bluuebunny/crossref_metadata_2025 huggingface dataset:
Age Influences the Expression of GAP-43 in the Rat Hippocampus following Seizure
Authors: Schmoll H. , Ramboiu S. , Platt D. , Herndon J.G. , Kessler Ch. , Popa-Wagner A.
Published: June 2005

Background: Normal aging is associated with impairments in learning and memory and motor function. One viable hypothesis is that these changes reflect an age-related decrease in brain plasticity. Objective: The aim of the present study was to identify age-related changes in the time course of expression of the axonal growth associated protein 43 (GAP-43) in a rat model of brain plasticity. Methods: We examined by Northern blotting, in situ hybridization, and immunohistochemistry the effects of age on the time course of the expression GAP-43 following pentylenetetrazole-induced seizure in the hippocampus of 3-, 18-, and 28-month-old rats. Results: In this model of brain plasticity, young rats displayed a decrease in GAP-43 mRNA levels in CA1, CA3, and polymorphic regions, lasting from 10 h to 3 days after seizure. This was followed by recovery, with peak expression between days 10 and 20. The baseline levels of GAP-43 mRNA decreased with age, especially in the CA3 region. Despite lower baseline levels, middle-aged rats showed the same pattern of upregulation of GAP-43 mRNA expression as the young animals. Old rats showed only minimal upregulation, however, and this occurred only in the polymorphic layer. The level GAP-43 protein itself was higher in old control rats than in the other two control groups, a condition that was transiently reversed by seizure activity. Conclusions: Middle-aged rats are still capable of a sustained, though diminished, response to seizure activity, while old rats lose this ability. Disruption of the temporal and anatomical coordination of expression of GAP-43 may contribute to the general decline in brain plasticity with age.
On How Insulin May Influence Ageing and Become Atherogenic throughout the Insulin-Like Growth Factor-1 Receptor Pathway: In vitro Studies with Human Vascular Smooth Muscle Cells
Authors: Ruiz-Torres Antonio , Lozano Rosario , Melón José , Carraro Raffaele
Published: June 2005

Background: It is known that growth factors play a role in ageing and atherogenesis, and insulin develops mitogenic activity in vitro. Objectives: This study focusses on the pathway by which insulin induces proliferation and mobility in vascular smooth muscle cells (SMCs) compared with that of insulin-like growth factor-1 (IGF-1), because they are two basic phenomena for atherogenesis that could also help to understand the role of insulin in the ageing process. Methods: Bromodeoxyuridine DNA incorporation, chemotaxis and the appearance of membrane ruffles were measured in cultured SMCs after incubation with insulin or IGF-1 in the presence of insulin or IGF-1 receptor-blocking antibodies. Results: Insulin-induced SMC proliferation through the IGF-1 receptors; indeed, the blockade of insulin receptors does not inhibit the mitogenic influence of insulin. On the contrary, insulin-induced cell migration was inhibited by blocking the insulin receptor but not the IGF-1 receptor. Nevertheless, in less differentiated SMCs from non-confluent cultures, the migratory response was significantly higher and insulin lost its receptor specificity. It was stimulated through receptors both for insulin and IGF-1. In these cases the IGF-1 action was similar. Insulin-induced F-actin rearrangements took place through both types of receptors, but IGF-1 was a little more specific through its own receptors. Conclusion: The pathway activated by insulin to induce SMC proliferation is not different from that of IGF-1, whereas the unspecific mechanism inducing mobility in growing cells seems to be related to a higher sensitivity response. Cells with the highest mitotic activity have the highest mobility in which stimulation of receptor specificity is lost for either insulin or IGF-1. Extrapolating these results to in vivo, insulin could become relevant for inducing stabilization and also side effects in ageing.
Clinical Features of Elderly Patients Submitted to Coronary Artery Bypass Graft
Authors: Santos Franklin Santana , Velasco Irineu Tadeu
Published: June 2005

Objective: To describe the clinical features as well as morbidity and mortality of elderly patients submitted to coronary artery bypass graft (CABG). Design: Randomized, single-center, observational study. Methods: A prospective study was carried out in a tertiary referral teaching hospital (Heart Institute-Brazil). A total of 220 inpatients submitted to elective CABG were evaluated and data collected from the pre-, intra- and postoperative periods. Instruments: The patients were assessed according to the Geriatric Depression Scale. A diagnosis of delirium was determined according to DSM-IV criteria. Results: Of these 220 patients 64.5% were males and 35.5% females. The mean age was 71 years. The most important preoperative findings were a higher incidence of comorbidities such as hypertension (73%), diabetes mellitus (35%), dyslipidemia (27%), and previous myocardial infarction (41%).The majority of patients were found to have three or more vessels obstructed at angiography (74%). The major intraoperative findings were that a high number of the patients received more than 3 grafts (74%). A large proportion (72%) of patients needed a blood transfusion and the overall incidence of clinical complications was 33%. The overall postoperative mortality rate for this observational study was 5%. A large number of patients presented complications (56%) such as hypotension (22%), atrial fibrillation (22%), and delirium (34%). Conclusions: Although elderly patients have a somewhat increased, however acceptable, operative mortality rate, we believe that this patient group can benefit from CABG.
Biochemical Changes in Response to Intensive Resistance Exercise Training in the Elderly
Authors: Bautmans Ivan , Njemini Rose , Vasseur Sabine , Chabert Hans , Moens Lisa , Demanet Christian , Mets Tony
Published: June 2005

Background: It is assumed that low-grade inflammation, characterized by increased circulating IL-6 and TNF-α, is related to the development of sarcopenia. Physical exercise, especially high intensity resistance training, has been shown to be effective in restoring the strength deficit in the elderly. Intensive exercise is accompanied by significant release of IL-6 and TNF-α into the blood circulation, but does not result in muscle wasting. Exercise-induced changes in heat-shock protein (Hsp), responsible for cellular protection during stressful situations, might interfere with the acute phase reaction and muscle adaptation. Objective: To investigate if intensive strength training in elderly persons induces changes in Hsp70 expression, and if these changes are related to changes in the acute phase reaction or muscle adaptation. Methods: 31 elderly persons (aged 68.4 ± 5.4 years) performed 6 weeks’ intensive strength training. At baseline and after 6 weeks, muscle strength, functional performance (physical activity profile, 6-min walk, 30- second chair stand, grip strength, chair sit & reach and back scratch), linear isokinetic leg extension, circulating IL-6, TNF-α, IL-10 and TGF-β, and Hsp70 in monocytes (M) and lymphocytes (L) immediately after sampling (IAS), after incubation at 37 and 42°C were determined. In 12 participants, cytokines were determined in untrained and trained conditions before and after a single training session. Results: After 6 weeks’ training, muscle strength and functional performance improved significantly, together with decreased Hsp70 IAS and Hsp70 37°C and increased Hsp70 42°C (all p < 0.05). Strength gains correlated positively with baseline Hsp70 37°C and training-induced changes of Hsp70 42°C in M and L. In an untrained condition, training induced an increase of IL-6 (p < 0.05) and a tendency of IL-10 to decrease (p = 0.06). In a trained condition the decrease of IL-10 disappeared. Baseline physical activity and 6-min walk distance correlated negatively with circulating IL-6 (p < 0.05); except for a negative correlation between TGF-β and Hsp70 37°C L (p < 0.05), no significant relationships were found between cytokines and Hsp70. After the training program, Hsp70 37°C was negatively related to circulating TNF-α, IL-10 and TGF-β. Conclusion: Strength training in the elderly induces changes in Hsp70 expression, associated to strength gains and circulating cytokines.
Effects of Aging on Visual Attentional Focusing
Authors: Pesce Caterina , Guidetti Laura , Baldari Carlo , Tessitore Antonio , Capranica Laura
Published: June 2005

Background: Visual attentional performance is affected by aging, but there are methodological barriers to the understanding of this phenomenon that are due, above all, to the concomitant deterioration of sensory or central factors such as visual acuity and information processing speed. Objective: The aim of the present study was to verify the effects of aging on visual attentional focusing by analyzing the space- and object-based components as well as the exogenous and endogenous dimensions of the attentional allocation. Methods: Focusing of visual attention was investigated in 14 youngsters, 14 younger adults and 14 older adults (age ranges 12–15, 24–38 and 60–75 years, respectively). In two discrimination reaction time (RT) experiments, attention was cued by means of spatial cues of different size followed by compound stimuli at a shorter (150 ms) and a longer (500 ms) stimulus-onset asynchrony (SOA). The compound stimuli contained a predefined target letter at a local or global level. Results: Older adults showed generally slower RTs and higher rates of delayed responses than younger individuals and reduced discrimination speed of local objects at 150-ms SOA, particularly when attention was invalidly cued to focus at a larger spatial scale. Conclusions: This pattern of results suggests that aging causes a dysfunction of the space-based and the object-based components of the attentional ‘zooming in’. Such information may be of practical relevance for developing attentional training programs for older adults.
What Can We Learn from Animal Models of Alopecia areata?
Authors: McElwee Kevin J. , Yu Mei , Park Sung-Wook , Ross Elizabeth K. , Finner Andreas , Shapiro Jerry
Published: June 2005

Alopecia areata (AA) is a hair loss disease marked by a focal inflammatory infiltrate of dystrophic anagen stage hair follicles by CD4+ and CD8+ lymphocytes. Although AA is thought to be an autoimmune disorder, definitive proof is lacking. Moreover, characterization of the primary pathogenic mechanisms by which hair loss is induced in AA is limited. In this context, animal models may provide a vital contribution to understanding AA. Recent research using animal models of AA has focused on providing evidence in support of a lymphocyte-mediated pathogenic mechanism consistent with AA as an autoimmune disease. In the future, research with both humans and animal models shall likely concentrate on identifying the primary antigenic epitopes involved in AA and the genetics of AA susceptibility. With a comprehensive understanding of the key elements in AA pathogenesis, new avenues for therapeutic research and intervention will be defined.
Trichoscan: What Is New?
Authors: Hoffmann Rolf
Published: June 2005

The treatment of androgenetic alopecia (AGA) is usually long lasting, and the effects of treatment attempts are difficult to measure. Consequently, there was a need for a sensitive tool to monitor hair loss and treatment response. Therefore, we developed the Trichoscan as a method which combines epiluminescence microscopy with automatic digital image analysis for the measurement of human hair. The Trichoscan is able to analyze all important parameters of hair growth (density, diameter, growth rate, vellus and terminal hair density) with an intraclass correlation of approximately 91% within the same Trichoscan operator and an intraclass correlation of approximately 97% for different Trichoscan operators. The application of the technique was demonstrated by comparison of the hair parameters in 9 men with frontal balding which were treated for 6 months with 5% minoxidil. Even in this small cohort of patients, we noticed after 3 months of treatment compared to baseline a significant increase in hair density (+21.3 hairs/cm2; p = 0.047) and cumulative hair thickness (+0.61 mm; p = 0.008) and after 6 months a significant increase in hair density (+34 hairs/cm2; p = 0.011) and cumulative hair thickness (+0.88 mm; p = 0.010). The study shows that the Trichoscan has many advantages. It can be used for clinical studies to compare placebo versus treatment or to compare the relative potencies of different hair-growth-promoting substances. It can be used for studying AGA or other forms of diffuse hair loss, and it can be adopted to study the effect of drugs or laser treatment on hypertrichosis or hirsutism. The drawbacks, however, are that the Trichoscan still needs a hair dye for contrast enhancement and the measurement area must be clipped before analysis. This mini-review summarizes recent attempts to optimize the technique and shows new options such as the calculation of follicular units or the ‘anagen hair count’.
Is Baldness Bad for the Heart?
Authors: Gutersohn Thomas , Scheidegger E. Paul
Published: June 2005

Various skin conditions are considered to be characteristic markers for elevated coronary disease risk. Over and above these established signs there are reports on other skin signs with possible associations with elevated coronary disease risk, i.e. the horizontal earlobe crease, high breast hair density, precocious graying and male pattern hair loss. A review of the literature is presented in this article, and the relevance of these symptoms is discussed as they are related to the possible myocardial disease risk. The available data on this topic are impressive, but on close assessment most of the studies are marred by methodical errors.
The Alzheimer Variant of Lewy Body Disease: A Pathologically Confirmed Case-Control Study
Authors: Perneczky R. , Mösch D. , Neumann M. , Kretzschmar H. , Müller U. , Busch R. , Förstl H. , Kurz A.
Published: June 2005

The objective of the study was to identify clinical features that distinguish patients with dementia with Lewy bodies (DLB), who were classified as Alzheimer’s disease (AD) patients, from patients with AD. We examined a group of 27 patients from our memory clinic, originally diagnosed with AD, of whom 6 were postmortem found to have DLB. For the present study, we compared cognitive, noncognitive and neurological symptoms between the two groups. We found that there were no differences on ratings of dementia and scales for activities of daily living. Patients with DLB performed better on the MMSE and the memory subtest of the CAMCOG, but there was no difference in any other cognitive domain. Furthermore, genetic risk factors, including family history of dementia or allele frequency of the apolipoprotein ε4, did not discriminate between the two groups, and there were no differences on CCT scans. Taken together, our findings suggest that Lewy body pathology may be present in patients who do not show the typical clinical features which distinguish DLB from AD.
No Genetic Association between ATP Binding Cassette Proteins and Japanese Sporadic Alzheimer’s Disease
Authors: Ohkubo Taku , Shibata Nobuto , Ohnuma Tohru , Higashi Shinji , Usui Chie , Ueki Akira , Nagao Masatsugu , Arai Heii
Published: June 2005

The identification of the ε4 variant of apolipoprotein E as a genetic risk factor for late-onset Alzheimer’s disease (AD) suggests that cholesterol may play a direct role in the pathogenesis of the disease. Recent studies have suggested that the ATP-binding cassette (ABC) protein G5 (ABCG5) may be involved in the regulation of intestinal cholesterol absorption. Furthermore, genetic variation of this locus may affect blood cholesterol concentrations. We therefore studied whether the ABCG5 C1950G (Gln640Glu) polymorphism affects the risk of AD. In addition, there was no difference in mean baseline cholesterol concentrations between individuals with the C/C genotype and carriers of the G allele. Recent studies have shown that genetic regions including the ABCA12 gene might also be associated with the risk of AD. The ABCA12 gene, located <1 Mb from the peak marker on chromosome 2q34, is also a member of the ABC transporter superfamily. In the current study, two common polymorphisms of the ABCA12 gene, rs952718 (T/G) and rs956133 (A/G), were analyzed in our subjects. These polymorphisms showed no association with the risk of AD. Furthermore, we observed weak linkage disequilibrium between these two single nucleotide polymorphisms. These results indicate that the common polymorphisms of the ABCG5 and ABCA12 genes investigated here are not associated with AD.
Acquired Sociopathy and Frontotemporal Dementia
Authors: Mendez Mario F. , Chen Andrew K. , Shapira Jill S. , Miller Bruce L.
Published: June 2005

Background: It is not understood why some patients withfrontotemporal dementia (FTD) manifest sociopathic behavior. Objective: To examine the prevalence and characteristics of sociopathic behavior in FTD patients as compared to those with Alzheimer’s disease (AD). Methods and Participants: We surveyed a group of FTD patients and a group of AD patients for sociopathic behavior, evaluated the characteristics surrounding their acts, and compared the groups on neuropsychological tests and functional neuroimaging. Twenty-eight outpatients with FTD (15 men, 13 women; 61.9 ± 7.1 years; Mini-Mental State Examination score 23.6 ± 8.1) were compared with 28 patients with clinically probable AD (13 men, 15 women; 66.1 ± 9.2 years; Mini-Mental State Examination score 21.3 ± 5.3). Main outcome measures included: (a) the prevalence of sociopathic acts; (b) a structured interview; (c) neuropsychological tests including the Frontal Assessment Battery, and (d) clinically obtained positron emission tomography or single photon emission tomography scans. Results: Sixteen (57%) of the FTD patients had sociopathic behavior compared to two (7%) of the AD patients (χ2 = 13.84, p < 0.001). Sociopathic acts among FTD patients included unsolicited sexual acts, traffic violations, physical assaults, and other unacceptable behaviors. On interview, the FTD patients with sociopathic acts were aware of their behavior and knew that it was wrong but could not prevent themselves from acting impulsively. They claimed subsequent remorse, but they did not act on it or show concern for the consequences. Among FTD patients with sociopathy, neuropsychological assessment showed impaired motor inhibition, and functional neuroimaging showed right frontotemporal involvement. Conclusion: The results suggest that sociopathy in FTD results from a combination of diminished emotional concern for the consequences of their acts and disinhibition consequent to right frontotemporal dysfunction. In many jurisdictions, FTD patients with sociopathy would not pass legal criteria for ‘not guilty by reason of insanity’.
Significance of Silent Infarcts in Acute Ischemic Stroke Patients Aged 80 Years and Older
Authors: Minn Yang-Ki , Cho Soo-Jin , Lee Ju-Hun , Kim Su-Yeon , Kim Chul-Ho , Kwon Ki-Han , Lee Byung-Chul
Published: June 2005

Background: The significance of silent infarcts (SIs) is unknown in very elderly patients with first-ever acute ischemic stroke. Methods: Fifty patients aged 80 years and older with first-ever acute ischemic stroke were studied. The conventional risk factors for stroke, the scores of age-related white matter changes, and the findings on echocardiography were compared between patients with and without SIs. Results: Thirty-eight patients (76%) had one or more SIs. The patients without SIs frequently had atrial fibrillation (50% vs. 13.2%, p = 0.014) or spontaneous echo contrast or thrombi on echocardiography (57.1% vs. 0%, p = 0.026) and showed lower scores on age-related white matter changes (0.5 ± 0.67 vs. 1.13 ± 0.58, p = 0.002) than did patients with SIs. There were no differences in other risk factors for stroke between the two groups. Conclusion: In patients aged 80 years and older, the absence of SIs with a first-ever acute ischemic stroke may suggest the presence of cardiac embolic sources or atrial fibrillation.
The Prometheus® Device for Extracorporeal Support of Combined Liver and Renal Failure
Authors: Rifai Kinan , Ernst Thomas , Kretschmer Ulrich , Hafer Carsten , Haller Hermann , Manns Michael Peter , Fliser Danilo
Published: June 2005

Background/Aims: Prometheus® is a newly developed extracorporeal liver support system that combines removal of albumin-bound substances (adsorption on resin adsorbers) and water-soluble substances (diffusion during high-flux hemodialysis). Therefore, it is a promising treatment option for patients with hepatorenal syndrome (HRS). Methods: We studied 10 patients with HRS in a prospective clinical study. All patients underwent 2 consecutive Prometheus treatments. A variety of clinical and biochemical parameters were assessed. Results: Prometheus treatment was uncomplicated and safe. A statistically significant improvement of serum creatinine and urea concentrations as well as blood pH was observed after Prometheus treatment. Furthermore, liver detoxification was supported by a significant decrease of serum levels of conjugated bilirubin, bile acids and ammonia. Conclusions: Prometheus is a safe treatment for patients with HRS. Both, albumin-bound and water-soluble substances were effectively removed. Controlled studies will evaluate the effect of this new treatment option on survival in patients with HRS.
Benefit of Glucose-Free Dialysis Solutions on Glucose and Lipid Metabolism in Peritoneal Dialysis Patients
Authors: Martikainen Terhi , Teppo Anna-Maija , Grönhagen-Riska Carola , Ekstrand Agneta
Published: June 2005

Background: Glucose absorbed from conventional peritoneal dialysis (PD) solutions contributes to unfavorable metabolic effects. Its replacement with a glucose-free osmotic agent such as icodextrin (ID) or amino acids (AA) may have some benefit on glucose and lipid metabolism. Methods: Serum lipids, insulin sensitivity and substrate oxidation (calorimetry) were measured before and after 8 weeks use of ID or AA in 22 patients. Calorimetry and blood tests (HbA1c, lipids) were also performed after 8 weeks of simultaneous use of ID and AA in 8 patients. Results: Cholesterol declined during the use of AA (4.8 ± 0.3–4.5 ± 0.3 mmol/l, p = 0.045). Triglycerides decreased during the use of both ID (2.2 ± 0.2–1.9 ± 0.1 mmol/l, p = 0.019) and AA (1.9 ± 0.2–1.6 ± 0.1 mmol/l, p = 0.024). Free fatty acids declined during the use of AA. There were no significant changes in insulin sensitivity. Glucose oxidation decreased and lipid oxidation increased during the use of ID, the changes in substrate oxidation were accentuated during the simultaneous use of ID and AA. Conclusion: Replacement of glucose with ID or AA had a benefit on glucose and lipid metabolism.
Ultrapure Dialysate Reduces Plasma Levels of β2-Microglobulin and Pentosidine in Hemodialysis Patients
Authors: Furuya Ryuichi , Kumagai Hiromichi , Takahashi Masaaki , Sano Koji , Hishida Akira
Published: June 2005

Background: β2-Microglobulin (β2MG) and carbonyl stress are reported to contribute to the development of dialysis-related amyloidosis. The aim of this study was to determine whether the purity of dialysate affects plasma levels of β2MG and pentosidine (a surrogate marker of carbonyl stress) in hemodialysis patients. Methods: Sixteen patients on hemodialysis with a polysulfone membrane participated in this study. We switched the dialysate from conventional dialysate (endotoxin level 0.055–0.066 endotoxin units (EU)/ml) to ultrapure dialysate (endotoxin level <0.001 EU/ml), followed patients for 6 months, and then switched back to conventional dialysate once again. Plasma levels of β2MG, pentosidine, CRP and interleukin-6 (IL-6) were determined before the switch to ultrapure dialysate, 1 and 6 months after the switch to ultrapure dialysate, and 1 month after the switch back to conventional dialysate. Results: The switch from conventional to ultrapure dialysate significantly decreased plasma levels of β2MG, from 30.1 ± 1.4 to 27.1 ± 1.4 mg/dl (p < 0.05) and pentosidine, from 1,535.8 ± 107.5 to 1,267.6 ± 102.9 nmol/l (p < 0.01) after 1 month of use. The change of dialysate also significantly decreased plasma levels of CRP, from 0.28 ± 0.09 to 0.14 ± 0.05 mg/dl (p < 0.05) and IL-6, from 9.4 ± 2.7 to 3.5 ± 0.8 pg/ml (p < 0.01) over the 1-month period. These changes in plasma levels of β2MG, pentosidine, CRP and IL-6 were maintained over 6 months after switching to ultrapure dialysate and returned to basal levels by switching back to a conventional dialysate. Conclusions: Ultrapure dialysate decreases plasma levels of β2MG, pentosidine and inflammatory markers in hemodialysis patients. The use of ultrapure dialysate might be useful in preventing and/or treating complications of dialysis, such as dialysis-related amyloidosis, atherosclerosis and malnutrition.
Impact of Menopause on the Augmentation of Arterial Stiffness with Aging
Authors: Takahashi Kazuhiro , Miura Sayaka , Mori-Abe Akiko , Kawagoe Jun , Takata Keiko , Ohmichi Masahide , Kurachi Hirohisa
Published: June 2005

Background/Aims: Aortic stiffness, determined by pulse wave velocity (PWV), is an independent marker of cardiovascular risk. PWV is mainly influenced by age-associated alterations in arterial wall structure and blood pressure. The present study was conducted to assess the impact of menopause on the brachial-ankle PWV (baPWV) in healthy women. Methods: Fifty premenopausal women aged 22–54 years and 40 postmenopausal women aged 40–73 years were recruited for this study. Subjects with hypertension, diabetes, and hyperlipidemia were strictly excluded. The results of baPWV were analyzed chronologically by 10- or 5-year age intervals. Results: There was no significant difference in baPWV between premenopausal and postmenopausal women in their 40s and 50s. The baPWV of postmenopausal women aged over 60 years was significantly higher than that of postmenopausal women in their 50s. To clarify the age-dependent elevation in baPWV in detail, women their 50s and 60s were divided into subgroups by 5-year age intervals. There was no significant difference in baPWV among the 50–54-, 55–59- and 60–64-year subgroups. baPWV significantly increased in the 65–69- year subgroup (p< 0.05). There was a significant relationship between baPWV and age in premenopausal (r = 0.452, p = 0.001) and postmenopausal (r = 0.581, p < 0.0001) women. The slope of the regression line for baPWV plotted against age was steeper in postmenopausal than in premenopausal women. Conclusions: This study produces suggestive evidence that menopause amplifies the age-dependent increase in arterial stiffness.
Importance of Adequate Initial Antimicrobial Therapy
Authors: Ramphal Reuben
Published: June 2005

Background: It has become an article of faith that appropriate antibiotic therapy is needed for best outcomes during a serious infection. Despite this long-held view, there is some debate about the role of appropriate outcome in serious infections, in particular with nosocomial pneumonia. Therefore, more recent data on adequacy of antibiotic therapy and outcomes were reviewed. Methods: The medical literature from 1997 to 2004 was surveyed for articles that directly dealt with appropriate therapy. Search terms included ‘appropriate and inappropriate antibiotic therapy’, ‘adequate antibiotic therapy’, ‘resistance and antibiotic failures’ and ‘delayed therapy’. The data were abstracted to obtain their essential findings. Results: In bacteremia, data are most persuasive that appropriate and timely therapy significantly influences outcomes. Areas where this may not be the case are studies where coagulase-negative staphylococci are isolated in large numbers or in studies where the incidence of appropriate therapy is high. One area where data are not conclusive concerns the treatment of enteric bacteria carrying extended spectrum betalactamases, where the only cephalosporin of concern is ceftazidime. There is not enough data to compare carbapenems with specific cephalosporins to conclude that these are the most appropriate agents. The studies in regard to nosocomial pneumonias are not as conclusive as those with bacteremias. There appears to be a subset of patients that do not respond to therapy or do not survive, which confounds studies of this population; however, most studies favor a role of appropriate therapy. Conclusions: Appropriate antibiotic therapy has several dimensions. It improves outcomes in most serious diseases. Timing of administration and appropriateness, based on susceptibility, are the most important determinants, but dosing intervals and dose probably play similarly important roles in outcomes that have not been examined exhaustively in humans. Other aspects of appropriate therapy that deserve attention include a shift to more ‘resistance’-proof antibiotics in empiric therapy, which may be accompanied by better outcomes.
In vitro Activity of Telithromycin against Respiratory Tract Pathogens in Comparison with Other Antimicrobial Agents
Authors: Ling Thomas K.W. , Lee Ching Ching
Published: June 2005

This study was done to evaluate the in vitro activity of a new ketolide telithromycin in comparison with clarithromycin, erythromycin, moxifloxacin and levofloxacin against Streptococcus pneumoniae (n = 67), Haemophilus influenzae (n = 139), and Moraxella catarrhalis (n = 46)collected between January and June 2003 in Hong Kong. Among the H. influenzae isolates, 25.2% produced β-lactamase, while 97.8% of M. catarrhalis isolates produced β-lactamase. Half of the S. pneumoniae isolates were nonsusceptible to penicillin, and 90.9% of these strains were resistant to clarithromycin and erythromycin. One (1.5%) S. pneumoniae strain was resistant to levofloxacin (MIC = 8 mg/l) and all isolates were sensitive to moxifloxacin and telithromycin with MIC <1 mg/l. H. influenzae isolates were sensitive to all fluoroquinolones tested and 2.2% of H. influenzae were resistant to clarithromycin. M. catarrhalis isolates were sensitive except 1 strain which was resistant to levofloxacin (MIC = 4 mg/l) and moxifloxacin (8 mg/l). All M. catarrhalis strains were sensitive to telithromycin with MIC90 = 0.5 mg/l. Telithromycin demonstrated high activity and no resistance was found in all these major respiratory tract pathogens.
FHD: An Index to Evaluate Drug Elimination by Hemodialysis
Authors: Launay-Vacher Vincent , Izzedine Hassane , Baumelou Alain , Deray Gilbert
Published: June 2005

Background: In hemodialyzed patients, physicians have to (1) adjust drug dosage for a creatinine clearance lower than 10–15 ml/min and (2) know whether or not the drug will be removed by the dialysis session to decide whether it may be administered before or after the session on dialysis days. However, of several indices being used to evaluate drug removal by dialysis none is appropriate and we suggest a novel index named FHD, which reflects the role of hemodialysis clearance of a drug in its overall clearance during the session. Methods: Pharmacokinetic simulations were performed to test the influence of dialysis on the pharmacokinetics of some drugs, whether FHD was considered or not, to determine when to administer the drug. FHD was then calculated for several drugs and its value compared with other indices. Five hemodialysis patients from our department for whom the time of drug administration was determined according to FHD were included in a small study and their drugs’ trough concentrations were monitored. Results: FHD emphasized that considering hemodialysis clearance alone may lead to false interpretations of the potential dialyzability of some drugs. In our patients, who received their treatment according to the ‘FHD rule’, monitoring of trough levels gave satisfactory results. Conclusion: The use of the ‘FHD rule’ should be tested on a long-term administration basis to confirm our conclusion. FHD could be the index of choice to determine when to administer a drug, before or after the session, in hemodialysis patients.
Mast Cell Tryptase in Mast Cell Granules Enhances MCP-1 and Interleukin-8 Production in Human Endothelial Cells
Authors: Kinoshita Makoto , Okada Masaharu , Hara Masatake , Furukawa Yutaka , Matsumori Akira
Published: June 2005

Objective—Recent studies have highlighted the pathogenetic importance of chronic inflammation in cardiovascular disorders such as congestive heart failure and atherosclerosis. Mast cells release a wide variety of immune mediators that may initiate inflammatory responses, whereas endothelial cells (ECs) play a prominent role in the pathogenesis of cardiovascular diseases by secreting cytokines. The purpose of this study was to clarify the role of mast cells as an activator of ECs.

Methods and Results—ECs harvested from human umbilical cord veins were stimulated with mast cell granules (MCGs) prepared from sonicated human leukemic mast cells. The supernatants and total RNA from cells were collected. Levels of interleukin (IL)-1β, tumor necrosis factor-α, and granulocyte colony-stimulating factor remained unchanged up to 24 hours. In contrast, levels of monocyte chemoattractant protein-1 (MCP-1) and IL-8 increased significantly within 6 hours. Northern blot analysis revealed an increase in MCP-1 and IL-8 mRNA expression in MCG-treated ECs. Induction of these chemokines was attenuated by antitryptase neutralizing antibody. Furthermore, MCP-1 and IL-8 were induced in ECs by incubation with human mast cell tryptase, but not with chymase.

Conclusions—These results indicate that the production of MCP-1 and IL-8 in ECs was induced by MCG and amplified by tryptase.
Protective Mechanisms of Inosine in Platelet Activation and Cerebral Ischemic Damage
Authors: Hsiao George , Lin Kuang H. , Chang Yi , Chen Ta L. , Tzu Nien H. , Chou Duen S. , Sheu Joen R.
Published: June 2005

Objective—

Inosine is a naturally occurring nucleoside degraded from adenosine. Recent studies have demonstrated that inosine has potent immunomodulatory and neuroprotective effects. In the present study, we further investigated the inhibitory effects of inosine on platelet activation in vitro and in vivo, as well as in attenuating middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats.

Methods and Results—

Inosine concentration-dependently (0.5 to 6.0 mmol/L) inhibited platelet aggregation stimulated by agonists. Inosine (1.5 and 3.0 mmol/L) inhibited phosphoinositide breakdown, [Ca
+2
]i, and TxA
2
formation in human platelets stimulated by collagen (1 μg/mL). In addition, inosine (1.5 and 3.0 mmol/L) markedly increased levels of cyclic guanylate monophosphate (GMP) and cyclic GMP-induced vasodilator-stimulated phosphoprotein Ser
157
phosphorylation. Rapid phosphorylation of a platelet protein of molecular weight 47 000 (P47), a marker of protein kinase C activation, was triggered by collagen (1 μg/mL). This phosphorylation was markedly inhibited by inosine (3.0 mmol/L). Inosine (1.5 and 3.0 mmol/L) markedly reduced hydroxyl radical in collagen (1 μg/mL)-activated platelets. In in vivo studies, inosine (400 mg/kg) significantly prolonged the latency period of inducing platelet plug formation in mesenteric venules of mice, and administration of 2 doses (100 mg/kg) or a single dose (150 mg/kg) of inosine significantly attenuated MCAO-induced focal cerebral ischemia in rats.

Conclusions—

Platelet aggregation contributes significantly to MCAO-induced focal cerebral ischemia. The most important findings of this study suggest that inosine markedly inhibited platelet activation in vitro and in vivo, as well as cerebral ischemia. Thus, inosine treatment may represent a novel approach to lowering the risk of or improving function in thromboembolic-related disorders and ischemia-reperfusion brain injury.
Atherosclerosis in Patients With Autoimmune Disorders
Authors: Frostegård Johan
Published: June 2005

Recent findings indicate that presence of activated immune competent cells and inflammation are typical of atherosclerosis, the main cause of cardiovascular disease (CVD). The risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE), and is also raised in other autoimmune diseases such as rheumatoid arthritis. Autoimmunity-related CVD and atherosclerosis are important clinical problems. They may also shed light on interactions between immune reactions and atherosclerosis development and manifestations, not least in women, who have a much higher risk of autoimmune disease than men. In general, a combination of traditional and nontraditional risk factors, including dyslipidemia (and to a varying degree, hypertension, diabetes, and smoking), inflammation, antiphospholipid antibodies (aPLs), and lipid oxidation, contribute to CVD in autoimmune diseases. Premature atherosclerosis is likely to be a major underlying mechanism, although distinctive features, if any, of autoimmunity-related atherosclerosis compared with “normal” atherosclerosis are not clear. One interesting possibility is that factors such as inflammation, neoepitopes on endothelial cells, or aPLs make atherosclerotic lesions in autoimmune disease more prone to rupture than in “normal” atherosclerosis. Some cases of autoimmunity-related CVD may be more related to thrombosis than atherosclerosis. Whether premature atherosclerosis is a general feature of autoimmune diseases such as SLE or only affects a subgroup of patients whereas others do not have an increased risk remains to be demonstrated. Treatment of patients with autoimmune disease should also include CVD aspects and be focused on traditional risk factors as well as on disease-related factors. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation present in atherosclerotic lesions.
Important Role of Apoptosis Signal-Regulating Kinase 1 in Ischemia-Induced Angiogenesis
Authors: Izumi Yasukatsu , Kim-Mitsuyama Shokei , Yoshiyama Minoru , Omura Takashi , Shiota Masayuki , Matsuzawa Atsushi , Yukimura Tokihito , Murohara Toyoaki , Takeya Motohiro , Ichijo Hidenori , Yoshikawa Junichi , Iwao Hiroshi
Published: June 2005

Objective—

We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis.

Methods and Results—

Unilateral hindlimb ischemia was induced surgically in C57BL/6J wild-type (WT) mice or mice deficient in ASK1 (ASK1
−/−
). ASK1 activity in WT mouse hindlimb was increased dramatically after ischemia. By laser Doppler analysis, well-developed collateral vessels and angiogenesis were observed in WT mice in response to hindlimb ischemia, whereas these responses were reduced in ASK1
−/−
mice. Immunostaining revealed that infiltration of macrophages and T lymphocytes was suppressed in the ischemic tissues of ASK1
−/−
mice compared with WT mice. The expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) proteins in ischemic tissues was weaker in ASK1
−/−
mice compared with WT mice. In vitro study on endothelial cells indicated that dominant-negative ASK1 significantly attenuated hydrogen peroxide–induced VEGF and MCP-1 production. Furthermore, in vivo blockade of MCP-1 by its neutralizing antibody suppressed the recovery of the blood flow and capillary formation after ischemia.

Conclusions—

ASK1 pathway promotes early angiogenesis by inducing inflammatory cell infiltration and VEGF and MCP-1 expression. ASK1 may provide the basis for the development of new therapeutic strategy for angiogenesis.
Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia
Authors: Vossen Carla Y. , Walker Isobel D. , Svensson Peter , Souto Juan C. , Scharrer Inge , Preston F. Eric , Palareti Gualtiero , Pabinger Ingrid , van der Meer Felix J.M. , Makris Mike , Fontcuberta Jordi , Conard Jacqueline , Rosendaal Frits R.
Published: June 2005

Objective—

Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin.

Methods and Results—

Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year.

Conclusions—

Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.
Genetic Deletion or Antibody Blockade of α1β1 Integrin Induces a Stable Plaque Phenotype in ApoE−/− Mice
Authors: Schapira Kitty , Lutgens Esther , de Fougerolles Antonin , Sprague Andrew , Roemen Anouk , Gardner Humphrey , Koteliansky Victor , Daemen Mat , Heeneman Sylvia
Published: June 2005

Objective—

Adhesive interactions between cells and the extracellular matrix play an important role in inflammatory diseases like atherosclerosis. We investigated the role of the collagen-binding integrin α1β1 in atherosclerosis.

Methods and Results—

ApoE−/− mice were α1-deficient or received early or delayed anti-α1 antibody treatment. Deficiency in α1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, α1-deficient mice had a reduced macrophage and CD3+ cell content, collagen and smooth muscle cell content increased, lipid core sizes decreased, and cartilaginous metaplasia occurred. Anti-α1 antibody treatment reduced the macrophage content in initial plaques after early and delayed treatment, decreased the CD3+ cell content in advanced plaques after delayed treatment, and increased the collagen content in initial and advanced plaques after delayed treatment. Migration assays performed on α1-deficient macrophages on collagen I and IV substrata revealed that α1-deficient cells can migrate on collagen I, but not IV. Anti-α1 antibody treatment of ApoE−/− macrophages also inhibited migration of cells on collagen IV.

Conclusions—

Our results suggest that α1β1 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions by adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a stable plaque phenotype.
Caveolin-1 Is Essential for Activation of Rac1 and NAD(P)H Oxidase After Angiotensin II Type 1 Receptor Stimulation in Vascular Smooth Muscle Cells
Authors: Zuo Lian , Ushio-Fukai Masuko , Ikeda Satoshi , Hilenski Lula , Patrushev Nikolay , Alexander R. Wayne
Published: June 2005

Objective—

Angiotensin II (Ang II) is a potent mediator of vascular hypertrophy in vascular smooth muscle cells (VSMCs). These effects are mediated through the Ang II type 1 receptor (AT
1
R) and require its trafficking through caveolin-1 (Cav1)–enriched lipid rafts and reactive oxygen species (ROS) derived from Rac1-dependent NAD(P)H oxidase. The specific role(s) of Cav1 in AT
1
R signaling is incompletely understood.

Methods and Results—

Knockdown of Cav1 protein by small interfering RNA (siRNA) inhibits Ang II–stimulated Rac1 activation and membrane translocation, H
2
O
2
production, ROS-dependent epidermal growth factor receptor (EGF-R) transactivation, and subsequent phosphorylation of Akt without affecting ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation. Ang II stimulates tyrosine phosphorylation of Sos-1, a Rac–guanine nucleotide exchange factor, which is inhibited by Cav1 siRNA, demonstrating involvement of Cav1 in Rac1 activation. Detergent-free fractionation showed that EGF-Rs are found basally in Cav1-enriched lipid raft membranes and associate with Cav1. Ang II stimulates AT
1
R movement into these microdomains contemporaneously with the egress of EGF-R. Both aspects of this bidirectional receptor trafficking are inhibited by Cav1 siRNA. Moreover, Cav1 siRNA inhibits Ang II–induced vascular hypertrophy.

Conclusions—

Cav1 plays an essential role in AT
1
R targeting into Cav1-enriched lipid rafts and Rac1 activation, which are required for proper organization of ROS-dependent Ang II signaling linked to VSMC hypertrophy.
Relationship of Monocyte Count and Peripheral Arterial Disease
Authors: Nasir Khurram , Guallar Eliseo , Navas-Acien Ana , Criqui Michael H. , Lima João A.C.
Published: June 2005

Background—

Although white blood cell (WBC) count has been consistently associated with cardiovascular end points, little information is available on the independent contribution of specific white blood cell types. The objective of this study is to assess the independent association of WBC types and other inflammatory markers with the presence of reduced ankle-brachial blood pressure index (ABI), a marker of subclinical peripheral arterial disease (PAD).

Methods & Results—

Cross-sectional study in 3949 individuals ≥40 years of age without known cardiovascular disease who participated in the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES). PAD was defined as an ABI <0.9 in at least 1 leg. After adjustment for traditional cardiovascular risk factors, the odds ratios of PAD comparing the highest to the lowest quartiles were 2.24 (95% confidence interval 1.24 to 4.04) for monocytes, 1.74 (0.87 to 3.45) for neutrophils, 2.53 (1.62 to 3.96) for C-reactive protein, and 2.68 (1.03 to 6.94) for fibrinogen. When WBC types and inflammatory markers were simultaneously included in the full model, the corresponding odds ratios were 1.91 (95% confidence interval 1.06 to 3.42) for monocytes, 1.15 (0.49 to 2.69) for neutrophils, 1.37 (0.75 to 2.49) for C-reactive protein, and 2.21 (0.88 to 5.57) for fibrinogen.

Conclusions—

Monocytes were the only WBC type significantly and independently associated with PAD in a representative sample of the U.S. population after adjustment for other inflammatory markers. These findings reflect the potential role of circulating monocyte counts as markers of atherosclerosis.