bluuebunny/crossref_metadata_2025 huggingface dataset:
Susceptibility Studies of Malaysian Plasmodium falciparum Clones to Type II Antifolate Drugs after 3 Years of Continuous in vitro Culture
Authors: Ang Hooi Hoon , Cheang Hung Seong , Mak Joon Wah
Published: October 2005

Background: Exposure of Plasmodium falciparum to increasing sublethal drug concentrations followed by drug treatment led to the development of many resistant parasites. Therefore, the susceptibility of these clones to the type II antifolate drugs, cycloguanil and pyrimethamine, before and after subculturing them in vitro for a period of 3 years, was studied. Methods: Thirty fresh clones were obtained from five different blood samples infected with P. falciparum isolates. They were tested for their susceptibility to the above drugs during the investigation period. Results: None of these clones changed their susceptibilities, before and after the investigation period. Conclusion: This study gives further evidence that there is no alteration of the susceptibilities of the clones to the above drugs during the investigation period.
Management of Sore Throat by Family Physicians in Northeastern Poland: Possible Benefits of Applying Clinical Algorithm
Authors: Chlabicz Sławomir , Ołtarzewska Alicja Małgorzata , Sawicka-Powierza Jolanta
Published: October 2005

Background: The objective of this study was to describe current sore throat management practices among family physicians and to estimate potential benefits of applying clinical algorithm – Centor’s scale (presence of tonsillar exudates, fever, lymphadenopathy and absence of cough) in decision-making process. Methods: Each of 44 participating family physicians was asked to fill in questionnaires for 30 consecutive patients with respiratory tract infection. Results: Almost all decisions were made on clinical grounds. Among 169 adult patients with the clinical diagnosis of bacterial pharyngitis only 55% fulfilled 3 or more criteria on Centor’s scale. Conclusions: Family physicians overdiagnose bacterial pharyngitis. Screening adult patients with Centor’s criteria would probably lead to a reduction in the prescribing of antibiotics.
Pharmaceutical Cost Comparison Analysis of Antimicrobial Use for Surgical Prophylaxis on Gastrectomy Patients in a Tertiary Care Hospital
Authors: Ise Yuya , Hagiwara Ken , Onda Mitsuko , Kamei Miwako , Katayama Shirou , Nishizawa Kenji , Hirano Masaaki , Kiyama Teruo
Published: October 2005

The present study investigated the clinical effects and therapeutic cost of cefazolin (CEZ) and ampicillin/sulbactam (SBT/ABPC) compared to analyze cost-effectiveness for surgical prophylaxis in gastric cancer patients. 157 inpatients who underwent surgery for gastric cancer were investigated. There was no difference between the two groups with regard to sex, age, incidence of complication, stage of cancer, operative time and blood loss, length of hospitalization, the appearance of systematic inflammatory responses syndrome and the prophylactic effect of infection. Meanwhile, decision analysis indicated that the anticipated therapeutic cost per patient in CEZ group was less than that of SBT/ABPC group (USD 142.72 and USD 187.17, respectively). In this case, CEZ use was more cost-effective, insofar as only drug cost was considered.
Combined Effects of Panipenem and Aminoglycosides on Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa in vitro
Authors: Katou Ken , Nakamura Atsushi , Kato Takashi , Tonegawa Ken , Kutsuna Takeo , Niwa Toshiaki , Morita Hiroki , Itoh Makoto
Published: October 2005

Background: Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are the main causes of refractory infections that are often resistant to antimicrobial agents. In these cases, combination of agents with antimicrobial activity is being examined. However, few studies have investigated combined effects with antimicrobial agents including carbapenem and aminoglycosides. Methods: We evaluated the effects of panipenem (PAPM) combined with 3 aminoglycosides, arbekacin, amikacin, and netilmicin, and vancomicin (VCM) with an agar dilution checkerboard technique and the fractional inhibitory concentration index against 47 strains of MRSA and 56 strains of P. aeruginosa. Results: PAPM combined with VCM achieved a synergic effect against MRSA in 80.9%. PAPM combined with aminoglycosides showed only additive effects against MRSA and P. aeruginosa. When comparing the activity of Mueller-Hinton agar (MHA) medium with MHA medium diluted 40-fold (1/40 MHA) against P. aeruginosa, the mean minimum inhibitory concentration of PAPM was decreased to 1/16. Conclusions: Combination of PAPM and VCM is effective against MRSA. Combinations of PAPM and aminoglycosides showed additive effects against MRSA and P. aeruginosa.
The Proangiogenic Capacity of Polymorphonuclear Neutrophils Delineated by Microarray Technique and by Measurement of Neovascularization in Wounded Skin of CD18-Deficient Mice
Authors: Schruefer Ruth , Sulyok Silke , Schymeinsky Jürgen , Peters Thorsten , Scharffetter-Kochanek Karin , Walzog Barbara
Published: October 2005

Growing evidence supports the concept that polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. We employed an oligonucleotide microarray technique to gain further insight into the molecular mechanisms underlying the proangiogenic potential of human PMN. In addition to 18 known angiogenesis-relevant genes, we detected the expression of 10 novel genes, namely midkine, erb-B2, ets-1, transforming growth factor receptor-β2 and -β3, thrombospondin, tissue inhibitor of metalloproteinase 2, ephrin A2, ephrin B2 and restin in human PMN freshly isolated from the circulation. Gene expression was confirmed by the RT-PCR technique. In vivo evidence for the role of PMN in neovascularization was provided by studying neovascularization in a skin model of wound healing using CD18-deficient mice which lack PMN infiltration to sites of lesion. In CD18-deficient animals, neovascularization was found to be significantly compromised when compared with wild-type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation-mediated angiogenesis which may be a consequence of the broad spectrum of proangiogenic factors expressed by these cells.
Looking for Trouble: A Search for Developmental Defects of the Hypothalamus
Authors: Caqueret Aurore , Yang Chun , Duplan Sabine , Boucher Francine , Michaud Jacques L.
Published: October 2005

The hypothalamus is a critical integrator of several homeostatic processes that are required for the survival of vertebrates. Disruption of the development of the hypothalamus thus has the potential of perturbing important physiological processes with lifelong consequences. We review current knowledge about how cell types are specified and circuits are formed within the developing hypothalamus. We emphasize the potential clinical impact of the perturbations of these pathways using the regulation of energy balance as a model. We predict that disruption of hypothalamic development is a common, previously unsuspected cause of disorders of homeostatic processes such as obesity and high blood pressure.
Hyperbaric Oxygen Therapy of Cerebral Ischemia
Authors: Helms Ann K. , Whelan Harry T. , Torbey Michel T.
Published: October 2005

Background: Hyperbaric oxygen (HBO) therapy of cerebral ischemia has been evaluated in a number of human and animal studies; however, there is presently no consensus on its efficacy. Methods: We present a review of animal and human studies on HBO therapy of cerebral ischemia as well as present potential mechanisms of action of HBO. Results: Animal studies of HBO have shown promise by reducing infarct size and improving neurologic outcome. HBO has also been shown to inhibit inflammation and apoptosis after cerebral ischemia. Early reports in humans also suggested benefit in stroke patients treated with HBO. Recent randomized, controlled human studies, however, have not shown benefit, although all were limited by small sample size. Important differences between animal and human studies suggest HBO might be more effective in stroke within the first few hours and at a pressure of 2–3 ATA. Conclusions: The clinical usefulness of HBO in the treatment of cerebral ischemia is not yet certain. Attention to emerging pathophysiologic data should be taken into consideration in design of any future clinical trials of HBO in acute ischemic stroke.
The Discovery of Encephalic Arteries
Authors: Tatu Laurent , Moulin Thierry , Monnier Guy
Published: October 2005

Up until the 17th century, ideas surrounding the discovery of encephalic arteries were to remain largely influenced by the political and religious ideologies of the era. Parts of the encephalic arterial system have been called after several anatomists from this earlier period. From the 18th century onwards, scientists and doctors in particular, liberated themselves from the political and religious trends which had governed their work in previous centuries. Some progress was made by applying the clinico-anatomical method to neurology, but it was only at the end of the 19th century and the beginning of the 20th century that discoveries about encephalic arteries had gained ground. During the same period, anatomists in several countries were producing detailed descriptions of this arterial system. Moreover, this period saw the advent of the first generation of vascular neurologists, one of whom, Charles Foix, is considered as the founder of the discipline.
Intravenous Thrombolysis for Acute Ischaemic Stroke: Preliminary Experience with Recombinant Tissue Plasminogen Activator in the UK
Authors: Walters M.R. , Muir K.W. , Harbison J. , Lees K.R. , Ford G.A.
Published: October 2005

Objective: To present the preliminary experience of implementing intravenous thrombolytic therapy for acute ischaemic stroke in three UK stroke centres. Background: Recombinant tissue plasminogen activator for ischaemic stroke received approval from UK regulatory authorities in April 2003. Since 1997, a small number of UK centres had used thrombolytic therapy in highly selected stroke patients. We present the early experience of that treatment in Glasgow and Newcastle. Design: Patients were selected and treated in accordance with the American Heart Association guidelines. Additionally, radiologic criteria employed in the European-Australasian Acute Stroke Studies were applied.National Institutes of Health Stroke Scale (NIHSS) scores were measured on admission, and Modified Rankin Scale (MRS) scores were assessed at 3 months for all patients with stroke treated prior to initiation of the Safe Implementation of Thrombolysis in Stroke monitoring program for implementation of thrombolysis in stroke in April 2001. Intracranial and systemic haemorrhagic complications were recorded. Results: 120 patients received thrombolytic treatment (approximately 1% of all admissions with presumed stroke). Mean age was 69 years (range 22–93) and initial median NIHSS score was 17 (range 3–31). In the two centres for which temporal data were available, the mean delay between symptom onset and treatment was 139 min (range 20–185). Sixteen episodes of cerebral haemorrhage or haemorrhagic transformation of any degree occurred, of which 5 (4%) were symptomatic. One patient deteriorated and died before repeat CT imaging could be performed. One non-fatal episode of systemic bleeding occurred. One patient was lost to follow-up. At 3 months, 31% of recipients had achieved good (MRS 0–1) outcome, 22% moderate (MRS 2–3) outcome and 21% (MRS 4–5) poor outcome. Twenty-one per cent died within 3 months of stroke. Observed frequency of bleeding complications and protocol violations (6%) was similar to those reported elsewhere. Conclusion: A small proportion of stroke patients received thrombolytic treatment. Patients treated were more severely affected than in other published European and North American series. Outcomes and complications were consistent with experience elsewhere.
Spouses’ Quality of Life 1 Year after Stroke: Prediction at the Start of Clinical Rehabilitation
Authors: Visser-Meily Anne , Post Marcel , Schepers Vera , Lindeman Eline
Published: October 2005

Background and Purpose: The purpose of this prospective study was to identify early predictors of spouses’ quality of life at 1 year after stroke. Methods: At the start of clinical rehabilitation patient and caregiver characteristics, psychological factors, harmony in the relationship and social support were assessed. One year after stroke, caregiver burden (Caregiver Strain Index), life satisfaction (Life Satisfaction Checklist) and depressive symptoms (Goldberg Depression Scale) were assessed in 187 participants. Multiple regression analyses were performed. Results: About 80% of the spouses reported low quality of life on one or more of the measures; 52% reported depressive symptoms, 54% significant strain and only 50% was satisfied with life as a whole. The regression analysis identified ‘passive coping strategy of the caregiver’ as the most important predictor. ADL dependency was the only baseline patient characteristic significantly related to burden and life satisfaction, but explained just 0–4% of the variance. Conclusions: A large proportion of caregivers perceive impaired quality of life 1 year after stroke. Caregivers at risk should be identified at the start of rehabilitation by means of coping measurement instruments or selected anamneses on coping.
Effect of Generalized Sympathetic Activation by Cold Pressor Test on Cerebral Hemodynamics in Diabetics with Autonomic Dysfunction
Authors: Zvan B. , Zaletel M. , Pogacnik T. , Bajrovic F.F.
Published: October 2005

Background: We examined the effects of the cold pressor test on the cerebral circulation in diabetics with autonomic dysfunction without orthostatic hypotension using transcranial Doppler. Methods: Twenty diabetics with autonomic dysfunction and 19 age-matched healthy controls participated in the study. The mean arterial blood velocity was measured in the middle cerebral artery during the cold pressor test together with the mean arterial blood pressure. Results: The mean arterial blood velocity significantly (p < 0.01) increased during the 1st, 2nd, and 3rd min of the cold pressor test by 10.6, 14.1, and 13.4%, respectively, in the control subjects and by 5.8, 7.2, and 6.8%, respectively, in the diabetics. Simultaneously, the mean arterial blood pressure significantly (p < 0.01) increased by 12, 26, and 23%, respectively, in the controls and by 9.4, 12.4 and 12.9%, respectively, in the diabetics. The increases in the mean arterial velocity as well as in the mean arterial blood pressure were significantly higher in the controls than in the diabetics (p < 0.01). The change in the mean arterial blood pressure related significantly to the change in the mean arterial blood velocity both in the controls (p < 0.01, r = 0.76) and in the diabetics (p < 0.01; r = 0.59). The slope of the regression line was significantly steeper in the controls (b = 0.42, SE = 0.05) as compared with the diabetics with autonomic dysfunction (b = 0.27, SE = 0.05; p = 0.02). Moreover, also the relative increase in the cerebrovascular resistance index was higher in the controls than in the diabetics (p < 0.05). Conclusion: These findings in the diabetics with autonomic neuropathy, but without orthostatic hypotension, suggest a failure in the cerebral autoregulation due to impaired cerebrovascular neurogenic control.
Predictive Value of Soluble Intercellular Adhesion Molecule-1 for Risk of Ischemic Events in Individuals with Cerebrovascular Disease
Authors: Ehrensperger Eric , Minuk Jeffrey , Durcan Liam , Mackey Ariane , Wolfson Christina , Fontaine Anne-Marie , Côté Robert
Published: October 2005

Background and Purpose: Cellular adhesion molecules may play a critical role in the inflammatory process leading to atherosclerosis. The purpose of this study was to determine whether soluble intercellular adhesion molecule-1 (sICAM-1) is a predictor of future ischemic events in high-risk individuals and also whether it is associated with carotid artery stenosis. Methods: We conducted a prospective study of sICAM-1 concentration in 3 groups: (1) subjects with recent (<7 days) ischemic stroke or TIA, (2) asymptomatic subjects with carotid stenosis ≧ 50% and (3) asymptomatic individuals with vascular risk factors. Subjects were followed for a minimum of 3 years. sICAM-1 levels were compared between the groups and correlated with the risk of ischemic events and the degree of carotid artery stenosis. Results: We studied 275 subjects. Mean sICAM-1 levels were significantly higher in those with recent ischemic stroke or TIA compared to those with risk factors alone. During follow-up, ischemic events occurred almost nine times more frequently in subjects in group 1 compared to group 3. sICAM-1 concentration was not predictive of future ischemic events (OR 1.001, 95% CI 0.998–1.004). There was no significant association between sICAM-1 concentration and carotid artery stenosis (OR 1.001, 95% CI 0.999–1.004). Conclusions: Mean sICAM-1 levels were higher in subjects with recent cerebral ischemia. No association between sICAM-1 and carotid artery stenosis was observed. Neither baseline nor subsequent sICAM-1 levels were predictive of the risk of future ischemic events.
Superficial Temporal Artery Duplex Ultrasonography for Improved Cerebral Hemodynamics after Extracranial-Intracranial Bypass Surgery
Authors: Hirai Yuko , Fujimoto Shigeru , Toyoda Kazunori , Inoue Tooru , Uwatoko Takeshi , Makihara Noriko , Yasumori Kotaro , Ibayashi Setsuro , Iida Mitsuo , Okada Yasushi
Published: October 2005

Background: To investigate the utility of superficial temporal artery (STA) duplex ultrasonography (STDU) for evaluating the improvement of the cerebral hemodynamics after extracranial-intracranial (EC-IC) bypass. Methods: This study included 40 consecutive patients who underwent EC-IC bypass for occlusive disease of cerebral arteries. STDU was performed to measure the flow velocity, pulsatility index, and diameter of the operated STA before and 14 days after EC-IC bypass. Regional cerebral blood flow (rCBF) and acetazolamide (ACZ) reactivity of the ipsilateral middle cerebral artery (MCA) territory were evaluated by quantitative single-photon emission computed tomography with the ACZ challenge test. We investigated the correlation between STA flow velocity/diameter and rCBF/ACZ reactivity in the ipsilateral MCA territory. Results: Mean flow velocity (MFV; 26.3 ± 8.8 to 55.3 ± 16.3 cm/s, p < 0.0001) and diameter (1.57 ± 0.24 to 2.26 ± 0.29 mm, p < 0.0001) of the STA, and rCBF (29.1 ± 3.1 to 35.0 ± 6.4 ml/100 g/min, p < 0.0001) and ACZ reactivity (–0.02 ± 0.10 to 0.28 ± 0.21, p < 0.0001) of the MCA territory increased after EC-IC bypass compared with the baseline values. STA MFV was significantly correlated with the rCBF 14 days after EC-IC bypass (R = 0.70, p < 0.0001). A cutoff value of postsurgical STA MFV greater than 48.5 cm/s yielded the highest diagnostic accuracy (sensitivity 86%; specificity, 82%) for rCBF ≧32 ml/100 g/min after EC-IC bypass. Conclusions: STDU was available for evaluating postsurgical patency of the bypass flow and the rCBF of the ipsilateral MCA territory. The mean blood flow velocity of the operated STA is a highly sensitive parameter for predicting rCBF in the ipsilateral MCA territory after EC-IC bypass.
Nutritional and Hypoglycemic Effect of Fruit Pulp of Annona squamosa in Normal Healthy and Alloxan-Induced Diabetic Rabbits
Authors: Gupta Rajesh Kumar , Kesari Achyut Narayan , Watal Geeta , Murthy P.S. , Chandra Ramesh , Tandon Vibha
Published: October 2005

Thenutritive value of the pulp of the edible fruit of Annona squamosa and its effect on various biochemical parameters has been assessed in normal and alloxan-induced diabetic rats. Different doses (2.5, 5.0, 10.0 g/kg b.w.) of fresh fruit pulp of A. squamosa were given to the three groups each of normal healthy and diabetic rabbits orally daily for 1 month. There was a control group of normal as well as diabetic animals which did not receive fruit pulp. Protein efficiency ratio (PER), digestibility coefficient (DC), biological value (BV) and net protein utilization (NPU) were calculated and improvement in the nutritional level was studied by comparing with the control group. Effect of the fruit pulp was also studied on various biochemical parameters, namely fasting blood glucose (FBG), total cholesterol (TCH), HDL-cholesterol, triglyceride (TG), total protein (TPR), alkaline phosphatase (ALKP), serum glutamate oxaloacetate and pyruvate transaminases (SGOT and SGPT), serumcreatinine (CRTN) and serum bilirubin (BIL). Protein andglucose in urine were also estimated. Total hemoglobin and glycohemoglobin (HbAc) were estimated in blood before and after 1 month of feeding fruit pulp. Fruit pulp increased the net protein utilization by 29.3 in normal healthy rabbits with 10 g/kg b.w. and 34.1 in induced diabetic (induced by alloxan) animals with 5 g/kg b.w. of the fruit pulp feeding when compared with the control group of rabbits (p < 0.001). Feeding fruit pulp with the same amount increased the total hemoglobin content by 21.0% in normal rabbits and 10.8% in diabetic rabbits. Fruit pulp also reduced the total cholesterol level by 45–46% in normal and 32.4% in diabetic animals with increased HDL-cholesterol. Feeding pulp improved the liver function in normal as well as diabetic rabbit as shown by reduction in the serum SGOT, SGPT, ALKP and bilirubin levels. The optimal improvement in nutritive value of normal animals was found with 5.0–10.0 g/kg b.w. of the fruit pulp feeding, while in diabetic animals it was 2.5–5.0 g/kg b.w. In the diabetic animals pulp feeding between 2.5 and 5.0 g/kg b.w. showed improvement in the glucose tolerance. Further, 5 g/kg b.w. of fruit pulp brought down urine sugar, urine protein and glycohemoglobin in diabetic rabbits. Feeding pulp had increased utilization of dietary protein, body weight as well as the ratio of gain in body weight per gram of protein consumed. It had a protective effect on liver and heart as indicated by reduction in the SGOT, SGPT, ALKP and serum bilirubin levels.
Plasma Vasopressin, an Etiologic Factor of Motion Sickness in Rat and Human?
Authors: Li Xia , Jiang Zheng-Lin , Wang Guo-Hua , Fan Ji-Wei
Published: October 2005

Arginine vasopressin (AVP) is considered as an etiologic hormone in motion sickness. However, the possible role of plasma AVP in motion sickness is still controversial. A number of studies have found a gender difference in susceptibility to motion sickness in humans and experimental animals, with female subjects being more susceptible. However, the existence of a gender difference in the AVP response to motion sickness is not known. This study was designed to verify the assumption that plasma vasopressin plays a role in motion sickness.Changes in plasma vasopressin were observed after motion sickness-inducing rotatory stimuli in both sexes in human subjects and rats receiving or not antimotion sickness treatments. Plasma vasopressin levels in motion sickness rats exhibited a decrease after rotation in female, but not in male rats. The vasopressin content of the pituitary increased in both sexes. Plasma vasopressin in rats of both sexes tended to increase after a 15-day adaptive training of rotation, but pituitary vasopressin content was not affected under this condition. In contrast, in human subjects, plasma vasopressin levels increased after rotation in all males, but not in females. When antimotion sickness drugs (domperidone 10 mg + flunarizine 5 mg) were administered, plasma vasopressin levels were elevated in both females and males. It is concluded that plasma vasopressin increases after motion sickness-induced stimulation provided subjects have become trained to motion sickness. These results do not support an etiologic role of plasma vasopressin in the genesis of motion sickness.
Percutaneous Computed Tomography-Guided Transdiscal Low Cervical Cordotomy for Cancer Pain as a Method to Avoid Sleep Apnea
Authors: Raslan Ahmed M.
Published: October 2005

Objective: Study of percutaneous computed tomography (CT)-guided transdiscal low cervical cordotomy undertaken to treat pain in cancer patients. Methods: At the Department of Neurosurgery, Ain Shams University, Cairo, Egypt, 8 cancer pain patients, with either impaired pulmonary function or a previous cordotomy on an opposite side (sleep apnea was a feared complication) that prevented the possibility of undergoing a C1–2 cordotomy, underwent a percutaneous CT-guided transdiscal low cervical cordotomy (C4–5 or C5–6) to treat cancer pain. Results: Seven patients experienced initial improvement. One patient re-experienced pain within 2 weeks and 1 patient experienced no pain relief. In 6 patients in whom the cordotomy procedure was completed, satisfactory or complete pain relief, throughout a 6-month follow-up period was reported. In contrast, in 2 patients in whom the cordotomy was not completed there was no persistent pain relief. Conclusion: Percutaneous CT-guided cordotomy remains a successful procedure to control pain in cancer patients, and is an affordable viable option under circumstances where economic disadvantage is an overriding determinate.
Weaknesses in the classification criteria for antithrombotic-related major bleeding events
Authors: Gregory Elliott C. , Stoddard Gregory , Haug Peter , Lagor Charles
Published: October 2005

We asked two physicians to review the medical records (electronic and paper) of 100 patients on antithrombotics. The physicians used published classification criteria to identify all of the bleeding events that the patients experienced. The goal of the review was to investigate whether the physicians would identify the same antithrombotic related major bleeding events (ARMBEs) for each patient. The correct identification and classification of multiple bleeding events is a prerequisite for studies of antithrombotic treatment practices during hospitalization that predispose patients to ARMBEs. In addition, we were interested in the reasons for disagreement between the physicians, so that we could find ways of improving their agreement. The reviewers identified 299 bleeding events for the 100 patients. They disagreed on whether 29 of the events represented an ARMBE occurring during hospitalization. With a kappa statistic of 0.49 (95% confidence interval, 0.31 to 0.66) the agreement was moderate. The reviewers most often disagreed either because they misinterpreted the data (12 events) or because the classification criteria for ARMBEs were not explicit enough (9 events). Disagreement took two main forms: either the reviewers disagreed on ARMBEs by not identifying the same bleeds (11 events) or by not applying the severity criteria appropriately (7 events). Because the main type of disagreement was not identifying the same bleeds, a study investigating the antithrombotic treatment practices that predispose patients to ARMBEs would be threatened. We therefore proposed supplementing the existing classification criteria with additional rules to avoid ambiguities in patients with multiple events.
Analyses of cellular multimerin 1 receptors: in vitro evidence of binding mediated by αΙΙbβ3 and αvβ3
Authors: Adam Frédéric , Zheng Shilun , Joshi Nilesh , Kelton David , Sandhu Amin , Suehiro Youko , Jeimy Samira , Santos Aurelio , Massé Jean-Marc , Kelton John , Cramer Elisabeth , Hayward Catherine
Published: October 2005

Multimerin 1 (MMRN1) is a large, soluble, polymeric, factor V binding protein and member of the EMILIN protein family.In vivo, MMRN1 is found in platelets, megakaryocytes, endothelium and extracellular matrix fibers, but not in plasma. To address the mechanism of MMRN1 binding to activated platelets and endothelial cells, we investigated the identity of the major MMRN1 receptors on these cells using wild-type and RGE-forms of recombinant MMRN1. Ligand capture, cell adhesion, ELISA and flow cytometry analyses of platelet-MMRN1 binding, indicated that MMRN1 binds to integrins αIIbβ3 and αvβ3. Endothelial cell binding to MMRN1 was predominantly mediated by αvβ3 and did not require the MMRN1 RGD site or cellular activation. Like many other αvβ3 ligands, MMRN1 had the ability to support adhesion of additional cell types, including stimulated neutrophils. Expression studies, using a cell line capable of endothelial-like MMRN1 processing, indicated that MMRN1 adhesion to cellular receptors enhanced its extracellular matrix fiber assembly. These studies implicate integrin-mediated binding in MMRN1 attachment to cells and indicate that MMRN1 is a ligand for αIIbβ3 and αvβ3.
Plasma markers of angiogenesis in pregnancy induced hypertension
Authors: Nadar Sunil , Karalis Ioannis , Al Yemeni Eman , Blann Andrew , Lip Gregory
Published: October 2005

This study tests the hypothesis that abnormalities in plasma indices of angiogenesis, such as Vascular Endothelial Growth Factor (VEGF) and angiopoietins (Ang-1, Ang-2), as well as their soluble receptors Flt-1 (sflt-1) and Tie 2 (sTie-2) respectively, are present in women with in pregnancy-induced hypertension (PIH). We also measured platelet levels of VEGF and Ang-1 (pVEGF and pAng-1 respectively). We studied 69 consecutive women with PIH (34 without proteinuria, and 35 with proteinuria, i.e. preeclampsia) who were compared to 64 consecutive women with normotensive pregnancies and 30 normotensive non-pregnant women, in a cross-sectional study. Using ELISA, we measured levels of plasma VEGF, Ang-1 &2, Tie-2 and sflt-1, and also the levels of angiogenic markers within the platelet [platelet VEGF (pVEGF) and platelet Ang-1 (pAng1)] by lysing a fixed number of platelets with 0.5% tween. Results show that levels of plasma VEGF, Ang-1, Ang2, sFlt-1 and Tie-2 were significantly different between the study groups. Post hoc analyses revealed plasma Ang-1 was highest in the preeclampsia group (p<0.001), whilst Ang-2 was highest in the normotensive pregnant group (p-=0.018). Plasma Tie-2 was highest in the PIH group. VEGF levels were significantly different between the preeclampsia group and the PIH group (p<0.05). Platelet VEGF levels were higher in the non-pregnant group than in the pregnant group, but there were no significant differences in the platelet levels of Ang-1 between the different groups. Ang-2, sFlt-1 and Tie-2 were undetectable in the platelet lysate in any of the patient groups or controls. Blood pressure was a major determinant of the different angiogenic factors studied. Abnormal indices of angiogenesis are evident in PIH and preeclampsia, with higher levels of sFlt-1 and lower levels ofVEGF; in PIH, increased levels of Ang-1 and Tie-2, but reduced Ang-2, are evident compared to normal pregnancy. These abnormalities may have implications for the pathogenesis of PIH and preeclampsia.
Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss
Authors: Blumenfeld Zeev , Leiba Ronit , Lanir Naomi , Brenner Benjamin , Sarig Galit
Published: October 2005

Recurrent pregnancy loss (PL) is associated with maternal thrombophilia and prophylaxis with low molecular weight heparin (LMWH) can improve pregnancy outcome in this setting. The aim of this study was to investigate the modulation of systemic hemostatic parameters by enoxaparin in women with recurrent PL and to evaluate plasmatic parameters that would potentially enable monitoring LMWH prophylaxis effect during pregnancy. Study group included 87 women with thrombophilia and PL treated with enoxaparin 40 mg daily vs. 40 mg twice daily. The control group comprised 40 women with normal pregnancies. Blood samples have been collected throughout the period starting at 5-10 weeks of gestation until 6-10 weeks postpartum. The determined plasmatic markers included: anti-Xa activity, total and free tissue factor pathway inhibitor (TFPI), D-dimer, prothrombin fragment 1+2 (PT1+2), activated protein C resistance (APC-SR) and free protein S. Successful pregnancy outcome was recorded in 70 (80.5%) women treated with enoxaparin, with-out correlation to enoxaparin dosage. Seventeen women (19.5%) had pregnancy loss at 16±7 (6-32) weeks of gestation. Anti-Xa levels at 10-15 weeks of gestation were higher (0.39±0.38 u/ml) in the successful pregnancy outcome group compared to the abortion group (0.22±0.2 u/ml). Prophylactic anti-Xa activity levels (0.28±0.13 u/ml) were documented from 15 weeks of gestation until delivery in the successful pregnancy outcome group. Significant increase in anti-Xa, total TFPI and free TFPI levels (P<0.001) was achieved after beginning of LMWH prophylaxis in successful pregnancy outcome group but not in the abortion group. D-dimer and PT1+2 levels appeared to be significantly increased while APC-SR and free protein S levels gradually decreased during pregnancy, with no difference between study groups. These results suggest that LMWH prophylaxis during pregnancy enables modulation of systemic hemostatic parameters via inhibition of factor Xa and increase in plasmatic total and free TFPI levels.
Homocysteine and thrombosis: from basic science to clinical evidence
Authors: Brożek Jan , Szczeklik Andrzej , Undas Anetta
Published: October 2005

Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine. Rapidly accumulating evidence links elevated homocysteine levels to thrombosis via several mechanisms such as increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented factor V activity, impaired fibrinolytic potential, and vascular injury, including endothelial dysfunction. Molecular mechanisms underlying prothrombotic actions of homocysteine are incompletely understood and involve oxidative stress, DNA hypomethylation, and proinflammatory effects. Current evidence from retrospective and prospective studies supports the concept that higher total plasma homocysteine concentration is associated with increased risk of coronary artery disease, stroke, and venous thromboembolism. Hyperhomocysteinemia is currently considered a relatively weak prothrombotic factor. It is still unclear whether administration of vitamins, that reduce homocysteine levels acting as cofactors of the enzymes involved in the methionine metabolism, may decrease the risk of arterial and/or venous thromboembolic events. Ongoing clinical trials might help clarify this issue.
Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation
Authors: Hatada Tsuyoshi , Nobori Tsutomu , Okabayashi Kazuhiro , Maruyama Kazuo , Abe Yasunori , Uemoto Shinji , Yamada Shingo , Maruyama Ikuro , Wada Hideo
Published: October 2005

High Mobility Group Box chromosomal protein 1 (HMGB1) is a nuclear DNA-binding protein acting as a proinflammatory cytokine when released in the extracellular space from necrotic cells, activated macrophages and dendritic cells. HMGB1 acts on a specific receptor, RAGE (receptor for advanced glycation endproducts), and induces prolonged inflammation, organ failure, septicaemia and death. The aim of the study was to determine the diagnostic value of plasma HMGB1 concentration and its role in the development of organ failure in patients with disseminated intravascular coagulation (DIC). Plasma HMGB-1 levels were measured in patients with suspected DIC and their relationships with DIC, organ failure and clinical outcome were determined. The study took place at the intensive care facility, Mie University School of Medicine and comprised 201 patients with suspected DIC. Plasma HMGB1 was below the detection limit in normal subjects, but moderately elevated in patients with infectious diseases (4.54 ± 8.18 ng/ml, mean±SD), malignancies (2.15 ± 5.34 ng/ml), and traumas (6.47 ± 13.13 ng/ml). DIC was associated with significantly high plasma HMGB1 (14.05 ± 12.56 ng/ml) in these patients. The highest HMGBI levels were in patients with organ failure (8.29 ± 10.99 ng/ml) and non-survivors (16.58 ± 11.01 ng/ml). HMGB1 plasma levels correlated with the DIC score and sepsis-related organ failure assessment (SOFA) score. In conclusion, our data suggest that HMGB-1 is a potentially suitable prognostic marker of OF or DIC.
Fibrinogen Saint-Germain II: Hypofibrinogenemia due to heterozygous γ N345S mutation
Authors: de Mazancourt Philippe , Maghzal Ghassan , Brennan Stephen , Mosesson Michael , de Raucourt Emmanuelle
Published: October 2005

We have identified a novel heterozygous fibrinogen γ chain mutation, γN345S (Fibrinogen Saint-Germain II), in a subject with hypofibrinogenemia. There was no evidence by mass spectrometry of plasma fibrinogen containing the mutant chain. The hypofibrinogenemia was discovered in a 26-year-old man who experienced extensive deep venous thrombosis of the left leg associated with pulmonary embolism. Investigation of potential thromboembolic risk factors revealed heterozygosity of the factor V R506Q mutation (factor V Leiden) and heterozygosity of the prothrombin gene G20210A mutation. The hypofibrinogenemia may be contributory to the thrombophilic manifestations.
Circulating B-type natriuretic peptides in patients with acute coronary syndromes
Authors: Jarai Rudolf , Wojta Johann , Huber Kurt
Published: October 2005

Fifty percent of patients who experience death or develop heart failure after acute coronary syndromes (ACS) have extremely elevated concentrations of plasma B-type natriuretic peptides. These elevations, however, seem not to reflect permanent ventricular dysfunction or heart failure and are assumed to exist already at the onset of ischemic symptoms. The underlying mechanisms of BNP/Nt-proBNP elevations in patients withACS are still not known at present. Furthermore, the relationship of elevated BNP/Nt-proBNP with mortality but not with atherothrombotic complications of underlying disease makes it difficult to choose optimal therapeutic strategies based on plasma levels of these peptides. The remarkably high short- and long-term mortality rate associated with increases of BNP/Nt-proBNP elevations clearly show the need of further investigation to focus on this high-risk group of patients in order to clarify underlying pathomechanisms and to find optimal therapeutic approaches.
High levels of homocysteine, lipoprotein (a) and plasminogen activator inhibitor-1 are present in patients with abdominal aortic aneurysm
Authors: Marcucci Rossella , Giusti Betti , Pratesi Giovanni , Lari Barbara , Sestini Ilaria , Lo Sapio Patrizia , Pulli Raffaele , Pratesi Carlo , Abbate Rosanna , Franco Gensini Gian , Sofi Francesco
Published: October 2005

Over the last few years, there has been increasing interest in the investigation of the pathogenesis of AAA, and a role for some novel risk factors, in particular thrombophilic risk factors, has been suggested. The aim of this study was to evaluate a number of thrombophilic parameters in a large group of patients with AAA. In 438 patients with AAA, and in 438 healthy subjects, selected to be comparable for age and gender with patients and without instrumental evidence of AAA, a pattern of thrombophilic parameters [homocysteine (Hcy), lipoprotein (a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), anticardiolipin antibodies (ACA), MTHFR C677T polymorphism, prothrombin gene G20210A variant and Factor V Leiden mutation] has been evaluated. A significant difference for Hcy, PAI-1 and Lp(a) plas-After adjustment for the traditional cardiovascular risk factors, a significant increased risk of having AAA has been observed for high levels of Hcy (OR: 7.8; p<0.0001), Lp(a) (OR: 2.4; p<0.0001) and PAI-1 (OR:3.2;p<0.0001). The association has been confirmed after exclusion of patients with other localization of atherosclerosis. Moreover, a significant association between larger abdominal aortic diameters and the number of thrombophilic parameters has been reported (r = 0.13; p = 0.005). In conclusion, a significant association between abnormal levels of some metabolic parameters related to thrombosis such as Hcy, Lp(a) and PAI-1 and AAA has been observed.
Molecular Basis of Arrhythmias
Authors: Shah Manish , Akar Fadi G. , Tomaselli Gordon F.
Published: October 2005

The characterization of single gene disorders has provided important insights into the molecular pathogenesis of cardiac arrhythmias. Primary electricalal diseases including long-QT syndrome, short-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia have been associated with mutations in a variety of ion channel subunit genes that promote arrhythmogenesis. Pathological remodeling of ionic currents and network properties of the heart critical for normal electrical propagation plays a critical role in the initiation and maintenance of acquired arrhythmias. This review focuses on the molecular and cellular basis of electrical activity in the heart under normal and pathophysiological conditions to provide insights into the fundamental mechanisms of inherited and acquired cardiac arrhythmias. Improved understanding of the basic biology of cardiac arrhythmias holds the promise of identifying new molecular targets for the treatment of cardiac arrhythmias.
Genetic Inflammatory Factors Predict Restenosis After Percutaneous Coronary Interventions
Authors: Monraats Pascalle S. , Pires Nuno M.M. , Agema Willem R.P. , Zwinderman Aeilko H. , Schepers Abbey , de Maat Moniek P.M. , Doevendans Pieter A. , de Winter Robbert J. , Tio René A. , Waltenberger Johannes , Frants Rune R. , Quax Paul H.A. , van Vlijmen Bart J.M. , Atsma Douwe E. , van der Laarse Arnoud , van der Wall Ernst E. , Jukema J. Wouter
Published: October 2005

Background—

Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have identified genes that may predispose to restenosis, but confirmation by large prospective studies is lacking. Our aim was to identify polymorphisms and haplotypes in genes involved in inflammatory pathways that predispose to restenosis.

Methods and Results—

The GENetic DEterminants of Restenosis (GENDER) project is a multicenter prospective study, including 3104 consecutive patients after successful PCI. Forty-eight polymorphisms in 34 genes in pathways possibly involved in the inflammatory process were analyzed. The 16Gly variant of the β
2
-adrenergic receptor gave an increased risk of target vessel revascularization (TVR). The rare alleles of the CD14 gene (−260T/T), colony-stimulating factor 2 gene (117Thr/Thr), and eotaxin gene (−1328A/A) were associated with decreased risk of TVR. However, through the use of multiple testing corrections with permutation analysis, the probability of finding 4 significant markers by chance was 12%.

Conclusions—

Polymorphisms in 4 genes considered involved in the inflammatory reaction showed an association with TVR after PCI. Our results may contribute to the unraveling of the restenotic process. Given the explorative nature of this analysis, our results need to be replicated in other studies.
Vascular Endothelial Growth Factor Gene Therapy Increases Survival, Promotes Lung Angiogenesis, and Prevents Alveolar Damage in Hyperoxia-Induced Lung Injury
Authors: Thébaud Bernard , Ladha Faruqa , Michelakis Evangelos D. , Sawicka Monika , Thurston Gavin , Eaton Farah , Hashimoto Kyoko , Harry Gwyneth , Haromy Alois , Korbutt Greg , Archer Stephen L.
Published: October 2005

Background—

Bronchopulmonary dysplasia (BPD) and pulmonary emphysema, both significant global health problems, are characterized by a loss of alveoli. Vascular endothelial growth factor
(
VEGF) is a trophic factor required for endothelial cell survival and is abundantly expressed in the lung.

Methods and Results—

We report that VEGF blockade decreases lung VEGF and VEGF receptor 2 (VEGFR-2) expression in newborn rats and impairs alveolar development, leading to alveolar simplification and loss of lung capillaries, mimicking BPD. In hyperoxia-induced BPD in newborn rats, air space enlargement and loss of lung capillaries are associated with decreased lung VEGF and VEGFR-2 expression. Postnatal intratracheal adenovirus-mediated VEGF gene therapy improves survival, promotes lung capillary formation, and preserves alveolar development in this model of irreversible lung injury. Combined VEGF and angiopoietin-1 gene transfer matures the new vasculature, reducing the vascular leakage seen in VEGF-induced capillaries.

Conclusions—

These findings underscore the importance of the vasculature in what is traditionally thought of as an airway disease and open new therapeutic avenues for lung diseases characterized by irreversible loss of alveoli through the modulation of angiogenic growth factors.
The Influence of Meteorological Conditions on the Wet Deposition of Mercury in Southern Florida
Authors: Dvonch J. Timothy , Keeler Gerald J. , Marsik Frank J.
Published: October 2005

Source–receptor relationships for mercury (Hg) and other trace elements wet deposited in southeastern Florida were investigated using daily event precipitation samples collected over a 1-yr period in 1995–96. Data collected in Davie, Florida, showed significantly higher (2.2 times) volume-weighted mean (VWM) Hg concentrations during the spring and summer seasons relative to winter. A meteorological tracer analysis, utilizing the ratio of trace elements lanthanum (La) to cerium (Ce), determined that “feed” air to precipitation cells arriving at the site incorporated local urban emissions more frequently during the spring and summer seasons. Using Weather Surveillance Radar-1988 Doppler (WSR-88D) data, analysis of precipitation-cell path histories for events collected at 17 sites in southeastern Florida over 1 month in the summer of 1995 showed significantly higher (2.0 times) VWM Hg concentrations in events with easterly cell paths than in those with westerly paths for storms arriving at Everglades sites. Significantly higher VWM concentrations for known anthropogenic elements vanadium (V) and nickel (Ni) (oil combustion) and lead (Pb) and antimony (Sb) (waste incineration) were also observed in events with easterly paths. In addition, events arriving from the east (offshore) that impacted the coastal sites were significantly lower in Hg (a factor of 2.6) than were events from the east that impacted the urban sites (after events moved inland over emission sources). This study demonstrates that source–receptor relationships can be established by analyzing the meteorological conditions corresponding to each precipitation event, and it supports the previous finding that local anthropogenic sources played the dominant role in the wet deposition of Hg to southern Florida and the Everglades during the study period.
Validation of an Urban Surface Exchange Parameterization for Mesoscale Models—1D Case in a Street Canyon
Authors: Roulet Yves-Alain , Martilli Alberto , Rotach Mathias W. , Clappier Alain
Published: October 2005

A detailed urban parameterization scheme is used in and above a street canyon. To validate this new scheme, the model is run offline on a vertical column (one-dimensional simulations), using measurements from a 30-m-high tower for upper boundary conditions. Measurements were obtained during the intensive observation period of the Basel Urban Boundary Layer Experiment (BUBBLE). Vertical profiles of meteorological variables are simulated in the street canyon. The validation of the parameterization is made with measurements from the tower in the street canyon and directly above roof height. The results show that the urban parameterization scheme is able to catch most of the typical processes that are induced by an urban surface near the ground. The fit to measured profiles is improved in comparison with a model using the traditional approach for urban parameterization (variation of z0 to take into account the presence of a city).