bluuebunny/crossref_metadata_2025 huggingface dataset:
Controls on the spatial distribution of soil moisture and solute transport in a sloping reclamation cover
Authors: Kelln Chris , Barbour S. Lee , Qualizza Clara
Published: April 2008

A detailed field study was conducted to map the spatial distribution of soil moisture and salt transport within a sloping clay-rich reclamation cover overlying a saline-sodic shale overburden landform. The soil moisture data suggest that: lower-slope positions are wetter in spring due to the down-slope movement of surface run-off; infiltration occurs via preferential flow paths while the ground is frozen; and, interflow occurs along the cover–shale surface when the ground thaws. Soil moisture conditions also remain wetter in lower-slope positions throughout the summer and fall. Salt transport from the shale into the overlying cover is affected predominantly by soil moisture conditions and lateral groundwater flux. Quasi one-dimensional modelling of in situ profiles of pore-water Na+ concentration demonstrate that: (i) increased soil moisture conditions in lower-slope positions accelerate salt transport into the cover through diffusion; (ii) snow melt infiltration water bypasses the soil matrix higher in the cover profile; (iii) drier conditions in the mid- and upper-slope positions limit salt transport through diffusion; (iv) advection accelerates upward salt transport in lower-slope positions; and, (v) interflow and (or) deep percolation are key mechanisms mitigating vertical salt movement in lower- and upper-slope positions.
VceR negatively regulates the vceCAB MDR efflux operon and positively regulates its own synthesis in Vibrio cholerae 569B
Authors: Alatoom Adnan A. , Aburto Ricardo , Hamood Abdul N. , Colmer-Hamood Jane A.
Published: April 2008

The vceCAB (vce) operon encodes the multidrug resistance pump VceCAB (VCE), which contributes to resistance of Vibrio cholerae to carbonyl cyanide m-chlorophenylhydrazine (CCCP), deoxycholate, and pentachlorophenol by several-fold. vceR, which encodes the TetR-type repressor VceR and is divergently transcribed from vce, has been characterized in Escherichia coli . Detailed characterization of vceR in V. cholerae 569B confirmed the repressive effect of VceR on VCE function and indicated several novel features of VceR. Deletion of vceR increased resistance of strain 569B to CCCP and deoxycholate modestly, but did not affect resistance to pentachlorophenol. Transcriptional analysis revealed that vce expression was not only increased in strain 569BΔvceR::Ω by 2-fold but continued to rise throughout the growth cycle. Using a vceR–lux transcriptional fusion plasmid, we examined whether vceR is autoregulated in strain 569B. Expression of vceR from the vceR–lux fusion was significantly lower in strain 569BΔvceR::Ω than in strain 569B. In addition, exposure to CCCP reduced vceR expression from the vceR–lux fusion in strain 569B but not in strain 569BΔvceR::Ω. Despite differences in the VceR binding site in strain 569B from the previously recognized 28 bp sequence in V. cholerae CVD101, purified recombinant VceR bound to the 24 bp sequence from strain 569B. We propose that VceR modulates vce expression by binding in vivo to the 24 bp sequence within the vceR–vce intergenic region; unlike many TetR repressors that are negatively autoregulated, VceR positively regulates vceR expression in trans.
Occurrence of highly fluoroquinolone-resistant and methicillin-resistantStaphylococcus aureusin domestic animals
Authors: Lin Ann E. , Davies Julian E.
Published: April 2008

We describe phenotypic and genotypic analyses carried out on multidrug-resistant Staphylococcus aureus isolated from domestic animals. The sequence type ST239 methicillin-resistant Staphylococcus aureus isolated from dogs were highly resistant to fluoroquinolones, and new combinations of GyrA and GrlA mutations were identified. These findings are consistent with a role for animal carriage in the dissemination of important human pathogens in the community.
LUCAS-TYPE CONGRUENCES FOR CYCLOTOMIC ψ-COEFFICIENTS
Authors: SUN ZHI-WEI , WAN DAQING
Published: April 2008

Let p be any prime and a be a positive integer. For l, n ∈ {0,1,…} and r ∈ ℤ, the normalized cyclotomic ψ-coefficient [Formula: see text] is known to be an integer. In this paper, we show that this coefficient behaves like binomial coefficients and satisfies some Lucas-type congruences. This implies that a congruence of Wan is often optimal, and two conjectures of Sun and Davis are true.
HEIGHTS AND LOGARITHMIC gcd ON ALGEBRAIC CURVES
Authors: ABOUZAID MOURAD
Published: April 2008

Let F(x,y) be an irreducible polynomial over ℚ, satisfying F(0,0) = 0. Skolem proved that the integral solutions of F(x,y) = 0 with fixed gcd are bounded [13] and Walsh gave an explicit bound in terms of d = gcd (x,y) and F [16]. Assuming that (0,0) is a non-singular point of the plane curve F(x,y) = 0, we extend this result to algebraic solution, and obtain an asymptotic equality instead of inequality. We show that for any algebraic solution (α,β), the quotient h(α)/ log d is approximatively equal to degyF and the quotient h(β)/ log d to degxF; here h(·) is the absolute logarithmic height and d is the (properly defined) "greatest common divisor" of α and β.
WATT'S MEAN VALUE THEOREM AND CARMICHAEL NUMBERS
Authors: HARMAN GLYN
Published: April 2008

It is shown that Watt's new mean value theorem on sums of character sums can be included in the method described in the author's recent work [6] to show that the number of Carmichael numbers up to x exceeds x⅓ for all large x. This is done by comparing the application of Watt's original version of his mean value theorem [8] to the problem of primes in short intervals [3] with the problem of finding "small" primes in an arithmetic progression.
BOUNDS FOR A MEAN VALUE OF CHARACTER SUMS
Authors: WATT NIGEL
Published: April 2008

We obtain new upper bounds for the mean squared modulus of sums ∑n∈ℕAnχ(n), where the sequence (An) is fixed and the variable χ belongs to the set of non-principal Dirichlet characters for some modulus q. It is assumed that, for some M, some complex sequence (cm) satisfying cm= 0 for m ∉ (M/2,M], and some α(x) and β(y) (smooth functions with compact support), one has An= ∑uvm = nα(u)β(v)cm(n ∈ ℕ). There is a natural analogy between the bounds obtained and bounds on mean values of Dirichlet polynomials previously obtained by Deshouillers and Iwaniec. Our proofs make use of results from the spectral theory of automorphic functions, including the bound of Kim and Sarnak for the eigenvalues of Hecke operators acting on certain spaces of Maass cusp forms. The results depend on the size of P, the largest prime factor of q, and improve as logq(P) is diminished. In separate work, Harman has given an application of our results to the theory of Carmichael numbers.
ON THE BROKEN 1-DIAMOND PARTITION
Authors: MORTENSON ERIC
Published: April 2008

We introduce a crank-like statistic for a different class of partitions. In [4], Andrews and Paule initiated the study of broken k-diamond partitions. Their study of the respective generating functions led to an infinite family of modular forms, about which they were able to produce interesting arithmetic theorems and conjectures for the related partition functions. Here we establish a crank-like statistic for the broken 1-diamond partition and discuss its role in congruence properties.
ON AN EXTREMAL PROBLEM RELATED TO THE COMPLETENESS OF A SYSTEM OF EXPONENTIALS IN THE DISK
Authors: Braichev G. G. , Sherstyukov V. B.
Published: April 2008

In this paper, we pose several problems of finding the extremal ρ-type and the lower ρ-type of the canonical product with real positive zeros having prescribed averaged upper and/or lower ρ-density, ρ ∈ (0; 1). We obtain new results that can be considered as a development of the classical theorems on the connection between different growth characteristics of entire functions and densities of their distributions of zeros.
A STRUCTURE THEOREM FOR PERFECT ABUNDANT SEMIGROUPS
Authors: Guo Xiaojiang , Shum K. P.
Published: April 2008

The direct product of a cancellative monoid and a rectangular band is called a can-cellative plank. In this paper, we describe the semigroups which can be expressed as a strong semilattice of cancellative planks. Our result not only generalizes the well known 1951 Clifford theorem for completely regular semigroups having central idempotents, but also the theorem for C-rpp monoids, that is, left abundant monoids having central idempotents, given by Fountain in 1977. Some recent results of the authors concerning rpp semigroups belonging to a class we call perfect are strengthened.
ON THE GENERALIZED-LEE-RT-PSEUDO-METRIC (THE GLRTP-METRIC) ARRAY CODES CORRECTING BURST ERRORS
Authors: Jain Sapna
Published: April 2008

In [16], the author introduced a new pseudo-metric on the space Matm×s(Zq) which is the module space of all m × s matrices with entries from the finite ring Zq generalizing the classical Lee metric (see [17]) and the array RT- metric (see [19]) and named this pseudo-metric as the Generalized-Lee-RT-Pseudo-Metric (or the GLRTP-Metric). In this paper, we obtain some lower bounds for two dimensional array codes correcting burst errors (see [10]) with weight constraints under the GLRTP-metric.
Biochemistry and Physiology of Mammalian Secreted Phospholipases A2
Authors: Lambeau Gérard , Gelb Michael H.
Published: April 2008

Phospholipases A2 (PLA2s) are esterases that hydrolyze the sn-2 ester of glycerophospholipids and constitute one of the largest families of lipid hydrolyzing enzymes. The mammalian genome contains 10 enzymatically active secreted PLA2s (sPLA2s) and two sPLA2-related proteins devoid of lipolytic enzymatic activity. In addition to the well-established functions of one of these enzymes in digestion of dietary phospholipids and another in host defense against bacterial infections, accumulating evidence shows that some of these sPLA2s are involved in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. More speculative results suggest the involvement of one or more sPLA2s in promoting atherosclerosis and cancer. In addition, the mammalian genome encodes several types of sPLA2-binding proteins, and mounting evidence shows that sPLA2s may have functions related to binding to cellular target proteins in a manner independent of their lipolytic enzymatic activity.
The Efficiency of Cellular Energy Transduction and Its Implications for Obesity
Authors: Harper Mary-Ellen , Green Katherine , Brand Martin D.
Published: April 2008

We assess the existence, mechanism, and functions of less-than-maximal coupling efficiency of mitochondrial oxidative phosphorylation and its potential as a target for future antiobesity interventions. Coupling efficiency is the proportion of oxygen consumption used to make adenosine triphosphate (ATP) and do useful work. High coupling efficiency may lead to fat deposition; low coupling efficiency to a decrease in fat stores. We review obligatory and facultative energy expenditure and the role of a futile cycle of proton pumping and proton leak across the mitochondrial inner membrane in dissipating energy. Basal proton conductance is catalyzed primarily by the adenine nucleotide translocase but can be mimicked by chemical uncouplers. Inducible proton conductance is catalyzed by specific uncoupling proteins. We discuss the opportunities and pitfalls of targeting these processes as a treatment for obesity by decreasing coupling efficiency and increasing energy expenditure, either directly or through central mechanisms of energy homeostasis.
Exercise training enhances in vivo tuberculosis purified protein derivative response in the elderly
Authors: Okutsu Mitsuharu , Yoshida Yuko , Zhang Xiumin , Tamagawa Akira , Ohkubo Takayoshi , Tsuji Ichiro , Nagatomi Ryoichi
Published: April 2008

We investigated the effect of 25 wk of exercise training on in vivo immune measures that depend on T helper 1 (Th1) and T helper 2 (Th2) immune responses in the elderly as a substudy of a randomized controlled trial to investigate health benefits of regular exercise training for the elderly. Sixty-five healthy elderly volunteers were randomly assigned to either an exercise training group ( n = 32) or a sedentary control group ( n = 33). The area of skin reaction to purified protein derivative (PPD) of tuberculin that depends on Th1 activation and the concentrations of serum IgG subclasses and IgE were evaluated before and after 25-wk intervention. All participants completed 25 wk of training. Thirty-one participants of the exercise group and all control group underwent immunological analyses, but only 30 from the exercise group and 21 from the control group had the PPD skin reaction assessment. Repeated-measures ANOVA revealed a significant interaction between time and exercise intervention, which appeared as an enhanced skin reaction to tuberculin PPD ( P < 0.05) and a reduced serum IgG4 concentration, the production of which depends on Th2-dependent class switching ( P < 0.05), in the exercise group after 25 wk. No immune variables changed in the control group. These result supports the hypothesis that exercise training favors in vivo Th1 immune response in elderly persons.
Impact of intermittent hypoxia on long-term facilitation of minute ventilation and heart rate variability in men and women: do sex differences exist?
Authors: Wadhwa Harpreet , Gradinaru Ciprian , Gates Gregory J. , Badr M. Safwan , Mateika Jason H.
Published: April 2008

Following exposure to intermittent hypoxia, respiratory motor activity and sympathetic nervous system activity may persist above baseline levels for over an hour. The present investigation was designed to determine whether sustained increases in minute ventilation and sympathovagal (S/V) balance, in addition to sustained depression of parasympathetic nervous system activity (PNSA), were greater in men compared with women following exposure to intermittent hypoxia. Fifteen healthy men and women matched for age, race, and body mass index were exposed to eight 4-min episodes of hypoxia during sustained hypercapnia followed by a 15-min end-recovery period. The magnitude of the increase in minute ventilation during the end-recovery period, compared with baseline, was similar in men and women (men, 1.52 ± 0.03; women, 1.57 ± 0.02 fraction of baseline; P < 0.0001). In contrast, depression of PNSA and increases in S/V balance were evident during the end-recovery period, compared with baseline, in men (PNSA, 0.66 ± 0.06 fraction of baseline, P < 0.0001; S/V balance, 2.8 ± 0.7 fraction of baseline, P < 0.03) but not in women (PNSA, 1.27 ± 0.19 fraction of baseline, P = 0.3; S/V balance, 1.8 ± 0.6 fraction of baseline, P = 0.2). We conclude that a sustained increase in minute ventilation, which is indicative of long-term facilitation, is evident in both men and women following exposure to intermittent hypoxia and that this response is independent of sex. In contrast, sustained alterations in autonomic nervous system activity were evident in men but not in women.
Effects of chronic electrical stimulation on paralyzed expiratory muscles
Authors: DiMarco Anthony F. , Kowalski Krzysztof E.
Published: April 2008

Following spinal cord injury, the expiratory muscles develop significant disuse atrophy characterized by reductions in their weight, fiber cross-sectional area, and force-generating capacity. We determined the extent to which these physiological alterations can be prevented with electrical stimulation. Because a critical function of the expiratory muscles is cough generation, an important goal was the maintenance of maximal force production. In a cat model of spinal cord injury, short periods of high-frequency lower thoracic electrical spinal cord stimulation (SCS) at the T10 level (50 Hz, 15 min, twice/day, 5 days/wk) were initiated 2 wk following spinalization and continued for a 6-mo period. Airway pressure (P)-generating capacity was determined by SCS. Five acute, spinalized animals served as controls. Compared with controls, initial P fell from 43.9 ± 1.0 to 41.8 ± 0.7 cmH2O (not significant) in the chronic animals. There were small reductions in the weight of the external oblique, internal oblique, transverses abdominis, internal intercostal, and rectus abdominis muscles (not significant for each). There were no significant changes in the population of fast muscle fibers. Because prior studies (Kowalski KE, Romaniuk JR, DiMarco AF. J Appl Physiol 102: 1422–1428, 2007) have demonstrated significant atrophy following spinalization in this model, these results indicate that expiratory muscle atrophy can be prevented by the application of short periods of daily high-frequency stimulation. Because the frequency of stimulation is similar to the expected pattern of clinical use for cough generation, the daily application of electrical stimulation could potentially serve the dual purpose of maintenance of expiratory muscle function and airway clearance.
Multiplanar Computed Tomographic Analysis of the Frontal Recess Region in Chinese Subjects without Frontal Sinus Disease Symptoms
Authors: Han Demin , Zhang Luo , Ge Wentong , Tao Jianhua , Xian Junfang , Zhou Bing
Published: April 2008

The purposes of this study were to determine the prevalence of frontal-ethmoidal cells and to evaluate variation in the superior attachment of the uncinate process in Chinese subjects. 202 normal Chinese subjects (404 sides) underwent spiral computed tomography and multiplanar reconstruction images were evaluated. Agger nasi cells showed a prevalence of 94.1%. Of all the frontal cells identified in 159 sides (39.6%) of frontal recesses, the prevalence of type I, type II and type III cells was 24.4, 7.0 and 8.2%, respectively. Suprabullar, frontal bullar and interfrontal septal cells were identified in 148 sides (36.6%), 36 sides (9.0%) and 25 subjects (12.4%), respectively. 244 uncinate processes (60.4%) had 1 superior attachment and the remainder (39.6%) had 2 superior attachments. The prevalence of terminal recesses was 89.1%. Our results characterized normal frontal recess pneumatization patterns in Chinese subjects. That, together with variation in the superior attachment of the uncinate process, emphasized the role of agger nasi cells and the uncinate process in endoscopic frontal sinus surgery.
Magnesium Sulphate Therapy in Women with Pre-Eclampsia and Eclampsia in Kuwait
Authors: Omu A.E. , Al-Harmi J. , Vedi H.L. , Mlechkova L. , Sayed A.F. , Al-Ragum N.S.
Published: April 2008

Objective: To evaluate the outcome of the use of MgSO4 therapy in women with severe pre-eclampsia in Kuwait from January 2002 to December 2004. Subjects and Methods: The study involved 450 women managed at the Maternity Hospital in Kuwait with a blood pressure of 160/110 mm Hg and proteinuria of >0.3–5 g/24 h. A loading dose of 4 g MgSO4 was administered intravenously over 20 min and then the maintenance dose continued at 1 g/h for 24 h postpartum. Magnesium sulphate toxicity was monitored by urine output, deep tendon reflexes and serum magnesium levels and managed with an infusion of 10 ml of 10% calcium gluconate and cessation of magnesium infusion. Adjunct therapy included intravenous hydralazine 10 mg and labetalol 100 mg. The mode of delivery was determined after stabilizing the patient. Results: The women included Kuwaitis (n = 200, 44.4%), Asians (n = 129, 28.7%) and other Arabs (n = 116, 25.8%) with a mean age of 29.7 ± 6.7 years (primigravida: n = 233, 51.8%; other parities: n = 217, 48.2%). Antenatal complications included intra-uterine growth restriction (n = 136, 30.2%), oliguria (n = 39, 8.7%), haemolysis, elevated liver enzymes and low platelet count syndrome (n = 30, 6.6%), abruptio placentae (n = 20, 4.4%), eclampsia (n = 15, 3.3%), and preterm birth (n = 253, 55.2%). Caesarean section (n = 241, 53.6%) was the main mode of delivery. The perinatal mortality rate was 27 per 1,000. Magnesium sulphate toxicity observed as reduced tendon reflexes occurred in 14 (3.1%) patients and flushing, nausea and vomiting and blocked nostrils in 86 (19.1%). There was no association between adverse outcomes and maternal serum magnesium concentrations and no maternal mortality occurred. Conclusion: Magnesium sulphate was effective in preventing recurrence of eclamptic fits and safe for both mother and fetus.
Laparoscopic Removal of an Incidental Ectopic Liver: Short Report of a Case
Authors: Algin Cem , Yaylak Faik , Gurlek Olgun Esra , Caglikulekci Mehmet
Published: April 2008

Ectopic liver is a rare clinical entity, which may be rarely of clinical importance. It is generally reported to be small in size and without a connection to the mother liver. A case of an incidental ectopic liver nodule that was connected with a vascular peduncle to the Couinad segment IVa of the liver has been reported. Microscopic examination revealed chronic inflammatory changes, which should be considered to be the result of intermittent circulatory disturbances.
Some Observations on the Septum Pellucidum
Authors: Pearce J.M.S.
Published: April 2008

The thin, vertically placed partition consisting of two laminae separated by a narrow chink constitutes the cavity of the septum pellucidum, known from the time of Sylvius. Traumatic lesions in boxers, rare congenital expanding cysts causing hydrocephalus, and a number of septo-optic dysplasias give clinical significance to the septum and its related cavum.
Possession States in Northern Sri Lanka
Authors: Somasundaram Daya , Thivakaran T. , Bhugra Dinesh
Published: April 2008

Background: Possession states are still commonly seen in developing societies as acceptable cultural phenomena in normal persons as well as in those with psychiatric illness. ‘Possession’ is defined here as the experience of being taken over, controlled or occupied by another spirit or force. Sampling and Methods: This is a descriptive cross-sectional study of possession states among psychiatric patients, general population and popular adepts in Northern Sri Lanka, using semi-structured questionnaires and clinical observations. Results: Thirty psychiatric patients were identified as having possession states. They were compared with 30 controls each from the general population admitted to a general hospital outpatient department and selected popular adepts in the community. The latter are individuals who are well known as having possession states. An analysis of social factors and other variables showed that education, marital status, age, employment, strength of belief, alterations in personality, past or family psychiatric history, previous exposure to similar phenomena, help-seeking behavior and treatment outcome differed between the three groups. Religion of the subjects or recent changes in values showed no correlation with possession while monetary gain from possession states showed only a partial correlation. Western medical treatment was of value only when possession states were seen as part of psychotic illness. Discussion: Possession is a spectrum of experiential and behavioral phenomena seen in culturally acceptable form in normal people, popular adepts, as well as manifestations of psychotic illness. Possession states which fit normal cultural stereotypes could, if necessary, be better managed by traditional methods. However, clinicians need to be familiar with culturally abnormal forms of possession which are manifestations of psychotic illness that benefit from western psychiatric treatment.
Visual Perceptual Organization Deficits in Alzheimer’s Dementia
Authors: Uhlhaas Peter J. , Pantel Johannes , Lanfermann Heinrich , Prvulovic David , Haenschel Corinna , Maurer Konrad , Linden David E.J.
Published: April 2008

Background: Deficits in visual processing are a prominent feature of Alzheimer’s disease (AD), yet the cognitive and neuropathological mechanisms underlying these deficits are poorly understood. In the current study, we examined the hypothesis that perceptual organization is specifically impaired in AD compared to other dementias. Methods: We examined perceptual organization with a psychophysically well-controlled measure of contour integration in patients with AD (n = 17), vascular dementia (n = 5), frontotemporal dementia (n = 5) and mild cognitive impairment (n = 10) and 11 age-matched healthy controls. Results: Patients with AD differed significantly in their ability to detect contours comprised of Gabor elements as detection relied increasingly on long-range spatial interactions. Impairments in contour integration were particularly pronounced in AD patients with atrophy and gliosis of white matter in the occipital lobe. Deficits in perceptual organization were not found in patients with other dementias and participants with mild cognitive impairment. Conclusions: These results suggest that a subgroup of AD patients is characterized by a specific deficit in visual perceptual organization, which might reflect the impaired functional integrity of occipital cortico-cortical pathways.
Estrogen Receptor-α Variants Increase Risk of Alzheimer’s Disease in Women with Down Syndrome
Authors: Schupf Nicole , Lee Joseph H. , Wei Michelle , Pang Deborah , Chace Constance , Cheng Rong , Zigman Warren B. , Tycko Benjamin , Silverman Wayne
Published: April 2008

Background: Genetic variants that affect estrogen activity may influence the risk of Alzheimer’s disease (AD). Two tightly linked polymorphisms (PvuII and XbaI) in the first intron of estrogen receptor 1 (ESR1), the gene for ER-α, have been reported to influence estrogen receptor expression and may influence the risk of AD. Methods: We examined the relation of polymorphisms in ESR1 to the risk of AD in women with Down syndrome. The subjects (181 women with DS, 41–78 years of age) were followed at 14- to 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record reviews and neurological examinations was used to classify dementia. Genomic DNA was genotyped for 5 single-nucleotide polymorphisms in the upstream region and the first exon/intron of the ESR1 gene. Their association with dementia risk was evaluated, adjusting for covariates. Results: Women with at least 1 copy of the C allele at rs2234693 (PvuII) and those homozygous for the C allele at rs2077647 had an almost 3-fold increase in the risk of AD, compared with women without the C allele. The increased risks were independent of the apolipoprotein E genotype. Conclusion: These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.
Does Change in Gait while Counting Backward Predict the Occurrence of a First Fall in Older Adults?
Authors: Beauchet Olivier , Allali Gilles , Annweiler Cédric , Berrut Gilles , Maarouf Nabil , Herrmann François R. , Dubost Véronique
Published: April 2008

Background: Dual-task-based assessment tests failed to establish a dependable relationship between dual-task-related gait changes and the risk of falls in the elderly. Objective: The aim of this study was to examine whether changes in gait while counting backward could be associated with the occurrence of a first fall among older adults. Methods: Walking while counting backward was investigated prospectively in a cohort of 187 older adults living independently in senior housing facilities. During enrollment, walking time, number of steps, and frequency of lateral line stepping-over and stops were measured while walking only and while walking with backward counting aloud. Information on the incident falls during the follow-up year was collected monthly. Results: Walking time and the number of steps increased significantly under the dual-task condition compared to the single-task condition among fallers and non-fallers (p < 0.001). Compared to non-fallers, fallers had significantly lower scores in the Mini-Mental State Examination (p = 0.029) and higher scores in the 15-item Geriatric Depression Scale (p = 0.003) and Timed Up & Go Test (p = 0.006) and increased walking time under both walking conditions (p = 0.030 for single-task condition and p = 0.007 for dual-task condition). After adjusting for these variables, depressive symptoms (adjusted OR = 2.6 with p = 0.041 and adjusted OR = 2.5 with p = 0.045 when walking time while walking only and walking with backward counting is considered, respectively) and walking time while walking only (OR = 2.3 with p = 0.032) were significantly associated with falls. Conclusion: Dual-task-related gait changes were poorly associated with the occurrence of a first fall and provided no additional predictive value compared to gait performance under a single task, suggesting that changes in basic clinical gait parameters while counting backward are unsuccessful to predict the first fall among older adults.
Plasma-derived biological medicines used to promote haemostasis
Authors: Freedman John , Semple John W. , Ofosu Frederick A.
Published: April 2008

Several biological medicines derived from human and animal plasmas can effectively improve haemostasis in individuals with inherited or acquired defects in haemostasis. Factor VIII and factor VIII/vWF and factor IX concentrates are used to treat haemophilia A, von Willebrand disease and hemophilia B respectively. Cryoprecipitates are used to treat hypofibrinogenemia and von Willebrand disease where desmopressin (DDAVP) is ineffective or when plasma-derived factor VIII/vWF concentrates are unavailable. Thrombin-containing topical haemostatic agents and fibrin sealants are used to control perioperative bleeding. Intravenous immunoglobulin has several uses, including management of patients with autoimmune thrombocytopenias and patients with acquired factor VIII deficiency. Similar to most protein- based biological medicines, all the above products can elicit some level of antibody response, with clinical consequences that vary from mild anaphylaxis to loss of product efficacy. An ongoing potential safety concern with any biological medicine derived from blood/plasma is transmission of blood-borne pathogens. This safety concern has lessened significantly in the past decade as a result of the institution of more effective pre- and post-donation screening that tests for potential pathogens, and institution of pathogen reduction strategies to which many plasma-derived biological medicines are now routinely subjected. This article considers the manufacture, standardization, clinical efficacy and adverse event profiles of the plasma-derived biological medicines currently used to promote haemostasis in patients with inherited or acquired functional defects in haemostasis. It also considers approaches employed to minimize infectivity of biological medicines derived from human and animal plasmas and to manage patients who develop antibodies (inhibitors) to clotting factor concentrate infusions.
Recombinant clotting factors
Authors: Pipe Steven
Published: April 2008

The recombinant era for haemophilia began in the early 1980s with the cloning and subsequent expression of functional proteins for both factors VIII and IX. Efficient production of recombinant clotting factors in mammalian cell culture systems required overcoming significant challenges due to the complex post-translational modifications that were integral to their procoagulant function. The quick development and commercialization of recombinant clotting factors was, in part, facilitated by the catastrophic impact of viral contamination of plasma-derived clotting factor concentrates at the time. Since their transition into the clinic, the recombinant versions of both factor VIII and IX have proven to be remarkable facsimiles of their plasma-derived counterparts. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. The development of recombinant VIIa was a further advance bringing a recombinant option to haemophilia patients with inhibitors. Recombinant DNA technology remains the platform to address ongoing challenges in haemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. In turn, the ongoing development of new recombinant clotting factor concentrates is providing alternatives for patients with other inherited bleeding disorders.
The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors
Authors: Rehak Matus , Rehak Jiri , Müller Marc , Faude Susanne , Faude Frank , Siegemund Annelie , Krcova Vera , Slavik Ludek , Hasenclever Dirk , Scholz Markus , Wiedemann Peter
Published: April 2008

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62–3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19–2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.
Automated registration of tail bleeding in rats
Authors: Henriksen Lars , Andresen Per , Lauritzen Brian , Jensen Kåre , Juhl Trine , Tranholm Mikael , Johansen Peter
Published: April 2008

An automated system for registration of tail bleeding in rats using a camera and a user-designed PC-based software program has been developed. The live and processed images are displayed on the screen and are exported together with a text file for later statistical processing of the data allowing calculation of e.g. number of bleeding episodes, bleeding times and bleeding areas. Proof-of-principle was achieved when the camera captured the blood stream after infusion of rat whole blood into saline. Suitability was assessed by recording of bleeding profiles in heparintreated rats, demonstrating that the system was able to capture on/off bleedings and that the data transfer and analysis were conducted successfully. Then, bleeding profiles were visually recorded by two independent observers simultaneously with the automated recordings after tail transection in untreated rats. Linear relationships were found in the number of bleedings, demonstrating, however, a statistically significant difference in the recording of bleeding episodes between observers. Also, the bleeding time was longer for visual compared to automated recording. No correlation was found between blood loss and bleeding time in untreated rats, but in heparinized rats a correlation was suggested. Finally, the blood loss correlated with the automated recording of bleeding area. In conclusion, the automated system has proven suitable for replacing visual recordings of tail bleedings in rats. Inter-observer differences can be eliminated, monotonous repetitive work avoided, and a higher through-put of animals in less time achieved. The automated system will lead to an increased understanding of the nature of bleeding following tail transection in different rodent models.
Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy
Authors: Marcucci Rossella , Caporale Roberto , Paniccia Rita , Romano Eloisa , Gensini Gian Franco , Abbate Rosanna , Gori Anna Maria , Cesari Francesca
Published: April 2008

A high platelet turnover rate produce a population of immature reticulated platelets (RP) that could confer, despite of antiplatelet drugs, a residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. To assess the influence of RP on platelet reactivity in CAD patients on dual antiplatelet therapy we measured RP in 372 patients by using the Sysmex XE-2100 haematology analyzer and platelet function by optical platelet aggregometry (PA) on platelet-rich-plasma induced by 1 mmol arachidonic acid (AA-PA) and 10 μM ADP (ADP-PA). RPR was defined as either AA-PA >20% or ADP-PA >70%. RP were expressed as a percentage of RP of the total optical platelet count (immature platelet fraction; IPF) and as the percentage of RP highly fluorescent (higly fluorescent immature platelet fraction; H-IPF). Moderate but significant positive correlations between PA, IPF, H-IPF, and mean platelet volume (MPV) were found. According to tertiles of IPF, H-IPF and MPV, a significant trend for an increase of platelet aggregation by AA and ADP was evidenced. Furthermore, a significant difference for IPF, H-IPF and MPV between patients with and without RPR was observed. A linear regression analysis showed that IPF, H-IPF and MPV significantly affected PA measured by AA and ADP. At multivariate linear regression analysis these associations were confirmed. Moreover, a logistic regression analysis demonstrated that IPF, H-IPF and MPV significantly influenced the risk of RPR, and in the multivariate model these results remained significant. This study indicates that a high rate of platelet turnover is a new mechanism associated with platelet reactivity in high risk CAD patients on dual antiplatelet therapy.
Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects
Authors: Vince Rebecca , Sandström Marie , Taylor Lee , McNaughton Lars , Laden Gerard , Madden Leigh
Published: April 2008

An increased risk of death or severe injury due to late-morning thrombotic events is well established. Tissue factor (TF) is the initiator of the coagulation cascade, and endothelial stresses, coupled with production of pro-coagulant microparticles (MP) are also important factors in loss of haemostasis. TF and vascular cell adhesion molecule-1 (VCAM-1) -positive cell microparticles were assessed periodically over a 24-hour (h) period in healthy human subjects to ascertain if they followed a circadian rhythm. Eleven healthy male subjects were assessed in a temperature-controlled environment with dietary intake consistent between subjects. Blood samples were taken every 4 h by venipuncture, and TF and VCAM-1 positive microparticles were quantified by flow cytometry. A significant circadian rhythm was observed in VCAM-1 MP (p=<0.0001), and a trend was shown, although not statistically significant (p=0.065) in TF microparticles. A peak was observed at 9 a.m. for VCAM-1 positive MP, followed by a decrease and subsequent peak at 9 p.m. and a minimum at 5 a.m. TF-positive MP followed a strikingly similar trend in both variation and absolute numbers with a delay. A circadian rhythm was observed in VCAM-1 and less so TF-positive MP. This has significant implications in terms of the well known increased risk of cardiovascular thrombotic events matching this data. To our knowledge this is the first such report of quantified measurements of these MP over a 24-h period and the only measurement of a 24-h variation of in-vivo blood-borne TF.
Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism
Authors: Kulle Bettina , Luxembourg Beate , Blouin Katja , Spannagl Michael , Lindhoff-Last Edelgard , Berger Mario , Moscatelli Henriette , Schambeck Christian
Published: April 2008

A suggestive locus on chromosome 8 could be shown to be associated with familial high factor VIII (FVIII) levels in venous thromboembolism. The ADAMDEC 1 gene is a candidate expressing an ectodomain sheddase. However, the ectodomain of the clearance receptor for FVIII, the low-density lipoprotein receptor-related protein (LRP), is subject to proteolysis by metalloproteases like ADAMDEC1. Other LRP-interacting proteins are lipoprotein lipase (LPL) and t-PA. For an association study, 165 thrombotic patients with high FVIII levels (from the MAISTHRO, i.e. Main-Isar-thrombosis register) were included. All patients with known causes for high FVIII levels had been previously excluded. The patients were compared with 214 healthy blood donors. Polymorphisms with usually a minor allele frequency > 5 %, i.e. 24 SNPs and two insertion/deletion polymorphisms of LPL gene, eight SNPs of the t-PA gene, and five SNPs of the ADAMDEC1 gene, were analyzed. Haplotype differences were calculated using PHASE. A new polymorphism in intron 7 of the t-PA gene with a minor allele frequency of 2.2% was identified. Analysis of each SNP by the Cochrane-Armitage trend test did not show any significant association between genotype and disease status. Interestingly, the ADAMDEC1 haplotype (rs12674766, rs10087305, rs2291577, rs2291578, rs3765124) differed between cases and controls (p=0.04). In particular, the TGTGG haplotype showed a difference. In conclusion, the ADAMDEC 1 haplotype may indicate an underlying mechanism for high FVIII levels. The only moderate linkage disequilibrium may be due to a possible causal polymorphism in distant introns or the promoter region against a polygenic background.
Modulation of Endothelial Cell K
Ca
3.1 Channels During Endothelium-Derived Hyperpolarizing Factor Signaling in Mesenteric Resistance Arteries
Authors: Dora Kim A. , Gallagher Nicola T. , McNeish Alister , Garland Christopher J.
Published: April 2008

Arterial hyperpolarization to acetylcholine (ACh) reflects coactivation of K
Ca
3.1 (IK
Ca
) channels and K
Ca
2.3 (SK
Ca
) channels in the endothelium that transfers through myoendothelial gap junctions and diffusible factor(s) to affect smooth muscle relaxation (endothelium-derived hyperpolarizing factor [EDHF] response). However, ACh can differentially activate K
Ca
3.1 and K
Ca
2.3 channels, and we investigated the mechanisms responsible in rat mesenteric arteries. K
Ca
3.1 channel input to EDHF hyperpolarization was enhanced by reducing external [Ca
2+
]
o
but blocked either with forskolin to activate protein kinase A or by limiting smooth muscle [Ca
2+
]
i
increases stimulated by phenylephrine depolarization. Imaging [Ca
2+
]
i
within the endothelial cell projections forming myoendothelial gap junctions revealed increases in cytoplasmic [Ca
2+
]
i
during endothelial stimulation with ACh that were unaffected by simultaneous increases in muscle [Ca
2+
]
i
evoked by phenylephrine. If gap junctions were uncoupled, K
Ca
3.1 channels became the predominant input to EDHF hyperpolarization, and relaxation was inhibited with ouabain, implicating a crucial link through Na
+
/K
+
-ATPase. There was no evidence for an equivalent link through K
Ca
2.3 channels nor between these channels and the putative EDHF pathway involving natriuretic peptide receptor-C. Reconstruction of confocal z-stack images from pressurized arteries revealed K
Ca
2.3 immunostain at endothelial cell borders, including endothelial cell projections, whereas K
Ca
3.1 channels and Na
+
/K
+
-ATPase α
2
/α
3
subunits were highly concentrated in endothelial cell projections and adjacent to myoendothelial gap junctions. Thus, extracellular [Ca
2+
]
o
appears to modify K
Ca
3.1 channel activity through a protein kinase A–dependent mechanism independent of changes in endothelial [Ca
2+
]
i
. The resulting hyperpolarization links to arterial relaxation largely through Na
+
/K
+
-ATPase, possibly reflecting K
+
acting as an EDHF. In contrast, K
Ca
2.3 hyperpolarization appears mainly to affect relaxation through myoendothelial gap junctions. Overall, these data suggest that K
+
and myoendothelial coupling evoke EDHF-mediated relaxation through distinct, definable pathways.
DP-b99, a Membrane-Activated Metal Ion Chelator, as Neuroprotective Therapy in Ischemic Stroke
Authors: Diener Hans-Christoph , Schneider Dietmar , Lampl Yair , Bornstein Natan M. , Kozak Alexander , Rosenberg Gilad
Published: April 2008

Background and Purpose—

DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke.

Methods—

One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed.

Results—

No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99– and 75 placebo-treated patients in the intent-to-treat cohort was (mean±SD) 12.2±4.0 and 12.6±3.3, respectively; the time to needle (mean±SD) was 6:36±1:47 and 6:28±1:33 hours, respectively; and the age (mean±SD) was 73.3±9.9 and 72.0±9.6 years, respectively. The 90-day median change from baseline (the primary end point) was −6.0 and −5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (
P
=0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (
P
=0.03).

Conclusions—

In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex.