bluuebunny/crossref_metadata_2025 huggingface dataset:
Disease insight and treatment perception of men on active surveillance for early prostate cancer
Authors: Van Den Bergh Roderick C.N. , Van Vugt Heidi A. , Korfage Ida J. , Steyerberg Ewout W. , Roobol Monique J. , Schröder Fritz H. , Essink‐Bot Marie‐Louise
Published: July 2009

Study Type – Survey (prospective cohort) Level of Evidence 1b

OBJECTIVE

To investigate the levels of knowledge of prostate cancer and the perception of active surveillance (AS) in men on AS, as AS for early prostate cancer instead of radical treatment might partly solve the over‐treatment dilemma in this disease, but might be experienced as a complex and contradictory strategy by patients.

PATIENTS AND METHODS

In all, 150 Dutch men recently diagnosed with early prostate cancer participating in a prospective protocol‐based AS programme (PRIAS study) received questionnaires, including a 15‐item measure on their general knowledge of prostate cancer, and open‐ended questions on the most important disadvantages and advantages of AS, and on the specific perception of AS. We assessed knowledge scores and explored potentially associated factors, the stated (dis)advantages and specific perceptions.

RESULTS

The questionnaire response rate was 86% (129/150). Participants provided correct answers to a median (interquartile range) of 13 (12–14) of 15 (87%) knowledge items. Younger and higher educated men had higher knowledge scores. In line with a priori hypotheses, the most frequently reported advantage and disadvantage of AS were the delay of side‐effects and the risk of disease progression, respectively. Specific negative experiences included the feeling of losing control over treatment decisions, distress at follow‐up visits, and the desire for a more active participation in disease management. No conceptually wrong understandings or expectations of AS were identified.

CONCLUSIONS

We found adequate knowledge of prostate cancer levels and realistic perceptions of the AS strategy in patients with early prostate cancer and on AS. These findings suggest adequate counselling by the physician or patient self‐education.
Synchronous Ventricular Pacing without Crossing the Tricuspid Valve or Entering the Coronary Sinus—Preliminary Results
Authors: HENZ BENHUR D. , FRIEDMAN PAUL A. , BRUCE CHARLES J. , OKUMURA YASUO , JOHNSON SUSAN B. , DANIELSEN ANDREW , PACKER DOUGLAS L. , ASIRVATHAM SAMUEL J.
Published: July 2009

Background: Right ventricular apical (RVA) pacing promotes tricuspid regurgitation (TR), electromechanical dyssynchrony, and ventricular dysfunction. We tested a novel intramyocardial bipolar lead to assess whether stimulation of the atrioventricular septum (AVS) produces synchronous ventricular activation without crossing the tricuspid valve (TV).

Methods: A lead with an active external helix and central pin was placed on the AVS and the RVA in three dogs. High‐density electroanatomic (EA) mapping was performed of both ventricles endocardially and epicardially. Intracardiac echocardiography was used to access ventricular synchrony.

Results: The lead was successfully deployed into the AVS in all cases with consistent capture of the ventricular myocardium without atrial capture or sensing. The QRS duration was less with AVS compared with RVA pacing (89 ± 4 ms vs. 100 ± 11 ms [P < 0.0001, GEE P = 0.03]). There was decreased delay between color Doppler M‐mode visualized peak contraction of the septum and the mid left ventricular free wall with AVS compared with RVA pacing (89 ± 91 ms vs. 250 ± 11 ms [P < 0.0001, GEE P = 0.006]). Activation time between the mid septum and mid free wall was shorter with AVS versus RVA pacing (20.4 ± 7.7 vs. 30.8 ± 11.6 [P = 0.01, GEE P = 0.07]). The interval between QRS onset to earliest free wall activation was shorter with AVS vs. RVA pacing (19.2 ± 6.4 ms vs. 31.1 ± 11.7 ms [P = 0.005, GEE P = 0.02]).

Conclusion: The AVS was successfully paced in three dogs resulting in synchronous ventricular activation without crossing the TV.
The Relationship Between Endocardial Voltage and Regional Volume in Electroanatomical Remodeled Left Atria in Patients with Atrial Fibrillation: Comparison of Three‐Dimensional Computed Tomographic Images and Voltage Mapping
Authors: PARK JAE HYUNG , PAK HUI‐NAM , CHOI EUN JEOUNG , JANG JIN KUN , KIM SOOK KYOUNG , CHOI DONG HOON , CHOI JONG IL , HWANG CHUN , KIM YOUNG‐HOON
Published: July 2009

Background: Long‐standing atrial fibrillation (AF) changes left atrial (LA) morphology, and the LA size is related to recurrence after radiofrequency catheter ablation (RFCA). We hypothesize that LA morphology, based on embryological origin, affects the outcome of RFCA.

Methods: We analyzed 3D computed tomographic (CT) images of LA in 70 patients with AF (54 males, 55.6 ± 10.5 years old, paroxysmal AF (PAF):persistent AF (PeAF) = 32:38) who underwent RFCA. Each LA image was divided into venous atrium (VA), anterior LA (ALA), LA appendage (LAA), and both antrum. Absolute and relative volumes were calculated, and the lengths of linear ablation sites were measured.

Results: (1) In patients with the mean LA voltage ≤ 2.0 mV, LA volume, especially ALA, was larger (P < 0.01) compared to those with LA voltage > 2.0 mV. (2) The total LA volume was significantly larger (P < 0.01) and LAA voltages (P < 0.05) and conduction velocities (P < 0.05) were lower in patients with PeAF than in those with PAF. (3) In patients with recurrence, LA volume was generally larger (P < 0.01) than in those without recurrence. In PAF patients with recurrence, the relative volume of ALA was significantly larger (P < 0.01) than those without recurrence.

Conclusions Morphologically remodeled LA has low endocardial voltage, and enlargement of ALA is more significant in electroanatomically remodeled LA. The disproportional enlargement of ALA was observed more often in PAF patients with recurrence after ablation than those without recurrence.
Restasis® for the treatment of ‘dry eye’ in Aotus nancymaae
Authors: Schuler A.M. , Tustin G.T. , Abee C.R. , Scammell J.G.
Published: July 2009

Background  This case report describes the treatment of three male owl monkeys (Aotus nancymaae) diagnosed with chronic dry eye with a topical cyclosporine product, Restasis®, approved for use in humans. These owl monkeys had ocular disease resulting from procedures performed at a biotechnology company. They were moved to the Center for Neotropical Primate Research and Resources at University of South Alabama to be incorporated into the breeding colony.

Materials and methods  Schirmer tear testing was performed initially and during the course of treatment to monitor efficacy of twice daily administered Restasis®. The goals of treatment were to reduce pain and/or distress and if possible to quantitatively increase tear production.

Results and discussion  All animals had improvements in conjunctival inflammation and had an increase in tear production.
A novel ATP‐binding cassette transporter is responsible for resistance to viologen herbicides in the cyanobacterium Synechocystis sp. PCC 6803
Authors: Prosecka Jana , Orlov Artem V. , Fantin Yuri S. , Zinchenko Vladislav V. , Babykin Michael M. , Tichy Martin
Published: July 2009

The charged quaternary ammonium compounds – methyl, ethyl and benzyl viologens – generate reactive oxygen species in photosynthetic cells. Three independent methyl viologen‐resistant spontaneous mutants of Synechocystis sp. PCC 6803 were identified, in which the conserved R115 residue of the Slr1174 protein was replaced with G115, L115 and C115. The Slr1174 protein of the DUF990 family is related to the permease subunit of an ABC‐2‐type transporter and its R115 mutation was found to be solely responsible for the observed methyl viologen resistance. Bioinformatic analysis showed that in various bacterial genomes, two genes encoding another permease subunit and the ATPase component of an ATP‐binding cassette transporter form putative operons with slr1174 orthologs, suggesting that the protein products of these genes may form functional transporters. The corresponding genes in Synechocystis sp. PCC 6803, i.e. slr0610 for the permease and slr1901 for the ATPase, did not form such an operon. However, insertional inactivation of any slr1174, slr0610 or slr1901 genes in both the wild‐type and the R115‐resistant mutant resulted in increased sensitivity to methyl, ethyl and benzyl viologens; moreover, single‐ and double‐insertion mutants did not differ in their viologen sensitivity. Our data suggest that Slr1901, Slr1174 and Slr0610 form a heteromeric ATP‐binding cassette‐type viologen exporter, in which each component is critical for viologen extrusion. Because the greatest increase in mutant sensitivity was observed in the case of ethyl viologen, the three proteins have been named EvrA (Slr1901), EvrB (Slr1174) and EvrC (Slr0610). This is the first report of a function for a DUF990 family protein.
The School Nurse's Role in Treatment of the Student With Autism Spectrum Disorders
Authors: Bellando Jayne , Lopez Maya
Published: July 2009

PURPOSE.  Some healthcare concerns have been found to be commonly associated with Autism Spectrum Disorders (ASD). Identification and treatment of these medical issues can improve the functioning of the child with ASD. This article will offer practical suggestions for the school nurse.

CONCLUSIONS.  As a “front‐line” medical professional in the schools, the school nurse is positioned to provide guidance on implementing interventions for the student with ASD.

PRACTICE IMPLICATIONS.  By being knowledgeable about current research and treatment options for the various associated medical conditions, the school nurse can help the student achieve academic success in the school setting.
Review of the Evidence for Treatment of Children with Autism with Selective Serotonin Reuptake Inhibitors
Authors: West Lis , Brunssen Susan H. , Waldrop Julee
Published: July 2009

PURPOSE.  To review the potential role of serotonin dysregulation in autism and the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating core deficits and associated symptoms of autism in children. The literature was searched for reports of SSRI use in children with autism. Data are presented from prospective clinical trials that evaluated treatment outcomes.

CONCLUSIONS.  Some SSRIs show moderate success in managing specific behaviors. Only fluoxetine shows evidence of decreasing global autism severity.

PRACTICE IMPLICATION.  Definitive conclusions concerning selection criteria, dosage, safety, and efficacy cannot be drawn given the current state of evidence.
Helping Families Find the Best Evidence: CAM Therapies for Autism Spectrum Disorders and Asperger's Disorder
Authors: Abbey Dana
Published: July 2009

Dana Abbey
 
Column Editor: Roxie L. Foster

Family‐Centered Care provides a forum for sharing information about basic components of caring for children and families, including respect, information sharing, collaboration, family‐to‐family support, and confidence building.
Clinical Aspects of Endometriosis
Authors: MURPHY ANA A.
Published: July 2009

Abstract: Endometriosis is one of the most commonly encountered gynecologic diseases requiring medical and/or surgical therapy. It is a leading cause of hysterectomy in the United States and has significant associated morbidity. The most frequent symptoms of genital tract endometriosis are dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Endometriosis occurs in the pelvis, most commonly the ovaries and the dependent areas covered with peritoneum. Diagnosis requires surgical intervention and is usually made by laparoscopy. In women being evaluated for pelvic pain, the diagnosis of endometriosis is made frequently (40‐60%) and varies with the population being studied. Infertility and endometriosis have long been associated. Although women with infertility may have pelvic pain, subfertility (20‐30%) can be the only presenting symptom. In asymptomatic women, the diagnosis of endometriosis ranges from 2% to 22% of reproductive‐age women. Its true incidence and natural history remain to be clarified. Endometriosis is a significant public health issue because of the large number of women it affects and the significant morbidity associated with this disease.
Endometriosis and Infertility
Authors: BARBIERI ROBERT L. , MISSMER STACEY
Published: July 2009

Abstract: Two major methodological problems that impact clinical research in endometriosis are the absence of a low‐cost, highly reliable method for diagnosing endometriosis and the possibility that endometriosis is actually multiple different diseases that we have not yet been able to differentiate. Animal models of endometriosis clearly demonstrate that advanced endometriosis causes reduced fertility. In humans, endometriosis and infertility are commonly associated. However, few data from high‐quality clinical trials demonstrate that endometriosis causes infertility in humans. Future research should focus on the implications of the observation that, in ovarian endometriosis cysts, the epithelium is monoclonal. This observation suggests that nonrandom somatic mutations cause ovarian endometriosis cysts. If somatic mutations cause ovarian endometriosis cysts, it is likely that a small number of genes can be identified that play a central role in pathogenesis of this disease.
Premenstrual and Menstrual Changes in the Macaque and Human Endometrium
Authors: BRENNER ROBERT M. , NAYAK NIHAR R. , SLAYDEN OV D. , CRITCHLEY HILARY O. D. , KELLY RODNEY W.
Published: July 2009

Abstract: According to current theory, endometriosis is initiated during retrograde menstruation when menstrual fragments flow out of the fimbriated end of the fallopian tubes and become established on the ovarian surface or other sites in the peritoneal cavity. In recent years, new data have accumulated on the properties of menstruating tissue itself, and several laboratories agree that this tissue is rich in matrix metalloproteinases (MMPs) that may facilitate endometriotic implantation. Recently, we found that vascular endothelial growth factor (VEGF) and its receptor VEGFR‐2 (KDR) were dramatically upregulated in the stromal cells of the superficial endometrial zones by progesterone (P) withdrawal during the premenstrual phase. A unique role of VEGF at this stage of the cycle may be to stimulate MMP expression in stromal cells because VEGF, KDR, and MMPs were all coordinately induced in these cells in the superficial zone of the primate endometrium by P withdrawal. The rich content of MMPs and VEGF in the menstrual fragments could facilitate attachment and angiogenesis of menstrual fragments in ectopic sites. In addition, a variety of chemokines, cytokines, and cellular regulators are induced by P withdrawal in the premenstrual human endometrium. These include NFκB, prostaglandins, interleukin‐8 (IL‐8), cyclooxygenase‐2 (COX‐2), and monocyte chemotactic peptide‐1 (MCP‐1), among others. The perivascular expression of several of these factors may facilitate the rapid invasion of leukocytes into the endometrium, especially in the superficial zones. Consequently, menstrual fragments may be rich in IL‐8 and MCP‐1, both of which would add to the angiogenic potential of such fragments in ectopic sites. In sum, menstrual tissue is rich in VEGF, KDR, MMPs, leukocytes, chemokines, cytokines, and prostaglandins, all factors that may facilitate attachment and angiogenesis when menstrual fragments exit from the tubes and implant on pelvic sites. Additional research on these and other factors in premenstrual and menstrual endometrium may deepen our understanding of both the establishment and progression of this debilitating disease.
The Potential Role of Exposure to Environmental Toxicants in the Pathophysiology of Endometriosis
Authors: RIER SHERRY E.
Published: July 2009

Abstract: Humans and animals are exposed daily to a complex mixture of polyhalogenated aromatic hydrocarbons (PHAHs). Previous work has shown that exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is associated with a dose‐dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Dioxin‐like chemicals can also exert effects in combination with TCDD via the aryl hydrocarbon receptor. Using a rhesus model of chronic TCDD exposure and endometriosis, serum concentrations of TCDD and 19 dioxin‐like PHAHs were quantified 13 years after termination of exposure to TCDD. In additional studies, the immune status of TCDD‐exposed monkeys was evaluated. For TCDD‐exposed and unexposed animals, TCDD exposure correlated with an increased serum TCDD concentration. Furthermore, TCDD exposure and an elevated serum TCDD concentration were associated with increased serum levels of triglycerides, 1,2,3,6,7,8‐hexachlorodibenzofuran (HxCDF), PCB77, and PCB126. Importantly, the animals with elevated serum levels of PCB77 and PCB126 and increased total serum TCDD equivalents (TEQs) had a high prevalence of endometriosis, and the severity of disease correlated with the serum concentration of PCB77. In immune studies, TCDD exposure correlated with increased tumor necrosis factor alpha (TNFα) production by peripheral blood mononuclear cells (PBMC) in response to stimulation by T cell mitogen and decreased NK cytolytic activity. Elevated serum concentrations of TCDD, 1,2,3,6,7,8‐HxCDF, and PCB126 correlated with increased numbers of CD3+/CD25− and CD3−/CD25+ leukocytes and enhanced secretion of TNFα by mitogen‐stimulated PBMC. This evidence suggests that TCDD exposure and endometriosis in the rhesus monkey may be associated with increased serum concentrations of specific coplanar PCB compounds and long‐term alterations in systemic immunity. Furthermore, the data suggest a potential involvement of an increased body burden of PCB compounds in the etiology of endometriosis in the rhesus. Recent advances in the detection and assay of individual PHAH congeners in biological samples have made it possible to assess total PHAH body burden in humans and animals. Future studies are expected to exploit this advance to assess the health impact of PHAH body burdens in both exposed individuals and the general population. Serum PHAH concentrations and TEQs in TCDD‐exposed monkeys with endometriosis are similar to or lower than blood levels in the general human population; thus, it is important to consider the implications of these findings for human health and the prevalence of endometriosis in humans. Additional studies are warranted, particularly in human subjects, to explore the potential implications of these data.
Environmental Contaminants and Dietary Factors in Endometriosis
Authors: FOSTER WARREN G. , AGARWAL SANJAY K.
Published: July 2009

Abstract: Endometriosis is an estrogen‐dependent disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. The etiology of this disease remains elusive, but is clearly influenced by genetic, immune, and endocrine factors. Exposure to environmental contaminants has recently been added to the list of potential factors that contribute to the pathogenesis of endometriosis. The objective of this paper is to review the weight of the evidence from hospital‐based case‐control studies and animal experiments for an association between exposure to environmental contaminants and endometriosis.
The Molecular Basis for Implantation Failure in Endometriosis
Authors: GIUDICE LINDA C. , TELLES TRACEY L. , LOBO SHALINI , KAO LEE
Published: July 2009

Abstract: Endometriosis is a benign gynecologic disorder associated with pelvic pain and infertility, with the latter being due, in part, to failure of embryonic implantation in the maternal endometrium. Adequacy of the endometrium for fertility has been classically investigated by histologic evaluation of a mid‐late luteal phase biopsy and, historically, normal histology has been reassuring. However, recent studies demonstrate histologically normal, but biochemically abnormal, endometrium during the window of implantation in some women with endometriosis. In the pregenomic era, a “one‐by‐one” approach has been adopted to investigate proteins and genes expressed in the window of implantation, and several genes or gene products have been found to be aberrantly expressed in endometrium of women with endometriosis either during the implantation window or at other times of the cycle. Some of these are related to failure of implantation, while others likely contribute to the establishment and growth of endometriotic lesions. The time has come for a genome‐wide approach to evaluate uterine endometrium for embryonic implantation. Knowing the biochemical mechanisms underlying normal implantation and the abnormalities in endometriosis will facilitate development of new diagnostic criteria beyond histologic evaluation and will permit identification and validation of molecular targets for future drug discovery. This monograph reviews (a) some of the evidence of compromised fertility in women with endometriosis and treatments targeted to improve their fertility; (b) the concept of the window of implantation; (c) genes/gene products aberrantly expressed in endometrium during the window of implantation or other times of the cycle in women with endometriosis; and (d) the use of microarray technology to investigate endometrial gene expression in human endometrial stromal cells and preliminary data resulting from a collaborative consortium effort of a genome‐wide investigation of gene expression in the window of implantation of women with versus without endometriosis.
Using Rats as a Research Model for the Study of Endometriosis
Authors: SHARPE‐TIMMS KATHY L.
Published: July 2009

Abstract: Although there are disadvantages of extrapolating data across species, the rat model may be used to study events involved in the pathogenesis and pathophysiologies of endometriosis or novel therapeutic approaches for this disorder that are not accessible in humans. Rat endometriotic tissues are similar to human lesions in vivo, and rat endometriotic tissues and cells perform in a similar manner as human endometriotic tissues and cells in organ explant culture and isolated cell culture. The rat model permits studies of mechanisms and regulators in a controlled manner free from confounding influences such as individual patient variation and environmental influences. The primary method used for induction of endometriosis in rats has been autotransplantation of uterine squares (implants) into the peritoneal cavity. Beyond mere growth of endometrium in ectopic locations, rats with endometriosis display similar symptoms, including a reduction in fertility and fecundity, and the endometriotic implants react similarly to therapeutics as those of humans with the disease. Similar alterations in gene expression and protein production have been observed in endometriotic tissues from rats and humans that may, in part, be causative agents involved in the pathogenesis or pathophysiologies of endometriosis.
Experimental Endometriosis
Authors: BRUNER‐TRAN KAYLON L. , WEBSTER‐CLAIR DEBORAH , OSTEEN KEVIN G.
Published: July 2009

Abstract: Endometriosis is a complex disease that can develop as a consequence of retrograde menstruation, occurring in association with the cyclic loss of endometrial tissue in primates and humans. In addition, progression of disease parallels a woman's exposure to ovarian steroids, rarely occurring prior to menarche and generally resolving following menopause. Because of the cost of developing primate models to study endometriosis, numerous small animal models have been established to approach various elements related to the pathophysiology of this disease. Our laboratory has developed an experimental endometriosis model using nude mice as a xenographic host for human tissues. Our goal is to approach the basic cellular mechanisms of estrogen and progesterone action that link these hormones to the development or prevention of endometriosis. In our initial studies, we have sought to understand steroid‐associated regulation of matrix metalloproteinases (MMPs) with regard to the development of experimental endometriosis. Using both short‐term organ cultures and nude mice as xenographic hosts of human tissue, we have demonstrated a critical role of progesterone and progesterone‐associated cytokines in preventing the initial establishment of experimental disease. Women with endometriosis appear to lack normal endometrial responsiveness to progesterone, resulting in altered expression of several MMPs and an enhanced ability of these tissues to establish ectopic lesions in nude mice. Developing a better understanding of the impairments in the normal endometrial physiology of women with endometriosis should aid in the development of better treatment or diagnostic strategies.
The Treatment of Endometriosis
Authors: OLIVE DAVID L. , PRITTS ELIZABETH A.
Published: July 2009

Abstract: The treatment of endometriosis focuses upon amelioration of two symptoms: pain and infertility. The treatment of endometriosis‐associated pain has been well studied and all major medical therapies appear to be superior to placebo. In addition, none seems to be drastically better than another. Surgical therapy also appears to be efficacious, albeit with a relatively high rate of recurrence of symptoms following conservative surgical intervention. There are no trials comparing the relative value of medical versus surgical therapy. Combination surgery/medical therapy has several high‐quality trials for evaluation, but its value remains unclear. The treatment of endometriosis‐associated infertility presents a different picture: medical therapy has not been shown to be of any value and may prove detrimental to fertility. Surgical treatment does improve fertility, probably for all stages of disease. Assisted reproduction also seems to be efficacious, with both controlled ovarian hyperstimulation and intrauterine insemination as well as in vitro fertilization shown to be of benefit. Finally, the combination of in vitro fertilization and either medical or surgical therapy may be beneficial with advanced endometriosis, but further study is required.
Modern Concepts of Brainstem Anatomy
Authors: BÜTTNER‐ENNEVER J. A. , HORN A.K. E. , GRAF W. , UGOLINI G.
Published: July 2009

Abstract: The extraocular muscles, unlike the skeletal muscles, contain non‐twitch muscle fibers. Recent experiments have located the non‐twitch motoneurons. They lie around the periphery of the oculomotor, trochlear and abducens nuclei, separate from the more usual twitch motoneurons that cluster within the boundaries of the classical motor nuclei. The premotor inputs to non‐twitch neurons were traced by the injection of rabies virus into the distal tip of the lateral rectus muscle. Retrogradely labeled cells were found in areas associated with the neural integrator, vergence and smooth pursuit premotor areas, but not the saccadic premotor burst neurons or the direct vestibulo‐ocular pathways. The rabies tracing emphasizes for the first time that the central mesencephalic reticular formation (cMRF) and the supraoculomotor area exert direct premotor control over the non‐twitch motoneurons. Because the two sets of motoneurons do not receive the same afferents, they must have different functions; these are not yet clarified. These results are not compatible with the concept of a single final common pathway from motoneurons to eye muscles.

Putative sensory receptors, palisade endings, are located at the tips of non‐twitch muscle fibers reminiscent of an inverted muscle spindle, which would make the non‐twitch motoneurons, γ‐motoneurons. We propose that twitch motoneurons are the major source of tension used for eye movements, whereas non‐twitch motoneurons are more important for fine alignment of the eyes. Furthermore, the non‐twitch motoneurons could be controlled through sensory feedback networks (including perhaps proprioceptive signals from the palisade endings) that are relayed through the superior colliculus and via cMRF to the non‐twitch motoneurons. The clinical repercussions of these hypotheses are discussed.
Effects of Cortical Lesions on Saccadic
Authors: PIERROT‐DESEILLIGNY CH. , PLONER C. J. , MÜRI R. M. , GAYMARD B. , RIVAUD‐PÉCHOUX S.
Published: July 2009

Abstract: Our knowledge of the cortical control of saccadic eye movements (saccades) in humans has recently progressed mainly because of lesion and transcranial magnetic stimulation (TMS) studies, but also because of functional imaging. It is now well known that the frontal eye field is involved in the control of intentional saccades, the parietal eye field in that of reflexive saccades, the supplementary eye field (SEF) in the initiation of motor programs comprising saccades, the pre‐SEF in the learning of these programs, and the dorsolateral prefrontal cortex (DLPFC) in saccade inhibition, prediction and spatial working memory. Saccades may also be used as a convenient model of motricity to study general cognitive processes such as motivation and spatial memory. Thus, it has been shown that the posterior part of the anterior cingulate cortex, called the cingulate eye field, is involved in motivation and the preparation of all intentional saccades, but not in reflexive saccades. Recently, our understanding of the cortical control of spatial memory has noticeably progressed by using the simple visuo‐oculomotor model represented by the memory‐guide saccade paradigm, in which a single saccade is made to the remembered position of a unique visual item presented a while before. Transcranial magnetic stimulation studies have determined that after a brief stage of spatial integration in the posterior parietal cortex (inferior to 300 ms), short‐term spatial memory (i.e., up to 15‐20 seconds) is controlled by the DLPFC. Behavioral and lesion studies have shown that medium‐term spatial memory (between 15 and 20 seconds and a few minutes) is specifically controlled by the parahippocampal cortex, before long‐term memorization (i.e., after a few minutes) in the hippocampal formation. These different but complementary study methods used in humans have thus contributed to a better understanding of both eye movement physiology and general cognitive processes preparing motricity as whole.
Vergence‐Mediated Modulation of the Human Horizontal Angular VOR Provides Evidence of Pathway‐Specific Changes in VOR Dynamics
Authors: LASKER DAVID M. , RAMAT STEFANO , CAREY JOHN P. , MINOR LLOYD B.
Published: July 2009

Abstract:The horizontal vestibulo‐ocular reflex (VOR) evoked by passive, high‐acceleration, head‐on‐body rotations (head thrusts) while viewing a far (124‐cm) or near (15‐cm) target was recorded (scleral search coil) in four subjects with normal vestibular function and in one subject with unilateral vestibular hypofunction. For responses in the subjects with normal vestibular function, the latency of responses relative to the onset of head movement was 7.5 ± 1.5 ms for the VOR and 21.6 ± 1.2 ms for the vergence‐mediated increase in VOR gain. The gain of the VOR at the peak of the velocity response while viewing a far target was 1.01 ± 0.06; while viewing a near target, it was 1.25 ± 0.08 (p<0.003). The responses were modeled with two pathways based on the different latencies. The “far‐viewing” pathway was represented by a constant gain term. The “near‐viewing” pathway was represented by a first‐order lead term, a gain that was dependent on viewing distance, and a delay. Analysis of the responses revealed that the lead term was greater for the adducting than the abducting eye. In the subject with unilateral vestibular hypofunction, ipsilesional responses showed no change in VOR gain with respect to viewing distance. Contralesional responses retained the vergence‐dependent increase in gain. A bilateral model was developed based on the data from the subjects with normal vestibular function. Simulations of this model when inputs were eliminated from one side predict the changes observed in the subject with unilateral vestibular hypofunction. The response asymmetries arise because the near‐viewing pathway is more susceptible to inhibitory cutoff than is the far‐viewing pathway.
Development of New Treatments for Congenital Nystagmus
Authors: DELL'OSSO LOUIS F.
Published: July 2009

Abstract: The use of ocular motor data as the basis for the development of both nonsurgical and surgical therapies for congenital nystagmus (CN) has been underway since the mid‐1960s. This paper presents three nonsurgical therapies (composite prisms, soft contact lenses, and afferent stimulation) and a new surgical therapy (four‐muscle tenotomy) hypothesized from analysis of ocular motor data. The expanded nystagmus acuity function test was developed to both predict and measure the effectiveness of CN therapies and for intersubject comparisons. Base‐out prisms may be used to damp CN during distance fixation in patients whose CN damps during near fixation and who are binocular (i.e., they have no strabismus). Soft contact lenses may be used in those whose CN damps with afferent stimulation of the ophthalmic division of the trigeminal nerve. Cutaneous afferent stimulation (rubbing, vibration, or electricity) of the forehead or neck damps CN in some individuals. Finally, as first demonstrated in an achiasmic Belgian sheepdog and later in humans, tenotomy of the four horizontal rectus muscles and reattachment at their original sites may also damp CN. Taken together, these findings suggest the existence of one or more proprioceptive feedback loops acting to change the small‐signal gain of the extraocular plant. Four‐muscle tenotomy provides a needed therapeutic option for the many individuals with CN for whom other surgical therapies are contraindicated. Tenotomy may also prove useful in see‐saw nystagmus (it abolished it in the aforementioned canine) or other types of nystagmus; further studies of the latter are required.
Alcohol and Cardiovascular Diseases
Authors: KLATSKY ARTHUR L.
Published: July 2009

Abstract: Studying its history generally provides insights relevant to current understanding of a subject: the health effects of alcohol consumption is no exception to this rule. Perceiving past errors in the hopes of avoiding their repetition is crucial. Because there are clear disparities in the relationships of alcohol drinking to various cardiovascular conditions, attempts to simplify the subject of alcohol and cardiovascular diseases have delayed understanding this area. Thus, the following are considered separately: cardiomyopathy, arsenic and cobalt beer‐drinkers' disease, cardiovascular beri‐beri, systemic hypertension, cardiac arrhythmias, stroke, atherosclerotic coronary heart disease (CHD), total mortality, and definitions of safe drinking limits. The basic disparity underlying all alcohol‐health relations is between effects of lighter and heavier drinking.
Wine, Diet, Antioxidant Defenses, and Oxidative Damage
Authors: PÉREZ DRUSO D. , STROBEL PABLO , FONCEA ROCÍO , DÍEZ M. SOLEDAD , VÁSQUEZ LUIS , URQUIAGA INÉS , CASTILLO OSCAR , CUEVAS ADA , SAN MARTÍN ALEJANDRA , LEIGHTON FEDERICO
Published: July 2009

Abstract: Oxidative stress is a central mechanism for the pathogenesis of ischemic heart disease and atherogenesis, for cancer and other chronic diseases in general, and it also plays a major role in the aging process. Dietary antioxidants constitute a large group of compounds that differ in mechanism of action, bioavailability and side effects. A systematic analysis of the role of the various antioxidants in chronic diseases is hampered by the difficulty of employing death or clinical events as end points in intervention studies. Therefore, valid markers for oxidative stress, which show dose response and are sensitive to changes in dietary supply of antioxidants, are potentially of great value when trying to establish healthy dietary patterns, or when one component, like red wine, is evaluated specifically. To evaluate potential oxidative stress markers we have studied the effect of different diets plus wine supplementation on antioxidant defenses and oxidative damage. In three experimental series, four groups of young male university students, one of older men and other of older women, 20‐24 volunteers each, received Mediterranean or occidental (high‐fat) diets alone or supplemented with red wine, white wine, or fruits and vegetables. Measurements included, leukocyte DNA 8‐OH‐deoxyguanosine (8OHdG), plasma 7β‐hydroxycholesterol, TBARS and well‐characterized antioxidants, and plasma and urine polyphenol antioxidants. In all experimental groups that received red wine, consumption resulted in marked decrease in 8OHdG. The changes observed in 8OHdG correlate positively with the other markers of oxidative damage, and shows a clear inverse correlation with the plasma level of well established antioxidants and with measurements of total antioxidant capacity. Urinary total polyphenol content as well as the sum of some specific plasma species also correlate inversely with 8OHdG. In conclusion, the results identify 8OHdG as a very promising general marker of oxidative stress in nutrition intervention studies in humans, and red wine shows a remarkable protective effect.
Protective Effects of a Novel Niacin‐Bound Chromium Complex and a Grape Seed Proanthocyanidin Extract on Advancing Age and Various Aspects of Syndrome X
Authors: PREUSS HARRY G. , BAGCHI DEBASIS , BAGCHI MANASHI
Published: July 2009

Abstract: Aging is the progressive accumulation of changes with time that are responsible for the ever‐increasing likelihood of disease and death. The precise cascade of pathological events mainly responsible for aging are still not clearly understood, but enhanced production of free radicals and its deleterious effects on proteins, nucleic acids, and fats, as well as enhanced glycosylation of proteins and DNA are prevalent during aging. Insulin resistance may be a common etiology, at least in part, behind the pathobiological alterations of advancing age. Prevalent age‐related disorders such as cardiovascular diseases, obesity, and cancer have been associated with impaired glucose/insulin metabolism and its consequences. This leads to future strategies to combat the aging process and chronic disorders such as the components of syndrome X associated with aging. Increasing the intake of antioxidants and/or substances recognized to enhance insulin sensitivity is a natural means of combatting the glucose/insulin perturbations and free radical damage. Accordingly, ingestion of niacin‐bound chromium and natural antioxidants such as grape seed proanthocyanidin extract has been demonstrated to improve insulin sensitivity and/or ameliorate free radical formation and reduce the signs/symptoms of chronic age‐related disorders including syndrome X. These natural strategies possess a highly favorable risk/benefit ratio.
Cellular Protection with Proanthocyanidins Derived from Grape Seeds
Authors: BAGCHI DEBASIS , BAGCHI MANASHI , STOHS SIDNEY J. , RAY SIDHARTHA D. , SEN CHANDAN K. , PREUSS HARRY G.
Published: July 2009

Abstract: Grape seed proanthocyanidins have been reported to possess a broad spectrum of pharmacological and medicinal properties against oxidative stress. We have demonstrated that IH636 proanthocyanidin extract (GSPE) provides excellent protection against free radicals in both in vitro and in vivo models. GSPE had significantly better free radical scavenging ability than vitamins C, E and β‐carotene and demonstrated significant cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal cells. GSPE protected against tobacco‐induced apoptotic cell death in human oral keratinocytes and provided protection against cancer chemotherapeutic drug‐induced cytotoxicity in human liver cells by modulating cell cycle/apoptosis regulatory genes such as bcl2, p53 and c‐myc. Recently, the bioavailability and mechanistic pathways of cytoprotection by GSPE were examined on acetaminophen‐induced hepatotoxicity and nephrotoxicity, amiodarone‐induced pulmonary toxicity, doxorubicin‐induced cardiotoxicity, DMN‐induced immunotoxicity and MOCAP‐induced neurotoxicity in mice. Serum chemistry changes, integrity of genomic DNA and histopathology were assessed. GSPE pre‐exposure provided near complete protection in terms of serum chemistry changes and DNA damage, as well as abolished apoptotic and necrotic cell death in all tissues. Histopathological examination reconfirmed these findings. GSPE demonstrated concentration‐/dose‐dependent inhibitory effects on the drug metabolizing enzyme cytochrome P450 2E1, and this may be a major pathway for the anti‐toxic potential exerted by GSPE. Furthermore, GSPE treatment significantly decreased TNFα‐induced adherence of T‐cells to HUVEC by inhibiting VCAM‐1 expression. These results demonstrate that GSPE is highly bioavailable and may serve as a potential therapeutic tool in protecting multiple target organs from structurally diverse drug‐ and chemical‐induced toxicity.
Polyphenols in Red Wines Prevent NADH Oxidation Induced by Peroxynitrite
Authors: VALDEZ LAURA B. , ACTIS‐GORETTA LUCAS , BOVERIS ALBERTO
Published: July 2009

Abstract: It is known that red wines have antioxidant properties owing to the presence of polyphenols and hydroxycinnamates. It has been reported that these compounds are efficient scavengers of peroxynitrite (ONOO−). We assayed the ONOO−‐scavenging activity of plant polyphenols, hydroxycinnamates, and red wines using a fluormetric assay that involves the participation of ONOO− (200 μM) as oxidant and NADH (50‐100 μM) as a target molecule. NADH oxidation was prevented by pure polyphenols and hydroxycinnamates. With the wines, the Cabernet Sauvignon showed more potent ONOO−‐scavenging ability than the Malbecs and the blended wines. These results correlate well with the total phenol content determined by Folin‐Ciocalteau assay.
Melatonin
Authors: REITER RUSSEL J. , TAN DUN‐XIAN
Published: July 2009

Abstract: Melatonin, a molecule with antioxidant properties that is widely distributed in the animal kingdom, has now been shown to exist in the plant kingdom, including edible plants. Our findings show that melatonin is not only an endogenously produced antioxidant, but that it is also consumed in the diet. Since melatonin concentrations in the blood correlate with the total antioxidant status of this fluid, it is likely that dietary melatonin could be important in protecting against oxidative damage.
EPR, Free Radicals, Wine, and the Industry
Authors: TROUP GORDON J. , HUNTER CHARLES R.
Published: July 2009

Abstract: The achievements and uses of electron paramagnetic resonance in the wine industry are pointed out. For example, it first detected stable free radicals in red and white wines and showed that the radical concentration, and therefore the antioxidant action, of white wines was increased by skin and oak exposure. It is expected that EPR will be used more in the future.
In Vitro Systems for Tissue Engineering
Authors: GODBEY W. T. , ATALA A.
Published: July 2009

Abstract: Tissue engineering, by necessity, encompasses a wide array of experimental directions and scientific disciplines. In vitro tissue engineering involves the manipulation of cells in vitro, prior to implantation into the in vivo environment. In contrast, in vivo tissue engineering relies on the body's natural ability to regenerate over non‐cell‐seeded biomaterials. Cells, biomaterials, and controlled incubation conditions all play important roles in the construction and use of modern in vitro systems for tissue engineering. Gene delivery is also an important factor for controlling or supporting the function of engineered cells both in vitro and post implantation, where appropriate. In this review, systems involved in the context of in vitro tissue engineering are addressed, including bioreactors, cell‐seeded constructs, cell encapsulation, and gene delivery. Emphasis is placed upon investigations that are more directly linked to the treatment of clinical conditions.
The Use of Cells in Reparative Medicine
Authors: PARENTEAU NANCY L. , YOUNG JANET HARDIN
Published: July 2009

Abstract: Cells are the functional elements of reparative medicine and tissue engineering. The use of living cells as a therapy presents several challenges. These include identification of a suitable source, development of adequate methods, and proof of safety and efficacy. We are now well aware that stem or pluripotent cells offer an exciting potential source for a host of functional cell types. Their true potential will only be realized through continued effort to increase basic scientific understanding at all levels, the development of adequate methods to achieve a functional phenotype, and attention to safety issues associated with adequate control of cell localization, proliferation, and differentiation. There is also new understanding regarding the immunology of parenchymal cells and new promising approaches to immune modulation, which will open the door to broader therapies using allogeneic cell sources without prohibitive immune suppression. Control of cell growth and phenotypic expression does not end in the culture vessel, but goes beyond to the patient. A living therapy is not static but dynamic, as is the host response. The cells or tissue construct in most cases will not behave as a whole‐organ transplant. It is therefore important that we understand a cell or tissue therapy's ability to react and interact within the host since clinical effectiveness has proven to be one of the most difficult milestones to achieve. A living cell therapy offers great potential to alter the human condition, encompassing alteration of the current biological state of a targeted tissue or organ, augmentation of depleted or lost function, or absolute functional tissue replacement. The extent to which we are able to achieve effective cell therapies will depend on assimilating a rapidly developing base of scientific knowledge with the practical considerations of design, delivery, and host response.
Tissue Engineering
Authors: GOLDSTEIN STEVE A.
Published: July 2009

Abstract: The issues that should be considered as part of the design and evaluation of tissue engineering constructs with respect to their targeted clinical application are reviewed. This paper provides a general framework for the process of bringing tissue‐engineering constructs from the laboratory bench to the patient's bedside, rather than presenting a detailed review of the engineering or biologic principles or mechanisms that are necessary for successful tissue engineering. Many of the principles are animated by using examples from current studies being developed in my laboratory or those of my collaborators. In all likelihood, multiple solutions or approaches will be found that lead to successful tissue‐engineering constructs. The focus here is on the identification of critical parameters to be considered rather than specific design solutions. The review is therefore organized to reflect feasible sequences of activities formulated to take tissue engineering from concept to clinical reality.
Differential Inflammatory and Immunological Responses in Tissue Regeneration and Repair
Authors: SICARD RAYMOND E.
Published: July 2009

Abstract: Repair and regeneration, contrasting resolutions to injury, evoke distinct inflammatory responses. Wound repair evokes a more robust peripheral leukocytosis and is accompanied by a larger inflammatory infiltrate into the wound site. Proliferation of thymocytes and splenocytes was enhanced following injury; however, the ability to be stimulated by myoblasts in coculure is lost by splenocytes harvested from rats undergoing wound repair. These data reflect differences in inflammatory and immunological responses between repair and regeneration and suggest potentially important dialogues occur between injured tissues and inflammatory cells that direct the course of injury resolution.