bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurogenesis and Neuroprotection in the Adult Brain
Authors: MANEV HARI , UZ TOLGA , MANEV RADMILA , ZHANG ZHIJING
Published: July 2010

Abstract: 5‐Lipoxygenase (5‐LOX) and cyclooxygenase‐2 (COX‐2) are two enzymes that are critical for the synthesis of eicosanoids, the inflammatory metabolites of arachidonic acid. Both 5‐LOX and COX‐2 are expressed in the brain, including in CNS neurons. The physiologic role of these proteins in neuronal functioning is not clear. In non‐neuronal tissues these two enzymes often assume similar roles: in addition to their function in inflammation, 5‐LOX and COX‐2 appear to be associated with cell proliferation, that is, with tumor growth. High 5‐LOX expression has been noticed in the proliferating brain or pancreatic tumor cells; reduction in tumor cell proliferation and/or destruction of tumor cells was achieved with 5‐LOX inhibitors. Proliferation of immature neurons/neuroblasts is an important component of mitotic neurogenesis. We investigated the role of 5‐LOX in proliferation using cultures of human neuronal precursor cells, NT2. We found that these cells express 5‐LOX mRNA and we used 3H‐thymidine incorporation as a measure of cell proliferation; this was reduced by treating the cultures with 5‐LOX inhibitor AA‐861. We propose that the 5‐LOX pathway plays a crucial role in mitotic neurogenesis. Additional studies should explore whether 5‐LOX may participate in neurogenesis related pathologies and whether it should be considered a target for procedures aimed at altering neurogenesis for therapeutic purposes.
The Failure of Neuronal Protective Agents Versus the Success of Thrombolysis in the Treatment of Ischemic Stroke
Authors: JONAS SARAN , AIYAGARI VENKATESH , VIEIRA DORICE , FIGUEROA MIGUEL
Published: July 2010

Abstract: Agents claimed to be neuroprotective in animal stroke models have all failed in human trials. Thrombolysis has been reported as beneficial in animal and human stroke. We explore the reasons for this disparity, using a review of published results of agents tested both in animal stroke models and in human stroke trials. In animals the effect of neuroprotective agents and of thrombolytic agents on infarct size is time‐dependent: early initiation of treatment works best; and benefit is progressively—and eventually totally—lost with increasing delay of time of first treatment. The animal data also show that, overall, the beneficial effects of the neuroprotective agents are weaker, and are totally lost sooner, than those of thrombolytics. The human data show that the failed trials of the neuroprotective agents had entry windows that went far beyond the windows of (any) success seen in tests of these agents in animals. By contrast, human thrombolysis trials uniformly restricted time of entry to windows in which these agents have shown beneficial effect in animals. In clinical stroke trials, neuroprotective agents failed to produce benefit because their effects at best are too weak, and they were used at times predictable from the animal models as too late. Thrombolytic therapy, which has a stronger effect than neuroprotective agents in animal models, was used clinically during the early window of optimal effectiveness, and produced beneficial results. “Too little/too late” is the recipe for failure in the treatment of ischemic stroke.
Marijuana Abusers Are at Increased Risk for Stroke
Authors: HERNING RONALD I. , BETTER WARREN E. , TATE KIMBERLY , CADET JEAN L.
Published: July 2010

Abstract: We have recorded blood flow velocity in the anterior and middle cerebral arteries by transcranial Doppler sonography in abstinent marijuana abusers (n= 16) and control subjects (n= 19) to assess the effects of prolonged marijuana use of the cerebrovascular system. The pulsatility index, a measure of cerebrovascular resistance, and systolic velocity were significantly (p < 0.005) increased in marijuana abusers compared to the control subjects. These findings suggest that cerebral perfusion observed in 18–30 year old marijuana abusers is comparable to that of normal 60 year‐olds. Thus, chronic abuse of marijuana might be a risk factor for stroke.
Arterial Baroreceptors and Experimental Diabetes
Authors: SALGADO HELIO C. , FAZAN RUBENS , FAZAN VALÉRIA P. S. , DIAS DA SILVA VALDO J. , BARREIRA AMILTON A.
Published: July 2010

Abstract: Alterations of the autonomic reflex control of the cardiovascular system have been demonstrated in clinical and animal models of insulin‐dependent diabetes mellitus. Established neuroaxonal dystrophy is considered the neuropathological hallmark of chronic experimental diabetes. However, the afferent arm of the arterial baroreflex, that is, the carotid sinus nerve and the aortic depressor nerve, has received much less attention in studies dealing with this physiopathological model. The attenuation of the pressure response to bilateral carotid occlusion in conscious rats indicates a derangement of the baroreflex, probably involving an alteration of the carotid sinus nerve. There is histological evidence obtained from adult spontaneous insulin‐dependent diabetic rats (strain BB/S) of a carotid sinus nerve with signs of axonal swelling and intramyelinic edema, suggesting diabetic neuropathy. The study of aortic baroreceptor activity in anesthetized rats with short‐ and long‐term streptozotocin diabetes by means of cross‐spectral analysis of baroreceptor activity versus arterial pressure revealed a dysfunction in the afferent arm of the baroreflex even during a short period of diabetes. The morphology of the aortic depressor nerve of streptozotocin‐diabetic rats indicated axonal atrophy by visual analysis remarkably at the distal segments of the nerves. This finding was confirmed by morphometric study of the myelinated fibers. In conclusion, although studies of the arterial baroreceptors related to experimental diabetes are scanty in the literature, there is electrophysiological and histological evidence demonstrating that the carotid sinus and the aortic depressor nerves are abnormal in this experimental model.
The Bezold‐Jarisch Reflex
Authors: AVIADO DOMINGO M. , AVIADO DOMINGO GUEVARA
Published: July 2010

Abstract: The Bezold‐Jarisch reflex is an eponym for a triad of responses (apnea, bradycardia, and hypotension) following intravenous injection of veratrum alkaloids in experimental animals. The observation was first reported in 1867 by von Bezold and Hirt, and confirmed in 1938–1940 by Jarisch. The triad depends on intact vagi and is mediated through cranial nervous medullary centers controlling respiration, heart rate, and vasomotor tone. The respiratory effects are mediated through pulmonary vagal afferents and the bradycardia and vasodepression through cardiac vagal afferents. The veratrum alkaloids activate all known receptors in the carotid‐aortic and cardiopulmonary areas. The cardiopulmonary receptors (baroreceptors, cough receptors, and parenchymal stretch receptors) also respond to other chemical substances: nicotine, capsaicin, venom, antihistaminics, halogenated anesthetics, diguanides, and serotonin (5‐hydroxytryptamine). Derivatives of last‐mentioned amine activate Type 1, 2, or 3 receptors and have potential therapeutic use. Since several types of cardiopulmonary receptors participate in the Bezold‐Jarisch reflex, it has been difficult to develop a blockade to one type of receptor for therapeutic use (cough, bronchospasm, pulmonary hypertension, or coronary vasospasm). Axon reflexes influence pulmonary blood vessels, bronchial blood vessels, and bronchial smooth muscles. These intrapulmonary reflexes need further study as to how they relate to the Bezold‐Jarisch reflex in health and disease. The cardiopulmonary and carotid‐aortic reflexes can serve as defense mechanisms against chemical hazards that are likely to be inhaled in the workplace and in the environment.
Nicotinic Acetylcholine Receptors on Vagal Afferent Neurons
Authors: COOPER ELLIS
Published: July 2010

Abstract: Nicotinic acetylcholine receptors (nAChRs) play an important role in various processes involved in regulating systemic blood pressure. These receptors are expressed at excitatory cholinergic synapses between sympathetic preganglionic neurons and postganglionic sympathetic neurons and link the integrative activities of the CNS with peripheral effector mechanisms of the sympathetic nervous system. Nicotinic AChRs are also expressed on a subset of vagal afferent neurons, including those involved in baroreceptor reflexes. This review discusses the developmental expression of nAChRs on vagal afferent neurons and two factors that influence the differentiation of these neurons: ganglionic satellite cells and neurotrophins. In addition, this review discusses two important properties of neuronal nAChRs: inward rectification and calcium permeability. At the molecular level, intracellular polyamines, acting as gating particles, effectively block the receptor pore in a voltage‐dependent manner, producing inward rectification. Moreover, a critical structural determinant underlies both the block by intracellular polyamines and calcium permeability. Finally, this review discusses the modulation and block of neuronal nAChRs by extracellular polyamines and the possible implications for neurodegenerative diseases.
Cellular Mechanisms Regulating Synaptic Vesicle Exocytosis and Endocytosis in Aortic Baroreceptor Neurons
Authors: HAY MEREDITH , HOANG CAROLINE J. , PAMIDIMUKKALA JAYA
Published: July 2010

Abstract: The purpose of this chapter is to review some of the recent progress in the understanding of the cellular and biophysical mechanisms that are involved in the regulation of arterial baroreceptor neurotransmssion. Synaptic depression or fatigue following repeated neuronal stimulation has been shown at central baroreceptor synapses in vivo and in vitro. As most of the central neurons have a limited number of vesicles, vesicle retrieval or endocytosis following exocytosis is thought to play a major role in preserving synaptic transmission. We have hypothesized that central baroreceptor terminals may inhibit their own synaptic transmission via feedback activation of presynaptic metabotropic glutamate receptors (mGluRs). We have analyzed the effects of mGluR autoreceptors (group III mGluRs) on voltage‐gated calcium channels using standard patch‐clamp techniques and on the process of exocytosis and endocytosis in aortic baroreceptor neurons using the quantitative imaging dye FM1–43 and FM2–10. Usng the whole‐cell patch‐clamp technique, we have found that activation of group III mGluRs with L‐AP4 inhibits peak calcium channel current. Furthermore, activation of group III mGluRs with L‐AP4 markedly decreases stimulation‐induced exocytosis in aortic baroreceptor neurons, as measured with FM1–43, and inhibits synapsin I phosphorylation. These results suggest that activation of group III mGluRs may inhibit synaptic transmission by (1) inhibiting calcium influx, (2) decreasing synaptic vesicle exocytosis, and (3) modulating the mechanisms governing synaptic vesicle recovery and endocytosis. These effects of mGluRs on baroreceptor synaptic vesicles may contribute to the baroreceptor/nucleus tractus solitarius synaptic depression observed in vivo.
Response Properties of Baroreceptive NTS Neurons
Authors: PATON JULIAN F. R. , LI YU‐WEN , SCHWABER JAMES S.
Published: July 2010

Abstract: Neurons in the nucleus of the solitary tract (NTS) responding to activation of arterial baroreceptors were recorded intracellularly using patch pipettes in an in situ arterially perfused working heart‐brain stem preparation of rat. Seven of 15 (i.e., 46%) of NTS neurons showed adaptive (nonlinear) excitatory synaptic response patterns during baroreceptor stimulation followed by an “evoked hyperpolarization.” This evoked hyperpolarization was stimulus intensity dependent and capable of shunting out a subsequent baroreceptor input. We suggest that this adaptive response behavior may be mediated, in part, by calcium‐dependent potassium currents (IKCa) since neurons showed spike frequency adaptation during step depolarizations and an after‐hyperpolarization after repetitive firing. Furthermore, in in vivo anesthetized rats, NTS microinjections of either charybdotoxin (225 fmol) or apamin (4.5 pmol) to block IKCa increased the baroreceptor reflex gain. Our data purport that the responsiveness of baroreceptive NTS neurons can be regulated by intrinsic membrane conductances such as IKCa. Modulation of such conductances during either physiological (exercise) or pathophysiological (essential hypertension) conditions may lead to changes in both the operating point and gain of the baroreceptor reflex.
Differential Regulation of Sympathetic Outflows to Vasoconstrictor and Thermoregulatory Effectors
Authors: MORRISON SHAUN F.
Published: July 2010

Abstract:The medullary premotor neurons determining the sympathetic outflow regulating cardiac function and vasoconstriction are located in the rostral ventrolateral medulla (RVLM). The present study sought evidence for differential characteristics and baroreceptor reflex sensitivities between the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis and cardiovascular SNA such as that controlling mesenteric vasoconstriction via the splanchnic (SPL) nerve. The tonic discharge of sympathetic nerves is determined by the inputs to functionally specific sympathetic preganglionic neurons from supraspinal populations of premotor neurons. Under normothermic conditions, BAT SNA was nearly silent, while SPL SNA exhibited sustained, large‐amplitude bursts. Disinhibition of neurons in the rostral raphe pallidus (RPa), a potential site of sympathetic premotor neurons controlling BAT SNA, or icv injection of prostaglandin E2, a pyrogenic stimulus, elicited a dramatic increase in BAT SNA. SPL SNA was strongly influenced by the baroreceptor reflex as indicated by a high coherence to the arterial pressure, while activated BAT SNA exhibited no correlation with the arterial pressure. Since these characteristics and reflex responses in sympathetic outflow have been shown to arise from the ongoing or altered discharge of sympathetic premotor neurons, the marked differences between SPL SNA and BAT SNA provide strong evidence supporting the hypothesis that vasoconstriction and thermogenesis (metabolism) are controlled by distinct populations of sympathetic premotor neurons, the former in the RVLM and strongly baroreceptor‐modulated and the latter potentially in the RPa exhibiting little influence of baroreceptor reflex activation.
The Interaction of Angiotensin II and Osmolality in the Generation of Sympathetic Tone during Changes in Dietary Salt Intake
Authors: BROOKS VIRGINIA L. , SCROGIN KARIE E. , McKEOGH DONOGH F.
Published: July 2010

Abstract:At rest, sympathetic nerves exhibit tonic activity which contributes to arterial pressure maintenance. Significant evidence suggests that the absolute level of sympathetic tone is altered in a number of physiologic and pathophysiologic states. However, the mechanisms by which such changes in sympathetic tone occur are incompletely understood. The purpose of this review is to present evidence that humoral factors are essential in these changes and to detail specifically an hypothesis for the mechanisms that underlie the changes in sympathetic tone that are produced during increases or decreases in dietary salt intake. It is proposed that the net effect of changes in dietary salt on sympathetic activity is determined by the balance between simultaneous and parallel sympathoinhibitory and sympathoexcitatory humoral mechanisms. A key element of the sympathoinhibitory mechanism is the chronic sympathoexcitatory effects of angiotensin II (ANG II). When salt intake increases, ANG II levels fall, and the sympathoexcitatory actions of ANG II are lost. Simultaneously, a sympathoexcitatory pathway is triggered, possibly via increases in osmolality which activate osmoreceptors or sodium receptors. In normal individuals, the sympathoinhibitory effects of increased salt predominate, sympathetic activity decreases, and arterial pressure remains normal despite salt and water retention. However, in subjects with salt‐sensitive hypertension, it appears that the sympathoexcitatory effects of salt predominate, possibly due to an inability to adequately suppress the levels or actions of ANG II. The net result, therefore, is an inappropriate increase in sympathetic activity during increased dietary salt which may contribute to the hypertensive process.
Arterial Baroreceptor and Cardiopulmonary Reflex Control of Sympathetic Outflow in Human Heart Failure
Authors: FLORAS JOHN S.
Published: July 2010

Abstract: Several observations indicate that the arterial baroreflex control of sympathetic nerve activity is preserved, even in advanced heart failure. These include: (1) augmentation of muscle sympathetic nerve activity burst amplitude and duration following a premature beat; (2) rapid recognition of changes in blood pressure induced by ventricular arrhythmias; (3) muscle sympathetic alternans and a steep inverse relationship between changes in diastolic pressure and the subsequent sympathetic burst amplitude during pulsus alternans; (4) similar inhibition of muscle sympathetic nerve activity in subjects with normal and impaired left ventricular systolic function by increases in intrathoracic aortic transmural pressure; (5) documentation, by cross‐spectral analysis, of similar gain in the transfer function between blood pressure and muscle sympathetic nerve activity in these two groups; and (6) during sodium nitroprusside infusion, similar reflex increases in total body norepinephrine spillover in normal and heart‐failure subjects. When nonhypotensive lower‐body negative pressure was applied to test the hypothesis that selective reduction of atrial and pulmonary pressures would exert a cardiac sympathoinhibitory response in heart failure, there was no effect in control subjects, but cardiac norepinephrine spillover fell by 25% (P <. 05) in those with systolic dysfunction. In summary, human heart failure is characterized by a rapidly responsive and sensitive arterial baroreflex, and by activation of a cardiac sympathoexcitatory reflex related to increased cardiopulmonary filling pressures.
Cerebral Autoregulation in Orthostatic Intolerance
Authors: SCHONDORF RONALD , BENOIT JULIE , STEIN REUBEN
Published: July 2010

Abstract: Many of the primary symptoms of orthostatic intolerance (fatigue, diminished concentration) as well as some of the premonitory symptoms of neurally mediated syncope (NMS) are thought to be due to cerebral hypoperfusion. Transcranial Doppler measurements of middle cerebral artery blood velocity (CBV) is at present the only technique for assessing rapid changes in cerebral blood flow, and hence for evaluating dynamic cerebral autoregulation. However, controversies exist regarding data interpretation. At syncope, during the collapse of blood pressure (BP), diastolic CBV diminishes, whereas systolic CBV is maintained. Some consider this increase in CBV pulsatility to be indicative of a paradoxical increase in cerebrovascular resistance (CVR) prior to syncope. Others note that mean CBV decreases much less than does mean BP, implying that cerebral autoregulatory mechanisms are intact and functioning at syncope. Similarly, there is no evidence of impaired dynamic cerebral autoregulation, as measured by standard linear transfer‐function analysis, in patients with NMS. Some patients with exaggerated postural tachycardia (POTS) have been found to have an excessive decrease in CBV during head‐up tilt. Controversy exists as to whether this decrease results from an excessive sympathetic outflow to the cerebral vasculature or from hyperventilation. However, many other equally symptomatic patients with a similar hemodynamic profile of exaggerated tachycardia during head‐up tilt have normal CBV changes during this maneuver and have normal dynamic cerebral autoregulation as determined by transfer‐function analysis. Whether these discrepancies reflect different pathologies in patients with POTS is currently unknown.
Human Endothelial Cell Presentation of Antigen and the Homing of Memory/Effector T Cells to Skin
Authors: POBER JORDAN S. , KLUGER MARTIN S. , SCHECHNER JEFFREY S.
Published: July 2010

Abstract: Dermal microvascular endothelial cells (ECs) form a continuous lining that normally bars blood‐borne T lymphocytes from entering the skin, but as part of the response to foreign antigen, dermal ECs undergo alterations in their surface proteins so as to provide signals to circulating T cells that lead to their activation and recruitment. Several observations suggest that human dermal microvascular ECs may help initiate cutaneous immune reactions by presentation of cognate antigens to circulating T memory cells: (1) antigen‐specific inflammatory responses in the skin, as in other organs, involve accumulation of memory and effector T cell populations that are enriched in cells specific for the eliciting antigen; (2) recall responses to intradermal protein antigens in the skin start very rapidly within two hours of challenge; (3) dermal microvascular ECs in humans and other large mammals basally display high levels of class I and class II MHC molecules, the only known purpose of which is to present antigenic peptides to lymphocytes; (4) the lumen of dermal capillaries are narrower than the diameter of circulating T cells, ensuring surface contact; and (5) cultured human ECs effectively present antigens to resting memory T cells isolated from the circulation. Upon contact with activated T cells or their secreted products (cytokines), dermal ECs themselves become activated, increasing their capacity to recruit memory and effector T cell populations in an antigen‐independent manner. Specifically, activated ECs express inducible leukocyte adhesion molecules such as E‐selectin, ICAM‐1, and VCAM‐1; and several lines of evidence, including neutralizing antibody experiments and gene knockouts, have supported a role of these molecules in T cell recruitment. Dermal ECs have unique expression patterns of adhesion molecules that can determine the subsets of memory T cells that are recruited into the skin. For example, slow internalization of E‐selectin allows more persistent expression of this protein on the surface of dermal ECs, favoring interactions with CLA‐1+ T cells. VCAM‐1 expression, normally confined to venular EC may extend to capillaries within the dermal papillae and contribute to epidermal inflammation, recruiting α4β7 integrin‐expressing T cells that also express the cadherin‐binding integrin αEβ7. New models involving transplantation of normal and genetically modified human dermal ECs into immunodeficient mice may be used to further explore these properties.
Crosstalk between Tumor T Lymphocytes and Reactive T Lymphocytes in Cutaneous T Cell Lymphomas
Authors: BAGOT M. , NIKOLOVA M. , SCHIRM‐CHABANETTE F. , WECHSLER J. , BOUMSELL L. , BENSUSSAN A.
Published: July 2010

Abstract: We have established several tumor T cell lines, both from the skin and from the blood of a patient with an MHC class II−/class I+, CD4+ cutaneous T cell lymphoma (CTCL). These cell lines, like the initial tumor cells, had a CD3+CD4+CD8− phenotype. We also isolated two cytotoxic T lymphocyte clones from the tumor site of this CTCL patient. These clones displayed a CD4+CD8dim+ (TC5) and CD4+CD8− (TC7) phenotype and mediated a specific MHC class I‐restricted cytotoxic activity toward noncultured tumor cells and autologous tumor cell lines. Despite surface expression of Fas on tumor cells and Fas‐L induction on TC5 and TC7 cell membrane after coculture with autologous tumor cells, the CD4+ CTL clones did not use this cytotoxic mechanism to lyse their specific target. TC7 used a granzyme/perforin‐dependent pathway, whereas TC5 used a TRAIL‐dependent mechanism. Quantitative analysis of cytokine mRNA expression indicated that while the tumor cells displayed a Th2‐type profile, the CTL clones expressed Th1‐type cytokines. Pre‐incubation of TIL clones with autologous tumor cells in a short‐term culture induced their activation and subsequent amplification of the Th1‐type response, which indicates a direct contribution of the malignant cells in the Th1/Th2 imbalance. However, we found that tumor cells produced high amounts of TGF‐β, which could explain the inhibition of a specific antitumor immune response. Another mechanism to avoid the host immune response was the expression of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors by tumor‐specific lymphocytes. Finally, we present recent data on new antigen structures expressed both by long‐term CTCL lines and uncultured tumor cells.
The Clonotypic T Cell Receptor Is a Source of Tumor‐associated Antigens in Cutaneous T Cell Lymphoma
Authors: BERGER CAROLE L. , LONGLEY JACK , HANLON DOUGLAS , GIRARDI MICHAEL , EDELSON RICHARD
Published: July 2010

Abstract: To develop cancer vaccines for the treatment of cutaneous T cell lymphoma (CTCL), immunogenic peptides were identified by two approaches. First, through the use of “reverse immunology” the peptide sequence of the idiotypic region of the β chain of the T cell receptor (TCR) was determined and a series of overlapping peptides synthesized and tested for CD8 T cell recognition. In two patients, the idiotypic CDR3 region provided immunogenic epitopes that were recognized in a class I‐restricted fashion by autologous CD8 T cell lines. In a second strategy, peptides were isolated directly from class I MHC molecules on the CTCL surface and sequenced. A peptide with partial homology to sequences contained in the conserved variable portion of the clonotypic TCR β chain was recognized as immunogenic by autologous CD8 T cells. Therefore, both approaches demonstrated that the clonotypic TCR in CTCL is a source of immunogenic tumor epitopes. To confirm that recognition of TCR‐derived sequences provides immunoprotection against tumor growth, a murine model of T cell lymphoma was studied. The immunogenicity of a thymoma, which lacks cell surface TCR expression, was enhanced by transfection of the β chain of the TCR. The studies reviewed in this paper demonstrate that the TCR can serve as one source for immunogenic tumor peptides in T cell lymphoma in vitro and in vivo. Presentation of TCR epitopes on dendritic cells that express high levels of MHC, costimulatory, and adhesion molecules may provide an effective means for immunization against T cell malignancy.
Clinical Trials and Efficacy Assessment in the Therapy of Cutaneous T Cell Lymphoma
Authors: HEALD PETER
Published: July 2010

Abstract: The ability of clinical trials to measure cutaneous T cell lymphoma (CTCL) has allowed physicians and regulatory reviewers to assess the response of the disease to experimental therapies. The goals of therapy are remission, palliation, and improvement of survival. Given the chronic nature of the disease, surrogate markers for survival are used in clinical trials. The surrogate markers and the validity of the surrogate markers used to date will be compared and contrasted. Tumor burden measurements by way of skin scoring are the parameters most commonly used to assess the response to therapy. Skin scoring systems have used global mapping, severity recording, or target lesions to assess any change in response to an intervention. The advantages and limitations of global and focal scoring are presented, along with examples of skin scoring systems for the five most recently completed trials for CTCL. Measures of palliation are performed via questionnaires. General and CTCL‐specific questionnaires have been developed that assess both discrete and global manifestations of the disease. Those measures of palliation that have been shown to correlate with skin scoring are presented for inclusion into future studies. In addition, study terms such as relapse and freedom from relapse can now be defined with reproducible molecular techniques. Every stage of CTCL warrants further clinical trials, and guidelines for future investigations are proposed.
Photoactivational Cytokine‐modulatory Action of 8‐Methoxypsoralen plus Ultraviolet A in Lymphocytes, Monocytes, and Cutaneous T Cell Lymphoma Cells
Authors: TOKURA YOSHIKI , SEO NAOHIRO , YAGI HIROAKI , TAKIGAWA MASAHIRO
Published: July 2010

Abstract: Treatment with 8‐methoxypsoralen (8‐MOP) and ultraviolet A light (UVA) has been reported to modulate cytokine production in various cells. Our study was conducted to see the effects of 8‐MOP/UVA on the expression/production of cytokines in peripheral blood lymphocytes and monocytes in relation to the therapeutic mechanisms of extracorporeal photochemotherapy. 8‐MOP/UVA augmented the expression of mRNAs for interferon‐γ (IFN‐γ) and interleukin (IL)‐2 and reduced those for IL‐4 and IL‐10 in peripheral blood mononuclear cells (PBMCs) from normal subjects and Sézary syndrome patients. This enhancement of Th1 cytokines was caused by increment of cytokine production by Th1 cells but not by conversion of Th2 cells to produce Th1 cytokines. The number of IFN‐γ‐secreting lymphocytes was markedly increased in 8‐MOP/UVA‐treated PBMCs 20 h after treatment, and its amount was elevated in culture supernatants. However, this enhanced production of IFN‐γ was found only until three days after 8‐MOP phototreatment, and its level was rapidly declined by five days after treatment. In addition to this Th1‐polarized action, 8‐MOP/UVA‐treated PBMCs produced enhanced amounts of IL‐8 upon stimulation with anti‐CD3/CD28 antibodies. Phototreated CD4+ but not CD8+ cells provided excellent T cell help for monocytes to produce IL‐8 via a direct cell‐to‐cell contact mechanism. These findings suggest that 8‐MOP/UVA has a transient but biologically active Th1‐skewing action in T cells, and the phototreated T cells simultaneously stimulate monocytes to produce IL‐8. It is suggested that 8‐MOP/UVA exerts a beneficial therapeutic effect on malignant Th2 neoplasms as a Th1‐skewing cytokine modifier and that 8‐MOP‐phototreated CD4+ T cells allow monocytes to become effective tumor antigen‐presenting cells for tumor‐specific cytotoxic T cells.
Microdose Gentamicin Administration via the Round Window Microcatheter
Authors: HOFFER MICHAEL E. , KOPKE RICHARD D. , WEISSKOPF PETER , GOTTSHALL KIM , ALLEN KEITH , WESTER DERIN
Published: July 2010

Abstract: Transtympanic gentamicin is becoming increasingly popular in the treatment of Meniere's disease. In this report we examine our experience with the use of microdose gentamicin via the Round Window Microcatheter for the treatment of Meniere's disease. Thirty‐six patients were treated with gentamicin administration via the Round Window Microcatheter between July 1997 and August 2000. The patients all underwent 10 days of continuous treatment with a total dose of 2.4–3.75 mg of gentamicin (10 mg/ml). All patients had extensive pre‐, intra‐, and post‐therapy auditory and vestibular testing. In this group, vertigo was eliminated in 89% of the patients, and tinnitus and pressure were significantly reduced in over 60% of the patients. Only one patient suffered a significant hearing loss and, most importantly, in all but one patient vestibular function was improved or normalized after treatment. Round Window Microcatheter‐administered microdose gentamicin is an exciting new treatment for Meniere's disease. Preliminary results indicate that vertigo can be controlled without a significant reduction in cochlear or vestibular function in most patients. These results suggest that this therapy may be acting at a non‐hair cell site. Our results are compared to the published literature examining transtympanic injection. In addition, the underlying science supporting this type of treatment is examined.
Exercise and Drug Therapy Alter Recovery from Labyrinth Lesion in Humans
Authors: STRUPP MICHAEL , ARBUSOW VIKTOR , BRANDT THOMAS
Published: July 2010

Abstract: Acute unilateral vestibular failure is characterized by rotatory vertigo, horizontal‐rotatory nystagmus, and postural imbalance, all of which last from days to weeks. These signs and symptoms are caused by a vestibular tone imbalance between the two labyrinths. Recovery results from a combination of peripheral restoration of labyrinthine function (usually incomplete) and central vestibular compensation (CVC) of the vestibular tone imbalance. Acute unilateral failure is most often caused by vestibular neuritis, which is most likely due to the reactivation of a latent HSV‐1 infection. Therefore, therapeutic strategies to improve the outcome of VN are theoretically based on two principles: (a) vestibular exercises and drugs to improve CVC and (b) drug treatment of the assumed viral inflammation. The following conclusions can be drawn from studies in animals and/or humans: (1) There is strong evidence that vestibular exercises may improve vestibulo‐spinal compensation. These exercises should begin as early as possible after symptom onset. Moreover, slower exercises are likely to be more effective than faster exercises because slower ones seem to depend more on the vestibular system. (2) Despite extensive data from animal experiments indicating that drugs have a favorable effect on CVC, this has not been clinically proven and thus cannot be recommended yet. (3) Preliminary results of an interim analysis from an ongoing randomized, prospective study showed that methylprednisolone (plus an antiviral agent?) may be useful for improving peripheral vestibular function in vestibular neuritis.
How Endolymph Pressure Modulates Semicircular Canal Primary Afferent Discharge
Authors: RABBITT R. D. , YAMAUCHI A. M. , BOYLE R. , HIGHSTEIN S. M.
Published: July 2010

Abstract: Histological observation of endolymphatic hydrops in subjects suffering from Meniere's disease/syndrome and the presence of vestibular symptoms in experimentally induced endolymphatic hydrops have led to considerable debate regarding the potential role of inner‐ear pressure. Could a condition influencing endolymphatic volume regulation lead to transient changes in translabyrinthine pressure sufficiently large to alter primary afferent discharge rates? To investigate this question we built a highly sensitive laser‐based pressure sensor and recorded endolymphatic pressure modulations within the horizontal semicircular canal ampulla in response to mechanical stimuli for simple head rotation and controlled volume injection. The most sensitive primary afferents responded to changes in endolymph pressures as low as 0.005 Pa (re: perilymph)—a pressure considerably lower than that observed in most experimentally induced hydropic conditions. This threshold pressure was generated by a ∼25 picoliter volume injection stimulus. Semicircular canal afferent responses to endolymphatic pressure can be explained on the basis of pressure‐induced hydrops, which causes dilation of the ampulla, deformation of the cupula, hair bundle movement, and afferent discharge. Primary afferent responses to maintained stimuli were transient in nature and recovered to pre‐stimulus background discharge rates following a period of adaptation. Results demonstrate that the semicircular canals are indeed sensitive to small changes in translabyrinthine pressure in addition to head‐movement‐related changes in transcupular pressure.
Clinical Experience with a Surgical Approach to Hydrops
Authors: NEELY J. GAIL
Published: July 2010

Abstract: This work was based upon the need to look at the role of surgical intervention in cases of presumed hydrops encountered in usual medical practice. A retrospective cohort study of 292 consecutive cases diagnosed as Meniere's disease was used to identify subjects severely enough affected to elect surgical relief. Two nested case‐control design studies were subsequently conducted: one to compare surgical failures (4 cases) with successes (15 controls); and the other to compare the surgical group (19 cases) with a uniform random sample of all presenting Meniere's disease cases (10 controls). These data suggest the following testable hypotheses: (1) the younger the age of onset, the higher the probability that surgical intervention will be required to control episodic vertigo; (2) the younger the age of onset, the higher the probability of the failure of nondestructive surgery; and (3) patients destined for surgical intervention are likely to require at least twice as much office‐based medical care as the general group of presenting Meniere's patients. A biological question arising from these data is, Does age influence the putative homeostatic pathophysiology implicated in hydrops?
Current Concepts of Vestibular Nucleus Function
Authors: McCREA ROBERT , GDOWSKI GREG , LUAN HONGGE
Published: July 2010

Abstract: The vestibular nerve sends signals to the brain that code the movement and position of the head in space. These signals are used for a variety of functions, including the control of reflex and voluntary movements and the construction of a sense of self‐motion. In order to carry out these functions, sensory vestibular signals need to be transformed in a variety of ways. Transformations are thought to occur at an early stage of sensory processing in the brain, and in many cases are apparent in the responses of neurons in the vestibular nuclei that receive direct inputs from the vestibular nerve. Several specific examples of sensory transformation in the vestibular nuclei are presented, and current hypotheses about the mechanisms that are used to produce the transformations are discussed.
Signal Processing by Vestibular Nuclei Neurons Is Dependent on the Current Behavioral Goal
Authors: CULLEN KATHLEEN E. , ROY JEFFERSON E. , SYLVESTRE PIERRE A.
Published: July 2010

Abstract: The vestibular sensory apparatus and associated vestibular nuclei are generally thought to encode angular head velocity during our daily activities. However, in addition to direct inputs from vestibular afferents, the vestibular nuclei receive substantial projections from cortical, cerebellar, and other brainstem structures. Given this diversity of inputs, the question arises: How are the responses of vestibular nuclei neurons to head velocity modified by these additional inputs during naturally occurring behaviors? Here we have focused on the signal processing done by two specific classes of neurons in the vestibular nuclei: (1) position‐vestibular‐pause (PVP) neurons that mediate the vestibulo‐ocular reflex (VOR), and (2) vestibular‐only (VO) neurons that are thought to mediate, at least in part, the vestibulo‐collic reflex (VCR).

We first characterized neuronal responses to passive rotation in the head‐restrained condition, and then released the head to record the discharges of the same neurons during self‐generated head movements. VOR interneurons (i.e., PVP neurons) faithfully transmitted head velocity signals when the animal stabilized its gaze, regardless of whether the head motion was actively or passively generated; their responses were attenuated only when the monkey's behavioral goal was to redirect its axis of gaze relative to space. In contrast, VCR interneurons (i.e., VO neurons) faithfully transmitted head velocity signals during passive head motion, but their responses were greatly (and similarly) attenuated during all behaviors (i.e., gaze shifts, gaze pursuit, gaze stabilization) during which the monkey's behavioral goal was to move its head relative to the body. To characterize the mechanism(s) that underlie this differential processing, we tested neurons during passive rotation of the head relative to the body, as well as during a task in which a monkey actively “drove” both its head and body together in space. We conclude that neither passive activation of neck proprioceptors nor knowledge of self‐generated head‐in‐space motion directly mediate the observed reductions in head‐velocity‐related modulation. Instead, we propose that the VOR and VCR pathways use efference copies of oculomotor and neck movement commands, respectively, for the differential processing of vestibular information.
Strategies for Balance Rehabilitation
Authors: HERDMAN SUSAN J. , SCHUBERT MICHAEL C. , TUSA RONALD J.
Published: July 2010

Abstract: Identification of fall risk for patients with known vestibular hypofunction is important because it affects the management and the level of independence of these patients. Patients with bilateral vestibular loss, overall, have a greater incidence of falls than the general community‐dwelling population over the age of 65 years. In younger patients, the incidence of falls may be related to severity of vestibular loss and to overconfidence or a lack of caution in activities. Preliminary reports suggest that vestibular rehabilitation can reduce the fall risk in patients with vestibular loss.
Ovulation Induction Disrupts Luteal Phase Function
Authors: TAVANIOTOU ASIMINA , SMITZ JOHAN , BOURGAIN CLAIRE , DEVROEY PAUL
Published: July 2010

Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin‐releasing hormone (GnRH)‐agonist treatment, or after GnRH‐antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH‐agonist cycles, mid‐luteal biopsies have revealed increased glandulo‐stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased αvβ3‐integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.
Decidual Cell‐Expressed Tissue Factor Maintains Hemostasis in Human Endometrium
Authors: LOCKWOOD CHARLES J. , KRIKUN GRACIELA , SCHATZ FREDERICK
Published: July 2010

We showed that decidualized stromal cells of luteal phase and pregnant human endometrium express tissue factor (TF), the primary initiator of hemostasis, thereby suggesting a mechanism by which perivascular decidual cells can mitigate the risk of hemorrhage during endovascular trophoblast invasion. Progestins enhanced TF mRNA and protein levels in monolayers of human endometrial stromal cells (HESCs), with estradiol (E2) + progestin, further enhancing TF levels despite a lack of response to E2 alone. This differential ovarian steroid response has been found for several decidualization markers. Further studies with cultured HESCs established that elevated TF levels are mediated by the progesterone receptor and are maintained for weeks in response to E2 plus progestin, thus simulating the chronic upregulation of TF levels observed in decidualized HESCs in vivo. Recent studies revealed that elevated TF expression during in vitro decidualization of HESCs involved both the EGFR and progesterone receptor. Thus, enhancement of TF mRNA and protein levels in the HESCs required co‐incubation with a progestin (MPA) and an EGFR agonist such as EGF or TGF‐α. In correspondence with co‐elevation of EGFR and TF in decidualized HESCs in sections of luteal phase and pregnant endometrium, EGFR levels proved to be progestin‐enhanced in the cultured HESCs. We established that progestin‐enhanced TF expression in HESCs was trancriptionally regulated, then evaluated the relative roles of SP and EGR‐1 sites on the TF promoter in regulating this expression. Transient transfections with a series of promoter constructs containing overlapping SP and EGR‐1 sites and with constructs in which the EGR‐1 and SP sites were systematically inactivated by site‐directed mutagenesis established the dominance of SP sites in both basal and progestin‐enhanced TF transcriptional activity. Additional experiments involving transient transfections with SP1overexpressing vectors and with a specific blocker of if Sp1 binding to its corresponding GC box specified the importance of the Sp1 transcription factor. These results were further validated by immunostaining, which revealed that the ratio of Sp1 to Sp3 increased during progestin‐regulated decidualization of HESCs in vitro and in vivo. The absence of canonical estrogen and progesterone response elements from either the TF or Sp1 gene promoters suggests that the EGFR may help to mediate progestin‐enhanced TF expression during decidualization of HESCs.
Endometrial Quality in Infertile Women with Endometriosis
Authors: PELLICER ANTONIO , NAVARRO JOSÉ , BOSCH ERNESTO , GARRIDO NICOLÁS , GARCIA‐VELASCO JUAN A. , REMOHÍ JOSÉ , SIMÓN CARLOS
Published: July 2010

Several analyses in our infertility (IVF) and oocyte donation programs were carried out to gain clinical knowledge of the factors involved in the etiology of endometriosis‐associated infertility. We first compared the IVF outcomes in women with tubal infertility and endometriosis. The results indicated that patients with endometriosis had a poorer IVF outcome in terms of reduced pregnancy rate per cycle, per transfer, and reduced implantation rate per embryo replaced. We then evaluated embryo development in vitro in women with and without endometriosis who underwent IVF and embryo replacement 72 hours after oocyte retrieval. We observed that compared to controls, patients with endometriosis had a significantly reduced number of blastomeres per embryo as well as an increased incidence of arrested embryos in vitro. In subsequent studies we compared fertility parameters in patients receiving donor oocytes. We noted that when donor oocytes came from patients without known endometriosis, embryo development and implantation rates were similar in patients with and without endometriosis. However, when the results of oocyte donation were classified according to the nature of the oocytes donated, patients who received embryos derived from oocytes from women with endometriotic ovaries showed a significantly reduced implantation rate compared to the controls. Taken together, these observations suggest that IVF in patients with endometriosis may be related to alterations within the oocyte, which, in turn, result in embryos of lower quality with a reduced ability to implant.