bluuebunny/crossref_metadata_2025 huggingface dataset:
Rehabilitating Arthur Young
Authors: Brunt Liam
Published: November 2003

Young was the most prolific and quantitative agricultural writer in England in the eighteenth century. Generally highly regarded by his contemporaries, his reputation among British agricultural historians is at an all‐time low. This article charts and explains Young's fall from grace. It rebuts the criticisms made of his methods and writings, and shows that Young is a well‐informed, accurate, reliable, and reasonable historical source. It demonstrates that the Farmer's tour is based on a broadly representative sample of English farms during the industrial revolution and argues that modern techniques of data analysis can overcome any errors or biases in Young's data.
Monetization and financial development in Southeast Asia before the Second World War
Authors: Huff W. G.
Published: November 2003

Using new statistics, this article analyses financial development in Southeast Asia over the seven decades 1870–1939. The region experienced substantial, and in some instances rapid, vent‐for‐surplus economic growth based on a narrow range of primary commodities. But in 1939 all Southeast Asian countries still had relatively undeveloped financial infrastructures dominated by metropolitan interests, considerably reliant on informal finance, and geared towards primary commodity exports. The article suggests that a lack of opportunities and a variety of country‐specific considerations were more important explanations than weak financial development for an absence of greater industrialization and agricultural modernization in Southeast Asia.
The prospects for super‐acuity: limits to visual performance after correction of monochromatic ocular aberration
Authors: Charman W. N. , Chateau N.
Published: November 2003

It has recently been suggested that correction of the monochromatic aberration of the eye could lead to substantial improvements in visual acuity and contrast sensitivity function. After consideration of the best‐corrected visual acuity of normal eyes, the optical and neural limits to visual performance are reviewed. It is concluded that, even if current problems with the accuracy of the suggested techniques of aberration correction, through corneal excimer laser ablation or customised contact lenses, can be overcome, changes in monochromatic ocular aberration over time, the continuing presence of chromatic aberration, errors of focus associated with lags and leads in accommodation, and other factors, are likely to result in only minor improvements in the high‐contrast acuity performance of most normal eyes being produced by attempted aberration control. Significant gains in contrast sensitivity might, however, be achievable, particularly under mesopic and scotopic conditions when the pupil is large, provided that correct focus can be maintained. In the immediate future, reduction of the high levels of aberration that are currently found in eyes that have undergone refractive surgery and in some abnormal eyes should bring useful benefits.
Pathogenesis of diabetic retinopathy and the renin‐angiotensin system
Authors: Funatsu Hideharu , Yamashita Hidetoshi
Published: November 2003

Despite the beneficial effects of good glycaemic control, loss of vision because of diabetic retinopathy (DR) still occurs. Recent studies have suggested that hypertension is a risk factor for the development and progression of DR and that blood pressure reduction can delay the progression of retinopathy. The renin‐angiotensin system is activated by chronic hyperglycaemia, and the vitreous fluid level of angiotensin II (AII) is elevated in patients with proliferative diabetic retinopathy and diabetic macular oedema. AII increases vascular permeability and promotes neovascularization. It has been suggested that an autocrine‐paracrine relationship may exist between AII and vascular endothelial growth factor in the ocular tissues. Accordingly, angiotensin‐converting enzyme inhibitors or AII Type 1 (AT1) receptor blockers may be useful therapeutic agents for preventing the progression of DR.
Drug‐induced bilateral transient myopia with the sulphonamide sulphasalazine
Authors: Santodomingo‐Rubido J. , Gilmartin B. , Wolffsohn J. S.
Published: November 2003

Whereas there are numerous reported ocular side effects from systemic sulpha medication, most are rare and reversible, with myopia being the most common reaction observed. A case report is presented of sudden bilateral onset of −1.0 DS of myopia (from −3.0 to −4.0 DS) in a young adult female following the addition of a sulphonamide (sulphasalazine) to oral non‐steroidal anti‐inflammatory treatment (meloxicam) for rheumatoid arthritis. The myopia regressed to −3.50 DS after 2 weeks when all medication was withdrawn and stabilised at this level when subsequent treatment was resumed after 8 weeks with the non‐steroidal anti‐inflammatory drug celecoxib. The case indicates that account needs to be taken of the possibility that relatively modest myopic shifts encountered in young adult contact lens wearers may be associated with concomitant systemic medication.
Clinical performance of non‐contact tonometry by Reichert AT550® in glaucomatous patients
Authors: Jorge J. , González‐Méijome J. M. , Díaz‐Rey J. A. , Almeida J. B. , Ribeiro P. , Parafita M. A.
Published: November 2003

Measuring intraocular pressure (IOP) by non‐contact tonometry (NCT) has been demonstrated to be a valid and reliable technique to be used in primary eye care; it is easier to use, it does not transmit infectious diseases, and it is not necessary to use anaesthetic or staining eye drops. Recently, a new NCT device has showed an excellent level of agreement with Goldmann tonometry, but there are no records of its performance in glaucomatous eyes. To rectify this, IOP was measured in twenty‐two patients (44 eyes) receiving medical treatment to control elevated IOP, with AT550® and Goldmann tonometry. Mean values of IOP were 18.98 ± 2.77 and 19.08 ± 3.02 mmHg using Goldmann and AT550®, respectively. Plots of differences against means displayed good agreement (mean difference ± limits of agreement, −0.09 ± 3.30); this value was not significantly different from zero (t‐test for dependent samples, p = 0.709). In conclusion, IOP values as measured with the AT550® NCT are clinically comparable with those obtained with Goldmann tonometry in glaucomatous patients. This validates this NCT not only for screening of IOP but to follow‐up glaucomatous patients with a rapid, non‐invasive method.
Improved illumination for the Perkins applanation tonometer
Authors: Ressiniotis Thomas , Zeki Sabah M. , Clarke Michael P. , Mitchell Keith W.
Published: November 2003

Aims:  To improve the Perkins tonometer measurements by using an augmented, monochromatic solid‐state light source of 470 nm wavelength.

Methods:  This prospective study comprised 44 patients of our ophthalmic department who were split into two groups of 21 and 23 patients, and were tested by two independent ophthalmologists. Intraocular pressure (IOP) was measured in both eyes, comparing the instrument with augmented source against the standard Perkins for both observers. A set of three consecutive IOP measurements was recorded on each patient's eye and the time required to make each of them was recorded. The mean of the three IOP values was used in the analyses.

Results:  For Observer 1, higher values of IOP with our augmented illumination against the standard were recorded, the mean difference of +0.59 mmHg being statistically significant (95% CI, 0.0 to +1.18 mmHg). For Observer 2, the mean difference of −0.22 mmHg was not significant (95% CI, −0.70 to +0.26 mmHg). Measurement times for observers were shorter when using the augmented illumination (Observer 1: mean difference = −2.0 s, S.E. = 1.4 s, CI, +0.8 to −4.9 s; Observer 2: mean difference = −5.0 s, S.E. = 1.3 s, CI, −2.5 to −7.5 s).

Conclusion:  The monochromatic blue light source may improve the performance of IOP measurements with the Perkins instrument under bright room conditions, making them faster and more convenient.
Visual acuity assessment: a comparison of two tests for measuring children's vision
Authors: Jones Deborah , Westall Carol , Averbeck Karin , Abdolell Mohamed
Published: November 2003

Purpose:  To compare the Kay Picture Test and the logMAR Crowded Test.

Methods:  Monocular visual acuity measurement was attempted on 103 paediatric subjects (aged between 2.5 and 16 years) attending eye clinics, using each of the visual acuity tests.

Results:  The results obtained with the two tests were found to be comparable as confirmed with the Intra‐class Correlation Coefficient, which revealed good agreement between the two tests. There was significant correlation between the visual acuity results measured and high conformity in the results from the weaker eye. There was a statistical difference in acuity scores between the tests; the Kay Picture Test gave a lower logMAR score with a mean difference of 0.08 logMAR. This 0.08 difference represents an actual difference of less than one line of acuity measure which can be considered to be clinically insignificant. There was a significant difference in the ability to perform each of the tests under binocular conditions, with more of the 50 children, aged 5 and under, able to perform the Kay Picture Test than the logMAR Crowded Test.

Conclusions:  The results obtained with the two tests are comparable. Both tests can be considered to be appropriate for amblyopia detection and the use of picture‐based logMAR tests should be considered for younger children.
Evaluating the visual experience: visual acuity and the visual analogue scale
Authors: Pointer Jonathan S.
Published: November 2003

Purpose:  To attempt a comparison of the visual experience [assessed using a visual analogue scale (VAS)] with visual acuity in a group of normally‐sighted adult optometric patients.

Methods:  A single‐item 100 mm paper VAS was administered to a sequence of 142 normally‐sighted pre‐presbyopic patients. Each individual was invited to indicate their recent subjective distance visual experience between the extremes of ‘dreadful’ (0 mm) and ‘perfect’ (100 mm). Each patient's binocular visual acuity was then determined at 6 m using a high‐contrast logMAR chart under usual consulting room conditions.

Results:  A weak association was revealed between the subjective indication of recent visual experience and the actual level of binocular acuity recorded in this normally‐sighted group of subjects. On the basis of group responses a statistically significant discontinuity in the scores recorded with the VAS was demonstrated between patients who attained a clinical acuity better or worse than 0.10 logMAR units (6/7.5). Patient gender, age, and whether spectacles were habitually worn for distance viewing, were each revealed to be not statistically significant features.

Conclusions:  For normally‐sighted optometric patients the subjective criterion of visual satisfaction would appear to be only loosely associated with the contemporaneous record of clinical acuity.
The relation between tear film tests in patients with dry eye disease
Authors: Nichols Kelly K. , Nichols Jason J. , Lynn Mitchell G.
Published: November 2003

Purpose:  The purpose of this report was to investigate the relation between dry eye diagnostic tests.

Methods:  Dry eye patients were enrolled to complete a clinical examination, including the following dry eye tests: a meibomian gland evaluation, tear meniscus height, fluorescein tear breakup time, fluorescein staining of the cornea, the Schirmer 1 test, the phenol red thread test, and rose bengal staining of the conjunctiva. Statistical analyses, including correlation coefficients, the Wilcoxon sign rank test, chi‐square test, and logistic regression were used to address the relation between these clinical tests of dry eye.

Results:  There was a strong relation between the Schirmer test and fluorescein staining in all four statistical analyses. Similarly, there was also a strong relation between the phenol red thread test and both fluorescein and rose bengal staining. Finally, the results of the Schirmer test were associated with the tear breakup time test in three of four analyses.

Conclusions:  The results indicate that tests of aqueous deficiency (volume or production) are associated with ocular surface desiccation. This important relation should be recognized when choosing dry eye tests as outcomes in clinical trials and epidemiological studies.
Proximity factor in image size magnification for optical instruments in general
Authors: Harris W. F.
Published: November 2003

A general expression is derived for the proximity factor in near image size magnification for an arbitrary instrument in front of an arbitrary eye. The proximity factor is a 2 × 2 matrix. The instrument and eye may be astigmatic and have decentred elements. The image on the retina may be blurred or not. The analysis is exact within the limitations of linear optics. The general results are specialized for the case of a stigmatic instrument and a stigmatic eye. The results are applied to the case of a thick, possibly bitoric, spectacle lens. The Appendix treats two numerical examples.
The Role of CSF‐1 in Normal and Neoplastic Breast Physiology
Authors: Sapi Eva , Kacinski Barry M.
Published: November 2003

Colony stimulating factor (CSF‐1) and its receptor (CSF‐1R, product of c‐fms proto‐oncogene) were initially implicated as essential for normal monocyte development as well as for trophoblastic implantation. However, recent findings have suggested that CSF‐1 and CSF‐1R might have additional roles in mammary gland development during pregnancy and lactation. Studies with osteopetrotic (op‐/op‐) mice, which bear a specific mutation that inactivates the CSF‐1 gene, demonstrated that op‐/op‐ mothers are incapable of normal milk production due to the incomplete development of their mammary glands during pregnancy. Also, significant increases in the levels of CSF‐1 and CSF‐1R proteins are observed in the epithelial cells of mammary gland during pregnancy and lactation. In vitro studies investigating the effect of the three major lactogenic hormones (prolactin, insulin, and glucocorticoids) on the expression of CSF‐1 and CSF‐1R have demonstrated that expression of CSF‐1 can be regulated by prolactin and insulin whereas CSF‐1R expression is regulated by glucocorticoids. This apparent role for CSF‐1/CSF‐1R in normal mammary gland development is very intriguing because this receptor/ligand pair has also been found to be important in the biology of breast cancer, where they regulate tumor cell invasion by a urokinase‐dependent mechanism. This review aims to summarize recent findings on the role of CSF‐1 and its receptor in normal and neoplastic mammary development which may elucidate potential relationships of growth factor‐induced biological changes in the breast during pregnancy and tumor progression.
Alternative Splicing and Programmed Cell Death
Authors: Jiang Zhi‐hong , Wu Jane Y.
Published: November 2003

Programmed cell death (PCD) is critical for development and homeostasis of multicellular organisms. Genetic and biochemical studies have revealed that PCD is under complex and delicate regulation. An important level of such regulation may be pre‐mRNA splicing as suggested by the observation that a number of PCD regulatory genes are expressed as functionally distinct or even antagonistic isoforms as a result of alternative splicing. Studies on alternative splicing of these genes are reviewed here. Expression and function of a large number of genes involved in PCD are regulated by alternative splicing, including death receptors and intracellular components of the death machinery. Alternative splicing affects not only intracellular distribution but also functional activity of these death regulators, providing a fine‐tuning mechanism in modulating a presumably tightly controlled process of cell death.
The Role of Alternative Pre‐mRNA Splicing in Regulating the Structure and Function of Skeletal Protein 4.1
Authors: Conboy John
Published: November 2003

Alternative pre‐mRNA splicing plays a major role in regulating cell type–specific expression of the protein 4.1 family of skeletal proteins. The biological importance of alternative splicing as a mechanism for 4.1 gene regulation is underscored by studies of the prototypical 4.1R gene in erythroid cells: activation of exon 16 inclusion in mRNA at the erythroblast stage greatly enhances the ability of newly synthesized 4.1R protein to bind spectrin and actin, and thus assemble into a stable membrane skeleton. This gain‐of‐function has profound effects on the biophysical properties of deformability and membrane strength that are critical to red cell survival in the circulation. Another example of developmentally regulated splicing occurs in differentiating mammary epithelial cells in culture, where cell morphogenesis is accompanied by a splicing switch that reversibly activates inclusion of alternative exon 17B. Tissue‐specific splices in the 4.1R gene have also been described in brain and muscle. Few other genes are known to be so richly endowed with regulated switches in pre‐mRNA splicing, making the 4. 1R gene an interesting paradigm for the role of alternative splicing as a mediator of cell function. Recent evidence that other members of the 4.1 gene family are also regulated by alternative splicing suggests, moreover, that this phenomenon is of general importance in regulating the structure of this class of skeletal proteins.
Hepatic Encephalopathy: An Update of Pathophysiologic Mechanisms
Authors: Hazell Alan S. , Butterworth Roger F.
Published: November 2003

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. Although the precise pathophysiologic mechanisms responsible for HE are not completely understood, a deficit in neurotransmission rather than a primary deficit in cerebral energy metabolism appears to be involved. The neural cell most vulnerable to liver failure is the astrocyte. In acute liver failure, the astrocyte undergoes swelling resulting in increased intracranial pressure; in chronic liver failure, the astrocyte undergoes characteristic changes known as Alzheimer type II astrocytosis. In portal‐systemic encephalopathy resulting from chronic liver failure, astrocytes manifest altered expression of several key proteins and enzymes including monoamine oxidase B, glutamine synthetase, and the so‐called peripheral‐type benzodiazepine receptors. In addition, expression of some neuroneal proteins such as monoamine oxidase A and neuronal nitric oxide synthase are modified. In acute liver failure, expression of the astrocytic glutamate transporter GLT‐1 is reduced, leading to increased extracellular concentrations of glutamate. Many of these changes have been attributed to a toxic effect of ammonia and/or manganese, two substances that are normally removed by the hepatobiliary route and that in liver failure accumulate in the brain. Manganese deposition in the globus pallidus in chronic liver failure results in signal hyperintensity on T1‐weighted Magnetic Resonance Imaging and may be responsible for the extrapyramidal symptoms characteristic of portal‐systemic encephalopathy. Other neurotransmitter systems implicated in the pathogenesis of hepatic encephalopathy include the serotonin system, where a synaptic deficit has been suggested, as well as the catecholaminergic and opioid systems. Further elucidation of the precise nature of these alterations could result in the design of novel pharmacotherapies for the prevention and treatment of hepatic encephalopathy.
Effect of Pentachlorophenol (PCP) on Frog Cornea Epithelium
Authors: Carrasquer Gaspar , Li Ming , Yang Shen , Schwartz Manuel , Dinno Mumtaz A.
Published: November 2003

Pentachlorophenol (PCP) is a toxic substance that affects many tissues adversely. Present experiments, using an in vitro preparation, were designed to study whether PCP affected the electrophysiological parameters of the bullfrog cornea epithelium, specifically, the Na+/K+ ATPase pump and the K+ conductance located in the basolateral membrane and the Cl− conductance located in the apical membrane. For this purpose, corneas were impaled with microelectrodes and experiments were done under short‐circuit current (Isc) conditions. Addition of PCP to a concentration of 5 × 10−5M to the tear solution gave a marked decrease in Isc; a marked depolarization of the intracellular potential, Vo; and minimal but significant decreases in the apical membrane fractional resistance, fRo, and in the transepithelial conductance, gt. Isc experiments in Cl−‐free solutions with amphotericin B in the tear solution confirm results indicating that PCP inhibits the active transepithelial transport mechanism and produces a small increase in the basolateral membrane resistance due to a decrease in the K+ conductance.
Dehydroepiandrosterone Protects Hippocampal Neurons Against Neurotoxin‐Induced Cell Death: Mechanism of Action2
Authors: Cardounel Arturo , Regelson William , Kalimi Mohammed
Published: November 2003

Dehydroepiandrosterone (DHEA), an adrenal cortex hormone secreted in large quantities in humans, protects cells of the clonal mouse hippocampal cell line HT‐22 against the excitatory amino acid glutamate (5 mM), and amyloid β‐protein (2 μM) toxicity in a dose‐dependent manner with optimum protection obtained at 5 μM concentration of DHEA. The protective effects of DHEA appear to be specific in that other related steroids and metabolites of DHEA, such as 5‐androstene‐3β,17β‐diol, etiocholan‐3α‐ol‐17‐one, etiocholan‐3β‐ol‐17‐one, testosterone, and 5α‐androstane‐3,17‐dione, offered no protection even at 50 μM concentrations. In addition, using immunocytochemical techniques, we observed that 20 hr of treatment with 5 mM glutamate remarkably increased glucocorticoid receptor (GR) nuclear localization in neuronal cells. Interestingly, 5 μM DHEA treatment for 24 hr, followed by 5 mM glutamate treatment for 20 hr almost completely reversed the copious nuclear localization of GR observed by glutamate treatment alone. Results obtained suggest that DHEA protects hippocampal neurons, at least in part, by its antiglucocorticoid action via decreasing hippocampal cells nuclear GR levels.
Butyrate‐Induced G2/M Block in Caco‐2 Colon Cancer Cells is Associated with Decreased p34cdc2 Activity
Authors: Harrison Lawrence E. , Wang Qing Mei , Studzinski George P.
Published: November 2003

Butyrate, a short‐chain fatty acid, has been reported to inhibit proliferation and stimulate differentiation in multiple cancer cell lines. Whereas the effects of butyrate on cellular differentiation are well documented, the relationship between butyrate‐induced differentiation and its effect on cell cycle traverse is less well understood. The purpose of this study was to investigate the effects of butyrate on the regulatory proteins of the G2/M traverse in the Caco‐2 colon cancer cell model. We demonstrated that the inhibition of proliferation and increased cellular differentiation after treatment of Caco‐2 cells with butyrate were associated with a significant G2/M cell cycle block. Although protein levels of the major G2/M regulatory protein, p34cdc2, were unchanged, a decrease in p34cdc2 activity was noted. Despite this decrease in activity, the inhibitory tyrosine phosphorylation of p34cdc2 was decreased, suggesting that other factors are responsible for the decreased kinase activity. The reduced activity of p34cdc2 provides a possible mechanism for the accumulation of Caco‐2 cells in the G2/M cell cycle compartment following exposure to butyrate. This cell system provides a new model for studies of G2/M cell cycle perturbations.
Postprandial Low‐Density Lipoproteins in Type 2 Diabetes are Oxidized More Extensively Than Fasting Diabetes and Control Samples
Authors: Diwadkar Veda A. , Anderson James W. , Bridges Susan R. , Gowri Maya S. , Oelgten Peter R.
Published: November 2003

This study examined the kinetics of low‐density lipoprotein (LDL) oxidation in the fasting and postprandial states of diabetic and control subjects to determine if LDL oxidation may contribute to accelerated atherosclerosis in diabetes. We compared in vitro oxidation of LDL from 12 control and 13 Type 2 diabetic subjects in the fasting and postprandial states. The extent of oxidation was assessed by length of lag phase, formation of conjugated dienes (CD), lipid peroxides, thiobarbituric acid reactive substances (TBARS), and percentage reduction in free amine groups. Diabetic subjects were significantly older and heavier. Comparisons between control and diabetic subjects in the postprandial state showed that the lag phase was significantly shorter in diabetic subjects than controls (P = 0.005), TBARS were significantly higher (P = 0.006), and levels of CD were higher at 60, 65, and 70 min (P < 0.01). In the fasting state, however, these comparisons were not significant. In diabetic subjects, postprandial samples had a significantly shorter lag phase (P = 0.003), higher TBARS (P = 0.006), and higher levels of CD at 60, 65 (P < 0.001), and 70 min (P = 0.0013) compared to fasting samples. Elevated levels of serum triglycerides in diabetic subjects were negatively correlated to lag phase, in fasting (P = 0.06) and postprandial states (P = 0.002). We conclude that accelerated oxidation of LDL seen in postprandial states in diabetes may be a critical contributor to cardiovascular risks. Elevated levels of serum triglycerides may contribute to the rapid oxidation of LDL seen in diabetic subjects.
Effects of Cord Blood Transfer on the Hematopoietic Recovery Following Sublethal Irradiation in MRL Ipr/Ipr Mice
Authors: Czarneski Jennifer , Lin Yi‐Chu , Ende Norman , Ponzio Nicholas M. , Raveche Elizabeth
Published: November 2003

The potential of cord blood (CB) to serve as a rich source of stem cells and stem cell factors is receiving increasing attention. In addition, perhaps because of the early ontogeny of these cells or the lack of surface antigens, cord blood stem cells do not appear to require close identity with the recipient. In the present pilot study, we investigated the presence of a hematopoiesis enhancing effect (HEE) by assaying the ability of human cord blood cells to augment hematopoiesis across a species barrier. For these experiments, autoimmune‐prone MRL‐Ipr/Ipr mice were exposed to sublethal levels of irradiation and cord blood administration to study the role of factors present in human cord blood in augmenting the rate of lymphopoiesis. This strain was chosen because of the increased presence of peripheral T and B subpopulations, namely the B‐1 and CD4/CD8 double negative T‐cell subpopulations, which do not arise directly from bone marrow precursors, but rather accumulate with age. MRL‐Ipr/Ipr mice were sublethally irradiated and reconstituted with syngeneic bone marrow (BM) cells or with human cord blood cells or peripheral blood mononuclear cells (PBMC), or were left unreconstituted. At 2 weeks post‐treatment, lymphoid populations in the spleen and lymph nodes were studied as a measure of hematopoiesis. Factors present in cord blood were able to augment hematopoiesis over that which occurred endogenously. At 2 weeks postirradiation, recipients of BM cells displayed the fastest rate of peripheral lymphoid recovery, nonreconstituted mice showed the slowest lymphoid recovery, and recipients of cord blood recovered their lymphoid populations at an intermediate rate. Similarly, myelopoiesis was increased in irradiated SJL/J recipients of human cord blood. Thus, human cord blood cells appear to produce/induce factors that may act as an adjunct to increase stem‐cell activity.
Negative Regulation of Human Heme Oxygenase in Microvessel Endothelial Cells by Dexamethasone
Authors: Deramaudt Therese B. , Da silva Jeane‐Louis , Remy Pierre , Kappas Attallah , Abraham Nader G.
Published: November 2003

Heme oxygenase‐1 (HO‐1) is a stress protein, and its induction has been suggested to participate in defense mechanisms against agents that promote oxidative injury such as endotoxins and heme. We have shown that the inflammatory cytokines, interleukin‐6 (IL‐6) and heme‐induced HO‐1 gene expression, were suppressed by dexamethasone (Dex) in a sustained manner. We examined the mechanism by which the anti‐inflammatory agent, Dex, inhibits IL‐6 and heme‐induced HO‐1 expression in rabbit coronary endothelial cells. Endothelial cells treated with heme (10 μM) and IL‐6 (25 ng/ml), increased HO‐1 mRNA 15‐ and 60‐fold, respectively. The activity of HO was increased 3‐fold after such treatment. Although Dex failed to inhibit heme‐mediated HO‐1 mRNA and HO activity, it was able to reverse IL‐6–stimulated HO activity. Several human HO‐1 promoter‐drive chloramphenicol acetyltransferase (CAT) constructs were examined to analyze IL‐6 and Dex‐mediated modulation of the HO‐1 gene in endothelial cells. CAT assays revealed that the HO‐1 promoter region between –180 and –1500 might contain a Dex‐mediated negative regulator. Gel mobility shift assays using nuclear extracts from IL‐6–treated endothelial cells showed a binding to the synthetic 21 base pairs of the HO‐1 sequence that contains the putative STAT3 sequence. STAT3‐specific probe inhibited nuclear binding protein to the putative HO‐1‐STAT3 sequence. This suggests that IL‐6 induction of human HO‐1 is mediated via the JAK‐STAT pathway and that Dex inhibition of gene expression is carried out by activation of a transcriptional protein in competition with the STAT3 binding site.
On the Role of Vitamin C and Other Antioxidants in Atherogenesis and Vascular Dysfunction
Authors: Frei Balz
Published: November 2003

Oxidative stress has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis and improve vascular function by two different mechanisms. First, lipid‐soluble antioxidants present in low‐density lipoprotein (LDL), including α‐tocopherol, and water‐soluble antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation through an LDL‐specific antioxidant action. Second, antioxidants present in the cells of the vascular wall decrease cellular production and release of reactive oxygen species (ROS), inhibit endothelial activation (i.e., expression of adhesion molecules and monocyte chemoattractants), and improve the biologic activity of endothelium‐derived nitric oxide (EDNO) through a cell‐ or tissue‐specific antioxidant action. α‐Tocopherol and a number of thiol antioxidants have been shown to decrease adhesion molecule expression and monocyte‐endothelial interactions. Vitamin C has been demonstrated to potentiate EDNO activity and normalize vascular function in patients with coronary artery disease and associated risk factors, including hypercholesterolemia, hyperhomocysteinemia, hypertension, diabetes, and smoking.
Opposing Effects of Estrogen and Progestins on LDL Oxidation and Vascular Wall Cytotoxicity: Implications for Atherogenesis
Authors: Zhu Xiaodong , Bonet Bartolome , Gillenwater Hiedi , Knopp Robert H.
Published: November 2003

Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this benefit are antioxidant effects on LDL and the arterial wall. Because progestins oppose the effect of estrogen in several systems, we asked if progestins oppose the antioxidant effect of estrogen. To study this question, LDL and various female sex hormones were incubated alone and combined in the absence or presence of bovine aortic endothelial cells, placental trophoblast, or macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence of cells, LDL incubated with copper in phosphate‐buffered saline enhanced the oxidation of LDL. When 17β‐estradiol was added to this system, an antioxidant effect was observed. Progestins inhibited this protective estrogenic effect. In endothelial cell culture, progestins also opposed the antioxidant effect of estrogen, with the strongest antiestrogenic effect seen with the synthetic progestins, levonorgestrel and medroxyprogesterone acetate (MPA). Endothelial cell cytotoxicity was proportional to the enhanced lipid peroxide formation observed with progestins or estrogen. Similar opposing effects were seen when estrogen and progesterone were added to primary cultures of placental trophoblast or macrophages. Thus, three cell culture systems modeling circulating arterial blood contact with cell surfaces demonstrated opposing effects of estrogens and progestins on LDL oxidation and cell cytotoxicity. These studies are in keeping with published reports that female sex steroids influence LDL oxidation in vivo and consequent arterial wall injury.
Oxidative Stress in the Pathogenesis of Preeclampsia
Authors: Hubel Carl A.
Published: November 2003

The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain poorly understood. There is substantial evidence to suggest that the diverse manifestations of preeclampsia, including altered vascular reactivity, vasospasm, and discrete pathology in many organ systems, are derived from pathologic changes within the maternal vascular endothelium. With the theme of endothelial cell dysfunction emphasized, this review focuses on the role of oxidative stress (an imbalance favoring oxidant over antioxidant forces) in the pathogenesis of preeclampsia. Data are summarized regarding 1) the role of the placenta in preeclampsia; 2) evidence and mechanisms of oxidative stress in the preeclampsia placenta; 3) markers of oxidative stress in the maternal circulation; and 4) the potential role of maternal dyslipidemia in generation of oxidative stress. A recurrent theme is that free radical reactions, promoted by “cross‐talk” between the diseased placenta and maternal dyslipidemia, promote a vicious cycle of events that make cause and effect difficult to distinguish but likely contribute to the progression of preeclampsia.
Prostaglandin E2 Mediates Activation of Hypothalamic Histamine by Interleukin‐1β in Rats
Authors: Kang Masahiro , Yoshimatsu Hironobu , Kurokawa Mamoru , Ogawa Ryuichi , Sakata Toshiie
Published: November 2003

The present study was designed to investigate the effects of peripheral interleukin‐1β (IL‐1β) on hypothalamic histamine (HA) systems. Intraperitoneal injection of IL‐1β increased the turnover rate of hypothalamic HA, which was assessed by accumulation of tele‐methylhistamine after pargyline treatment. IL‐1β increased the activities of both histidine decarboxylase (HDC), an HA synthesizing enzyme, and HA‐N‐methyltransferase (HMT), an HA catabolizing enzyme. Pretreatment with indomethacin completely blocked the effects induced by IL‐1β on hypothalamic HA. Infusion of prostaglandin E2 (PGE2) into the third cerebroventricle increased the hypothalamic HA turnover rate, and simultaneously activated both HDC and HMT dose‐dependently, but intravenous infusion of PGE2 had no effect on the dynamics of hypothalamic HA turnover. These results indicate that hypothalamic PGE2 activated by peripheral administration of IL‐1β, but not by peripheral PGE2, may enhance synthesis and release of hypothalamic HA by activation of HDC, and may facilitate degradation of extracellular histamine by activation of HMT.
Mechanisms of DNA Oxidation
Authors: Aust Ann E. , Eveleigh Jamie F.
Published: November 2003

Oxidative damage of DNA caused by a variety of chemical and physical agents appears to be linked to cancer. However, it is becoming increasingly clear that endogenous generation of oxidants, such as hydroxyl radical and peroxynitrite, lead to oxidation of DNA, and this may cause cancer in individuals where no obvious exposure to chemical or physical agents known to be carcinogenic has occurred. The mechanisms for generation of these two oxidants in living organisms will be discussed and their reactivities with DNA to produce oxidized products (e.g., 8‐oxo‐dG) will be presented with special emphasis on the individual characteristics of the generation and reactivity of each oxidant.
Oxidants and Skeletal Muscle Function: Physiologic and Pathophysiologic Implications
Authors: Clanton Thomas L. , Zuo Li , Klawitter Paul
Published: November 2003

Previous studies have demonstrated that skeletal muscles generate considerable reactive oxygen during intense muscle contraction. However, the significance of this phenomenon and whether it represents normal physiology or pathology are poorly understood. Treatment with exogenous antioxidants suggests that normal redox tone during contraction is influencing ongoing contractile function, both at rest and during intense exercise. This could represent the influence of redox‐sensitive proteins responsible for excitation‐contraction coupling or redox‐sensitive metabolic enzymes. Some conditions associated with intense exercise, such as local tissue hypoxia or elevated tissue temperatures, could also contribute to reactive oxygen production. Evidence that muscle conditioning results in upregulation of antioxidant defenses also suggests a close relationship between reactive oxygen and contractile activity. Therefore, there appears to be a significant role for reactive oxygen in normal muscle physiology. However, a number of conditions may lead to an imbalance of oxidant production and antioxidant defense, and these, presumably, do create conditions of oxidant stress. Ischemia‐reperfusion, severe hypoxia, severe heat stress, septic shock, and stretch‐induced injury may all lead to oxidant‐mediated injury to myocytes, resulting in mechanical dysfunction.
The Antioxidant Function of Metallothionein in the Heart
Authors: Kang Y. James
Published: November 2003

The antioxidant function of metallothionein (MT) was first suggested in the early 1980s. Studies in vitro have revealed that MT reacts directly with reactive oxygen species, including superoxide and hydroxyl radicals and hydrogen peroxide. These reactions have never been demonstrated in intact animal studies. Nevertheless, both pharmacologic and genetic studies have shown that MT functions in protection against oxidative injury in vivo. In particular, the antioxidant function of MT in the heart has been explored extensively. The data gathered from recent studies using a cardiac‐specific, MT‐overexpressing transgenic mouse model have provided direct evidence to support this physiological role of MT. Under acute and chronic oxidative stress conditions such as treatment with doxorubicin, ischemia‐reperfusion, and dietary copper restriction, MT‐overexpressing transgenic mouse hearts displayed a marked resistance to the injurious consequences, including biochemical, pathological, and functional alterations. This protective action of MT correlates with its inhibition of reactive oxygen species–induced lipid peroxidation. A critical elucidation of the mechanism of action of MT as an antioxidant in vivo remains to be achieved. However, the combination of recent understanding of the zinc cluster structure of MT and novel molecular genetic approaches has provided the basis for further advancement in this field.
Interaction of Antioxidants and Their Implication in Genetic Anemia
Authors: Chan Alvin C. , Chow Ching K. , Chiu Daniel
Published: November 2003

The generation of reactive oxygen species (ROS) is a steady‐state cellular event in respiring cells. Their production can be grossly amplified in response to a variety of pathophysiological conditions such as inflammation, immunologic disorders, hypoxia, hyperoxia, metabolism of drug or alcohol, exposure to UV or therapeutic radiation, and deficiency in antioxidant vitamins. Uncontrolled production of ROS often leads to damage of cellular macromolecules (DNA, protein, and lipids) and other small antioxidant molecules. A number of major cellular defense mechanisms exist to neutralize and combat the damaging effects of these reactive substances. The enzymic system functions by direct or sequential removal of ROS (superoxide dismutase, catalase, and glutathione peroxidase), thereby terminating their activities. Metal binding proteins, targeted to bind iron and copper ions, ensure that these Fenton metals are cryptic. Nonenzymic defense consists of scavenging molecules that are endogenously produced (GSH, ubiquinols, uric acid) or those derived from the diet (vitamins C and E, lipoic acid, selenium, riboflavin, zinc, and the carotenoids). These antioxidant nutrients occupy distinct cellular compartments and among them, there are active recycling. For example, oxidized vitamin E (tocopheroxy radical) has been shown to be regenerated by ascorbate, GSH, lipoic acid, or ubiquinols. GSH disulfides (GSSG) can be regenerated by GSSG reductase (a riboflavin‐dependent protein), and enzymic pathways have been identified for the recycling of ascorbate radical and dehydroascorbate. The electrons that are used to fuel these recycling reactions (NADH and NADPH) are ultimately derived from the oxidation of foods. Sickle cell anemia, thalassemia, and glucose‐6‐phosphate‐dehydrogenase deficiency are all hereditary disorders with higher potential for oxidative damage due to chronic redox imbalance in red cells that often results in clinical manifestation of mild to serve hemolysis in patients with these disorders. The release of hemoglobin during hemolysis and the subsequent therapeutic transfusion in some cases lead to systemic iron overloading that further potentiates the generation of ROS. Antioxidant status in anemia will be examined, and the potential application of antioxidant treatment as an adjunct therapy under these conditions will be discussed.
Developmental Profile of Prolactin Cells in the Anterior Pituitary of Postnatal Rats during the Lactational Stage
Authors: Yamamuro Yutaka , Aoki Tomohiro , Yukawa Masayoshi , Sensui Naoto
Published: November 2003

Changes in prolactin (PRL)‐, growth hormone (GH)‐ and PRL/GH‐containing cells in the anterior pituitary of pre‐ and postnatal male and female rats were determined using immunocytochemistry with double fluorescent antibodies. The pituitary glands from a fetus on Day 20 of gestation and pups on Days 0, 1, 4, 7, 12, and 20 of the postnatal period with sex distinction were monodispersed and subjected to immunocytochemistry. Following immunostaining, the three types of cells described above were counted (i.e., only PRL‐, only GH‐, and both PRL and GH‐positive cells in a visual field of microscope). Anterior pituitaries and blood were obtained from pups on Days 0, 1, 4, 7, 12, and 20 after birth and pooled with sex distinction, and bioactive PRL levels in the anterior pituitary and serum were measured using an Nb2 rat lymphoma cell bioassay. Double fluorescent‐labeled immunocytochemistry was able to distinguish reliably between PRL‐, GH‐, and PRL/GH‐containing cells. The PRL cells increased rapidly after parturition to 4 days of age and after 12 days of age in both genders. The latter increase was involved in the remarkable increase of PRL/GH‐containing cells, which were first found at term and remained at low levels until 12 days of age. The weight and PRL level of the anterior pituitary increased in both sexes throughout the lactational stage, but the levels in female rats at 20 days of age were significantly greater than those of male rats. Serum PRL concentration remained at low levels except on Day 0. The present results demonstrate that the development of PRL‐containing cells in postnatal rats during the lactational period is activated with two distinct stages, at term to Day 4 and after Day 12, and the development in the latter stage is involved with sexual dimorphism.
Lactic Acid Does Not Directly Activate Hypothalamic‐Pituitary Corticotroph Function
Authors: Petrides John S. , Deuster Patricia A. , Mueller Gregory P.
Published: November 2003

The role that metabolic products play in regulating the hypothalamic‐pituitary‐adrenal (HPA) axis during strenuous exercise is speculative. This investigation examined the extent to which lactic acid, a major metabolite of anaerobic exercise, directly affects hypothalamic‐pituitary function. Specifically, β‐endorphin secretion was measured from AtT‐20 (D‐16) mouse corticotroph tumor cells treated either acutely (15 min − 180 min) or chronically (1 day − 3 day) with physiologic levels of lactate (0.5 × 10−3M to 5 × 10−2M) or lactate in combination with the corticotroph releasing factors: corticotroph releasing hormone (CRH), arginine vasopressin (AVP), norepinephrine and/or epinephrine. Findings with AtT‐20 cell cultures were shown to be representative of responses in primary cultures of rat anterior pituitary. Lactic acid did not alter the spontaneous release of β‐endorphin by AtT‐20 cells under either acute or chronic conditions. While CRH, norepinephrine, and epinephrine evoked significant increases in β‐endorphin release, lactate, in combination with these secretagogues did not alter their effects. Similarly, lactic acid failed to alter basal or stimulated release of β‐endorphin by primary cultures of rat anterior pituitary. The addition of lactate (3 × 103M) to rat hypothalamic explants did, however, produce a modest but significant reduction in spontaneous CRH release, suggesting that lactate may facilitate the return to basal secretion following exercise. The present findings show that physiologic concentrations of lactate have no effect, either alone or in combination with other pituitary secretagogues, on corticotroph secretion. Whereas a physiologic action for lactate within the hypothalamus is possible, the present findings indicate that lactate is an inhibitor of CRH release. Thus, lactate does not appear to play a direct role in the profound activation of the HPA axis that occurs in response to strenuous exercise.
Prenatal Effects of Caffeine and Restraint Stress in Mice
Authors: Colomina  , Sanchez Domenec J. , Esparza Jose L. , Domingo Jose L.
Published: November 2003

The maternal and developmental toxicity of combined exposure to restraint stress and caffeine was assessed in mice. On Day 9 of gestation, six groups of pregnant mice were treated (p.o.) with a single dose of 30, 60, or 120 mg/kg of caffeine. Immediately after caffeine administration, three of these groups were subjected to restraint for 14 hr. Control groups included unrestrained and restrained pregnant mice not exposed to caffeine. An additional group of animals (unrestrained and not exposed to caffeine) was deprived of food for 14 hr. A two‐way (caffeine dose × restraint) analysis of variance revealed an overall effect (reduction) of restraint and caffeine exposure on maternal body weight gain and food consumption on gestation Days 9–11. Significant reductions were also observed in body weight at termination and corrected body weight change of dams concurrently exposed to 120 mg/kg of caffeine and restraint. By contrast, no significant effects of caffeine, restraint, or caffeine plus restraint on embryo/fetal development were noted. The doses of caffeine administered here are much higher than those usually consumed by the general population. Under the current experimental conditions, caffeine alone or combined with restraint stress was not embryotoxic or teratogenic in mice.