bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle
Authors: Chandler Randy J , Sloan Jennifer , Fu Hong , Tsai Matthew , Stabler Sally , Allen Robert , Kaestner Klaus H , Kazazian Haig H , Venditti Charles P
Published: October 2007

Background

Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.

Methods

To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.

Results

Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.

Conclusion

The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia
Authors: Southern Louise , Williams Jonathan , Esiri Margaret M
Published: October 2007

Background

Advanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimer's type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.

Methods

Brain Sections from 25 cases of the OPTIMA (Oxford Project to Investigate Memory and Ageing) cohort, with varying degrees of cerebrovascular pathology and cognitive dysfunction (but only minimal Alzheimer type pathology) were immunostained for N
ε
-(carboxymethyl)-lysine (CML), the most abundant AGE. The level of staining in vessels and neurons in the cortex, white matter and basal ganglia was compared to neuropsychological and other clinical measures.

Results

The probability of cortical neurons staining positive for CML was higher in cases with worse cognition (p = 0.01) or a history of hypertension (p = 0.028). Additionally, vascular CML staining related to cognitive impairment (p = 0.02) and a history of diabetes (p = 0.007). Neuronal CML staining in the basal ganglia related to a history of hypertension (p = 0.002).

Conclusion

CML staining in cortical neurons and cerebral vessels is related to the severity of cognitive impairment in people with cerebrovascular disease and only minimal Alzheimer pathology. These findings support the possibility that cerebral accumulation of AGEs may contribute to dementia in people with cerebrovascular disease.
A novel emergency department based prevention intervention program for people living with HIV: evaluation of early experiences
Authors: Lyons Michael S , Raab Dana L , Lindsell Christopher J , Trott Alexander T , Fichtenbaum Carl J
Published: October 2007

Background

HIV prevention is increasingly focused on people living with HIV (PLWH) and the role of healthcare settings in prevention. Emergency Departments (EDs) frequently care for PLWH, but do not typically endorse a prevention mission. We conducted a pilot exploratory evaluation of the first reported ED program to address the prevention needs of PLWH.

Methods

This retrospective observational cohort evaluation reviewed program records to describe the first six months of participants and programmatic operation. Trained counselors provided a risk assessment and counseling intervention combined with three linkage interventions: i) linkage to health care, ii) linkage to case management, and iii) linkage to partner counseling and referral.

Results

Of 81 self-identified PLWH who were approached, 55 initially agreed to participate. Of those completing risk assessment, 17/53 (32%, 95 CI 20% to 46%) reported unprotected anal/vaginal intercourse or needle sharing in the past six months with a partner presumed to be HIV negative. Counseling was provided to 52/53 (98%). For those requesting services, 11/15 (73%) were linked to healthcare, 4/23 (17%) were coordinated with case management, and 1/4 (25%) completed partner counseling and referral.

Conclusion

Given base resources of trained counselors, it was feasible to implement a program to address the prevention needs for persons living with HIV in an urban ED. ED patients with HIV often have unmet needs which might be addressed by improved linkage with existing community resources. Healthcare and prevention barriers for PLWH may be attenuated if EDs were to incorporate CDC recommended prevention measures for healthcare providers.
Analytical and numerical quantification and comparison of the local electric field in the tissue for different electrode configurations
Authors: Čorović Selma , Pavlin Mojca , Miklavčič Damijan
Published: October 2007

Background

Electrochemotherapy and gene electrotransfer are novel promising treatments employing locally applied high electric pulses to introduce chemotherapeutic drugs into tumor cells or genes into target cells based on the cell membrane electroporation. The main focus of this paper was to calculate analytically and numerically local electric field distribution inside the treated tissue in two dimensional (2D) models for different plate and needle electrode configurations and to compare the local electric field distribution to parameter U/d, which is widely used in electrochemotherapy and gene electrotransfer studies. We demonstrate the importance of evaluating the local electric field distribution in electrochemotherapy and gene electrotransfer.

Methods

We analytically and numerically analyze electric field distribution based on 2D models for electrodes and electrode configurations which are most widely used in electrochemotherapy and gene electrotransfer. Analytical calculations were performed by solving the Laplace equation and numerical calculations by means of finite element method in two dimensions.

Results

We determine the minimal and maximal E inside the target tissue as well as the maximal E over the entire treated tissue for the given electrode configurations. By comparing the local electric field distribution calculated for different electrode configurations to the ratio U/d, we show that the parameter U/d can differ significantly from the actual calculated values of the local electric field inside the treated tissue. By calculating the needed voltage to obtain E > U/d inside the target tissue, we showed that better electric field distribution can be obtained by increasing the number and changing the arrangement of the electrodes.

Conclusion

Based on our analytical and numerical models of the local electric field distribution we show that the applied voltage, configuration of the electrodes and electrode position need to be chosen specifically for each individual case, and that numerical modeling can be used to optimize the appropriate electrode configuration and adequate voltage. Using numerical models we further calculate the needed voltage for a specific electrode configuration to achieve adequate E inside the target tissue while minimizing damages of the surrounding tissue. We present also analytical solutions, which provide a convenient, rapid, but approximate method for a pre-analysis of electric field distribution in treated tissue.
Stress induced cardiomyopathy presenting as acute coronary syndrome: Tako-Tsubo in Mercogliano, Southern Italy
Authors: Cangella F , Medolla A , De Fazio G , Iuliano C , Curcio N , Salemme L , Mottola G , Agrusta Marco
Published: October 2007

Background

Tako-tsubo syndrome (TTS) in its typical (apical) and atypical (non-apical) forms is being increasingly recognized in the West owing to early systematic coronary angiography in acute coronary syndromes (ACS).

Aim of the study

To assess the incidence, the clinical characteristics and the outcome of TTS in a single high volume cath lab in Southern Italy over the last 6 years.

Methods

Among 1674 consecutive patients (pts) referred to our coronary care units in the last 6 years (2001–2006) for ACS we selected 6 (0.5%) pts (6 women; age 57 ± 6 years) who fulfilled the following 4 criteria: 1) transient left ventricular wall motion abnormalities resulting in ballooning at contrast ventricolographic or echocardiographic evaluation; 2) normal coronary artery on coronary angiography performed 5 ± 9 hours from hospitalization; 3) new electrocardiographic ischemic-like abnormalities (either ST-segment elevation or T-wave inversion) and 4) emotional or physical trigger event.

Results

At admission all pts had presumptive diagnosis of ACS and ECG revealed ST elevation in 3 (50%) and T wave inversion with QT elongation in 3 (50%). In the acute phase cardiogenic shock occurred in 2 (33%) and heart failure in 1(16%). Presenting symptoms were chest pain in 6 (100%), dyspnoea in 2 (33%) and lipotimia in 1 (16%). At echocardiographic-ventricolographic assessment, the mechanical dysfunction (ballooning) was apical in all 6 pts ("classic" TTS). In all patients wall motion abnormalities completely reversed within 4.5 ± 1.5 days. The region of initial recovery was the anterior and lateral wall in 4 cases and the lateral wall in 2 cases. Ejection fraction was 35 ± 8% in the acute phase and increased progressively at discharge (55 ± 6%) and at 41 ± 20 months follow-up (60 ± 4%, p < 0.001 vs. baseline). All patients remained asymptomatic with minimal (aspirin, beta blockers, antihypertensive and antidislipidemic therapy) treatment.

Conclusion

Classic TTS is a frequent serendipitous diagnosis after coronary angiography showed "surprisingly" normal findings in a clinical setting mimicking an ACS. Despite its long-term good prognosis life threatening complications in the acute phase can occur.
Utilization and spending trends for antiretroviral medications in the U.S. Medicaid program from 1991 to 2005
Authors: Jing Yonghua , Klein Patricia , Kelton Christina ML , Li Xing , Guo Jeff J
Published: October 2007

Background

HIV/AIDS incidence and mortality rates have decreased in the U.S. since 1996. Accompanying the longer life spans of those diagnosed with the disease, however, is a tremendous rise in expenditures on medication. The objective of this study is to describe the trends in utilization of, spending on, and market shares of antiretroviral medications in the U.S. Medicaid Program. Antiretroviral drugs include nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and fusion inhibitors (FIs).

Methods

Utilization and payment data from 1991 to 2005 are provided by the Centers for Medicare & Medicaid Services. Descriptive summary analyses were used to assess quarterly prescription numbers and amounts of payment.

Results

The total number of prescriptions for antiretrovirals increased from 168,914 in 1991 to 2.0 million in 1998, and 3.0 million in 2005, a 16.7-fold increase over 15 years. The number of prescriptions for NRTIs reached 1.6 million in 2005. Prescriptions for PIs increased from 114 in 1995 to 932,176 in 2005, while the number of prescriptions for NNRTIs increased from 1,339 in 1996 to 401,272 in 2005. The total payment for antiretroviral drugs in the U.S. Medicaid Program increased from US$ 30.6 million in 1991 to US$ 1.6 billion in 2005, a 49.8-fold increase. In 2005, NRTIs as a class had the highest payment market share. These drugs alone accounted for US$ 787.9 million in Medicaid spending (50.8 percent of spending on antiretrovirals). Payment per prescription for each drug, with the exception of Agenerase®, increased, at least somewhat, over time. The relatively expensive drugs in 2005 included Trizivir® ($1040) and Combivir® ($640), as well as Reyataz® ($750), Lexiva® ($700), Sustiva® ($420), Viramune® ($370), and Fuzeon® ($1914).

Conclusion

The tremendous growth in antiretroviral spending is due primarily to rising utilization, secondarily to the entry of newer, more expensive antiretrovirals, and, finally, in part to rising per-prescription cost of existing medications.
Elevated adipogenesis of marrow mesenchymal stem cells during early steroid-associated osteonecrosis development
Authors: Sheng Hui , Zhang Ge , Cheung Wing , Chan Chun , Wang Yi , Lee Kwong , Wang Hong , Leung Kwok , Qin Ling
Published: October 2007

Background

Increased bone marrow lipid deposition in steroid-associated osteonecrosis (ON) implies that abnormalities in fat metabolism play an important role in ON development. The increase in lipid deposition might be explained by elevated adipogenesis of marrow mesenchymal stem cells (MSCs). However, it remains unclear whether there is a close association between elevated adipogenesis and steroid-associated ON development.

Objective

The present study was designed to test the hypothesis that there might be a close association between elevated adipogenesis and steroid-associated ON development.

Methods

ON rabbit model was induced based on our established protocol. Dynamic-MRI was employed for local intra-osseous perfusion evaluation in bilateral femora. Two weeks after induction, bone marrow was harvested for evaluating the ability of adipogenic differentiation of marrow MSCs at both cellular and mRNA level involving adipogenesis-related gene peroxisome proliferator-activated receptor gamma2 (PPARγ2). The bilateral femora were dissected for examining marrow lipid deposition by quantifying fat cell number, fat cell size, lipid deposition area and ON lesions. For investigating association among adipogenesis, lipid deposition and perfusion function with regard to ON occurrence, the rabbits were divided into ON+ (with at least one ON lesion) group and ON- (without ON lesion) group. For investigating association among adipogenesis, lipid deposition and perfusion function with regard to ON extension, the ON+ rabbits were further divided into sub-single-lesion group (SON group: with one ON lesion) and sub-multiple-lesion group (MON group: with more than one ON lesion).

Results

Local intra-osseous perfusion index was found lower in either ON+ or MON group when compared to either ON- or SON group, whereas the marrow fat cells number and area were much larger in either ON+ or MON group as compared with ON- and SON group. The adipogenic differentiation ability of MSCs and PPARγ2 expression in either ON+ or MON group were elevated significantly as compared with either ON- or SON group.

Conclusion

These findings support our hypothesis that there is a close association between elevated adipogenesis and steroid-associated osteonecrosis development.
Revealing cell cycle control by combining model-based detection of periodic expression with novel cis-regulatory descriptors
Authors: Andersson Claes R , Hvidsten Torgeir R , Isaksson Anders , Gustafsson Mats G , Komorowski Jan
Published: October 2007

Background

We address the issue of explaining the presence or absence of phase-specific transcription in budding yeast cultures under different conditions. To this end we use a model-based detector of gene expression periodicity to divide genes into classes depending on their behavior in experiments using different synchronization methods. While computational inference of gene regulatory circuits typically relies on expression similarity (clustering) in order to find classes of potentially co-regulated genes, this method instead takes advantage of known time profile signatures related to the studied process.

Results

We explain the regulatory mechanisms of the inferred periodic classes with cis-regulatory descriptors that combine upstream sequence motifs with experimentally determined binding of transcription factors. By systematic statistical analysis we show that periodic classes are best explained by combinations of descriptors rather than single descriptors, and that different combinations correspond to periodic expression in different classes. We also find evidence for additive regulation in that the combinations of cis-regulatory descriptors associated with genes periodically expressed in fewer conditions are frequently subsets of combinations associated with genes periodically expression in more conditions. Finally, we demonstrate that our approach retrieves combinations that are more specific towards known cell-cycle related regulators than the frequently used clustering approach.

Conclusion

The results illustrate how a model-based approach to expression analysis may be particularly well suited to detect biologically relevant mechanisms. Our new approach makes it possible to provide more refined hypotheses about regulatory mechanisms of the cell cycle and it can easily be adjusted to reveal regulation of other, non-periodic, cellular processes.
Extracellular survivin up-regulates adhesion molecules on the surface of leukocytes changing their reactivity pattern
Authors: Mera Simona , Magnusson Mattias , Tarkowski Andrej , Bokarewa Maria
Published: October 2007

Rheumatoid arthritis (RA) is an autoimmune disease with joints as a principal target of inflammation. We have shown recently that the extracellular expression of the antiapoptotic protein survivin is associated with a destructive course of RA. Here, we address the potential impact of extracellular survivin on peripheral blood leukocytes (PBL). The binding of survivin to the surface of human PBL as well as the expression of adhesion molecules were assessed by FACS. The expression of adhesion molecules on leukocytes as a function of circulating survivin was analyzed in blood of 24 patients with RA and compared with eight healthy individuals. We show that extracellular survivin expresses immunomodulatory properties. It binds to the surface of the majority of granulocytes and a significant part of lymphocytes and monocytes inducing the activation of α-chains of β-integrins and their ligand ICAM-1. Survivin-induced expression of α-chains of β2-integrins is regulated by p38 MAPK and PI-3K but not by the NF-κB signaling pathway. Clinical relevance of our findings is supported by the in vivo association of high circulating survivin levels with an increased expression of CD11c on monocytes and granulocytes in RA patients. The results of our study demonstrate that extracellular survivin affects the phenotype of leukocytes having a possible impact on homing of inflammatory cells during arthritis.
17β-Estradiol: a novel hormone for improving immune and cardiovascular responses following trauma-hemorrhage
Authors: Choudhry Mashkoor A , Chaudry Irshad H
Published: October 2007

17β-Estradiol (i.e., estrogen or E2) is a female sex steroid, which plays an essential role in female reproductive physiology. However, several lines of evidence indicate that in addition to its role in reproductive physiology, E2 is critical for maintaining many other organ functions in stress conditions. These include immune, cardiovascular, and neuronal functions, as well as regulation of skin, bone, and lipid metabolism. Studies have examined the role of E2 as an adjunct in post-trauma responses, and this article will review whether E2 as an adjunct to fluid resuscitation following trauma-hemorrhage plays any role in improving/restoring immune and cardiovascular functions.
HMGB1 preconditioning: therapeutic application for a danger signalõ
Authors: Klune J R , Billiar T R , Tsung A
Published: October 2007

High mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. In contrast to the proinflammatory role of HMGB1, recent evidence suggests beneficial applications of HMGB1 in injury states. One such application is the use of HMGB1 as a preconditioning stimulus. Preconditioning is a phenomenon whereby a low level of stressful stimuli confers protection against subsequent injury. Preconditioning has been demonstrated in multiple species, can be induced by various stimuli, and is applicable in different organ systems. Only with the recent introduction of the concept of endogenous molecules, such as HMGB1, as signals and mediators for inflammation during injury states has the use of endogenous molecules been investigated for this use. This review will focus on the use of endogenous molecules, specifically HMGB1, as a preconditioning stimulus and its mechanism of protection, as well as other protective applications for HMGB1.
Glomerular Targets for Autoantibodies in Lupus Nephritis—An Apoptotic Origin
Authors: ZYKOVA SVETLANA N. , SEREDKINA NATALYA E. , REKVIG OLE PETTER
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is an autoimmune syndrome where different organs may individually or simultaneously be affected. Whether SLE is one disease entity or represents a variety of intrinsically unrelated organ manifestations is unknown. Variability of clinical presentations of SLE argues against the former. This does not, however, exclude that certain organ manifestations may be pathogenetically linked. It is believed that in situ binding of anti‐dsDNA antibodies by nucleosomes is involved in organ manifestations in SLE. This review will focus on nature and origin of target structures for anti‐dsDNA and anti‐nucleosome antibodies in glomerular capillary and mesangial matrix membranes. We will particularly discuss the potential role of apoptosis and release of apoptotic chromatin in terms of their putative impact in SLE.
Vascular Elasticity of Systemic Lupus Erythematosus Patients Is Associated with Steroids and Hydroxychloroquine Treatment
Authors: TANAY AMIR , LEIBOVITZ EYAL , FRAYMAN ANGELA , ZIMLICHMAN REUVEN , GAVISH DOV
Published: October 2007

Abstract:  We studied the large and small artery elasticity (AE) and systemic
vascular resistance (SVR) of systemic lupus erythematosus (SLE) patients according to treatment profile. Forty‐one SLE patients (90% female, mean age 48.7 ± 2.4 years) were compared to 96 healthy controls. The large and small AE and the SVR were derived from radial artery waveforms (model CR‐2000, HDI Inc.). Patients were categorized into groups according to treatment: steroid (12), hydroxychloroquine (HCQ) (9), steroid+HCQ (16), and no‐steroids‐no‐HCQ (4). The steroid group had reduced large AE and increased SVR as compared to the HCQ group (8.3 mmHg·mL·10 and 18.4 dyne·sec·10−3 versus 13.7 and 14.4, respectively). Mean large AE and the SVR of the HCQ group was similar to that of the controls (11.8 mmHg·mL·10 and 14.5 dyne·sec·10−3, respectively). Mean large AE and SVR of the steroid+HCQ group were better than the steroid group (10.4 mmHg·mL·10 and 16.0 dyne·sec·10−3). Patients that received steroids had higher rates of hypertension (36%) and diabetes (11%) compared to rest of the patients (15% and 0%, respectively). Small AE, blood pressure, CRP, and SLEDAI were similar between the groups. Among SLE patients, steroid treatment was associated with the highest degree of vascular damage, and HCQ was associated with the lowest degree of vascular damage. It is possible that the steroids are responsible in part to the increased large‐vessel manifestations observed in these patients, and that HCQ might have a protective effect on the vessel wall.
Occurrence of Malignancies in Hungarian Patients with Systemic Lupus Erythematosus
Authors: TARR TÜNDE , GYORFY BALÁZS , SZEKANECZ ÉVA , BHATTOA HARJIT PAL , ZEHER MARGIT , SZEGEDI GYULA , KISS EMESE
Published: October 2007

abstract:  As a result of increasing life expectancy of lupus patients, malignant disorders have become major determinants of morbidity and mortality. The objectives of this study were to analyze cancer‐associated morbidity and mortality, the type of malignancies in Hungarian lupus patients, and to analyze association with immune‐suppressive therapy, disease duration, and age of the patients. Data from 860 systemic lupus erythematosus (SLE) patients were retrospectively analyzed in a study period between 1970 and 2004. Results were compared to data from age‐ and sex‐matched population obtained from the Health for All database, and also to literature data. A total of 37 patients presented with cancer, reflecting 4.3% cancer‐associated morbidity. Patients were 47 (20–73) years old at the onset of malignancy, which appeared 13 (1–45) years later than SLE. Cancer prevalence was the highest in the first 5–10 years of lupus. Breast cancer was the most common malignancy (n= 11) followed by gastrointestinal tumors (n= 9), cervix cancer and hematologic malignancies (n= 5 for both), bronchial cancer (n= 4), bladder, skin, and ovarian cancer (n= 1 for each). Standardized incidence ratio was the highest for non‐Hodgkin lymphoma (standardized incidence ratio [SIR] 3.5, 95%CI 0.4–12.5) and cervix cancer (SIR 1.7, 95%CI 0.6–4.1). Although 76% of patients with cancer received immune‐suppressive therapy besides corticosteroids, no direct correlation could be confirmed between therapy and malignancy. Out of the 164 patients that expired during the study period, 18 were cancer‐related. As such the cancer‐associated mortality was 11% (18/164). This peaked during the last 4 years of the study period (8/24, 33%). Lupus patients are at high risk for particular types of malignant disorders, highlighting the importance of screening measures and focused patient examination.
Reduced Paraoxonase1 Activity Is a Risk for Atherosclerosis in Patients with Systemic Lupus Erythematosus
Authors: KISS EMESE , SERES ILDIKÓ , TARR TÜNDE , KOCSIS ZSOLT , SZEGEDI GYULA , PARAGH GYÖRGY
Published: October 2007

Abstract:  Excessive lipid peroxidation is a major factor of accelerated atherosclerosis, observed in patients with systemic lupus erythematosus (SLE). We aimed at the present study to determine the paraoxonase1 (PON1) and arylesterase activities, and lipid‐profile in 37 SLE patients and 30 age‐/sex‐matched controls. Association was analyzed between PON1 activity and SLEDAI, CRP, anti‐oxLDL, and antiphospholipid antibody (aPL) levels, steroid dose, and atherothrombotic events. The age of patients was 40.8 ± 13.9 year, follow‐up time 6.7 ± 6.2 year, SLEDAI 2 (0–15). PON1 and arylesterase activities were measured spectrophotometrically using paraoxon and phenyl acetate as substrates, respectively. Phenotypic distribution of PON1 was determined by dual substrate method. We measured anti‐oxLDL and aPL levels by ELISA, the CRP by automated immunoassay. PON1 activity (121.9 ± 65.9 U/mL) was reduced significantly (P < 0.001) in SLE as compared to control (188.1 ± 78.9 U/mL), but arylesterase activity was not different. A negative correlation was found between PON1 activity and age. PON1 activity did not correlate with other measured parameters. Reduced PON1 activity associated with clinical atherothrombotic complications (P < 0.01). High activity BB phenotype was not present in SLE. Lipid parameters (TC, LDL‐C, HDL‐C, ApoAI, and ApoB) were within normal range in both groups. Results indicated reduced PON1 activity in lupus patients despite long disease duration and low inflammatory activity, and it was evidenced as a risk for atherosclerotic complications. As the arylesterase activity was normal, further examinations are required to find other mechanisms, such as anti‐PON1 antibodies, genetic polymorphisms, and difference in distribution of HDL‐subfractions or enzyme abnormalities in HDL remodeling.
Annexin A5 as a Novel Player in Prevention of Atherothrombosis in SLE and in the General Population
Authors: CEDERHOLM ANNA , FROSTEGA˚RD JOHAN
Published: October 2007

Abstract:  During recent years it has become evident that atherosclerosis is an inflammatory disease. Furthermore, immune reactions and especially autoimmunity, were demonstrated to modulate atherosclerosis in animal experiments. An interesting example of how autoimmune reactions can influence atherosclerosis and consequences thereafter, is systemic lupus erythematosus (SLE)‐associated cardiovascular disease (CVD). Antithrombotic effect exerted by Annexin A5 (ANXA5) is thought to be mediated mainly by forming a mechanical shield over phospholipids (PLs) reducing availability of PLs for coagulation reactions. However, more specific properties of ANXA5 might be of importance for its antithrombotic function. Such examples include downregulation of surface‐expressed tissue factor (TF), as well as upregulation of urokinase‐type plasminogen activator (uPA) by ANXA5. Also, interaction of ANXA5 with ligands involved in hemostasis, such as sulfatide and heparin, has been demonstrated. We have recently described a novel mechanism potentially contributing to atherothrombosis in SLE, with ANXA5 binding to endothelium decreased in SLE, an effect caused by antiphospholipid antibodies (aPL). It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in the general population prone to CVD. Antiatherothrombotic potential of ANXA5 deserves further attention and careful studies as the mechanism behind the majority of clinically significant cardiovascular ischemic disease is atherothrombosis, formed on an underlying vulnerable atherosclerotic lesion. It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in a general population prone to CVD.
Antibodies toward High‐Density Lipoprotein Components Inhibit Paraoxonase Activity in Patients with Systemic Lupus Erythematosus
Authors: BATUCA J. R. , AMES P. R. J. , ISENBERG D. A. , DELGADO ALVES J.
Published: October 2007

Abstract:  Patients with systemic lupus erythematosus (SLE) have an increased incidence of vascular disease, and oxidative stress is recognized as an important feature in this condition, despite the underlying mechanisms not being fully understood. In these patients, an interaction between lipoproteins and the immune system has been suggested, but most studies have only looked at antibodies against oxidized low‐density lipoproteins. This study was undertaken to determine the presence of antibodies directed against high‐density lipoproteins (HDL) and to identify a possible association between these antibodies and paraoxonase (PON), an antioxidant enzyme present in HDL. Plasma from 55 patients with SLE was collected and IgG aHDL and antiapolipoprotein A‐I (aApo A‐I) antibodies were assessed by enzyme‐linked immunosorbent assay. Standardization of the method was performed in a control population of 150 healthy subjects. Plasma levels above 5 standard deviations of the mean of the control population were considered positive. PON activity was assessed by quantification of p‐nitrophenol formation (μmol/mL/min). Patients with SLE had higher titers of aHDL (P < 0.0001) and aApo A‐I (P < 0.0001) antibodies, and lower PON activity (P < 0.0001) than healthy controls. There was also a direct correlation between the titers of aHDL and aApo A‐I antibodies (r= 0.61; P < 0.0001). PON activity was inversely correlated with aApo A‐I (P= 0.0129) antibody levels. Anti‐HDL and aApo A‐I antibodies from patients with high titers were isolated and subsequently incubated with human HDL. These antibodies reduced PON activity up to a maximum of 70.2% and 78.4%, respectively. This study showed the presence of aHDL and aApo A‐I antibodies in patients with SLE. These antibodies were associated with reduced PON activity in plasma, and the in vitro inhibition assay confirmed a direct inhibition of the enzyme activity.
Induction of Endothelial Cell Apoptosis by IgG Antibodies from SLE Patients with Nephropathy
Authors: Van PAASSEN PIETER , DUIJVESTIJN A. , DEBRUS‐PALMANS L. , DAMOISEAUX J. , VROOMEN M. , COHEN TERVAERT J. W.
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is a prototype of an autoimmune disease with vasculopathy as demonstrated by the presence of vascular immune–complex deposition, inflammation, and thrombosis. A pivotal role in the initiation of vasculopathy is ascribed to vascular endothelium. In this respect, anti–endothelial cell antibodies (AECA), which are highly associated with SLE, are putative candidates for the initiation of SLE vasculopathy. In addition to the potency of AECA to induce a proinflammatory endothelial cell phenotype, AECA have also been described to trigger endothelial cell apoptosis. However, in SLE data are not uniform on the potentials of AECA to induce endothelial cell apoptosis in vitro. We have addressed this question in a cohort of SLE patients with nephropathy. AECA levels, and the apoptosis‐inducing potentials of serum IgG were measured at the time of renal complication and biopsy. Also serum antibody reactivity with various SLE‐related autoantigens including HSP60 was determined in patients. The results show that the SLE patient group has increased AECA levels as well as increased levels of induction of endothelial cell apoptosis by serum IgG. AECA and apoptosis values largely varied among the patients. Our data show that antibodies other than anti‐HSP60 are also involved in apoptosis induction. The results are discussed in the context of recent findings on the role of AECA in endothelial cell apoptosis and renal vasculopathy in SLE.
Effect of Prolactin on Lymphocyte Activation from Systemic Lupus Erythematosus Patients
Authors: CHAVEZ‐RUEDA KARINA , LEGORRETA‐HAQUET VICTORIA MA. , CERVERA‐CASTILLO HERNANDO , SÁNCHEZ LOURDES , JARA LUIS JAVIER , ZENTENO EDGAR , CHAVEZ‐SANCHEZ LUIS , BLANCO‐FAVELA FRANCISCO
Published: October 2007

Abstract:  The aim was to explore the role of prolactin (PRL) in the lymphocyte activation process in systemic lupus erythematosus (SLE) patients in an in vitro model. Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and healthy individuals. The mRNA for PRL and its receptor obtained by standard techniques, with an appropriate primer, were subjected to polymerase chain reaction (PCR) and visualized. The PBMCs were cultured with (a) medium alone as a negative control, (b) unspecific mitogen as a positive control, (c) PRL alone, (d) mitogen plus PRL, (e) mitogen plus antibody anti‐PRL, and (f) mitogen plus a nonrelated antibody. Then CD69 and CD154 were determined by flow cytometry analysis. Twelve inactive and 15 active SLE patients were studied. Twenty‐five percent of the active patients displayed hyperprolactinemia. Under basal conditions CD69 expression was associated with disease activity. The PBMCs activated in vitro were capable of producing and secreting PRL, measured by mRNA and Nb2 assay. In a similar way, the mRNA for the PRL receptor was visualized. Cells from SLE patients cultivated with PRL alone did not display increased CD69 and CD154 expression. The addition of PRL to the unspecific stimulated culture does not have an additive effect. In contrast, the addition of antibodies against PRL in order to block the autocrine PRL resulted in a striking reduction of CD69 and CD154 expression.
Pediatric Systemic Lupus Erythematosus with C1q Deficiency
Authors: KALLEL‐SELLAMI MARYAM , BAILI‐KLILA LILIA , ZERZERI YOUSR , LAADHAR LILIA , BLOUIN JACQUES , ABDELMOULA MOHAMED SLIM , ZITOUNI MONDHER , FREMEAUX‐BACCHI VÉRONIQUE , DRIDI MARIE FRANCE BEN , MAKNI SONDES
Published: October 2007

Abstract:  Hereditary deficiency of each component of the classical pathway is associated with increased susceptibility to lupus erythematosus (LE). Both the severity of the disease and the strength of this association are greatest for homozygous C1q deficiency, which is extremely rare. In fact, more than 90% of all individuals with deficiency of this component have LE. We report a 3‐year‐old female infant with history of discoid LE treated with topical corticosteroids for 1 year. She was referred to pediatric department for an exacerbation and extension of cutaneous lesions toward front‐arm, hands, legs and feet, a glomerulonephritis, and thrombopenia. Immunologic tests revealed a positive speckled antinuclear antibody at 1/1600 with positive anti‐Sm, anti‐SSA, and anti‐RNP antibodies. Test for anti‐DNA was negative. These findings were compatible with a transition to a systemic form of lupus. Systemic corticosteroid treatment was started; however, the patient died by a severe digestive hemorrhage. Hemolytic complement activity (CH50) was undetectable in serum despite normal levels of C3 and C4 suggesting a deficiency of an early component of the complement cascade. Measurement of hemolytic assay for C1 functional activity was less than 1%. C1q deficiency was confirmed by a double immunodiffusion and ELISA using sheep polyclonal anti‐C1q antibodies. C1q deficiency is a rare genetic disorder. Thirty‐eight of the 41 patients reported to date have developed systemic LE. C1q deficiency may cause systemic LE via a critical role of this component in the physiological clearance of apoptotic cells.
Hereditary Complement Deficiency and Lupus
Authors: KALLEL‐SELLAMI MARYAM , BAILI‐KLILA LILIA , ZERZERI YOUSR , LAADHAR LILIA , BLOUIN JACQUES , ABDELMALEK RIM , FREMEAUX‐BACCHI VÉRONIQUE , ZITOUNI MONDHER , MAKNI SONDES
Published: October 2007

Abstract:  The aim of the study was to assess the clinical and immunological profile of lupus erythematosus (LE) patients with inherited complement deficiency (ICD). A laboratory‐based study was conducted in which all LE patients with hypocomplementemia were included. ICD was assessed by hemolytic and antigenic assays. Type I C2 deficiency was assessed by polymerase chain reaction (PCR). ICD was diagnosed in four cases. In three systemic LE patients, ICD were: homozygous C2 deficiency in the first case, heterozygous C2 deficiency in the second, and homozygous C1q deficiency in the third case. In a discoid LE patient, a combined homozygous C2 and C6 deficiency was diagnosed. Almost all of our patients presented the classical clinical and immunological features of LE associated with ICD. Severe lupus with renal involvement and recurrent infections was present in half of the patients suggesting that these patients are prone to a serious management.
Autoantibodies against Protective Molecules—C1q, C‐Reactive Protein, Serum Amyloid P, Mannose‐Binding Lectin, and Apolipoprotein A1
Authors: SHOENFELD YEHUDA , KRAVITZ MARTINE SZYPER , WITTE TORSTEN , DORIA ANDREA , TSUTSUMI AKITO , TATSUYA ABE , DAYER JEAN‐MICHEL , ROUX‐LOMBARD PASCALE , FONTAO LIONEL , KALLENBERG CEES G.M. , BIJL MARC , MATTHIAS TORSTEN , FRASER ABIGAIL , ZANDMAN‐GODDARD GISELE , BLANK MIRI , GILBURD BORIS , MERONI PIER LUIGI
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of several autoantibodies. Among the multiple factors involved in SLE development, apoptotic defects and impaired clearance of cellular debris have gained considerable interest, as they contribute to autoantigen overload.
Several molecules of the innate immunity, also participate in the removal of damaged and apoptotic cells. Among them are C1q, C‐reactive protein (CRP), serum amyloid P protein (SAP), mannose‐binding lectin (MBL), and apolipoprotein A1 (APO A1).
To evaluate the prevalence of autoantibodies against CRP, SAP, MBL, APO A1, and C1q among SLE patients, and their relationship with disease activity, a total of 150 SLE patients were screened for the presence of elevated antibody titers against C1q, CRP, SAP, MBL, and APO A1, utilizing the enzyme‐linked immunosorbent assay (ELISA) method. Disease activity was assessed using the ECLAM or SLEDAI scores.
The study population comprised two groups of patients: 100 patients with quiescent disease (median ECLAM score 2) comprised the first group, and 50 patients with active disease (median SLEDAI score 16) comprised group 2. Elevated titers of anti‐CRP antibodies were significantly elevated only in group 1 (10% versus 4% of controls). Antibodies against SAP were evaluated only among patients in group 1, and were found at a significant high prevalence (20%). Elevated titers of anti‐MBL antibodies were significantly elevated only in group 1 (15% versus 3.6%); and antibodies directed against APO A1 were significantly elevated in 21% of group 1, and 50% of group 2 patients. Elevated titers of anti‐C1q were evaluated only in group 2, and were found at a significant prevalence of 66%. Significant correlation with disease activity was found only for anti‐APO A1 antibodies, and only in group 1. Several patients harbored more than one of the autoantibodies tested.
In patients with SLE, autoantibodies directed against protective molecules, that is, acute‐phase proteins involved in the disposal of cellular and nuclear debris, can be detected. These autoantibodies may play a pathogenic role in the development or perpetuation of autoimmunity in SLE.
Scleroderma Renal Crisis, Still a Life‐Threatening Complication
Authors: TEIXEIRA LUIS , MAHR ALFRED , BEREZNÉ ALICE , NOËL LAURE‐HÉLÈNE , GUILLEVIN LOÏC , MOUTHON LUC
Published: October 2007

Abstract:  Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). SRC occurs during the first 4 years of disease evolution in more than 75% of the cases, almost exclusively in patients with diffuse SSc. Other risk factors, including preceding corticosteroid therapy, have been associated with an increased occurrence of SRC. Prior to the late 1970s, SRC was a major cause of death in SSc patients. However, the prognosis has dramatically improved with the introduction of angiotensin‐converting enzyme inhibitors. Thus, prompt diagnosis and early initiation of angiotensin‐converting enzyme inhibitors therapy will improve the outcome. Nevertheless, additional antihypertensive treatments are often needed. Quite a large proportion of patients require dialysis, although this therapy may be stopped in approximately one‐third of patients. Patients remaining on dialysis after 2 years can be proposed for a renal transplantation.
Flow‐Mediated Vasodilation and Carotid Intima‐Media Thickness in Systemic Sclerosis
Authors: BARTOLI FRANCESCA , BLAGOJEVIC JELENA , BACCI MARZIA , FIORI GINEVRA , TEMPESTINI ALESSIO , CONFORTI MARIA LETIZIA , GUIDUCCI SERENA , MINIATI IRENE , DI CHICCO MAURO , DEL ROSSO ANGELA , PERFETTO FEDERICO , CASTELLANI SERGIO , PIGNONE ALBERTO , CERINIC MARCO MATUCCI
Published: October 2007

Abstract:  Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow‐mediated vasodilation (FMD) and carotid intima‐media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high‐resolution B‐mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41%± 4.56% versus 7.66%± 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 ± 0.29 mm versus 0.77 ± 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.
Exercise Doppler Echocardiography Identifies Preclinic Asymptomatic Pulmonary Hypertension in Systemic Sclerosis
Authors: PIGNONE ALBERTO , MORI FABIO , PIERI FRANCESCO , ODDO ANDREA , GALEOTA GIANNA , FIORI GINEVRA , DEL ROSSO ANGELA , PERFETTO FEDERICO , BECUCCI AURELIANO , LIVI RICCARDO , TEMPESTINI ALESSIO , BENVENUTI CHIARA , GRAMIGNA LEONARDO , FEDI ROBERTO , GENERINI SERGIO , MINELLI MARTINA , CINELLI MARINA , GUIDUCCI SERENA , ARCANGELI CHIARA , LETIZIA CONFORTI MARIA , BERNARDO PASQUALE , CERINIC MARCO MATUCCI
Published: October 2007

Abstract:  In systemic sclerosis (SSc), the involvement of the interstitium or vascular system of the lung may lead to pulmonary arterial hypertension (PAH). PAH is often asymptomatic or oligosymptomatic in early SSc and, when it becomes symptomatic, pulmonary vascular system is already damaged. Exercise echocardiography (ex‐echo), measuring pulmonary artery pressure (PAP) during exercise and allowing to differentiate physiologic from altered PAP responses, may identify subclinical PAH. Our aims were (a) to evaluate by ex‐echo the change of PAP in patients with SSc without lung involvement; and (b) to correlate PAP during exercise (ex‐PAP) values to clinical and biohumoral parameters of PAH. Twenty‐seven patients with limited SSc (lSSc) without interstitial lung involvement were studied. Patients underwent rest and exercise two‐dimensional and Doppler echocardiography by supine cycloergometer. Systolic PAP was calculated using the maximum systolic velocity of the tricuspid regurgitant jet at rest and during exercise values of systolic PAP exceeding 40 mmHg at ex‐echo were considered as abnormal, and biohumoral markers potentially related to PAH were assessed. Eighteen of 27 SSc patients presented an ex‐PAP >40 mmHg, while in 9 of 27 patients ex‐PAP values remained <40 mmHg (48.8 ± 4.5 mmHg versus 36.2 ± 3.1 mmHg; P < 0.001). Other echocardiographic and ergometric parameters, clinical tests, and biohumoral markers were not different in the two groups. Ex‐PAP significantly correlated with D‐dimer (P= 0.0125; r2= 0.2029). Ex‐echo identifies a cluster of SSc patients with subclinical PAH that may develop PAH. This group should be followed up and may be considered for specific therapies to prevent disease evolution.