synthase gene transactivity by c‐Jun N‐terminal kinase signalling pathway
Authors: Xing Feiyue , Liu Jing , Mo Yongyan , Liu Zhifeng , Qin Qinghe , Wang Jingzhen , Fan Zhenhua , Long Yutian , Liu Na , Zhao Kesen , Jiang Yong
Published: July 2008

Human endothelial nitric oxide synthase (eNOS) plays a pivotal role in maintaining blood pressure homeostasis and vascular integrity. It has recently been reported that mitogen‐activated protein kinases (MAPKs) are intimately implicated in expression of eNOS. However detailed mechanism mediated by them remains to be clarified. In this study, eNOS gene transactivity in human umbilical vein endothelial cells was up‐regulated by stimulation of lysophosphatidylcholine (LPC). The stimulation of LPC highly activated both extracellular signal‐regulated kinase 1/2 (ERK1/2) and c‐Jun N‐terminal kinase (JNK), with differences in the dynamic processes of activation between them. Unexpectedly, p38 MAPK could not be activated by the stimulation of LPC. The activation of JNK signalling pathway by overexpression of JNK or its upstream kinase active mutant up‐regulated the transactivity of eNOS significantly, but the activation of p38 signalling pathway down‐regulated it largely. The inhibition of either ERK1/2 or JNK signalling pathway by kinase‐selective inhibitors could markedly block the induction of the transactivity by LPC. It was observed by electrophoretic mobility shift assay that LPC stimulated both SP1 and AP1 DNA binding activity to go up. Additionally using decoy oligonucleotides proved that SP1 was necessary for maintaining the basal or stimulated transactivity, whereas AP1 contributed mainly to the increase of the stimulated transactivity. These findings indicate that the up‐regulation of the eNOS gene transactivity by LPC involves the enhancement of SP1 transcription factor by the activation of JNK and ERK1/2 signalling pathways and AP1 transcription factor by the activation of JNK signalling pathway.
Acitretin induces apoptosis through CD95 signalling pathway in human cutaneous squamous cell carcinoma cell line SCL‐1
Authors: Lin Xiu‐Ying , He Chun‐Di , Xiao Ting , Jin Xin , Chen Jiang , Wang Ya‐Kun , Liu Mei , Wang Kai‐Bo , Jiang Yi , Wei Hua‐Chen , Chen Hong‐Duo
Published: July 2008

Skin cancers are by far the most common human malignancies. Retinoids have shown promising preventive and therapeutic effects against a variety of human malignancies. The aim of this study was to investigate the apoptosis‐inducing effect of acitretin on human skin squamous cell carcinoma (SCC) SCL‐1 cells. We found that acitretin preferentially inhibited the growth of SCL‐1 cells in a dose‐ and time‐dependent manner, but not of non‐malignant keratinocyte HaCaT cells. This inhibition appeared to be due to induction of apoptosis as revealed by enzyme‐linked immunosorbent assay. AnnexinV/propidium iodide assay and morphological observation confirmed the pro‐apoptotic effect of acitretin on SCL‐1 cells. We further demonstrated that apoptosis was induced within 1–2 days and involved activation of caspases‐8, ‐9, ‐3 and poly (ADP‐ribose) polymerase (PARP). Caspase‐8 inhibitor effectively suppressed acitretin‐induced apoptosis whereas caspase‐9 inhibitor did not. Acitretin increased the levels of CD95 (Fas), CD95‐ligand and Fas‐associated death domain. Neutralizing ZB4 anti‐Fas antibody significantly inhibited the apoptosis in SCL‐1 cells induced by acitretin. These results suggest that acitretin is able to induce apoptosis in skin cancer cells possibly via death receptor CD95 apoptosis pathway without affecting the viability of normal keratinocyte.
Hypoxia response and microRNAs: no longer two separate worlds
Authors: Ivan Mircea , Harris Adrian L. , Martelli Fabio , Kulshreshtha Ritu
Published: July 2008

Introduction: miRs, small molecules with wide impact

A role for hypoxia in the regulation of miR expression

Role of HIF in the regulation of miR‐210

The ongoing search for miR‐210 targets

Perspectives: towards clinical applications of miR‐210 manipulation

MicroRNAs (miRs) are short non‐coding transcripts involved in a wide variety of cellular processes. Several recent studies have established a link between hypoxia, a well‐documented component of the tumour microenvironment, and specific miRs. One member of this class, miR‐210, was identified as hypoxia inducible in all the cell types tested, and is overexpressed in most cancer types. Its hypoxic induction is dependent on a functional hypoxia‐inducible factor (HIF), thus extending the transcriptional repertoire of the latter beyond ‘classic’ genes. From a clinical standpoint, miR‐210 overexpression has been associated with adverse prognosis in breast tumours and been detected in serum of lymphoma patients and could serve as a tool to define hypoxic malignancies. We discuss the role of miR‐210 and its emerging targets, as well as possible future directions for clinical applications in oncology and ischaemic disorders.
microRNAs: tiny regulators of synapse function in development and disease
Authors: Bicker Silvia , Schratt Gerhard
Published: July 2008

Introduction

miRNA biogenesis and mode of action

Regulation of miRNA expression

miRNAs as regulators in the developing nervous system

Synapse development and plasticity in vertebrates

miRNAs as regulators in post‐mitotic neurons

miRNA transport to the dendrite

miRNAs in diseases of the nervous system

Diagnostic and therapeutic persDiagnostic and therapeutic perspectives

Conclusion

The development and function of neuronal circuits within the brain are orchestrated by sophisticated gene regulatory mechanisms. Recently, microRNAs have emerged as a novel class of small RNAs that fine‐tune protein synthesis. microRNAs are abundantly expressed in the vertebrate nervous system, where they contribute to the specification of neuronal cell identity. Moreover, microRNAs also play an important role in mature neurons. This review summarizes the current knowledge about the function of microRNAs in the nervous system with special emphasis on synapse formation and plasticity. The second part of this work will discuss the potential involvement of microRNAs in neurologic diseases. The study of brain microRNAs promises to expand our understanding of the mechanisms underlying higher cognitive functions and neurologic diseases.
Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling
Authors: Gorman Adrienne M.
Published: July 2008

Neuronal cell death plays a role in many chronic neurodegenerative diseases with the loss of particular subsets of neurons. The loss of the neurons occurs during a period of many years, which can make the mode(s) of cell death and the initiating factors difficult to determine.In vitroandin vivomodels have proved invaluable in this regard, yielding insight into cell death pathways. This review describes the main mechanisms of neuronal cell death, particularly apoptosis, necrosis, excitotoxicity and autophagic cell death, and their role in neurodegenerative diseases such as ischaemia, Alzheimer's, Parkinson's and Huntington's diseases. Crosstalk between these death mechanisms is also discussed. The link between cell death and protein mishandling, including misfolded proteins, impairment of protein degradation, protein aggregation is described and finally, some pro‐survival strategies are discussed.
Differential bone marrow stem cell mobilization by G‐CSF injection or arterial ligation in baboons
Authors: Shi Qiang , Hodara Vida , Butler Stephanie D. , Thomas III Charles A. , Hubbard Gene B. , VandeBerg John L. , Wang Xing L.
Published: July 2008

Bone marrow stem cells (BMSCs) are mobilized in response to ischemic attacks, e.g. myocardial infarction, to repair the damage, or by cytokines, e.g. granulocyte colony‐stimulating factor (G‐CSF), which is used to harvest BMSCs for autologous transplantation. In order to optimize BMSC mobilization strategy for cardiovascular repair, we investigated whether BMSCs mobilized by G‐CSF share the same subtype profile as that by ischemia in a non‐human primate model. We subjected five baboons to subcutaneous G‐CSF injection and five baboons to femoral artery ligation. Blood BMSCs were measured by surface antigens; functional differentiation to endothelial cells (ECs) was assessed by colony‐forming capacity, expression of mature EC antigens and tube‐like formation. The number of circulating CD34+/CD45RA− cells spiked on day 3 post‐stimulation in both groups. While the number of CD34+ cells released by artery ligation was 2‐fold lower by comparison with the number released by G‐CSF administration, significantly more CD133+/KDR+/CXCR4+/CD31+ cells were detected in the baboons that underwent artery ligation. After culture in endothelial growth medium, mononuclear cells from baboons with artery ligation formed more EC colonies and more capillary‐like tubes (P < 0.05), expressed higher vWF and phagocytosed more Dil‐Ac‐LDL (P < 0.05). While G‐CSF and artery ligation can mobilize BMSCs capable of differentiating into ECs, BMSCs mobilized by the artery ligation simulating in vivo ischemic attacks have higher potential for vascular differentiation. Our findings demonstrate that different mobilization forces release different sets of BMSCs that may have different capacity for cardiovascular differentiation.
Interleukin‐6 and leptin as markers of energy metabolicchanges in advanced ovarian cancer patients
Authors: Macciò Antonio , Madeddu Clelia , Massa Daniela , Astara Giorgio , Farci Daniele , Melis Gian Benedetto , Mantovani Giovanni
Published: July 2008

The progression of the neoplastic disease is characterized by specific alterations of energy metabolism and by symptoms like fatigue, anorexia, nausea, anaemia, immunodepression and poor performance status (PS). The main cause of these symptoms and metabolic abnormalities is the chronic action of proinflammatory cytokines released both by tumour and immune cells. The present study aimed to assess the relationship between markers of inflammation (C‐Reactive Protein, Fibrinogen, proinflammatory cytokines) and energy metabolic status (BMI, leptin, oxidative stress) according to clinical parameters in 104 ovarian cancer patients at different stage and, moreover, to evaluate prospectively the changes of these parameters in accordance to tumour response in a subgroup of 70 advanced stage ovarian cancer patients. Advanced stage and poor PS were associated to high‐grade inflammation and impaired energy metabolism. Among inflammatory mediators, interleukin (IL)‐6 had a central role as predictive factor of leptin, reactive oxygen species and glutathione peroxidase. In turn, leptin considered the key marker of the nutritional status and energy metabolism, was independently determined from stage and IL‐6, not only from BMI. Moreover, the evaluation of the changes of these parameters during the course of the neoplastic disease in the subgroup of advanced ovarian cancer patients clearly unveils the central role of IL‐6 and leptin as early markers of the metabolic alterations and symptoms associated to disease progression in advanced stage ovarian cancer. Their assessment should be included in monitoring disease outcome, especially when cancer is no longer curable and quality of life becomes the primary endpoint.
Parenchymal and vascular Aβ‐deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease
Authors: Thal Dietmar Rudolf , Griffin W. Sue T. , Braak Heiko
Published: July 2008

Introduction

The deposition of Aβ

Neurotoxicity of Aβ

Contribution of CAA to the degeneration of neurons

Clinical impact of Aβ and its therapeutic possibilities

Conclusions

The deposition of the amyloid β‐protein (Aβ) is one of the pathological hallmarks of Alzheimer's disease (AD). Aβ‐deposits show the morphology of senile plaques and cerebral amyloid angiopathy (CAA). Senile plaques and vascular Aβ‐deposits occur first in neocorti‐cal areas. Then, they expand hierarchically into further brain regions. The distribution of Aβ plaques throughout the entire brain, thereby correlates with the clinical status of the patients. Imaging techniques for Aβ make use of the hierarchical distribution of Aβ to distinguish AD patients from non‐AD patients. However, pathology seen in AD patients represents a late stage of a pathological process starting 10–30 years earlier in cognitively normal individuals. In addition to the fibrillar amyloid of senile plaques, oligomeric and monomeric Aβ is found in the brain. Recent studies revealed that oligomeric Aβ is presumably the most toxic Aβ‐aggregate, which interacts with glutamatergic synapses. In doing so, dendrites are presumed to be the primary target for Aβ‐toxicity. In addition, vascular Aβ‐deposits can lead to capillary occlusion and blood flow disturbances presumably contributing to the alteration of neurons in addition to the direct neurotoxic effects of Aβ. All these findings point to an important role of Aβ and its aggregates in the neurodegenerative process of AD. Since there is already significant neuron loss in AD patients, treatment strategies aimed at reducing the amyloid load will presumably not cure the symptoms of dementia but they may stop disease progression. Therefore, it seems to be necessary to protect the brain from Aβ‐toxicity already in stages of the disease with minor neuron loss before the onset of cognitive symptoms.
Control of leucocyte differentiation from embryonic stem cells upon vasculogenesis and confrontation with tumour tissue
Authors: Hannig Madeleine , Figulla Hans‐Reiner , Sauer Heinrich , Wartenberg Maria
Published: July 2008

Embryonic stem (ES) cells spontaneously differentiate capillary‐like structures as well as leucocytes such as monocytes/macrophages, neutrophils, natural killer (NK) cells and cytototoxic T lymphocytes. The interplay between vasculogenesis and leucocyte differentiation as well as the population of tumour tissues with ES cell‐derived leucocytes and endothelial cells is, however, not sufficiently specified. In the present study, gene expression of the cell surface markers CD68 and CD14 (expressed on monocytes and macrophages), Mac‐1 (CD11b) (expressed on granulocytes, monocytes and NK cells) and CD16 (expressed on neutrophils) was investigated in murine CGR8 ES cells in relation to the endothelial cell markers CD31 and vascular endothelial (VE)‐cadherin. Expression of leucocyte markers increased from day 7–8 of cell culture on. Furthermore, addition of macrophage colony‐stimulating factor to the cell culture medium resulted in a threefold increase in the number of CD68+ monocytes/macrophages. Treatment of embryoid bodies with lipopolysaccharide (LPS) up‐regulated CD14 thus suggesting functionality of the CD14 LPS receptor. Differentiation of vascular structures positive for CD31 and VE‐cadherin preceded leucocyte differentiation by 2 days (i.e. from day 5–6 on) suggesting that vasculogenesis may be a determinant of leucocyte differentiation. Consequently the Flk‐1 antagonist SU5416 which inhibits vasculogenesis of ES cells significantly blunted leucocyte differentiation. Confrontation culture of embryoid bodies with multicellular breast tumour spheroids initiated significant increase of leucocyte cell numbers and invasion of leucocytes into the tumour tissue. In summary our data demonstrate that during ES cell differentiation vasculogenesis precedes leucocyte differentiation, and point towards the direction that leucocyte cell invasion into tumour tissue may initiate the pro‐inflammatory microenvironment necessary for tumour vascularization.
Paxgenes in embryogenesis and oncogenesis
Authors: Wang Qiuyu , Fang Wen‐Hui , Krupinski Jerzy , Kumar Shant , Slevin Mark , Kumar Patricia
Published: July 2008

Introduction

PAX proteins and embryogenesis

PAX genesand cancer

PAX3 genein embryogenesis and cancer

PAX2 in tumourigenesis

PAX5 in tumourigenesis

PAX8 in tumourigenesis

PAX and the treatment of cancer

Summary

The paired box genes are a family of nine developmental control genes, which in human beings(PAX)and mice (Pax) encode nuclear transcription factors. The temporal and spatial expressions of these highly conserved genes are tightly regulated during foetal development including organogenesis. PAY/Paxgenes are switched off during the terminal differentiation of most structures. Specific mutations within a number ofPAX/Paxgenes lead to developmental abnormalities in both human beings and mice. Mutation inPAX3causes Waardenburg syndrome, and craniofacial‐deafness‐hand syndrome. The Splotch phenotype in mouse exhibits defects in neural crest derivatives such as, pigment cells, sympathetic ganglia and cardiac neural crest‐derived structures. ThePAXfamily also plays key roles in several human malignancies. In particular,PAX3is involved in rhabdomyosarcoma and tumours of neural crest origin, including melanoma and neuroblastoma. This review critically evaluates the roles ofPAX/Paxin oncogenesis. It especially highlights recent advances in knowledge of how their genetic alterations directly interfere in the transcriptional networks that regulate cell differentiation, proliferation, migration and survival and may contribute to oncogenesis.
Distribution of Malassezia species in patients with psoriasis and healthy individuals in Tehran, Iran
Authors: Zomorodian Kamiar , Mirhendi Hosssien , Tarazooie Bita , Zeraati Hojjat , Hallaji Zahra , Balighi Kamran
Published: July 2008

Background:  Psoriasis is a non‐contagious disorder that affects the skin as red scaly patches. Although the role of Malassezia species in the pathogenesis of psoriasis is still not fully understood, it is thought that these lipophilic yeasts might be a trigger factor in the exacerbation of psoriatic lesions.

Methods:  Using culture in a specific medium followed by the polymerase chain reaction‐restriction fragment length polymorphism method, the presence of Malassezia species in the skin of 110 patients with psoriasis was compared with that in a control group of 123 healthy patients.

Results:  The recovery rate of Malassezia species from the skin of patients with psoriasis was significantly lower than that in the controls. In both psoriatic and healthy skin, Malassezia globosa was isolated as the predominant species. In psoriatic patients, the rate of colonization of Malassezia furfur and Malassezia restricta was almost twice that in the controls, whereas M. globosa was isolated more frequently from healthy individuals than from patients.

Conclusions:  Considering the higher lipase activity secretion by M. furfur in comparison with other Malassezia species, the enzymatic release of arachidonic acid and its metabolites by M. furfur may exacerbate the inflammatory and hyperproliferative changes observed in psoriasis.
Large CD30‐positive cells in benign, atypical lymphoid infiltrates of the skin
Authors: Werner Betina , Massone Cesare , Kerl Helmut , Cerroni Lorenzo
Published: July 2008

Background:  Cutaneous infectious and inflammatory diseases may contain a significant number of CD30‐positive cells, thus mimicking lymphomatoid papulosis (LyP) or anaplastic large cell lymphoma.

Methods:  We reviewed our cases of non‐neoplastic skin conditions with large, CD30‐positive cells and searched the literature for similar cases.

Results:  A total of 28 cases were included in the study: Milker’s nodule (n = 8), Herpes simplex virus infection (n = 7), lymphomatoid drug reaction (n = 3), molluscum contagiosum (n = 3), nodular scabies (n = 2), leishmaniasis (n = 1), syphilis (n = 1), pernio (n = 1), ruptured infundibular cyst (n = 1) and pseudolymphoma in a scar (n = 1). CD30‐positive cells were often arranged in clusters and revealed both Golgi and membrane positivity, similar to what was observed in LyP and CD30+ anaplastic large T‐cell lymphoma.

Conclusions:  Analysis of our data and of those published in the literature shows that viruses and drugs are the most common cause for occurrence of large CD30‐positive cells in cutaneous pseudolymphomatous infiltrates. Arrangement of these large, CD30‐positive cells in small clusters is not unique to cutaneous CD30‐positive lymphomas, and in many cases a precise diagnosis can be made only upon accurate clinicopathological correlation or using ancillary methods such as polymerase chain reaction analysis for viral DNA.
Homoharringtonine affects the JAK2‐STAT5 signal pathway through alteration of protein tyrosine kinase phosphorylation in acute myeloid leukemia cells
Authors: Tong Hongyan , Ren Yanling , Zhang Fengjuan , Jin Jie
Published: July 2008

Objectives:  Homoharringtonine (HHT) was efficient in therapying patients with acute myeloid leukemia (AML) in China, but little is known about the mechanism of its action. As the abnormal activation of JAK2 associated pathway is important to AML, we try to explore the effect of HHT on JAK2‐STAT pathway in AML cells, thus supplying theoretical basis for wider use of HHT.

Methods:  The cell viability was tested by MTT. Apoptosis was tested by flow cytometry. RT‐PCR was used to measure the expression of JAK2, STAT5 and the effect gene Bcl‐xL. The signal proteins such as p‐JAK2, p‐STAT5, p‐AKT, p‐ERK activated by abnormal activated JAK2 were tested by Western blotting.

Results:  HHT obviously inhibited the viability of primary AML cells and AML cell lines HEL, K562 and HL‐60 cells, AnnexinV‐PI double staining confirmed early apoptosis in a dose‐dependent manner. In immunoblotting analysis, when AML cells were affected by HHT for 6 h (much ahead of the time when apoptosis could be induced). The expressions of p‐JAK2, p‐STAT5, and p‐AKT were down‐regulated, while the total JAK2, STAT5 and AKT protein levels were stable. There were no changes in p‐ERK and BcL‐xL proteins. When it prolonged to 24 h, Bcl‐xL decreased obviously. Similar results were obtained by using JAK2 specific inhibitor AG490.

Conclusions:  HHT possibly acts as a broad‐spectrum PTK inhibitor and inhibits the phosphorylation of the signal proteins caused by oncogenic proteins such as JAK2V617F, BCR/ABL, thus blocking the survival and proliferative signal pathway of malignant cells.
Granulomatous rosacea and Crohn’s disease in a patient homozygous for the Crohn‐associated NOD2/CARD15 polymorphism R702W
Authors: Van Steensel M. A. M. , Badeloe S. , Winnepenninckx V. , Vreeburg M. , Steijlen P. M. , Van Geel M.
Published: July 2008

Abstract:  NOD2/CARD15 belongs to the N‐terminal caspase recruitment domain family of proteins involved in regulating NF‐kB activation in response to inflammatory stimuli transduced through Toll‐like receptors. Mutations and polymorphisms in the NOD2/CARD15 gene reduce antibacterial responses and are associated with granulomatous inflammatory conditions such as Blau syndrome and early‐onset sarcoidosis. The polymorphism R702W (arginine to tryptophan) is strongly associated with susceptibility to Crohn’s disease in Caucasian populations. Skin abnormalities (other than cutaneous manifestations of Crohn’s disease) have not been previously associated with R702W. We report on a female patient homozygous for R702W who developed granulomatous rosacea at the age of 12 years old. From the occurrence in the context of Crohn associated with R702W, we speculate that granulomatous rosacea may be an entity distinct from other forms of rosacea, which are associated with increased production of antibacterial proteins such as cathelicidin.
Factors triggering floodplain fish emigration: importance of fish density and food availability
Authors: Louca V. , Lindsay S. W. , Lucas M. C.
Published: July 2008

Abstract –  Emigration is a widespread phenomenon among fish species in seasonal habitats, but little is known about the factors which trigger individuals to emigrate to new habitats. In controlled experiments using Tilapia guineensis, a species widely occurring in the seasonal floodplains of West Africa, density of fish played a significant role in triggering fish migration, whereas a lack of food available caused an increase in exploratory behaviour but with no impact on successful emigration. The impact of fish density and subsequently interactions between individuals on emigration suggests that this may be an important causal factor of emigration in fish species exhibiting social interactions.
BAFF blockade for systemic lupus erythematosus: will the promise be fulfilled?
Authors: Ramanujam Meera , Davidson Anne
Published: July 2008

Summary: Systemic lupus erythematosus (SLE) is a complex immune disorder in which loss of tolerance to nucleic acid antigens and other cross‐reactive antigens is associated with the development of pathogenic autoantibodies that damage target organs including the skin, joints, brain, and kidney. B cells are essential to lupus pathogenesis, not only because they produce pathogenic autoantibodies but also because they have multiple effector functions in the immune system. There has been much recent interest therefore in targeting of B cells for the treatment of SLE and other autoimmune diseases. BAFF (B‐cell activation factor belonging to the tumor necrosis factor family) is a crucial homeostatic cytokine for B cells that is upregulated during inflammation and links adaptive with innate immunity. Excessive levels of BAFF may alter selection of autoreactive B cells and contribute to perpetuation of SLE by a variety of mechanisms. BAFF antagonists have been effective in the prevention and treatment of SLE in several different murine models. Three classes of BAFF antagonists have been developed for clinical use, and initial clinical trials have begun. However, immune modulation in SLE is complicated by differences in the immune defects between patients and at different disease stages. Further work will be needed both in animal models and humans to determine the most appropriate clinical applications for BAFF blockade.
Th17 cells in human disease
Authors: Tesmer Laura A. , Lundy Steven K. , Sarkar Sujata , Fox David A.
Published: July 2008

Summary:Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T‐helper 17 (Th17) cells, a unique CD4+T‐cell subset characterized by production of interleukin‐17 (IL‐17). IL‐17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune‐mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection. Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans. As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms. Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection.
The role of IL‐21 in regulating B‐cell function in health and disease
Authors: Ettinger Rachel , Kuchen Stefan , Lipsky Peter E.
Published: July 2008

Summary: Interleukin‐21 (IL‐21) belongs to a family of cytokines that includes IL‐2, IL‐4, IL‐7, IL‐9, and IL‐15, all of which bind to private (or shared) receptors as well as the common cytokine receptor γ‐chain as a component. Most cytokines in this family are critically important for both the maintenance and function of T cells and B cells. The receptor for IL‐21 is widely distributed on lymphohematopoietic cells, and IL‐21 plays many biologic roles, including maintenance and function of CD8+ memory T cells and natural killer cells, as well as promoting the generation of Th17 cells in the mouse. One principal non‐redundant role of IL‐21 is the promotion of B‐cell activation, differentiation or death during humoral immune responses. Furthermore, increased IL‐21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathologic features of autoimmune disease. In contrast, IL‐21 may function as a co‐adjuvant to enhance antibody responses and thereby facilitate host defense to malignances and infectious diseases. The critical role of IL‐21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterized by either overproduction of pathogenic autoantibodies or under production of protective antibodies.
Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease
Authors: Browning Jeffrey L.
Published: July 2008

Summary: The lymphotoxin (LT) system is part of the tumor necrosis factor family and is required for lymph node development. It has provided a wonderful tool for the dissection of processes critical not only for lymphoid organ development but also the maintenance of the adult immune architecture and the formation of ectopic organized lymphoid tissues in chronically inflamed sites. A soluble lymphotoxin‐β receptor‐immunoglobulin (LTβR‐Ig) fusion protein can block this pathway and is currently being tested in the treatment of autoimmune disease. This review focuses on the immunological consequences of combined LT and LIGHT inhibition with LTβR‐Ig administration as distinct from the developmental biology.