bluuebunny/crossref_metadata_2025 huggingface dataset:
TNF-α neutralization ameliorates obstruction-induced renal fibrosis and dysfunction
Authors: Meldrum K. K. , Misseri R. , Metcalfe P. , Dinarello C. A. , Hile K. L. , Meldrum D. R.
Published: December 2006

Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of TNF-α to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 h. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF-α expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-β1expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), α-smooth muscle actin accumulation (immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western blot). In a separate arm, the glomerular filtration rate (inulin clearance) of rats subjected to unilateral ureteral obstruction in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF-α and transforming growth factor-β1levels, collagen I and IV activity, interstitial volume, α-smooth muscle actin accumulation, angiotensinogen expression, and renal dysfunction, whereas treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF-α mediates obstruction-induced renal fibrosis and identify TNF-α neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.
Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep
Authors: Bennet Laura , Roelfsema Vincent , Dean Justin M. , Wassink Guido , Power Gordon G. , Jensen Ellen C. , Gunn Alistair Jan
Published: December 2006

The preterm fetus is capable of surviving prolonged periods of severe hypoxia without neural injury for much longer than at term. To evaluate the hypothesis that regulated suppression of brain metabolism contributes to this remarkable tolerance, we assessed changes in the redox state of cytochrome oxidase (CytOx) relative to cerebral heat production, and cytotoxic edema measured using cerebral impedance, during 25 min of complete umbilical cord occlusion or sham occlusion in fetal sheep at 0.7 gestation. Occlusion was followed by rapid, profound reduction in relative cerebral oxygenation and EEG intensity and an immediate increase in oxidized CytOx, indicating a reduction in electron flow down the mitochondrial electron transfer chain. Confirming rapid suppression of cerebral metabolism there was a loss of the temperature difference between parietal cortex and body at a time when carotid blood flow was maintained at control values. As occlusion continued, severe hypotension/hypoperfusion developed, with a further increase in CytOx levels to a plateau between 8 and 13 min and a progressive rise in cerebral impedance. In conclusion, these data strongly suggest active regulation of cerebral metabolism during the initial response to severe hypoxia, which may help to protect the immature brain from injury.
A theoretical model of selective cooling using intracarotid cold saline infusion in the human brain
Authors: Konstas Angelos-Aristeidis , Neimark Matthew A. , Laine Andrew F. , Pile-Spellman John
Published: December 2006

A three-dimensional mathematical model was developed to examine the transient and steady-state temperature distribution in the human brain during selective brain cooling (SBC) by unilateral intracarotid freezing-cold saline infusion. To determine the combined effect of hemodilution and hypothermia from the cold saline infusion, data from studies investigating the effect of these two parameters on cerebral blood flow (CBF) were pooled, and an analytic expression describing the combined effect of the two factors was derived. The Pennes bioheat equation used the thermal properties of the different cranial layers and the effect of cold saline infusion on CBF to propagate the evolution of brain temperature. A healthy brain and a brain with stroke (ischemic core and penumbra) were modeled. CBF and metabolic rate data were reduced to simulate the core and penumbra. Simulations using different saline flow rates were performed. The results suggested that a flow rate of 30 ml/min is sufficient to induce moderate hypothermia within 10 min in the ipsilateral hemisphere. The brain with stroke cooled to lower temperatures than the healthy brain, mainly because the stroke limited the total intracarotid blood flow. Gray matter cooled twice as fast as white matter. The continuously falling hematocrit was the main time-limiting factor, restricting the SBC to a maximum of 3 h. The study demonstrated that SBC by intracarotid saline infusion is feasible in humans and may be the fastest method of hypothermia induction.
Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β3-adrenoceptor
Authors: Gu Qihai , Lin You-Shuei , Lee Lu-Yuan
Published: December 2006

This study was carried out to determine whether epinephrine alters the sensitivity of rat vagal sensory neurons. In anesthetized rats, inhalation of epinephrine aerosol (1 and 5 mg/ml, 3 min) induced an elevated baseline activity of pulmonary C fibers and enhanced their responses to lung inflation (20 cmH2O, 10 s) and right atrial injection of capsaicin (0.5 μg/kg). In isolated rat nodose and jugular ganglion neurons, perfusion of epinephrine (3 μM, 5 min) alone did not produce any detectable change of the intracellular Ca2+concentration. However, immediately after the pretreatment with epinephrine, the Ca2+transients evoked by chemical stimulants (capsaicin, KCl, and ATP) were markedly potentiated; for example, capsaicin (50 nM, 15 s)-evoked Ca2+transient was increased by 106% after epinephrine ( P < 0.05; n = 11). The effect of epinephrine was mimicked by either BRL 37344 (5 μM, 5 min) or ICI 215,001 (5 μM, 5 min), two selective β3-adrenoceptor agonists, and blocked by SR 59230A (5 μM, 10 min), a selective β3-adrenoceptor antagonist, whereas pretreatment with phenylephrine (α1-adenoceptor agonist), guanabenz (α2-adrenoceptor agonist), dobutamine (β1-adrenoceptor agonist), or salbutamol (β2-adrenoceptor agonist) had no significant effect on capsaicin-evoked Ca2+transient. Furthermore, pretreatment with SQ 22536 (100–300 μM, 15 min), an adenylate cyclase inhibitor, and H89 (3 μM, 15 min), a PKA inhibitor, completely abolished the potentiating effect of epinephrine. Our results suggest that epinephrine enhances the excitability of rat vagal chemosensitive neurons. This sensitizing effect of epinephrine is likely mediated through the activation of β3-adrenoceptor and intracellular cAMP-PKA signaling cascade.
Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin
Authors: Tsai Wilson S. , Yeow Wen-Shuz , Chua Alex , Reddy Rishindra M. , Nguyen Duc M. , Schrump David S. , Nguyen Dao M.
Published: December 2006

Although expressing adequate levels of functional tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of cancer cells exhibit resistance to the cytotoxic effect of this ligand. Exposure of Apo2L/TRAIL-refractory cancer cells to cytotoxic chemotherapeutic agents enhances their sensitivity to Apo2L/TRAIL cytotoxicity. This study aims to elucidate the molecular mechanism responsible for the cisplatin-mediated enhancement of Apo2L/TRAIL sensitivity in cultured esophageal cancer cells. Exposure of cancer cells to sublethal concentrations of cisplatin resulted in profound potentiation of their susceptibility to Apo2L/TRAIL cytotoxicity as indicated by 2- to >20-fold reduction in Apo2L/TRAIL IC50 values. Significant activation of caspase-8, caspase-9, and caspase-3 was observed only in cells treated with cisplatin/Apo2L/TRAIL combination and not in those exposed to either agent alone. More importantly, activation of these key caspases was significantly abrogated by overexpression of Bcl2 or by the selective caspase-9 inhibitor. This observation strongly suggested that caspase-8 activation in cells treated with the cisplatin/Apo2L/TRAIL combination was secondary to the mitochondria-mediated amplification feedback loop and activation of the executioner caspase-3 was dependent on the recruitment of the intrinsic pathway characteristic of the type II cell. Profound combination-mediated cytotoxicity and induction of apoptosis was completely suppressed either by Bcl2 overexpression or by inhibition of caspase-9 activity, which conclusively pointed to the essential role of the mitochondria-dependent death signaling cascade in this process. Cisplatin sensitizes esophageal cancer cells to Apo2L/TRAIL cytotoxicity by potentiation of the mitochondria-dependent death signaling pathway that leads to amplification of caspase activation, particularly caspase-8, by the feedback loop to efficiently induce apoptosis. [Mol Cancer Ther 2006;5(12):2977–90]
Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib
Authors: Williamson Mark J. , Blank Jonathan L. , Bruzzese Frank J. , Cao Yueying , Daniels J. Scott , Dick Lawrence R. , Labutti Jason , Mazzola Anne M. , Patil Ashok D. , Reimer Corinne L. , Solomon Marjorie S. , Stirling Matthew , Tian Yuan , Tsu Christopher A. , Weatherhead Gabriel S. , Zhang Julie X. , Rolfe Mark
Published: December 2006

Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated. [Mol Cancer Ther 2006;5(12):3052–61]
Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells
Authors: Lee Ju-Hee , Park Jung-Hyun , Jung Yeonjoo , Kim Jee-Hyun , Jong Hyun-Soon , Kim Tae-You , Bang Yung-Jue
Published: December 2006

Thymidylate synthase (TS) overexpression is a key determinant of 5-fluorouracil (5-FU) resistance in human cancer cells. TS is also acutely up-regulated with 5-FU treatment, and, thus, novel strategies targeting TS down-regulation seem to be promising in terms of modulating 5-FU resistance. Here, we report that histone deacetylase inhibitors can reverse 5-FU resistance by down-regulating TS. By using cDNA microarrays and validation experiments, we found that trichostatin A reduced the expression of both TS mRNA and TS protein. Cotreatment with trichostatin A and cycloheximide restored TS mRNA expression, suggesting that TS mRNA is repressed through new protein synthesis. On the other hand, TS protein expression was significantly reduced by lower doses of trichostatin A (50 nmol/L). Mechanistically, TS protein was found to interact with heat shock protein (Hsp) complex, and trichostatin A treatment induced chaperonic Hsp90 acetylation and subsequently enhanced Hsp70 binding to TS, which led to the proteasomal degradation of TS protein. Of note, combined treatment with low-dose trichostatin A and 5-FU enhanced 5-FU–mediated cytotoxicity in 5-FU–resistant cancer cells in accordance with TS protein down-regulation. We conclude that a combinatorial approach using histone deacetylase inhibitors may be useful at overcoming 5-FU resistance. [Mol Cancer Ther 2006;5(12):3085–95]
Depressive Symptoms in Machado-Joseph Disease (SCA3) Patients and Their Relatives
Authors: Cecchin C.R. , Pires A.P. , Rieder C.R. , Monte T.L. , Silveira I. , Carvalho T. , Saraiva-Pereira M.L. , Sequeiros J. , Jardim L.B.
Published: December 2006

Objectives: It was the aim of this study to determine the depression scores of Machado-Joseph disease (MJD) patients, their spouses, and individuals at 50% risk for MJD, and second, to verify the existence of a correlation between depressive symptoms and the degree of motor incapacitation. Subjects and Methods: Two hundred and forty-six individuals aged ≧18 years were studied: 79 MJD patients (group 1), 43 spouses of MJD patients (group 2), 80 individuals at risk for MJD (group 3), and a control group (group 4) composed of 44 patients with multiple sclerosis (MS). The following two tools were applied: the Beck Depression Inventory and the Barthel index of physical incapacitation, both in an adapted Brazilian Portuguese version. Results: Moderate to severe depressive scores were found in 33.5% of patients in the MJD families, in 16.3% of the spouses, and in 6.3% of the individuals at risk. This linear reduction between MJD family members was statistically significant (p < 0.0001, ANOVA). Depressive scores were also associated with age and the female sex. A direct correlation between Beck Depression Inventory scores and motor incapacitation was found in MJD patients (r = 0.507, Pearson correlation, p < 0.0001). Although the depressive symptoms in the control group with MS were higher than those found in MJD patients (59% of MS patients showed moderate to severe scores), depression did not correlate with physical incapacitation, age, or education attainment in the MS group. Conclusions: Depressive symptoms are rather common in MJD patients and in their spouses (caregivers). In this condition, depression seemed to be more reactive than primarily related to the disease process itself.
Frequency of CYP2C9 Genotypes among Omani Patients Receiving Warfarin and Its Correlation with Warfarin Dose
Authors: Tanira Musbah O. , Al-Mukhaini Mohammed K. , Al-Hinai Ali T. , Al Balushi Khalid A. , Ahmed Ikhlas S.
Published: December 2006

Objectives: This study was conducted to determine the frequency of CYP2C9 alleles in Omani patients receiving warfarin and to correlate genotyping data with warfarin dosage. The Omani population has Asian and African ethnicities. Methods: CYP2C9 genotypes were determined by the polymerase chain reaction restriction fragment length polymorphism method. Non-parametric Kruskal-Wallis test was used to compare groups of continuous data for significance differences. Results: Genotyping data showed that 12.7 and 5.8% of the samples were heterozygous for the CYP2C9*2 and CYP2C9*3 alleles, respectively. The CYP2C9*2 allele frequency was 0.074 in our population. It was 0.029 for CYP2C9*3. Conclusion: This is the first report on the presence of CYP2C9*2 allele homozygocity in any Asian or African population.
Provision of Breast Cancer Risk Information to Women at the Lower End of the Familial Risk Spectrum
Authors: Ozakinci Gozde , Humphris Gerry , Steel Michael
Published: December 2006

Background: Breast cancer family clinics provide risk information as one of their key functions. Many referrals to these clinics are ‘low-risk’ women. Objective: It was the aim of this study to report on the generic risk status letters and printed materials (in the form of leaflets) provided to this category of counselees by UK cancer genetics centres. Methods: A postal survey was conducted requesting information materials from genetic centres. Results: Personalized risk letters and/or printed materials were received from 16 of 22 familial cancer centres in the UK. Personalized risk letters and printed materials currently provided to these counselees display inconsistencies and over-simplification that may lead to misunderstanding. Conclusion: There is a need for collaboration among cancer genetics centres to design more helpful and consistent literature.
Dialysis and Nanotechnology: Now, 10 Years, or Never?
Authors: Fissell W.H. , Humes H.D. , Fleischman A.J. , Roy S.
Published: December 2006

Nanotechnology, defined as the science of material features between 10–9 and 10–7 of a meter, has received extensive attention in the popular press as proof-of-concept experiments in the laboratory are published. The inevitable delay between feature articles and clinical endpoints has led to unwarranted skepticism about the applicability of the technology to current medical therapy. The theoretic advantages of micro- and nanometer scale engineering to renal replacement include the manufacture of high-hydraulic permeability membranes with implanted sensing and control structures. Recent data in membrane design and testing is presented, with a review of the challenges remaining in implementation of this technology.
Major Difficulties the US Nephrologist Faces in Providing Adequate Dialysis
Authors: Diaz-Buxo Jose A. , Crawford-Bonadio Terri L.
Published: December 2006

Aim: To identify the major difficulties nephrologists in the US face in providing adequate dialysis. Methods: To identify the perceived obstacles to achieving adequate dialysis in the US, 30 clinical support specialists responsible for nursing education and training were polled. Their responses together with those found in the recent literature were summarized and analyzed. Results: The obstacles identified fell into the following major categories: (1) economic; (2) personnel shortage; (3) education, and (4) cultural. The principal specific difficulties identified in providing adequate dialysis were the provision of sufficient time and frequency of dialysis, adequate volume control and vascular and peritoneal access. Conclusions: The obstacles we currently face are serious but can be conquered through better understanding of the problems and education of professionals, patients and payers. The simple improvement in two specific areas, the creation of more native arteriovenous fistulae and growth of home dialysis, are identified as the highest priorities to overcome these obstacles.
What Is Needed to Achieve a Hemoglobin of 11.0–13.0 g/dl in End-Stage Renal Disease
Authors: Fishbane Steven
Published: December 2006

Effective treatment of anemia in end-stage renal disease (ESRD) results in reduced fatigue and improved quality of life. The National Kidney Foundation’s 2006 anemia treatment guidelines recommend maintaining hemoglobin (Hb) at >11 g/dl, while noting that there is insufficient evidence to routinely maintain Hb levels ≧13.0 g/dl. Success in achieving Hb levels within these targets requires careful monitoring and adjustments to treatment. In addition, causes for diminished response and refractory anemia must be adequately evaluated. In this article, factors important for achieving Hb 11–13 g/dl in patients with ESRD are reviewed.
Vitamin C Neglect in Hemodialysis: Sailing between Scylla and Charybdis
Authors: Handelman Garry J.
Published: December 2006

In our efforts to meet the vitamin C requirements of dialysis patients we confront a medical dilemma – do we allow the patient to become depleted of vitamin C, with the accompanying hematological and other consequences (Scylla), or do we provide for adequate tissue levels of vitamin C, which has been thought to carry the risk of oxalosis (Charybdis). Many practitioners are certain that either one outcome (deficiency) or the other (oxalic acid toxicity) is inevitable, and much like Odysseus, no safe course is to be found. The recent accumulating evidence that vitamin C improves the management of anemia in dialysis patients compels us to find a safe passage through this dilemma. The serious vitamin C deficiency seen in many patients may also contribute to poor oral health and chronic fatigue. The evidence for oxalosis from vitamin C supplements stems from hemodialysis as practiced 20 years ago. Investigators using this therapy are not observing systemic oxalosis, and the most current data support the conclusion that vitamin C therapy is safe for dialysis patients. The question will be resolved by controlled trials that address both vitamin C effectiveness and safety.
Treatment Time and Ultrafiltration Rate Are More Important in Dialysis Prescription than Small Molecule Clearance
Authors: Twardowski Zbylut J.
Published: December 2006

Chronic hemodialysis sessions, as developed in Seattle in the 1960s, were long procedures with minimal intra- and interdialytic symptoms. Over the next three decades, dialysis duration was shorten to 4, 3, even 2 h in thrice weekly schedules. This method spread rapidly, particularly in the United States, after the National Cooperative Dialysis Study suggested that the time of dialysis is of minor importance as long as urea clearance multiplied by dialysis time and scaled to total body water (Kt/Vurea) equals 0.95–1.0. This number was later increased to 1.3, but the assumption that hemodialysis time is of minimal importance remained unchanged. However, Kt/Vurea measures only the removal of low molecular weight substances and does not consider the removal of larger molecules. Nor does it correlate with the other important function of hemodialysis, namely ultrafiltration. Rapid ultrafiltration is associated with cramps, nausea, vomiting, headache, fatigue, hypotensive episodes during dialysis, and hangover after dialysis; patients remain fluid overloaded with subsequent poor blood pressure control leading to left ventricular hypertrophy, diastolic dysfunction, and high cardiovascular mortality. Kt/Vurea should be abandoned as a measure of dialysis quality. The formula suggests that it is possible to decrease t as long as K is proportionately increased, but this is not true. Time of dialysis should be adjusted in such a way that patients would not suffer from symptoms related to rapid ultrafiltration, would not have other uremic symptoms and most patients would have blood pressure controlled without antihypertensive drugs.
Increasing AV Fistulae and Decreasing Dialysis Catheters: Two Aspects of Improving Patient Outcomes
Authors: Sands Jeffrey J.
Published: December 2006

Maximizing arteriovenous (AV) fistula prevalence and minimizing catheter use have become the dominant issues in hemodialysis vascular access management and offer the promise of improved patient outcomes with decreased overall expenditures. Recent efforts have increased AV fistula prevalence in the US to 42.9% with regional rates as high as 59.5% and with complementary declines in AV grafts. This should decrease access procedures but may not fully realize the potential reductions in mortality and cost possible if combined with catheter reduction. Successful catheter reduction requires similar approaches to those utilized in the Fistula First Program. Educating patients, the use of clearly defined protocols and updating payment systems to include chronic kidney disease care are crucial to continued progress. Expansion of the Fistula First Program to include a focus on decreasing catheter prevalence and complications should be considered as a requirement in the push toward the breakthrough targets of 66% AV fistula prevalence.
Control of Hypertension in Patients with Hypertension, Diabetes, and Impaired Fasting Glucose by Czech Primary Care Physicians
Authors: Souček Miroslav , Widimský Jiří , Lánská Věra
Published: December 2006

Aim: To examine prevalence and control of the blood pressure (BP) in the general population and in a subgroup of individuals with diabetes mellitus (DM) receiving primary care in the Czech Republic. Methods: A total of 150 primary care physicians examined and recorded the data of 15 consecutive patients (aged ≧45 years) each, irrespective of the visit purpose. A total of 2,211 patients were included; 403 of them had DM. Results: Of the patients screened, 78.4% had hypertension (BP ≧140 and/or ≧90 mm Hg) or were on antihypertensive therapy. In the DM patients, the prevalence of hypertension was higher than 91.3%. Hypertension control (target <130/<80 mm Hg) was only obtained in 18.4% of the general population and in 4.0% of the patients with hypertension and DM. Systolic BP control deteriorated significantly with age, with ≧140 mm Hg present in 75.9–93.1% in the age groups 65–74 years and ≧74 years as compared with 57.1–76.8% in the younger age groups (p = 0.02–0.008). A diastolic BP reduction to <80 mm Hg was achieved in only 8.9–17.2% of the patients. Conclusions: Our survey shows that the target BP is achieved in <5% of the hypertensive patients with DM. The poor hypertension control in patients with DM is primarily due to inadequate systolic BP control, deteriorating significantly with age. The results are alarming and emphasize the need for a more aggressive treatment strategy in patients with DM.
Candidate-Gene Association Study of Mothers with Pre-Eclampsia, and Their Infants, Analyzing 775 SNPs in 190 Genes
Authors: Goddard Katrina A.B. , Tromp Gerard , Romero Roberto , Olson Jane M. , Lu Qing , Xu Zhiying , Parimi Neeta , Nien Jyh Kae , Gomez Ricardo , Behnke Ernesto , Solari Margarita , Espinoza Jimmy , Santolaya Joaquin , Chaiworapongsa Tinnakorn , Lenk Guy M. , Volkenant Kimberly , Anant Madan Kumar , Salisbury Benjamin A. , Carr Janet , Lee Min Soeb , Vovis Gerald F. , Kuivaniemi Helena
Published: December 2006

Pre-eclampsia (PE) affects 5–7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAYTM System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.
Alcohol Drinking and Cognitive Functions: Findings from the Cardiovascular Risk Factors Aging and Dementia (CAIDE) Study
Authors: Ngandu Tiia , Helkala Eeva-Liisa , Soininen Hilkka , Winblad Bengt , Tuomilehto Jaakko , Nissinen Aulikki , Kivipelto Miia
Published: December 2006

Background: Moderate alcohol drinking is suggested to be beneficial for cognitive functions, but the results of previous studies have varied greatly. Little is known about the effects of midlife alcohol drinking on the cognitive functions later in life. Methods: Participants were derived from random, population-based samples studied in Eastern Finland in 1972, 1977, 1982, or 1987. A total of 1,341 participants were reexamined in 1998, after an average follow-up period of 21 years, at ages 65–79 years. Results: The participants who did not drink alcohol at midlife had a poorer performance in episodic memory, psychomotor speed, and executive function in late life as compared with infrequent and frequent drinkers, adjusted for sociodemographic and vascular factors. Also late-life nondrinkers had poorer psychomotor speed and executive function. These findings were evident especially among nonsmokers. Further, no interactions between apolipoprotein E4 and alcohol or sex and alcohol were found. Conclusions: Alcohol drinking both at midlife and later is favorably related to the function in several cognitive domains, including episodic memory, psychomotor speed, and executive function, in late life. However, it is not clear whether the association is causal, what is the possible mechanism, and what would be a safe limit of drinking for the best cognitive function.
Hyponatremia, Arginine Vasopressin Dysregulation, and Vasopressin Receptor Antagonism
Authors: Rai Amit , Whaley-Connell Adam , McFarlane Samy , Sowers James R.
Published: December 2006

Hyponatremia is often associated with arginine vasopressin (AVP) dysregulation that is regulated by the hypothalamo-neurohypophyseal tract in response to changes in plasma osmolality, commonly in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Potentially lethal complications of hyponatremia most frequently involve the central nervous system and include anorexia, fatigue, lethargy, delirium, seizures, hypothermia and coma, and require prompt treatment. Chronic hyponatremia also complicates patient care and is associated with increased morbidity and mortality, particularly among patients with congestive heart failure. Conventional treatments for hyponatremia (e.g. fluid restriction, diuretic treatment, and sodium replacement) may not be effective in all patients and can lead to significant adverse events. Preclinical and clinical trial results have shown that AVP receptor antagonism is a promising approach to the treatment of hyponatremia that directly addresses the effects of increased AVP and consequent decreased aquaresis, the electrolyte-sparing excretion of free water. Agents that antagonize V2 receptors promote aquaresis and can lead to increased serum sodium. Dual-receptor antagonism, in which both V2 and V1A receptors are blocked, may provide additional benefits in patients with hyponatremia.
FOLFOX-4 Stop and Go and Capecitabine Maintenance Chemotherapy in the Treatment of Metastatic Colorectal Cancer
Authors: Petrioli Roberto , Paolelli Loretta , Marsili Stefania , Civitelli Serenella , Francini Edoardo , Cioppa Tommaso , Roviello Franco , Nettuno Raffaele , Intrivici Chiara , Tanzini Gabriello , Lorenzi Marco , Francini Guido
Published: December 2006

Objective: Patients with metastatic colorectal cancer (MCC) usually receive FOLFOX-4, or other oxaliplatin (L-HOP)-based regimens, until the occurrence of progressive disease, with an increase in the incidence of neurotoxicity which is correlated to the cumulative dose of L-HOP. The aim of this study was to evaluate if FOLFOX-4 stop and go and capecitabine maintenance chemotherapy is associated with a low incidence of severe neurotoxicity in the treatment of MCC patients. Methods: Thirty-three patients were treated with FOLFOX-4 (L-HOP 85 mg/m2 day 1, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 22 h 600 mg/m2 days 1 and 2, every 2 weeks). Patients who achieved objective response (OR) or stable disease (SD) then received oral capecitabine 2,500 mg/m2 days 1–14 every 3 weeks; L-HOP was reintroduced as soon as progression occurred. Results: Twenty-eight of the 29 patients who achieved OR or SD then received capecitabine. FOLFOX-4 was reintroduced in 18 patients (56.2%). The median response duration (RD) was 9.2 months and median progression-free survival (PFS) was 8.6 months. Twenty-eight patients (87.5%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.1%). Conclusions: FOLFOX-4 stop and go and capecitabine maintenance chemotherapy was associated with a very low incidence of grade 3 neurotoxicity. Although the number of patients enrolled was far too low for a definite conclusion, RD and PFS were comparable to those usually reported in the treatment of MCC patients.
Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil
Authors: Ciaparrone M. , Quirino M. , Schinzari G. , Zannoni G. , Corsi D.C. , Vecchio F.M. , Cassano A. , La Torre G. , Barone C.
Published: December 2006

Objective: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). Methods: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes’ stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months (range 17–127). Results: Dukes’ stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival (OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS (p = 0.007) and OS (p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS (p = 0.007) and OS (p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS (p = 0.04) and OS (p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers (group with TS–/DPD–/TP–) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers (group with TS–/DPD–). The analysis of Dukes’ stage C cancer patients confirmed a significant benefit in terms of DFS and OS (p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression (p = 0.033). Conclusions: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes’ B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations.
Pravastatin Enhances Beneficial Effects of Olmesartan on Vascular Injury of Salt-Sensitive Hypertensive Rats, via Pleiotropic Effects
Authors: Yamamoto Eiichiro , Yamashita Takuro , Tanaka Tomoko , Kataoka Keiichiro , Tokutomi Yoshiko , Lai Zhong-Fang , Dong Yi-Fei , Matsuba Shinji , Ogawa Hisao , Kim-Mitsuyama Shokei
Published: December 2006

Objective—This work was undertaken to investigate comparative effect of AT1 receptor blocker (ARB), 3-hydroxy-3-methylglutaryl (HMG) coenzymeA (CoA) reductase inhibitor (statin), and their combination on vascular injury of salt-sensitive hypertension.

Methods and Results—Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were treated with (1) vehicle, (2) hydralazine (5 mg/kg/d), (3) olmesartan (0.5 mg/kg/d), (4) pravastatin (100 mg/kg/d), and (5) combined olmesartan and pravastatin for 4 weeks. Olmesartan or pravastatin significantly and comparably improved vascular endothelium-dependent relaxation to acetylcholine, coronary arterial remodeling, and eNOS activity of DS rats. Olmesartan prevented vascular eNOS dimer disruption or the downregulation of dihydrofolate reductase (DHFR) more than pravastatin, whereas Akt phosphorylation was enhanced by pravastatin but not olmesartan, indicating differential pleiotropic effects between olmesartan and pravastatin. Add-on pravastatin significantly enhanced the improvement of vascular endothelial dysfunction and remodeling by olmesartan in DS rats. Moreover, pravastatin enhanced the increase in eNOS activity by olmesartan, being associated with additive effects of pravastatin on phosphorylation of Akt and eNOS.

Conclusions—Olmesartan and pravastatin exerted beneficial vascular effects in salt-sensitive hypertension, via differential pleiotropic effects. Pravastatin enhanced vascular protective effects of olmesartan. Thus, the combination of ARB with statin may be the potential therapeutic strategy for vascular diseases of salt-sensitive hypertension.
The Prevalence and Quantification of Atherosclerosis in an Elderly Population Assessed by Whole-Body Magnetic Resonance Angiography
Authors: Hansen T. , Wikström J. , Johansson L.O. , Lind L. , Ahlström H.
Published: December 2006

Objective—

The principal aim of the present study was to explore the feasibility of using whole-body magnetic resonance angiography to assess atherosclerosis in different vascular territories in a cohort of elderly.

Methods and Results—

Three hundred six 70-year-old subjects (145 women, 161 men) recruited from a population-based cohort study (Prospective Investigation of the Vasculature in Uppsala Seniors, ie, the PIVUS study) underwent 1.5-T whole-body magnetic resonance angiography with gadodiamide. The arteries were divided into 26 segments. In total, 7956 vessel segments were evaluated with 7900 segments (99.3%) possible to evaluate. Of these, 7186 segments (91%) were normal. Luminal narrowing of ≥50% was observed in 9 (1.5%) of the renal arteries, 12 (1.8%) of the carotid arteries, in 31 segments (1.1%) of the pelvic/upper leg territories, and in 136 segments (6.2%) of territories in the lower leg. Approximately one-third of the sample had no vascular abnormalities, one-third had stenoses of <50%, and the remainder had stenoses ≥50% or occlusions. Six subjects (2%) had aortic aneurysms. In subjects without evident vascular disease, 26% had significant vascular abnormalities.

Conclusions—

Whole-body magnetic resonance angiography performed with a clinical scanner can be used for quantifying atherosclerosis in different vascular territories in a single examination in an elderly population.
The emancipation of visually impaired people in social science research practice
Authors: Duckett Paul , Pratt Rebekah
Published: December 2006

In 1999 we began research, funded by the ‘Thomas Pocklington Trust’, to explore the opinions of visually impaired people on visual impairment research. We found people wanted greater inclusion of visually impaired people in such research and participatory, empowering and emancipatory research was a priority for them. We also found, through reviewing the academic literature, that there was a dearth of such work in the field. In this article we revisit the topic to review research that has or has not been conducted since our first study to see if there has been a change in the use of emancipatory methods in the field. We have contextualized our review in a discussion on the field of disability studies and the international social policy context of disability issues. We found a growth of interest and activity in participatory, emancipatory and empowering research in the field of disability research more generally. There was also some indication that the social model of disability has had an impact on national and international social policy. However, our review found that there continues to be a dearth of emancipatory research in relation to visual impairment. The one study we did locate highlighted how participatory methods are not, in our view, necessarily consistent with the epistemological underpinnings of emancipatory methods. We believe the call from within disability studies for the greater use of emancipatory research methods has not been sufficiently realized in the field of visual impairment and more needs to be done to ground politically informed epistemological understandings in visual impairment research if more progress is to be made.
Feminist Criticism of the Old Testament: Why Bother?
Authors: Rooke Deborah W.
Published: December 2006

Despite the apparent contemporary irrelevance of the Old Testament, the Adam and Eve narrative in Genesis 2–3 is a deeply engrained element within Western cultural mythology. As such it virtually demands a feminist critique, because its common interpretation as a narrative demonstrating women's inferiority and legitimizing their subordination has a mutually reinforcing relationship with the patriarchal world-view that still pervades much of Western culture. A feminist reading of Genesis 2–3 highlights the difficulties with the traditional subordinationist reading, and suggests other possibilities for interpretation that relativize the absolutism of patriarchal authority claims, thereby making it possible to envisage, and work towards, a different world-order.
Can Stepmothers be Saved? Another Look at 1 Timothy 2.8-15
Authors: Upton Bridget Gilfillan
Published: December 2006

In this paper I attempt a new reading of the passage found in 1 Timothy 2.8-15, to try to show how it might be read by women today. The difficulties of reading such patriarchal texts from the canon of biblical literature are not trivialized or overlooked, and are addressed by a selective survey of how this passage has been read in different contexts through the history of interpretation. The resulting reading neither removes this problematic material from the canon, nor denies the oppressive uses it has been put to in keeping women out of positions of power in various church communities.
‘The Past Is Not A Husk Yet Change Goes On’: Reimagining (Feminist) Theology
Authors: Jasper Alison
Published: December 2006

Feminism is still often dismissed as an outmoded or discredited concept, out of touch with the feelings and desires of real women and men or antithetical to any proper vision of Christianity. So for the feminist theologian it is as important as ever to find ways of discriminating between truth and falsity and of discerning a future path. In this piece I try to articulate one possible feminist approach using insights from the work of philosophers Deleuze and Guattari—particularly on assemblages—and from the work of poet and theorist, Adrienne Rich, on revisioning. It is my sense that these tools may be able to help provide feminist theologians with the support we undoubtedly need if we are genuinely to be able to acknowledge the weight of our pasts and the risk of our futures without becoming overwhelmed or immobilized in a context which remains decidedly challenging.
Promising New Causal Explanations for Obesity and Obesity-Related Diseases
Authors: Power Carrie , Miller Sally K. , Alpert Patricia T.
Published: December 2006

Current explanations for obesity center around a predisposition in genotype and phenotype, possibly triggered by an inflammatory process or event, and exacerbated by environmental and psychological factors. It is likely that a variety of physiologic factors may act in combination to produce clinical obesity. Leptin resistance may be an important neurochemical cause of obesity; elevated leptin levels have been correlated with weight gain over extended time periods. Genetic studies support the postulate that a gene originating with our cave-dwelling ancestors, critical to survival when food was scare, has evolved into a trigger for obesity and related diseases. A variety of biochemical markers are prevalent in obesity and obesity-linked disease states. C-reactive protein, interleukin-6, and others are elevated in obesity, supporting the hypothesis that inflammation plays a role in the condition. Tumor necrosis factor-α is overexpressed in obesity and diabetes, suggesting that it may be part of the link between the 2 conditions.
Fictionalizing Jesus: Story and History in Two Recent Jesus Novels
Authors: Crook Zeba
Published: December 2006

From canonical and extra-canonical gospels to the modern phenomenon of the ‘Jesus novel’, people have been fictionalizing Jesus by filling in gaps in the historical and narrative record. This essay inaugurates a field of inquiry by contrasting two recent novels, Norman Mailer’s The Gospel According to the Son (1997) and Nino Ricci’s Testament (2002). In particular it examines how each of the novels depicts the role and character of Judas Iscariot, the question of Jesus’ performance of miracles, as well as how each novel depicts Jesus. In all, the remarkable historical plausibility of these novels, or parts of them, raises the very interesting issue of the relationship between story and history, between fiction and history.
Functional Independence Measure for Children: A Comparison of Chinese and Japanese Children
Authors: Wong Sheila S. N. , Wong Virginia C. N.
Published: December 2006

The Functional Independence Measure for Children (WeeFIM) is a simple-to-administer scale for assessing functional independence across 3 domains (self-care, mobility, cognition) in children. There are normative data from America and Japan. In 2001 to 2002, the authors created a normative Chinese WeeFIM profile and compared this with the American one. In this study, they aimed to compare their Chinese normative data with the Japanese one. Methods. A random sampling of 445 normal Chinese children from different social classes in Hong Kong was conducted in the community. It was conducted via face-to-face interviews with the mother, and a normative database was created. Results. Similar to the Japanese children, the WeeFIM total score and 3 main domain subscores (self-care, mobility, and cognition) increased progressively with age. In the self-care domain, Chinese children achieved modified independence or level 6 earlier in all items except toileting. For the mobility domain, the item chair transfer was achieved earlier in the Chinese children, whereas toilet transfer, stair, tub transfer, and locomotion were achieved later in Chinese children. As for cognition domain, the item problem solving was achieved earlier but comprehension, social interaction, and memory were achieved later in the Chinese children. The authors’ results showed the same pattern of increasing WeeFIM score with increasing chronological age, which is similar to the Japanese children. There are 3 patterns of WeeFIM score achievement in this Chinese cohort. As for the Japanese children, the 3 patterns of WeeFIM score achievement from independent to dependent are 1) rapid change, 2) gradual change, and 3) linear change. Conclusions. WeeFIM is a validated standardized tool for assessing the outcome of rehabilitation programs. It should be widely used to assess rehabilitative achievement in children from different ethnic origins. The authors’ previous study and this current study demonstrated that the authors’ normative WeeFIM profile showed similar results to the American and Japanese children. However, there are minor differences in the WeeFIM scoring in the 3 main domains, which might be due to cultural differences between ethnic groups. Thus, usage of the WeeFIM with a different age criteria in achieving independence according to local culture should be adopted.