bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of individual predisposition in orthostatic intolerance before and after simulated microgravity
Authors: Grenon S. M. , Hurwitz S. , Sheynberg N. , Xiao X. , Ramsdell C. D. , Mai C. L. , Kim C. , Cohen R. J. , Williams G. H.
Published: April 2004

Orthostatic intolerance (OI) is a major problem after spaceflight. Its etiology remains uncertain, but reports have pointed toward an individual susceptibility to OI. We hypothesized that individual predisposition plays an important role in post-bed rest OI. Twenty-four healthy male subjects were equilibrated on a constant diet, after which they underwent tilt-stand test (pre-TST). They then completed 14-16 days of head-down-tilt bed rest, and 14 of the subjects underwent repeat tilt-stand test (post-TST). During various phases, the following were performed: 24-h urine collections and hormonal measurements, plethysmography, and cardiovascular system identification (a noninvasive method to assess autonomic function and separately quantify parasympathetic and sympathetic responsiveness). Development of presyncope or syncope defined OI. During pre-TST, 11 subjects were intolerant and 13 were tolerant. At baseline, intolerant subjects had lower serum aldosterone ( P < 0.01), higher excretion of potassium ( P = 0.01), lower leg venous compliance ( P = 0.03), higher supine parasympathetic responsiveness ( P = 0.02), and lower standing sympathetic responsiveness ( P = 0.048). Of the 14 subjects who completed post-TST, 9 were intolerant and 5 were tolerant. Intolerant subjects had lower baseline serum cortisol ( P = 0.03) and a higher sodium level ( P = 0.02) compared with tolerant subjects. Thus several physiological characteristics were associated with increased susceptibility to OI. We propose a new model for OI, whereby individuals with greater leg venous compliance recruit compensatory mechanisms (activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and withdrawal of the parasympathetic nervous system) in the face of daily postural challenges, which places them at an advantage to face orthostatic stress. With head-down-tilt bed rest, the stimulus to recruit compensatory mechanisms disappears, and differences between the two subgroups attenuate.
Impact of Noise on Retinal Coding of Visual Signals
Authors: Passaglia Christopher L. , Troy John B.
Published: April 2004

Neural noise introduces uncertainty about the signals encoded in neural spike trains. Because of the uncertainty neurons can reliably transmit a limited amount of information. This amount is difficult to quantify for neurons that combine signals and noise in a complex manner, as many trials would be needed to estimate the joint probability distribution of stimulus and neural response accurately. The task is experimentally tractable, however, for neurons that combine signals with additive Gaussian noise. For such neurons, the joint probability distribution is well defined and information transmission rates can be computed from estimates of signal-to-noise ratio. Here we use power spectral analysis to specify the contributions of signal and noise to retinal coding of visual information. We show that in the spike trains of cat ganglion cells noise power is minimal and constant at temporal frequencies from 0.3 to 20 Hz and that it increases at higher frequencies to a plateau level that generally depends on stimulus contrast. We also show that trial-to-trial fluctuations in noise amplitude at different frequencies are uncorrelated and normally distributed. Although the contrast dependence indicates that noise at high temporal frequencies contributes nonlinearly to ganglion cell spike trains, cells in the primary visual cortex are not known to respond to stimulus modulations >20 Hz. Hence, noise in the retinal output would appear additive, white, and Gaussian from their perspective. This greatly simplifies analysis of information transmission from the eye to the primary visual cortex and perhaps other regions of the brain.
Coupling of Oscillatory Activity Between Muscles Is Strikingly Reduced in a Deafferented Subject Compared With Normal Controls
Authors: Kilner J. M. , Fisher R. J. , Lemon R. N.
Published: April 2004

Oscillatory activity in the primate motor cortex has been shown to be phase locked to oscillations in contralateral hand and forearm muscle activity in the 15- to 30-Hz frequency range. Recent studies have shown that the degree of coupling between the cortex and the periphery is strongly influenced by the type and degree of movements of the digits. It has also been suggested that changes in corticomuscular and muscle-muscle coherence could be modulated by peripheral sensory inputs. In the current study, we investigated task-dependent changes in the coherent coupling of electromyographic (EMG) activity recorded from different intrinsic (abductor pollicis brevis and first dorsal interosseous) and two extrinsic (flexor digitorum superficialis and extensor digitorum communis) hand muscles during performance of a precision-grip task by normal subjects and by a single subject who has a total loss of touch, vibration, pressure, and kinesthetic sensation below the neck. The task required a hold-move-hold pattern of grip force to be exerted on a compliant object with the dominant right hand. We found significant task-related modulation of 15- to 30-Hz coherence between EMG activity in hand muscles in the control subjects. In contrast, the deafferented subject showed very low levels of significant coherence in the 15- to 30-Hz range and no peak at this frequency in the power spectra of her EMG activity. These results suggest that the presence of sensory afferent signals are necessary for the modulation of 15- to 30-Hz oscillations in the motor system.
Incidence of Central Nervous System Tumors in Gironde, France
Authors: Elia-Pasquet Sandrine , Provost Dorothée , Jaffré Anne , Loiseau Hugues , Vital Anne , Kantor Guy , Maire Jean-Philippe , Dautheribes Michel , Darrouzet Vincent , Dartigues Jean-François , Brochard Patrick , Baldi Isabelle
Published: April 2004

The incidence of CNS tumors is subject to geographical and temporal variations which are poorly understood. The incidence of these tumors was studied in Gironde, a department of southwestern France with 1,058,911 inhabitants older than 16 years. We recorded any malignant or benign central nervous system (CNS) tumor diagnosed between May 1999 and April 2001 in adults living in Gironde. Three hundred and twenty-nine CNS tumors were diagnosed during the study period. The incidence of CNS tumors in adults was therefore 15.5 per 100,000. Overall, the incidence according to sex was 14.7 for males and 16.2 per 100,000 for females. The incidence rate increased according to age up to 80 years (3.7 per 100,000 for 20–29 years of age to 33.4 per 100,000 for 70–79 years of age) and reduced thereafter for gliomas. Our estimation of the incidence of CNS tumors ranks high among the earlier reports. Further analytic studies are ongoing.
Apolipoprotein E Polymorphism in Ischemic Cerebrovascular Diseases and Vascular Dementia Patients in Taiwan
Authors: Lin Hsiu-Fen , Lai Chiou-Lian , Tai Chih-Ta , Lin Ruey-Tay , Liu Ching-Kuan
Published: April 2004

This study aims to clarify the association between apolipoprotein E gene (ApoE) polymorphism, ischemic cerebrovascular diseases (ICVD) and vascular dementia (VaD) in Taiwan Chinese. 277 patients with ICVD, 49 patients with probable VaD and 112 controls were recruited for this study. Distributions of ApoE Ε4 carriers and allele frequencies were 28.5 and 14.5% for patients with ICVD, 20.4 and 10.2% for patients with VaD, whereas these values were 22.9 and 11.6% for controls. Distributions of ApoE Ε2 carriers and allele frequencies were 10.1 and 5.2% for ICVD patients, 6.1 and 3.1% for VaD patients, but 12.5 and 8.0% for controls. There were no differences between ICVD patients and controls, or VaD patients and controls in their Ε4 carriers. Those patients aged 65 and under, carrying the Ε2 allele, had a lower risk of developing ICVD and VaD than did their counterparts. These findings suggest that ApoE Ε4 plays no significant role in the development of ICVD and VaD, but that ApoE Ε2 has a protective effect with regard to the development of ICVD and VaD for Taiwan Chinese below the age of 65.
Hypocapnia Induces Caspase-3 Activation and Increases Aβ Production
Authors: Xie Zhongcong , Moir Robert D. , Romano Donna M. , Tesco Giuseppina , Kovacs Dora M. , Tanzi Rudolph E.
Published: April 2004

Background: At least half of all cases of early onset (<60) familial Alzheimer’s disease (FAD) are caused by any of over 150 mutations in three genes: the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutant forms of PS1 have been shown to sensitize cells to apoptotic cell death. Objective: We investigated the effects of hypocapnia, a risk factor for both cognitive and neurodevelopment deficits, on caspase-3 activation, apoptosis, and amyloid β-protein (Aβ) production, and assessed the influence of the PS1Δ9 FAD mutation on these effects. Method: For this purpose, we exposed stably transfected H4 human neuroglioma cells to conditions consistent with hypocapnia (PCO2 <40 mm Hg) and hypocapnia plus hypoxia (PO2 <21%). Results: Hypocapnia (20 mm Hg CO2 for 6 h) induced caspase-3 activation and apoptosis; the PS1Δ9 FAD mutation significantly potentiated these effects. Moreover, the combination of hypocapnia (20 mm Hg CO2) and hypoxia (5%O2) induced caspase-3 activation and apoptosis in a synergistic manner. Hypocapnia (5 and 20 mm Hg CO2 for 6 h) also led to an increased Aβ production. Conclusion: The findings suggest that hypocapnia (e.g. during general anesthesia) could exacerbate AD neuropathogenesis.
The TAT Protein Transduction Domain Enhances the Neuroprotective Effect of Glial-Cell-Line-Derived Neurotrophic Factor after Optic Nerve Transection
Authors: Kilic Ülkan , Kilic Ertugrul , Dietz Gunnar P.H. , Bähr Mathias
Published: April 2004

Glial-cell-line-derived neurotrophic factor (GDNF) acts as a potent survival factor for many neuronal populations, including retinal ganglion cells (RGC), indicating a potential therapeutic role of GDNF for neurological disorders. To enhance the tissue distribution and applicability of the neurotrophin, we linked it to a protein transduction domain derived from the HIV TAT protein and tested it in a well-established model for traumatic injury in the CNS: After optic nerve axotomy, the number of surviving RGCs was significantly increased in mice injected with TAT-GDNF on days 0, 3, 7, and 10 after surgery compared with GDNF- or PBS-injected animals. Moreover, TAT-GDNF reduced the number of activated caspase-3-positive cells. These results show that the neuroprotective effect of substances like neurotrophins may be enhanced by linking them to a domain that has been shown to mediate efficient transduction across biological membranes.
Modulation of Delayed-Type Hypersensitivity Responses in Hairless Guinea Pigs by Peptides Derived from Enkephalin
Authors: Sizemore Robert C. , Piva Marta , Moore LeeTerry , Gordonov Natalia , Heilman Edward , Godfrey Henry P.
Published: April 2004

Although opioid peptides such as methionine (met)-enkephalin have been previously shown to enhance or suppress immune responses, few studies in animal models have addressed the immunomodulatory activity of their metabolic derivatives. Hairless (IAF/HA-HO) guinea pigs immunized with Freund’s complete adjuvant containing Mycobacterium tuberculosis and repeatedly skin tested with purified protein derivative of tuberculin (PPD) display high levels of stable delayed-type hypersensitivity (DTH) to PPD. Met-enkephalin (YGGFM) and two of its metabolites (YGG, YG) enhanced and accelerated PPD-elicited DTH inflammatory reactions when injected together with elicitor in these animals. At 24 h, 5 × 10–3 pmol met-enkephalin significantly enhanced DTH responses by 30% over PPD alone, while 5 × 10–5 pmol of YGG and 5 × 10–9 pmol of YG significantly enhanced these responses by 62 and 32%, respectively. At much higher doses (5 × 103 pmol), met-enkephalin and its metabolites significantly suppressed DTH reactions by 25–32%. Tyrosine and glycine had no effect on PPD-elicited DTH. All DTH reactions (control, enhanced, suppressed) displayed typical perivascular mononuclear cell infiltrates. We conclude that the immunoactivity of met-enkephalin resides in its first two amino acids and suggest that cleavage of enkephalin molecules to YG occurs in serum and/or on the cell surface.
Minimal-invasive Biopsie und präoperative Markierung suspekter Mammaläsionen
Authors: Sittek H. , Kessler M. , Untch M. , Reiser M.
Published: April 2004

Bildgesteuerte minimal-invasive Nadelbiopsien stellen in der Diagnostik von Mammakarzinomen ein etabliertes Verfahren dar, welches bei korrekter Indikation und qualitätsgesicherter Durchführung der diagnostischen offenen Operation ebenbürtig, wenn nicht sogar überlegen ist. Eine offene diagnostische Biopsie sollte daher nur im begründeten Ausnahmefall durchgeführt werden. In Abhängigkeit von der Sichtbarkeit des histologisch abzuklärenden Befundes in den unterschiedlichen diagnostischen Verfahren muss die Nadelbiopsie mit dem bildgebenden Verfahren durchgeführt werden, in dem die suspekte Mammaläsion am sichersten identifiziert werden kann. Ist eine Läsion sowohl mammographisch wie auch sonographisch gleichermassen nachweisbar, so ist unter Berücksichtigung der Belastung der Patientinnen und der dabei entstehenden Kosten der sonographisch gesteuerten Hochgeschwindigkeitsstanzbiopsie der Vorzug zu geben. Bei suspekten Mikrokalzifikationen muss die Nadelbiopsie unter stereotaktischer Kontrolle erfolgen. Hier liefern die vakuumunterstützten Verfahren [Mammotome®, VacuFlash (BIP)/Vacora (Bard)] im Vergleich zur Hochgeschwindigkeitsstanzbiopsie deutlich bessere Ergebnisse und sollten in diesen Fällen, wie auch bei nur in der Magnetresonanztomographie sichtbaren Läsionen, bevorzugt Anwendung finden. Nicht palpable und in der bildgebenden Diagnostik suspekte, oder besser schon präoperativ durch minimal-invasive Verfahren histologisch als maligne gesicherte Läsionen sollten ausnahmslos präoperativ mit Draht markiert werden. Nur dadurch kann sichergestellt werden, dass die suspekte und nicht palpable Läsion intraoperativ sicher gefunden wird und mit ausreichendem Sicherheitssaum bei möglichster Schonung des gesunden Gewebes operativ entfernt werden kann. Die qualitätsgesicherte Diagnostik und Therapie des Mammakarzinoms sind eine interdisziplinäre Herausforderung und liefern optimale Ergebnisse nur bei optimaler Zusammenarbeit aller daran beteiligten Disziplinen.
Anti-Aging: Mythen und Fakten zur Diagnose und Therapie
Authors: Zech Nicolas H.
Published: April 2004

Anti-Aging ist eine junge Disziplin der Medizin, die momentan sehr kontrovers diskutiert wird. Bei Diagnose und Behandlung gibt es fast ebenso viele Anhänger wie Gegner, und oft wird dieses Fach auch einfach missverstanden, da es einerseits von Medien falsch dargestellt und andererseits oft von «Nicht-Spezialisten» praktiziert wird, die über keinerlei profunde Kenntnisse verfügen. Zudem fehlt der angewandten Diagnose und Therapie oft eine fundierte wissenschaftliche Basis, weswegen Anti-Aging in Verruf gerät. Diese Übersichtsarbeit möchte einen Beitrag dazu leisten, Anti-Aging ein wenig zu durchleuchten und zu demystifizieren. Da die «Anti-Aging»-Medizin sehr komplex ist, zielt diese Arbeit vor allem darauf ab, einen Einblick in gewisse Zusammenhänge zu vermitteln und Interesse an dieser neuen, aufregenden Disziplin zu wecken.
Study of Potassium Phytate Effects on Decreasing Urinary Calcium in Rats
Authors: Grases F. , Perelló J. , Simonet B.M. , Prieto R.M. , García-Raja A.
Published: April 2004

Background: Phytate as sodium salt has been used at high doses to treat stone-former patients with idiopathic hypercalciuria. The experimental and clinical hypocalciuric effects of dietary fiber have also been assigned to the presence of phytate as calcium-magnesium salt (phytin). As a consequence of the additional interest in phytate due to its capacity as crystallization inhibitor, now a study of the effects of potassium phytate on urinary calcium excretion is presented and compared with the effects caused by other phytate salts. Methods: To study the effect of calcium-magnesium phytate, 36 Wistar rats (6 groups) were fed with a purified diet in which phytate was practically absent (4068.02 Reference Diet). Three groups were fed with increasing calcium amounts and with the same amount of phytin, each one corresponding to one control group. To study the effects of magnesium-potassium, sodium and potassium phytate salts, 48 Wistar rats (8 groups) were fed with UAR-A04 diet (a standard diet which contains 0.8% of phytin). Two control groups fed with low and high calcium amounts and 6 treated groups were formed. The effect of the dose of potassium phytate on urinary calcium was carried out using 2 additional groups of 6 Wistar rats each one fed with UAR-A04 diet and increasing amounts of potassium phytate. Results: No significant changes in urinary calcium were observed when phytin (calcium-magnesium phytate) was supplied. The urinary calcium was clearly reduced by the three phytate salts assayed (magnesium-potassium, sodium, potassium), but the most significant decrease was noticed when the potassium phytate salt was administered. Phytate administration, independently of the salt or dose used, did not significantly affect the urinary oxalate. Conclusion: It can be clearly deduced that the effects of phytate on the urinary parameters, mainly calcium, fundamentally depend on the type of salt used. Thus, the most remarkable effects on urinary calcium reduction were caused by the potassium salt. Obviously, these findings must be confirmed in human studies.
Paratesticular Well-Differentiated, Adipocytic Type Liposarcoma Presenting as Inguinal Hernia
Authors: Kalyvas Konstantinos D. , Kotakidou Rodi , Trantos Anastasios , Yannakoyorgos Konstantinos , Hatzichristou Dimitrios G.
Published: April 2004

Paratesticular masses can pose difficult diagnostic and therapeutic problems to the physician. We report a rare case of paratesticular liposarcoma with the clinical symptomatology of an inguinal hernia. The treatment was surgical and included radical orchiectomy and wide excision of the tumor mass to the macroscopically healthy margins. The patient is well and with no evidence of recurrence 1 year after the operation. We review the literature, and discuss the role of radical orchiectomy, radiation, and chemotherapy in the treatment of paratesticular liposarcomas.
The Influence of Urine on the in vitro Antimicrobial Activity of Various Antibiotics against Different Escherichia coli Phenotypes
Authors: Büyükbaba-Boral Özden , Gönüllü Nevriye , Küçükbasmacı Ömer , Anğ-Küçüker Mine , Anğ Özdem
Published: April 2004

Background: The influence of urine on the in vitro activities of various antibiotics used in the therapy of urinary tract infections was assessed by the microbroth dilution method in this study. Methods: Thirty Escherichia coli strains were used: 10 E. coli strains susceptible to ampicillin, 10 strains resistant to ampicillin and ampicillin+sulbactam and ten extended spectrum beta-lactamase producer strains. The minimum inhibitory concentrations (MICs) of ampicillin, ampicillin + sulbactam, cephalothin, cefuroxime, ceftriaxone, amikacin, ciprofloxacin, sulfamethoxazole and trimethoprim were performed parallel in Mueller-Hinton broth and human urine by the microbroth dilution method. Results: The MIC90 of all antibiotics except cephalothin were higher in the urine. MICs performed in the urine were found significantly higher than those performed in broth. Conclusions: This study demonstrated that MICs of antibiotics are influenced by the human urine and that MICs of some antibiotics used in the treatment of urinary tract infections may be overestimated by the standard antibiotic testing methods.
Comparative in vitro Activities of Three New Quinolones and Azithromycin against Aerobic Pathogens Causing Respiratory Tract and Abdominal Wound Infections
Authors: Wenzler Sibylle , Schmidt-Eisenlohr Elke , Daschner Franz
Published: April 2004

Background: In our study the in vitro susceptibility of common pathogens that cause respiratory tract and abdominal wound infections was tested against two newer fluorquinolones (moxifloxacin and gatifloxacin) as well as levofloxacin and azithromycin. Methods: 50 isolates each of methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa and Haemophilus influenzae isolated from the respiratory tract and from wounds were tested for their susceptibility to moxifloxacin, gatifloxacin, levofloxacin and azithromycin. Results: Moxifloxacin proved to be the most active substance against the tested gram-positive pathogens. Gatifloxacin was the most active against P. aeruginosa. Moxifloxacin and gatifloxacin proved to be comparably active against the clinical isolates of E. coli and H. influenzae.Conclusions: Moxifloxacin and gatifloxacin display excellent activity against respiratory pathogens as well as nosocomial pathogens causing abdominal wound infections. When treating infections caused by P. aeruginosa the earlier fluorquinolones such as ciprofloxacin or ofloxacin are the substances of choice.
Streptococcal-A Tonsillopharyngitis: A 5-Day Course of Cefuroxime Axetil versus a 10-Day Course of Penicillin V
Authors: Scholz Horst
Published: April 2004

Background: The recommended duration of antibiotic treatment of tonsillopharyngitis caused by group A β-hemolytic streptococci (GABHS) with penicillin V (PenV) is mostly 10 days. However, compliance with 10-day courses is bad. Shorter therapeutic courses are necessary, especially in young children. Methods: In a prospective, randomized, multi-center study, children aged 1–17 years with acute tonsillopharyngitis and a positive culture for GABHS were treated with cefuroxime axetil (CAE) 20 mg/kg/day (max. 500 mg) b.i.d. for 5 days or with PenV 50,000 IU/kg (30 mg/kg) t.i.d. for 10 days. Patients were evaluated for clinical efficacy 2–4 and 7–9 days after the end of therapy. Throat swabs were taken 2–4 days after the end of therapy and at the first follow-up visit. Follow-up visits were carried out 7–8 weeks, 6 months and 12 months after study inclusion. Results: 1,952 patients (CAE for 5 days, 496 patients/PenV for 10 days, 1,456 patients) could be included in the intent-to-treat analysis. Two to 4 days after completion of the treatment course, the bacteriological eradication in group A (1–5 years) and group B (6–17 years) was 90.52 and 89.53% (CAE) vs. 84.13 and 84.20% (PenV), respectively; p = 0.0172; 0.0382; clinical success was 98.30% (CAE) versus 93.25% (PenV), p = 0.0017. Recurrent infections were significantly higher in younger children (group A) under both treatment regimens. Poststreptococcal sequelae (glomerulonephritis) were observed in only 1 case, in the PenV group. Conclusions: CAE b.i.d. for 5 days was at least as effective as PenV t.i.d. for 10 days. Incountries with a low incidence of rheumatic fever, CAE for 5 days can be recommended for the therapy of tonsillopharyngitis due to GABHS – also in young children.
Region-Specific Decline of Cerebral Glucose Metabolism in Patients with Frontotemporal Dementia: A Prospective 18F-FDG-PET Study
Authors: Grimmer T. , Diehl J. , Drzezga A. , Förstl H. , Kurz A.
Published: April 2004

Objective: The aim of this study was to examine the pattern of glucose uptake and the changes over time of metabolic deficits in patients with frontotemporal dementia (FTD). Methods: 10 patients who had received the clinical diagnosis of FTD underwent positron emission tomography scanning at the time of their first examination (baseline) and at follow-up (after 17.1 ± 6.0 months). For statistical analysis, we used the SPM 99 software. First, we compared the data of the patients at baseline with an age-matched healthy control group. Second, we compared glucose uptake at follow-up with baseline measurements. Results: Compared with normal controls, FTD patients showed significant metabolic deficits primarily in frontal cortical areas, but also in the caudate nuclei and the thalami. At follow-up, a significant progression of metabolic deficit was exclusively observed in the orbitofrontal parts of the frontal lobe and in the subcortical structures. Discussion: These findings demonstrate that the clinical progression in patients with FTD is accompanied by a region-specific decline in cerebral glucose metabolism.
Effects of Cholinergic Drugs and Cognitive Training on Dementia
Authors: Requena C. , López Ibor M.I. , Maestú F. , Campo P. , López Ibor J.J. , Ortiz T.
Published: April 2004

A study was performed on patients with Alzheimer’s disease (AD) in order to evaluate the efficacy of a combined treatment (donepezil plus cognitive training) in both cognitive processes and affective states. Eighty-six subjects, 25 men and 61 women, with an average age of 75.58 years, were studied. Almost all the subjects had a basic educational level. Donezepil was administered at a dose of 10 mg daily along with cognitive treatment involving images of everyday life and reminiscent music; the sessions took place on Monday to Friday and lasted three quarters of an hour. The study lasted 12 months. Subjects underwent test-retest with the following tests: Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog); the Geriatric Depression Scale (GDS) and the overall deterioration scale (FAST). The results showed that subjects receiving the combined treatment had a better response than those who did not receive any cognitive training. These subjects’ MMSE score decreased by 3.24 on average. The affective symptomatology of those receiving only drug treatment improved whereas the cognitive processes did not.
Polymorphism at Codon 66 of the Brain-Derived Neurotrophic Factor Gene Is Not Associated with Sporadic Alzheimer’s Disease
Authors: Combarros Onofre , Infante Jon , Llorca Javier , Berciano José
Published: April 2004

Memory acquisition and consolidation are associated with an increase in brain-derived neurotrophic factor (BDNF) in synapses, particularly those innervating the hippocampus and cerebral cortex. A polymorphism producing an amino acid substitution (valine to methionine) at codon 66 of the BDNF gene could affect intracellular processing and secretion of BDNF and lead to impairments in hippocampal function. Preliminary evidence in an Italian population indicates that this polymorphism is a predisposing factor for sporadic Alzheimer’s disease (AD). A case-control study utilizing a clinically well-defined group of 237 sporadic AD patients and 218 control subjects was performed to test this association. The current study does not demonstrate any significant difference in Val66Met BDNF genotype or allele frequencies between AD patients and controls. Our study in the Spanish population argues against the hypothesis that this polymorphism is causally related to AD.
Vascular Endothelial Growth Factor Gene Transfer Inhibits Neointimal Macrophage Accumulation in Hypercholesterolemic Rabbits
Authors: Khurana Rohit , Shafi Shahida , Martin John , Zachary Ian
Published: April 2004

Objective—

This study aims to determine the effects of periadventitial vascular endothelial growth factor (VEGF) gene transfer on neointima formation and macrophage accumulation induced by collar placement around the carotid artery in hypercholesterolemic rabbits.

Methods and Results—

Collar placement around the carotid artery in cholesterol-fed rabbits induced intimal thickening with increased neointimal macrophage content. Liposome-mediated VEGF gene transfer, confirmed by transgene-specific RT-PCR, caused a marked inhibition of both intimal thickening and macrophage accumulation compared with a lacZ control gene. VEGF gene transfer was not accompanied by a significant increase in adventitial neovascularization. Collaring of carotid arteries in hypercholesterolemic rabbits also upregulated endothelial VCAM-1 expression. Inhibition of neointimal macrophage infiltration in VEGF-transduced, collared arteries was associated with decreased endothelial VCAM-1.

Conclusions—

VEGF gene transfer inhibits collar-induced intimal thickening, macrophage accumulation, and VCAM-1 expression in cholesterol-fed rabbits. These findings support the concept that low-level VEGF expression can exert arterioprotective effects in the presence of high blood cholesterol.
Inhibition of Accelerated Graft Arteriosclerosis by Gene Transfer of Soluble Fibroblast Growth Factor Receptor-1 in Rat Aortic Transplants
Authors: Luo Wensheng , Liu Ailian , Chen Yong , Lim Hyung M. , Marshall-Neff Jennifer , Black James H. , Baldwin William , Hruban Ralph H. , Stevenson Susan C. , Mouton Peter , Dardik Alan , Ballermann Barbara J.
Published: April 2004

Objective—

Because increased fibroblast growth factor-1 (FGF-1) and FGF receptor (FGFR) expression correlate with the development of accelerated graft arteriosclerosis in transplanted human hearts, this study sought to determine whether local gene transfer of soluble FGFR-1, capable of binding both FGF-1 and FGF-2, could blunt the development of accelerated graft arteriosclerosis in the rat aortic transplant model.

Methods and Results—

A construct encoding the FGFR-1 ectodomain, capable of neutralizing FGF-2 action, was expressed in rat aortic allografts, using adenoviral gene transfer at the time of transplantation. Neointima formation was inhibited in aortic allografts transduced with soluble FGFR-1, compared with allografts transduced with Null virus.

Conclusions—

FGFs play a causal role in the development of accelerated graft arteriosclerosis in the rat aortic transplant model. Targeted interruption of FGF function could potentially reduce neointima formation in patients with heart and kidney transplants.
Electrocardiographic Recognition of the Epicardial Origin of Ventricular Tachycardias
Authors: Berruezo Antonio , Mont Lluis , Nava Santiago , Chueca Enrique , Bartholomay Eduardo , Brugada Josep
Published: April 2004

Background—

Some ventricular tachycardias (VTs) originating from the epicardium are not suitable for endocardial radiofrequency ablation and require an epicardial approach. The aim of this study was to define the ECG characteristics that may identify an epicardial origin of VTs.

Methods and Results—

We analyzed the 12-lead ECG recordings during epicardial and endocardial left ventricular pacing in 9 patients to verify the hypothesis that the epicardial origin of the ventricular activation widens the initial part of the QRS complex. Then, we analyzed the ECG pattern in 14 VTs successfully ablated from the epicardium after a failed endocardial approach (group A), in 27 VTs successfully ablated from the endocardium (group B), and in 28 additional VTs that could not be ablated from the endocardium (group C). Four distinct intervals of ventricular activation were defined and measured: (1) the pseudodelta wave, (2) the intrinsicoid deflection time in V2, (3) the shortest RS complex, and (4) the QRS complex. VTs from groups A and C showed a significantly longer pseudodelta wave, intrinsicoid deflection time, and RS complex duration compared with VTs of group B. There was no difference between groups A and C. A pseudodelta wave of ≥34 ms has a sensitivity of 83% and a specificity of 95%, an intrinsicoid deflection time of ≥85 ms has a sensitivity of 87% and a specificity of 90%, and an RS complex duration of ≥121 ms has a sensitivity of 76% and a specificity of 85% in identifying an epicardial origin of the VTs.

Conclusions—

ECG suggests VTs originating from the epicardium and those with an unsuccessful radiofrequency ablation from the endocardium.
C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function
Authors: Verma Subodh , Kuliszewski Michael A. , Li Shu-Hong , Szmitko Paul E. , Zucco Liana , Wang Chao-Hung , Badiwala Mitesh V. , Mickle Donald A.G. , Weisel Richard D. , Fedak Paul W.M. , Stewart Duncan J. , Kutryk Michael J.B.
Published: April 2004

Background—

Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown.

Methods and Results—

EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 μg/mL), rosiglitazone (1 μmol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations ≥15 μg/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell–specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator–activated receptor-γ (PPARγ) agonist.

Conclusions—

Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPARγ agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.
C242T
CYBA
Polymorphism of the NADPH Oxidase Is Associated With Reduced Respiratory Burst in Human Neutrophils
Authors: Wyche Keith E. , Wang Shaoshan S. , Griendling Kathy K. , Dikalov Sergey I. , Austin Harland , Rao Swapna , Fink Bruno , Harrison David G. , Zafari A. Maziar
Published: April 2004

Oxidative stress contributes to the pathogenesis of atherosclerosis. p22

phox

-based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242T
CYBA
polymorphism, whereas others have not. Because vascular p22

phox

is identical to neutrophil p22

phox

, we studied the association between the C242T, A640G, and −930
A/G
CYBA
polymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7±0.7, 7.9±0.6, and 5.9±1.2 μmol/L per minute per 10
6
neutrophils for the C242T CC, CT, and TT genotypes, respectively (
P
<0.05). In contrast, the A640G and the −930
A/G
polymorphisms did not alter the neutrophil respiratory burst. Phagocytic respiratory burst activity in homozygous individuals with the T allele of the C242T
CYBA
polymorphism is significantly lower than of wild-type carriers and heterozygous individuals. Because p22

phox

exists in both the neutrophil and vessel wall, vascular oxidative stress is likely diminished in individuals with this polymorphism.
Reperfusion-Induced Oxidative/Nitrative Injury to Neurovascular Unit After Focal Cerebral Ischemia
Authors: Gürsoy-Özdemir Yasemin , Can Alp , Dalkara Turgay
Published: April 2004

Background and Purpose—

Use of thrombolysis in stroke is limited by a short therapeutic window because delayed reperfusion may cause brain hemorrhage and edema. Available evidence suggests a role for superoxide, NO, and peroxynitrite in reperfusion-induced injury. However, depending on their cellular origin and interactions between them, these molecules may exert protective or deleterious actions, neither of which is characterized in the intact brain.

Methods—

Using fluorescent probes, we determined superoxide and peroxynitrite formation within neurons, astrocytes, and endothelium, and the association between oxidative/nitrative stress and vascular injury in mice brains subjected to 2-hour middle cerebral artery occlusion and 3 or 5 hours of reperfusion.

Results—

Both signals were colocalized, suggesting that the main source of peroxynitrite in the reperfused brain was a reaction between superoxide and NO. Superoxide and peroxynitrite formation was particularly intense in microvessels and astrocytic end-feet surrounding them, and overlapped with dense mitochondrial labeling. Sites of oxidative/nitrative stress on microvessels were colocalized with markers of vascular injury such as Evans blue (EB) leakage and matrix metalloproteinase-9 (MMP-9) expression, suggesting an association between peroxynitrite and microvascular injury. Supporting this idea, partial inhibition of endothelial NO synthesis at reperfusion with a low dose of L-nitroarginine (1 mg/kg IP) reduced 3-nitrotyrosine formation in microvessels and EB extravasation.

Conclusion—

During reperfusion, intense superoxide, NO, and peroxynitrite formation on microvessels and surrounding end-feet may lead to cerebral hemorrhage and edema by disrupting microvascular integrity. Combination of thrombolysis with agents diminishing oxidative/nitrative stress may reduce reperfusion-induced injury and extend the therapeutic window for thrombolysis.
Effect of Aspirin and Warfarin Therapy in Stroke Patients With Valvular Strands
Authors: Homma Shunichi , Di Tullio Marco R. , Sciacca Robert R. , Sacco Ralph L. , Mohr J.P.
Published: April 2004

Background—

Valvular strands are associated with ischemic stroke. The recurrent rate of adverse events in stroke patients with valvular strands has not been defined and, importantly, there are no randomized studies to evaluate efficacy of antithrombotic therapies in these patients.

Methods—

Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) enrolled 630 stroke patients, of whom 312 (49.5%) were randomized to warfarin and 318 (50.5%) were randomized to aspirin; 265 patients experienced cryptogenic stroke and 365 experienced stroke with known subtypes. Endpoints were recurrent ischemic stroke or death from any cause. All transesophageal echocardiography studies were blindly, centrally analyzed and all endpoints were blindly adjudicated.

Results—

Overall, of 619 studies analyzed, valvular strands were present in 39.4% of the patients (244/619), 5.8% (36/619) on the aortic valve and 27.8% (172/619) on the mitral valve, and 5.8% (36/619) on both valves. In an intention-to-treat analysis, there was no significant difference in the time to primary endpoints between patients with and without strands in the overall population (
P
=0.82; hazard ratio: 1.05; 95% CI: 0.70 to 1.57; 2-year event rates: 16.4% versus 15.5%). Among the patients with strands, there was no significant difference in the time to primary endpoints between those treated with warfarin or aspirin (
P
=0.21; hazard ratio: 0.67; 95% CI: 0.36 to 1.26; 2-year event rates: 13.5% versus 19.6%).

Conclusions—

While on medical therapy, valvular strands do not significantly increase recurrent adverse event rates in patients with ischemic stroke. Furthermore, the study does not provide evidence to support an advantage of warfarin or aspirin for this purpose.
Elevated Pulse Pressure During the Acute Period of Ischemic Stroke Is Associated With Poor Stroke Outcome
Authors: Aslanyan Stella , Weir Christopher J. , Lees Kennedy R.
Published: April 2004

Background—

It is controversial which component of blood pressure (BP) during acute period of stroke best predicts outcome. We hypothesized that elevated pulse pressure (PP), the difference between systolic BP (SBP) and diastolic BP (DBP), is independently associated with poor stroke outcome at 3 months.

Methods—

We analyzed both treatment groups from the Glycine Antagonist (Gavestinel) in Neuroprotection (GAIN) International trial (1455 ischemic stroke cases of mostly moderate severity). Cox proportional hazards and logistic regression modeling corrected for demography, medical history, heart rate, stroke severity, and clinical subtype.

Results—

Elevated weighted average PP during the first 60 hours was associated with poor outcome by mortality, Barthel index, National Institutes of Health Stroke Score (NIHSS) and Rankin scores. Elevated baseline PP was associated with Barthel index and Rankin score.

Conclusion—

Elevated PP is associated with poor stroke outcome at 3 months.
Serum Albumin Level as a Predictor of Ischemic Stroke Outcome
Authors: Dziedzic Tomasz , Slowik Agnieszka , Szczudlik Andrzej
Published: April 2004

Background and Purpose—

Animal studies showed that human albumin therapy is strongly neuroprotective in focal ischemia. The aim of our study was to determine if relatively high serum albumin level is associated with decreased risk of poor outcome in ischemic stroke patients.

Methods—

Seven hundred fifty-nine consecutive patients with acute ischemic stroke were included. Functional outcome was measured 3 months after stroke using modified Rankin Scale (mRS). Poor outcome was defined as mRS >3 or death. Serum albumin level was measured within 36 hours after stroke onset.

Results—

Patients with poor outcome had significantly lower serum albumin level than patients with nonpoor outcome (34.1±7.4 versus 36.8±6.7 g/L). On logistic regression analysis, serum albumin level remained independent predictor of poor outcome (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.26 to 0.70).

Conclusions—

Relatively high serum albumin level in acute stroke patients decreases the risk of poor outcome.
The Kappa Statistic: A Second Look
Authors: Eugenio Barbara Di , Glass Michael
Published: April 2004

In recent years, the kappa coefficient of agreement has become the de facto standard for evaluating intercoder agreement for tagging tasks. In this squib, we highlight issues that affect κ and that the community has largely neglected. First, we discuss the assumptions underlying different computations of the expected agreement component of κ. Second, we discuss how prevalence and bias affect the κ measure.
Rac2 is critical for neutrophil primary granule exocytosis
Authors: Abdel-Latif Dalia , Steward Melissa , Macdonald Dawn L. , Francis Gordon A. , Dinauer Mary C. , Lacy Paige
Published: April 2004

Neutrophil degranulation is important in many inflammatory disorders, although the intracellular mechanisms underlying this process remain poorly understood. The Rho GTPase, Rac2, has been implicated in control of degranulation in earlier studies. We hypothesized that Rac2 selectively regulates neutrophil primary granule release. Using bone marrow and peritoneal exudate neutrophils from rac2-/- mice in comparison with similar cells from wild-type C57Bl/6 mice, we found that primary granule myeloperoxidase and elastase release was absent in Rac2-/- neutrophils in response to chemoattractant stimulation, cytochalasin B/f-Met-Leu-Phe (CB/fMLP), and CB/leukotriene B4. Rac2-/- neutrophils also failed to exhibit mobilization of the primary granule marker CD63+ during CB/fMLP stimulation as determined by confocal microscopy. Priming of Rac2-/- neutrophils with tumor necrosis factor (TNF) or by peritoneal elicitation did not rescue the defect in primary granule release. However, phosphorylation of p38 mitogen-activated protein (MAP) kinase in Rac2-/- neutrophils was evident in response to CB/fMLP and/or TNF. Primary granule density and morphology were normal in Rac2-/- neutrophils. Secondary specific and tertiary granule release, measured by lactoferrin immunoassay and zymography, was normal in response to CB/fMLP and adhesion to fibronectin. These findings suggest an obligatory role for Rac2 in regulation of primary granule release by neutrophils.
G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact
Authors: van de Geijn Gert-Jan M. , Gits Judith , Aarts Lambertus H. J. , Heijmans-Antonissen Claudia , Touw Ivo P.
Published: April 2004

Truncated granulocyte colony-stimulating factor receptors (G-CSF-Rs) are implicated in severe congenital neutropenia (SCN) and the consecutive development of acute myeloid leukemia (AML). Mice expressing G-CSF-R truncation mutants (gcsfr-d715) show defective receptor internalization, an increased signal transducer and activator of transcription 5 (STAT5)/STAT3 activation ratio, and hyperproliferative responses to G-CSF treatment. We determined whether a lack of negative feedback by suppressor of cytokine signaling (SOCS) proteins contributes to the signaling abnormalities of G-CSF-R–d715. Expression of SOCS3 transcripts in bone marrow cells from G-CSF–treated gcsfr-d715 mice was approximately 60% lower than in wild-type (WT) littermates. SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays. In contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R–d715, STAT5 activation was no longer affected. This was due mainly to loss of the SOCS3 recruitment site Tyr729, with an additional contribution of the internalization defects of G-CSF-R–d715. Because Tyr729 is also a docking site for the Src homology 2–containing protein tyrosine phosphatase-2 (SHP-2), which binds to and inactivates STAT5, we suggest a model in which reduced SOCS3 expression, combined with the loss of recruitment of both SOCS3 and SHP-2 to the activated receptor complex, determine the increased STAT5/STAT3 activation ratio and the resulting signaling abnormalities projected by truncated G-CSF-R mutants.
Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin
Authors: Solovey Anna , Kollander Rahn , Shet Arun , Milbauer Liming C. , Choong Stephana , Panoskaltsis-Mortari Angela , Blazar Bruce R. , Kelm Robert J. , Hebbel Robert P.
Published: April 2004

Abnormal tissue factor (TF) expression has been demonstrated on blood monocytes and circulating endothelial cells in humans with sickle cell anemia. We have now studied sickle transgenic mice to help define the biology of endothelial TF expression in sickle disease. Using immunostaining of tissue sections, we find that this is confined almost exclusively to the pulmonary veins. About 15% and 13% of these exhibit TF-positive endothelium in the wild-type normal mouse and the normal human hemoglobin (HbA)–expressing control transgenic mouse, respectively. The mild sickle mouse is indistinguishable from normal (∼ 14% positive), but TF expression is significantly elevated in the moderate and severe mouse models of sickle disease (∼ 29% and ∼ 41% positive, respectively). Exposure of the mild sickle mouse to hypoxia for 3 hours, followed by reoxygenation, converted its TF expression phenotype to that of the severe sickle mouse (∼ 36% positive). Pretreatment with lovastatin eliminated excessive expression of TF in the posthypoxic mild sickle mouse (∼ 16% positive) and in the more severe mouse at ambient air (∼ 21% positive). In addition to identifying tissue expression of endothelial TF in the sickle lung, these studies implicate reperfusion injury physiology in its expression and suggest a rationale for use of statins in sickle disease.