bluuebunny/crossref_metadata_2025 huggingface dataset:
Corticotrophin‐releasing Hormone and Fetal Responses in Human Pregnancy
Authors: SANDMAN CURT A. , WADHWA PATHIK , GLYNN LAURA , CHICZ‐DEMET ALEKSANDRA , PORTO MANUEL , GARITE THOMAS J.
Published: February 2006

Abstract: During human pregnancy, maternal and fetal compartments of the human placenta produce and release corticotrophic‐releasing hormone (CRH). Elevations of placental CRH are associated with decreased gestational length (including preterm delivery). The effects of elevated placental CRH on human fetal neurological development are not known. Pregnant women in the 31st and 32nd week of gestation consented to procedures for collection of blood and measurement of fetal heart rate (FHR) in response to a series of 40 vibroacoustic stimuli (VAS). Measures of habituation and dishabituation were calculated from the FHR. All subjects were followed to delivery. Fetuses (N= 33) of women with highly elevated CRH were least responsive (p < .03) to stimulation after presentation of a novel (dishabituating) stimulus with control for parity, fetal gender, medical (antepartum) risk, and gestational length at term. In a larger sample (N= 156) a polynomial model predicted the pattern of FHR reactivity for the first 15 trials. Placental CRH concentration significantly predicted FHR reactivity after controlling for the effects of trial number, baseline FHR, inter‐trial interval, and presence of uterine contractions. Increased maternal CRH levels were significantly related to the length of gestation after controlling for the effects of fetal gender, parity, and medical risk (p= .05). The relationship between length of gestation and FHR was not significant suggesting separate actions of CRH on these events. Elevated placental CRH appears to accelerate certain developmental events (gestational length) and may influence the fetal nervous system. The impaired fetal responses to novelty and increased arousal observed in this study suggest that neurological systems may be targets for placental CRH during sensitive developmental periods.
Short‐ and Long‐term Consequences of Corticotropin‐releasing Factor in Early Development
Authors: HENNESSY MICHAEL B. , DAVIS HARRY N. , McCREA ANNE E. , HARVEY ANNE T. , WILLIAMS MICHAEL T.
Published: February 2006

Abstract: Corticotropin‐releasing factor (CRF) mediates various stress‐related responses in adult animals. Little is known about the effects of CRF during early development. Young mammals often vocalize when isolated in novel surroundings. Heightened levels of CRF inhibit vocalizing in isolated rat and guinea pig pups. Still lower levels of CRF may facilitate or permit vocalizing in rat pups. In guinea pigs, CRF appears to move pups from an initial active, to a subsequent passive, stage of behavioral responsiveness. CRF activity prior to birth can also affect the young. Exposing pregnant female rats to stressors during the last trimester of pregnancy alters the morphological and behavioral development of the offspring. Effects of gestational stress can be mimicked by injecting pregnant females with CRF during the last trimester. CRF appears to mediate both short‐ and long‐term responses to stressors during development in rodents.
The Ontogeny of Endomorphin‐1‐ and Endomorphin‐2‐like Immunoreactivity in Rat Brain and Spinal Cord
Authors: BARR GORDON A. , ZADINA JAMES E.
Published: February 2006

Abstract: Endomorphin‐1 and endomorphin‐2 are recently described peptides with high affinity and specificity for the μ opioid receptor. They are believed to be the endogenous ligands for that receptor. We describe the maturation of the endomorphins in brain and spinal cord using recently characterized antibodies to each. Endomorphin‐1‐like immunoreactivity was examined in brain, focusing on the periaqueductal gray of the midbrain and the diagonal band of Broca; endomorphin‐2‐like immunoreactivity is reported for the medulla and spinal cord. In these regions, and in all other regions studied but not described in this paper, the endomorphins were not seen at birth or at 3 days of age. Staining was present in 7‐day‐old and older animals. At these early ages, the pattern and density of staining are not fully developed, but appear complete by 21 days of age. The results suggest that both endomorphin‐1 and endomorphin‐2 develop relatively late compared to other opioid peptides.
Branin Tachykinins and the Regulation of Salt Intake
Authors: FLYNN FRANCIS W.
Published: February 2006

Abstract: The regulation of salt intake is achieved through the coordination of behavioral and pysicological responses. Brain neuropeptides, such as the tachykinins, play an important role in orchestrating both of these responses. Intraventicular injections of NK3 receptor agonists, such as senktide, are potent in suppressing salt intake. Experiment results show that intraventicular injections of senktide that suppress salt intake have no effect on the ingestion of other tastes, such as sucrose. The means by which senktide suppresses salt intake was investigated in a series of experiments. Taste reactivity and lick rate analyses suggest that the activation of NK3 receptors reduces salt intake by modulating the ora‐stimulating property of salt taste.
Neurotransmitter Interaction in Release of Intranuclear Oxytocin in Magnocellular Nuclei of the Hypothalamus
Authors: BEALER STEVEN L. , CROWLEY WILLIAM R.
Published: February 2006

Abstract: Oxytocin (OT) is released within the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus in response to several stimuli. However, the neurotransmitters that control this intranuclear OT release are unknown. In vivo microdialysis was used to examine the roles of norepinephrine and histamine in intranuclear OT release in conscious, lactating female rats. Administration of α‐ or β‐noradrenergic agonists, or histamine, increased OT release in the PVN. In addition, the increase in PVN OT evoked by exogenous histamine was prevented by simultaneous blockade of either H1 or H2 receptors. Furthermore, histamine‐induced release of intranuclear OT was also prevented by blockade of α‐adrenergic receptors. Finally, the increase in magnocellular OT release induced by suckling was abolished by administration of α‐adrenergic antagonists. These data demonstrate that norepinephrine and histamine are important neurotransmitters for release of intranuclear OT, and histamine releases intranuclear OT by stimulating norepinephrine release.
Endogenous Vasopressin Modulates the Cardiovascular Responses to Exercise
Authors: MICHELINI LISETE COMPAGNO , MORRIS MARIANA
Published: February 2006

Abstract: The role of brain‐stem vasopressinergic projections in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise is discussed on the basis of both changes in endogenous peptide content and heart rate changes observed during exercise. Dynamic running caused an increase in vasopressin content specifically in dorsal and ventral brain‐stem areas. Rats pretreated with vasopressin or the V1 receptor antagonist into the nucleus tractus solitarii (NTS) showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the blood pressure response. It is proposed that long‐descending vasopressinergic pathways from the hypothalamus to the NTS serves as one link between the two main neural controllers of the circulation, that is, the central command and feedback control mechanisms driven by the peripheral receptors signals. Therefore vasopressinergic input contributes to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.
Pharmacology of FMRFamide‐related Peptides in Helminths
Authors: GEARY TIMOTHY G. , MARKS NIKKI J. , MAULE AARON G. , BOWMAN JERRY W. , ALEXANDER‐BOWMAN SUSAN J. , DAY TIM A. , LARSEN MARTHA J. , KUBIAK TERESA M. , DAVIS JOHN P. , THOMPSON DAVID P.
Published: February 2006

Abstract: Nervous systems of helminths are highly peptidergic. Species in the phylum Nematoda (roundworms) possess at least 50 FMRFamide‐related peptides (FaRPs), with more yet to be identified. To date, few non‐FaRP neuropeptides have been identified in these organisms, though evidence suggests that other families are present. FaRPergic systems have important functions in nematode neuromuscular control. In contrast, species in the phylum Platyhelminthes (flatworms) apparently utilize fewer FaRPs than do nematodes; those species examined possess one or two FaRPs. Other neuropeptides, such as neuropeptide F (NPF), play key roles in flatworm physiology. Although progress has been made in the characterization of FaRP pharmacology in helminths, much remains to be learned. Most studies on nematodes have been done with Ascaris suum because of its large size. However, thanks to the Caenorhabditis elegans genome project, we know most about the FaRP complement of this free‐living animal. That essentially all C. elegans FaRPs are active on at least one A. suum neuromuscular system argues for conservation of ligand‐receptor recognition features among the Nematoda. Structure‐activity studies on nematode FaRPs have revealed that structure‐activity relationship (SAR) “rules” differ considerably among the FaRPs. Second messenger studies, along with experiments on ionic dependence and anatomical requirements for activity, reveal that FaRPs act through many different mechanisms. Platyhelminth FaRPs are myoexcitatory, and no evidence exists of multiple FaRP receptors in flatworms. Interestingly, there are examples of cross‐phylum activity, with some nematode FaRPs being active on flatworm muscle. The extent to which other invertebrate FaRPs show cross‐phylum activity remains to be determined. How FaRPergic nerves contribute to the control of behavior in helminths, and are integrated with non‐neuropeptidergic systems, also remains to be elucidated.
Neuropeptide Gene Families in the Nematode Caenorhabditis elegansa
Authors: LI CHRIS , NELSON LAURA S. , KIM KYUHYUNG , NATHOO ARIF , HART ANNE C.
Published: February 2006

Abstract: Neuropeptides have diverse roles in the function and development of the nervous system. With the completion of the sequencing of the C. elegans genome, rapid identification of nematode neuropeptide genes is possible. To date, 41 C. elegans neuropeptide genes have been identified. Of these genes, 20 genes, named flp (FMRFamide‐like peptide) genes, encode FMRFamide‐related proteins (FaRPs). Deletion of one of the flp genes, flp‐1, results in several behavioral defects, suggesting that at least one flp gene is not functionally redundant with other flp genes. Twenty‐one genes, named neuropeptide‐like protein (nlp) genes, encode peptides distinct from the FaRP family. The predicted nlp‐1 and nlp‐2 neuropeptides have modest similarity to buccalin and myomodulin, respectively. Cellular expression patterns and genetic analysis of flp and nlp genes suggest that neuropeptides in nematodes also have widespead and varied roles in nervous system function.
Comparison of FaRP Immunoreactivity in Free‐living Nematodes and in the Plant‐parasitic Nematode Heterodera glycines
Authors: MASLER E. P. , KOVALEVA E. S. , SARDANELLI S.
Published: February 2006

Abstract: The family of FMRFamide‐related peptides (FaRPs) is widely distributed among invertebrates, where the peptides serve as neuromodulators. Published reports indicate that numerous FaRP sequences exist in free‐living and animal parasitic nematodes. Using a FMRFamide ELISA, FaRP immu‐noreactivity was detected in extracts of the soybean cyst nematode, Heterodera glycines, in both sexes and at all developmental stages. HPLC‐ELISA results revealed a number of immunoreactive components in H. glycines preparations, and a comparison with extracts of the free‐living nematodes Caenorhabditis el‐egans and Panagrellus redivivus showed significant qualitative differences in FaRP immunoreactivity between the plant parasite and the two free‐living nematodes. Total and specific immunoreactivities varied during H. glycines development, with the highest specific activity in juveniles and males, and the highest total activity in mature females. Total female immunoreactivity was located primarily within the mature eggs. A significant portion, however, was as‐sociated with the female body, perhaps with egg laying.
Stimulation of α‐Amylase Release in the Scallop Pecten maximus by the Myosuppressins: Structure‐Activity Relationships
Authors: NACHMAN RONALD J. , GIARD WILFRID , LANGE ANGELA , FAVREL PASCAL
Published: February 2006

Abstract: The insect myosuppressin LMS (pGlu‐Asp‐Val‐Asp‐His‐Val‐Phe‐Leu‐Arg‐Phe‐NH2) elicits potent stimulation of the release of the digestive enzyme α‐amylase from cell suspensions of the stomach‐digestive gland complex of the scallop Pecten maximus. The myosuppressins are members of the FMRF‐amide‐like peptide superfamily, which immunocytochemical data confirm is present in the scallop. Structure‐activity studies indicated that the two most critical residues for bioactivity are Arg9 and Phe10. Bioactivity of the peptide can be maintained if the basic, aromatic residue His5 is replaced by another basic residue (Lys) and another aromatic residue (Trp), but not the aromatic Tyr, indicating a sensitivity to the introduction of a phenolic OH group. A restricted‐conformation analogue containing a cyclopropyl‐Ala residue in position 8 (Cpa‐MS) demonstrates an ability to antagonize the amylase secretion activity of LMS at μM concentrations. This result provides evidence that the myosuppressins adopt a tight turn in the C‐terminal tetrapeptide active core region while binding to the scallop digestive gland receptor. Cpa‐MS may provide a useful tool to neuroendocrinologists studying in vitro and in vivo digestive processes in mollusks and other invertebrates.
The Unique Neuropeptide Pattern in Abdominal Perisympathetic Organs of Insects
Authors: PREDEL REINHARD , ECKERT MANFRED , HOLMAN G. MARK
Published: February 2006

Abstract: We successfully isolated and identified the abundant neuropeptides of the abdominal perisympathetic organs of the American cockroach, including all myoactive compounds. Peptide sequence analysis and mass spectrometry of abundant substances that were not bioactive in different muscle assays yielded the following sequences: TDPLWQLPGAHLEQYLS‐NH2 (Pea‐YLSamide), AFLTLTPGSHVDSYVEA‐OH (Pea‐VEAacid), and SDLTW‐TYQSPGDPTNSKN‐OH (Pea‐SKNacid). The given structures led to the conclusion of an unique neuropeptide pattern in abdominal perisympathetic organs. We confirmed this assumption with immunocytochemical studies, using antisera raised against different myotropic neuropeptides of the abdominal perisympathetic organs. Moreover, mass spectrometric methods, developed for the investigation of single neurohemal organs, confirmed the neuropeptide pattern in these organs.
Adipokinetic Hormones: Coupling between Biosynthesis and Release
Authors: OUDEJANS ROB C. H. M. , HARTHOORN LUCIEN F. , DIEDEREN JACQUES H. B. , VAN DER HORST DICK J.
Published: February 2006

Abstract: During long‐distance flight of migratory locusts, the dramatic energy demand of the flight muscles is controlled by three adipokinetic hormones (AKHs). These peptide hormones regulate the mobilization of lipid and carbohydrate stored in the fat body to serve as energy substrates for the flight muscles. Despite the relatively huge quantities of the three AKHs that are stored in the corpora cardiaca, flight induces a differential 2‐4‐fold increase in the mRNAs for the three hormones. Moreover, newly synthesized AKHs can be released only during a restricted period of time, suggesting that by far most of the stored hormones are physiologically inactive. This raises the question of how the biosynthetic activity in the AKH‐producing cells is coupled to their secretory activity. The present review discusses the potential mechanisms by which generation and release of mixtures of bioactive neurohormones are controlled and how peptidergic neuroendocrine cells cope with variations in physiological stimulation, with the AKH‐producing cells serving as a model system.
The Kinin Peptide Family in Invertebrates
Authors: TORFS PIETER , NIETO JULIE , VEELAERT DIRK , BOON DORIS , VAN DE WATER GEERT , WAELKENS ETIENNE , DERUA RITA , CALDERÓN JORGE , DE LOOF ARNOLD , SCHOOFS LILIANE
Published: February 2006

Abstract: Kinins comprise a family of peptides that were first found in the central nervous system of insects and recently also in mollusks and crustaceans. After the isolation of the first members of the kinin family, the leukokinins from Leucophaea maderae, leukokinin‐related peptides were found in the cricket Acheta domesticus and the locust Locusta migratoria, all through their ability to induce Leucophaea maderae hindgut contraction. Subsequently, kinins were found in the mosquitoes Culex salinarius and Aedes aegypti and in the earworm Helicoverpa zea. The first noninsect member of this family was isolated from a mollusk, the pond snail Lymnaea stagnalis. Most recently our group has isolated the first kinins from crustaceans. Six kinins were isolated from the white shrimp Penaeus vannamei. To date, 35 members of this family have been isolated. The first relatively small family of insect kinins has grown into an expanding and rather large family with members in insects, crustaceans, and mollusks. In this paper we discuss the kinin family in terms of method of isolation, structure, in vitro and in vivo activity, distribution, receptors, and signal transduction. We will compare the crustacean and insect members of the kinin family, using the data available on crustacea.
Comparison of Active Conformations of the Insectatachykinin/tachykinin and Insect Kinin/Tyr‐W‐MIF‐1 Neuropeptide Family Pairs
Authors: NACHMAN RONALD J. , MOYNA GUILLERMO , WILLIAMS HOWARD J. , ZABROCKI JANUSZ , ZADINA JAMES E. , COAST GEOFFREY M. , VANDEN BROECK JOZEF
Published: February 2006

Abstract: A comparison of solution conformations of active, restricted‐conformation analogues of two sequence‐similar insect/vertebrate neuropeptide family pairs shed light on the potential existence of molecular evolutionary relationships. Analogues of the locustatachykinins and the mammalian tachykinin substance P, containing a sterically hindered Aib‐NMePhe/Tyr residue block, share similar low‐energy turn conformations incorporating a cis peptide bond. Conversely, restricted conformation analogues of the insect kinins and the mammalian opiate peptide Tyr‐W‐MIF‐1, with near identical C‐terminal tetrapeptide sequences, adopt different conformations. The insect kinins adopt a cisPro 1‐4 β‐turn, in which the Phe1 is critical for bioactivity. Tyr‐W‐MIF‐1 prefers a transPro 2‐5 turn, and an additional N‐terminal Phe severely inhibits μ‐opiate receptor binding. Comparisons of the chemical/conformational requirements for receptor interaction are consistent with a distant evolutionary relationship between the insectatachykinins and tachykinins, but not between the insect kinins and Tyr‐W‐MIF‐1. Therefore, analogues of the insect kinins with pest control potential can be readily designed to avoid mammalian interactions.
Electrical Injuries in Canadian Burn Care: Identification of Unsolved Problems
Authors: TREDGET EDWARD E. , SHANKOWSKY HEATHER A. , TILLEY WENDY A.
Published: February 2006

ABSTRACT: Over the past decade, the Firefighters' Burn Treatment Unit of the University of Alberta Hospital in Edmonton, Alberta, Canada, has treated 1399 in‐patients suffering from thermal injury. Regional burn care is provided in a 10‐bed intensive care unit with 18 plastic surgery reconstructive beds for a large referral region of central and northern Alberta, portions of the Northwest Territories, and neighboring provinces of British Columbia and Saskatchewan.

Of the total burn inpatients during this period, 74 electrical injuries were treated (5.3% of all admissions): 71 were males (95.9%) and 3 females (4.1%). The mean age of all patients was 33.9 ± 12.6 years (range 1‐67). Compared to our general population of thermally injured patients, those with electrical injuries had smaller injuries [9.9 ± 12.9% TBSA (range 1‐65) versus 15.1 ± 10.1], shorter length of hospitalization [18.6 ± 7.3 days (range 1‐80) versus 26.2 ± 0.8], and substantially lower mortality once reaching the hospital (0% versus 4%).

Electrical injuries were classified as flash in 30 cases, contact in 42 cases, and lightning in 2 cases; 74.3% of injuries occurred during work‐related activities. A total of 118 operative procedures were performed during the acute admission (1.6 procedures per patient), including 19 amputations: 12 in the upper and 7 in the lower extremity. The mean time of amputation was 9.3 ± 5.3 days after admission.

In contact injuries of the upper extremity, 14 patients suffered amputations or neurologic injury that required reconstruction with free tissue transfers and nerve grafts. Long‐term functional outcome of these patients using sensory testing, the Jebsen‐Taylor hand function test, and wound coverage has revealed that these patients have substantial persistent sensory impairment of their upper extremities postinjury despite reconstruction, although many remain active and functional with acceptable wound coverage.

Based on our analysis of electrical injury as it presents to one typical Canadian burn unit, our patients suffer limb loss on a delayed basis, which leads to substantial morbidity. Reconstruction of the upper extremity with microsurgical techniques after profound electrical injury has provided acceptable coverage, but in many instances is associated with poor or marginal sensory recovery limiting reemployment options for patients with upper extremity electrical burns. Further understanding of the cellular biology of delayed tissue loss after electric injury would offer the potential for reduction in amputation rate and improvement in functional outcome and overall morbidity.
The Use of Allografts in the Management of Exposed Calvarial Electrical Burn Wounds of the Skull
Authors: GROENEVELT F. , VAN TRIER A. J. M. , KHOUW Y. L. N.
Published: February 2006

ABSTRACT: Deep burns of the scalp and skull are often caused by high voltage electrical injuries. In an early stage, protection and preservation of the skull is important. Covering the wound with a full‐circulatory skin flap or a myocutaneous free flap is a reasonable selection, but is not our first choice. In our experience, preliminary use of glycerol‐preserved allograft wound dressing significantly improved the development of granulation tissue to perform an autograft at a later stage. With these allografts, there is a significantly shortened healing time compared with the results found in the literature.
Biological Effects of Electric Shock and Heat Denaturation and Oxidation of Molecules, Membranes, and Cellular Functions
Authors: TSONG TIAN YOW , SU ZHENG‐DING
Published: February 2006

ABSTRACT: Direct exposure of cells in suspension to intense electric pulses is known to produce damages to cell membranes and supramolecular organizations of cells, and denaturation of macromolecules, much like injuries and tears seen in electric trauma patients. Thus, the system has been used as a laboratory model for investigating the biochemical basis of electric injury. An intense electric pulse can produce two major effects on cells‐one caused by the field, or the electric potential, and the other by current, or the electric energy. The field‐induced transmembrane potential can produce electroconformational changes of ion channels and ion pumps and, when the potential exceeds the dielectric strength of the cell membrane (approximately 500 mV for a pulse width of a few ms), electroconformational damages and electroporations of membrane proteins and lipid bilayers. These events lead to passage of electric current through the membrane‐porated cells and to heating of cell membranes and cytoplasmic contents. The subsequent denaturation of cell membranes and cytoplasmic macromolecules brings about many complex biochemical reactions, including oxidation of proteins and lipids. The combined effects may cripple the cells beyond repair. This communication will focus on the thermal effects of electric shock. After a brief review of the current state of knowledge on thermal denaturation of soluble enzymes and muscle proteins, this paper will describe experiments on the thermal denaturation of cellular components and functions, such as nucleosomes, and the electron transport chain and ATP synthetic enzymes of the mitochondrial inner membranes. Data will show that lipid peroxidation and the subsequent loss of the energy‐transducing ability of the cells may occur even at moderate temperatures between 40 °C and 45 °C. However, lipid peroxidation may be prevented with reducing reagents such as mercaptoethanol, dithiothreitol, and ascorbic acid. Reactivation of denatured cellular proteins and functions may also be possible and a strategy for doing so is discussed.
Changes in Electroporation Thresholds of Lipid Membranes by Surfactants and Peptides
Authors: TUNG LESLIE , TROIANO GREG C. , SHARMA VINOD , RAPHAEL ROBERT M. , STEBE KATHLEEN J.
Published: February 2006

ABSTRACT: This article reviews recent work from our laboratory that explores how chemical additives may alter the threshold of electroporation of synthetic lipid bilayers. The addition of the nonionic block copolymeric surfactant, poloxamer 188 (P188), at a concentration of 1 mM increased the electroporation thresholds of planar lipid bilayer membranes made of azolectin. For a 10‐μs rectangular pulse, P188‐treated membranes were found to have a statistically higher threshold voltage, longer latency time to rupture, and lower postpulse conductance. Addition of the nonionic surfactant, octaethyleneglycol‐mono‐n‐dodecyl‐ether (C12E8), decreased the electroporation threshold of bilayer membranes made of 1‐palmitoyl‐2‐oleoyl‐phosphatidylcholine (POPC) by 10‐40% for 10‐μs‐ to 10‐s‐duration pulses, in a concentration‐dependent manner over concentrations ranging from 0.1 to 10 mM. Postpulse membrane conductance also increased. The opposite effects of the two surfactants on electroporation thresholds may result from their very different structures, which would encourage different modes of surfactant‐lipid interactions.

To examine protein‐lipid interactions and their effects on the electroporation threshold, the effects of a channel‐forming polypeptide, gramicidin D (gD), was studied on membrane conductance and electroporation threshold. Electroporation thresholds for 15‐ms pulses were unaffected by addition of gramicidin to POPC at a peptide:lipid concentration estimated to be 1:10,000, but increased significantly at ratios of 1:500 and 1:15, while membrane conductance increased monotonically with peptide concentration. A micropipette aspiration technique was applied to giant unilamellar POPC vesicles to measure changes in the membrane physical properties. When gD was added to give an estimated peptide:lipid ratio of 1:15, the membrane area expansivity modulus increased, indicating that the increase in electroporation threshold is correlated with a change in membrane stiffness. Thus, these findings demonstrate that surfactants or peptides can mediate the electroporation threshold of lipid bilayers.
Pharmaceutical Therapies for Sealing of Permeabilized Cell Membranes in Electrical Injuriesa
Authors: LEE RAPHAEL C. , HANNIG JURGEN , MATTHEWS KENNETH L. , MYEROV ADAM , CHEN CHIN‐TU
Published: February 2006

ABSTRACT:Several years ago, we proposed that loss of cell membrane structural integrity by electroporation is a substantial cause of tissue necrosis in victims of electrical trauma.1Specifically, this involves the permeabilization of the lipid bilayer by thermal and electrical forces. We further suggested that certain mild surfactants in low concentration could induce sealing of permeabilized lipid bilayers and salvage of cells that had not been extensively heat‐damaged. Successful restoration of membrane transport properties using the surfactant poloxamer 188 was reported in 1992.2The purpose of this study is to further examine the response of electroporated rat skeletal muscle membranes to poloxamer 188 (P188) therapy by direct assay of membrane transport properties. Experimental evidence accumulated to date suggests that P188 is effective in sealing permeabilized cell membranes bothin vitroandin vivo.
Early Repair Treatment of Electrical Burns and Recovery of Tendons and Nerves: Report of 194 Operations
Authors: CHANG ZHIDE , SHEN ZUYAO , SUN YONGHUA , WANG NAIZUO , CAO DAXIN
Published: February 2006

ABSTRACT: A new approach to treatment of electrically burned tendons and nerves by primarily covering with skin or myocutaneous flaps is recommended. Between 1964 and 1989, 194 operations using the new approach were performed on 147 patients, of which 179 operations were successful and only 15 procedures resulted in infection. Among 42 cases involving the wrist, the rate of functional recovery of the electrically burned tendons was 97.6%; the rate of recovery in 21 cases of electrically burned peripheral nerves was 80.9%.
Strategies in Disability Management: Corporate Disability Management Programs Implemented at the Work Site
Authors: KALINA CHRISTINE M.
Published: February 2006

ABSTRACT: Managers are challenged to demonstrate all programs as economically essential to the business, generating an appreciable return on investment. Further challenge exists to blend and integrate clinical and business objectives in program development. Disability management programs must be viewed as economically essential to the financial success of the business to assure management support for clinical interventions and return‐to‐work strategies essential for a successful program.

This paper discusses a disability management program integrating clinical and business goals and objectives in return‐to‐work strategies to effect positive clinical, social‐cultural, and business results. Clinical, educational, social, and economic challenges in the development, implementation, and continued management of a disability program at a large corporation with multiple global work sites are defined. Continued discussion addresses the effective clinical interventions and educational strategies utilized successfully within the workplace environment in response to each defined challenge.

A multiple disciplinary team approach, clinical and business outcome measures, and quality assurance indicators are discussed as major program components. This article discusses a successful program approach focusing on business process and methodology. These parameters are used to link resources to strategy, developing a product for implementing and managing a program demonstrating economic value added through effective clinical medical case management.
Life after Electrical Injury: Risk Factors for Psychiatric Sequelae
Authors: KELLEY KATHLEEN M. , TKACHENKO TATIANA A. , PLISKIN NEIL H. , FINK JOSEPH W. , LEE RAPHAEL C.
Published: February 2006

ABSTRACT: Long‐term cognitive and emotional deficits have been commonly reported in electrical injury (EI) survivors. However, it remains undetermined what factors may lead to the development of such effects in some patients and not in others. In this study, we hypothesized that certain elements of subjective EI experience may predict specific psychiatric sequelae. A group of 73 postacute EI patients were included in this retrospective study. Statistical associations were examined between major psychiatric diagnoses (posttraumatic stress disorder and major depression) and such EI descriptors as having experienced “no‐let‐go” or having been knocked away on contact, as well as loss of consciousness or altered states of consciousness at the scene of the accident (including amnesia for the event). The study results will help physicians determine which patients may be at increased risk of developing psychiatric symptoms and address these issues as part of their total rehabilitation plan.
An Open‐Label Study of CP‐101,606 in Subjects with a Severe Traumatic Head Injury or Spontaneous Intracerebral Hemorrhage
Authors: BULLOCK M. ROSS , MERCHANT RANDALL E. , CARMACK CYNTHIA A. , DOPPENBERG EGON , SHAH AJIT K. , WILNER KEITH D. , KO GRANT , WILLIAMS STEPHEN A.
Published: February 2006

ABSTRACT: CP‐101,606 is a postsynaptic antagonist of N‐methyl‐d‐aspartate (NMDA) receptors bearing the NR2B subunit. When administered intravenously (i.v.), it decreases the effects of traumatic brain injury (TBI) and focal ischemia in animal models. Therapeutic plasma concentrations (200 ng/ml) in animals, have been well tolerated in healthy human volunteers. The purpose of the present dose escalation study was to assess the safety, tolerability, and pharmacokinetics of CP‐101,606 in subjects who had suffered either an acute severe TBI (Glasgow Coma Scale 3–8) or spontaneous intracerebral hemorrhage. Thirty patients, 20 with a TBI and 10 with a stroke, were enrolled in the trial and began receiving an i.v. infusion of CP‐101,606 for 2 hours, 24 hours, or 72 hours within 12 hours of brain injury. For the first two hours, the drug was given a rate of 0.75 mg/kg/hr and then stopped (
n= 17

) or continued for 22 (
n= 2

) or 70 hours (
n= 11
) at 0.37 mg/kg/hr. Plasma and cerebrospinal fluid (CSF) were collected at serial times during and after treatment. There were no consistent changes in blood pressure or pulse nor any clinically significant hematological or electrocardiogram (ECG) abnormalities attributable to CP‐101,606. No adverse events or behavioral changes were considered to be related to the drug. Plasma concentrations of CP‐101,606 over 200 ng/ml were rapidly achieved in the blood and CSF within two hours and were sustained there as long as the drug was infused. CSF concentrations were slightly higher than that in plasma by the end of infusion suggesting good penetration of CP‐101,606 into the CSF. Outcome in the severe TBI patients, as measured by the Glasgow Outcome Score at six months, suggested that a two‐hour infusion yielded a range of scores similar to contemporary patients with a severe TBI treated at our hospital while the outcomes of the patients treated with either a 24‐ or 72‐hour infusion were better on average. Thus, these results indicate that CP‐101,606 infused for up to 72 hours is well tolerated, penetrates the CSF and brain, and may improve outcome in the brain‐injured patient.
Neuroprotective “Agents” in Surgery: Secret “Agent” Man, or Common “Agent” Machine?
Authors: ANDREWS RUSSELL J.
Published: February 2006

ABSTRACT: The search for clinically‐effective neuroprotective agents has received enormous support in recent years‐an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent “magic bullet” even more remote.

On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated.

In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery.

The progress over the last 20 years in guidance during surgery (CT and MRI image‐guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real‐time. As an example of such technology, the NASA Smart Probe project is considered.

In the long run (i.e., in 10 years or more), pharmacologic “agents” aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane “agents” based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.
Brain Adenosine Receptors as Targets for Therapeutic Intervention in Neurodegenerative Diseases
Authors: ABBRACCHIO MARIA P. , CATTABENI FLAMINIO
Published: February 2006

ABSTRACT: Adenosine acts as a neurotransmitter in the brain through the activation of four specific G‐protein‐coupled receptors (the A1, A2A, A2B, and A3 receptors). The A1 receptor has long been known to mediate neuroprotection, mostly by blockade of Ca2+ influx, which results in inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. However, the development of selective A1 receptor agonists as antiischemic agents has been hampered by their major cardiovascular side effects. More recently, apparently deleterious effects have been reported following the activation of other adenosine receptor subtypes, namely, the A2A and the A3 receptors. In particular, selective A2A receptor antagonists have been demonstrated to markedly reduce cell death associated with brain ischemia in the rat, suggesting that the cerebral A2A receptor may indeed contribute to the development of ischemic damage. The beneficial effects evoked by A2A antagonists may be due to blockade of presynaptic A2A receptors (which are stimulatory on glutamate release) and/or to inhibition of A2A receptor‐mediated activation of microglial cells. Even more puzzling data have been reported for the A3 receptor subtype, which can indeed mediate both cell protection and cell death, simply depending upon the degree of receptor activation and/or specific pathophysiological conditions. In particular, a mild subthreshold activation of this receptor has been associated with a reinforcement of the cytoskeleton and reduction of spontaneous apoptosis, which may play a role in “ischemic preconditioning” of the brain, according to which a short ischemic period may protect the brain from a subsequent, sustained ischemic insult that would be lethal. In contrast, a robust and prolonged activation of the A3 receptor has been shown to trigger cell death by either necrosis or apoptosis. Such apparently opposing actions may be reconciled by hypothesizing that adenosine‐mediated cell killing during ischemia may be aimed at isolating the most damaged areas to favor those parts of the brain that still retain a chance for functional recovery. In fact, both A3 receptor‐mediated cell death and A2A receptor‐mediated actions may be viewed as an attempt to selectively kill irreversibly damaged cells in the “core” ischemic area, in order to save space and energy for the surrounding live cells in the “penumbra” area. Hence, the pharmacological modulation of the A2A and A3 receptors via selective ligands may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events.
Stimulation of Adenosine A3Receptors in Cerebral Ischemia: Neuronal Death, Recovery, or Both?
Authors: von LUBITZ DAG K.J.E. , YE WEN , McCLELLAN JENNIFER , LIN RICK C.‐S.
Published: February 2006

ABSTRACT:The role of the adenosine A3receptor continues to baffle, and, despite an increasing number of studies, the currently available data add to, rather than alleviate, the existing confusion. The reported effects of adenosine A3receptor stimulation appear to depend on the pattern of drug administration (acute vs. chronic), dose, and type of the target tissue. Thus, while acute exposure to A3receptor agonists protects against myocardial ischemia, it is severely damaging when these agents are given shortly prior to cerebral ischemia. Mast cells degranulate when their A3receptors are stimulated. Degranulation of neutrophils is, on the other hand, impaired. While reduced production of reactive nitrogen species has been reported following activation of A3receptors in collagen‐induced arthritis, the process appears to be enhanced in cerebral ischemia. Indeed, immunocytochemical studies indicate that both pre‐ and postischemic treatment with A3receptor antagonist dramatically reduces nitric oxide synthase in the affected hippocampus. Even more surprisingly, low doses of A3receptor agonists seem to enhance astrocyte proliferation, while high doses induce their apoptosis. This review concentrates on the studies of cerebral A3receptors and, based on the available evidence, discusses the possibility of adenosine A3receptor serving as an integral element of the endogenous cerebral neuroprotective complex consisting of adenosine and its receptors.
Excitotoxicity, Oxidative Stress, and the Neuroprotective Potential of Melatonin
Authors: SKAPER S. D. , FLOREANI M. , CECCON M. , FACCI L. , GIUSTI P.
Published: February 2006

The Brain Consumes Large Quantities of Oxygen Relative to its Contribution to total body mass. This, together with its paucity of oxidative defense mechanisms, places this organ at risk for damage mediated by reactive oxygen species. The pineal secretory product melatonin possesses broad‐spectrum free radical scavenging and antioxidant activities, and prevents kainic acid‐induced neuronal lesions, glutathione depletion, and reactive oxygen species‐mediated apoptotic nerve cell death. Melatonin's action is thought to involve electron donation to directly detoxify free radicals such as the highly toxic hydroxyl radical, which is a probable end‐product of the reaction between NO· and peroxynitrite. Moreover, melatonin limits NO·‐induced lipid peroxidation, inhibits cerebellar NO· synthase, scavenges peroxynitrite, and alters the activities of enzymes that improve the total antioxidative defense capacity of the organism. Melatonin function as a free radical scavenger and antioxidant is likely facilitated by the ease with which it crosses morphophysiological barriers, e.g., the blood‐brain barrier, and enters cells and subcellular compartments. Pinealectomy, which eliminates the nighttime rise in circulating and tissue melatonin levels, worsens both reactive oxygen species‐mediated tissue damage and brain damage after focal cerebral ischemia and excitotoxic seizures. That melatonin protects against hippocampal neurodegeneration linked to excitatory synaptic transmission is fully consistent with the last study. Conceivably, the decreased melatonin secretion that is documented to accompany the aging process may be exaggerated in populations with dementia.
Role of Glycemia in Acute Spinal Cord Injury: Data from a Rat Experimental Model and Clinical Experience
Authors: SALA FRANCESCO , MENNA GAETANO , BRICOLO ALBINO , YOUNG WISE
Published: February 2006

ABSTRACT: While experimental and clinical evidence indicates that in brain injury blood glucose increases with injury severity and hyperglycemia worsens neurological outcome, the role of blood glucose in secondary mechanisms of neuronal damage after acute spinal cord injury has not yet been investigated. Data from spinal cord ischemia models suggests a deleterious effect of hyperglycemia, likely due to enhanced lactic acidosis, which is primarily dependent on the amount of glucose available to be metabolized. The purpose of this study is to summarize preliminary experimental and clinical observations on the role of blood glucose in acute spinal cord injury.

Between 1995 and 1996 we used the New York University (NYU) rat spinal cord injury model to test the following hypotheses: 1) Blood glucose levels increase with injury severity. 2) Fasting protects from hyperglycemia and prevents secondary damage to the spinal cord. 3) Postinjury‐induced hyperglycemia (dextrose 5% 2 gm/Kg) enhances spinal lesion volume.

From a clinical perspective, we reviewed blood glucose records of 47 patients admitted to the Department of Neurosrgery in Verona, between 1991 and 1995, within 24 hours of acute spinal cord injury in order to determine: a) the incidence of hyperglycemia (>140 mg/dl); b) the correlation between blood glucose and injury severity; and c) the role of methylprednisolone in affecting blood glucose.

Results indicate that in a graded spinal cord injury model: 1) Early after injury, more severe contusions support significantly higher blood glucose levels. 2) Fasting overnight does not directly affect spinal cord lesion volume but influences blood gases, and we observed that a slightly systemic acidosis plays a minor neuroprotective role. Fasting also ensures more consistent normoglycemic baseline blood glucose values. 3) Postinjury‐induced moderate hyperglycemia (160–190 mg/dl) does not significantly affect spinal cord injury.

In the clinical study, we observed that during the first 24 hours after spinal cord injury: a) Glycemia ranges between 90 and 243 mg/dl (mean value 143 mg/ dl), and close to 50% of the patients present blood glucose values higher than normal. b) Methylprednisolone administration is not associated to significantly higher blood glucose levels. c) There is a trend for larger glucose rises with more severe injury.
N‐Acetylserotonin, Melatonin and Their Derivatives Improve Cognition and Protect against β‐Amyloid‐Induced Neurotoxicity
Authors: BACHURIN S. , OXENKRUG G. , LERMONTOVA N. , AFANASIEV A. , BEZNOSKO B. , VANKIN G. , SHEVTZOVA E. , MUKHINA T. , SERKOVA T.
Published: February 2006

ABSTRACT: After a single injection of cholinergic neurotoxin ethylcholine aziridinium (AF64A, 3 nmol intracerebroventricularly (i.c.v.)), rats failed to perform the tasks in the active avoidance (learning and retention paradigms) and water maze tests. N‐Acetylserotonin (NAS), melatonin and their newly synthesized derivatives, CA‐15 and CA‐18, (0.3‐3.0 mg/kg daily for 12–14 days) reversed the effect of AF64A in a dose‐dependent manner with CA‐18 being the most active. Melatonin and NAS caused sedation absent in CA‐18‐treated rats. The studied compounds (25–500 μM for 72 hr) protected against β‐amyloid peptide (βAP) fragment 25–35‐induced neurotoxicity in cerebellar granule cell culture. Our results suggest that neuroprotecting properties of these compounds might mediate their cognition‐enhancing effects. The results obtained warrant the further search for the novel types of safe neuroprotectors among the synthetic NAS/melatonin derivatives.
Primary Cultures of Rat Cerebellar Granule Cells as a Model to Study Neuronal 5‐Lipoxygenase and FLAP Gene Expression
Authors: MANEV HARI , UZ TOLGA
Published: February 2006

ABSTRACT: Aging is associated with chronic neurodegenerative diseases and increased brain vulnerability that may lead to a worse outcome from brain insults in elderly than in young subjects. Inflammation is one of the patholphysiological mechanisms of both chronic and acute neurodegeneration. Leukotrienes are inflammatory lipid mediators whose formation from arachidonic acid is initiated by 5‐lipoxygenase (5‐LO). 5‐LO is also expressed in neurons and can be activated by brain injuries, whereas 5‐LO inhibitors can provide neuroprotection. The expression of the 5‐LO gene appears to be inhibited by the pineal hormone, melatonin, and stimulated by stress hormone glucocorticoids (e.g., corticosterone and the synthetic glucocorticoid dexamethasone). Melatonin deficiency and hyperglucocorticoidemia frequently develop with aging. We found that old or pinealectomized, i.e., melatonin‐deficient rats are more susceptible to kainate‐triggered excitotoxic limbic brain injury than the corresponding young or sham‐pinealectomized controls, and that pinealectomy, aging, or glucocorticoid treatment result in an enhanced expression of 5‐LO in limbic structures. We hypothesize that an aging brain is at a higher risk of neurodegeneration via aging‐suppressed melatonin secretion and/or aging‐increased glucocorticoid secretion and the resultant upregulation of 5‐LO expression. Furthermore, we propose that suppressing the 5‐LO expression and/or activity will increase the brain's resistance to injury. The results of our ongoing research are expected to elucidate the role of 5‐LO in aging and neurodegeneration and to indicate neuroprotective therapies that would target the 5‐LO pathway.