bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacologic Considerations for Therapeutic Success with Antiretroviral Agents
Authors: Fletcher Courtney V
Published: March 2004

OBJECTIVE:

To explore pharmacologic elements that contribute to therapeutic success with agents used for the treatment of HIV infection.

DATA SOURCES:

Primary articles were identified through MEDLINE (January 1990–January 1999) and secondary sources. Conference abstracts were selected by review of published proceedings.

STUDY SELECTION AND DATA EXTRACTION:

The author evaluated all articles, and relevant information was selected for incorporation into this review.

DATA SYNTHESIS:

Heterogeneity in the response to antiretroviral therapy has been attributed to virologic, immunologic, behavioral, and pharmacologic differences among patients. Patients receiving the same dose of an antiretroviral agent will not have the same systemic or intracellular concentration because of interpatient variability in drug absorption, distribution, metabolism, and excretion. Pharmacologic theory and available clinical data support relationships between drug concentration and anti-HIV effect. Thus, variability in drug concentrations contributes to variability in antiviral effect. Desirable pharmacologic characteristics for an antiretroviral drug include high oral bioavailability, a long elimination half-life, low intra- and interpatient pharmacokinetic variability, and a predictable dose–concentration–effect relationship.

CONCLUSIONS:

Treatment of the individual who is infected with HIV is a challenging long-term undertaking. Optimal management requires synthesis of a rapidly evolving base of basic and clinical knowledge. The selection of an antiretroviral regimen based on an understanding of the degree to which each individual agent possesses the desired pharmacologic characteristics should help the healthcare provider to translate the therapeutic principles of treatment of HIV infection into clinical reality for all patients.
Is Valproate Pharmacotherapy Associated with Polycystic Ovaries?
Authors: Chappell Kimberly A , Markowitz John S , Jackson Cherry W
Published: March 2004

OBJECTIVE:

To review and evaluate the published data associating the use of valproate with the development of polycystic ovaries.

DATA SOURCES:

A computerized search of MEDLINE (1966–May 1999) and Current Contents was performed. Also, bibliographies were cross-referenced to yield additional pertinent publications. All articles written in English were considered for review.

STUDY SELECTION AND DATA EXTRACTION:

All pertinent clinical studies and review articles associating valproate with polycystic ovaries and other endocrinologic disorders were evaluated.

DATA SYNTHESIS:

Valproate is among the most commonly used medications today effective in the treatment of a variety of neurologic and psychiatric disorders. An accumulating body of literature has suggested an increase in the incidence of polycystic ovarian syndrome among women treated with valproate. The syndrome is characterized as hyperandrogenism and chronic anovulation in the absence of identifiable adrenal or pituitary pathology. It is a highly prevalent syndrome, affecting 2–22% of women in the general population.

CONCLUSIONS:

Although a number of studies have found clear evidence of neuroendocrine perturbations in patients treated with valproate, there are presently limited data from large controlled studies involving valproate monotherapy. Nonetheless, there appears to be a greater incidence of polycystic ovaries associated with valproate use in comparison with other anticonvulsants. The mechanism by which valproate may induce polycystic ovarian syndrome is unknown, but could possibly be secondary to valproate-induced weight gain or direct interference with steroid metabolism. Further study of the potential association of valproate treatment with the development of polycystic ovarian syndrome is warranted. Until the issue is clarified, clinicians should at least be aware of the possibility of valproate-induced polycystic ovarian syndrome and monitor patients accordingly.
Safety Issues with Herbal Products
Authors: Marrone Christopher M
Published: March 2004

OBJECTIVE:

TO review safety issues associated with the use of herbal products.

DATA SOURCES:

Literature accessed through MEDLINE and other Internet search engines. Key search terms included herbs, dietary supplements, and safety.

DATA SYNTHESIS:

A misconception exists among consumers that herbal remedies are safe because they are natural. In an effort to provide healthcare practitioners with information necessary for a patient discussion, a review of safety concerns with herbal products was conducted.

CONCLUSIONS:

Several safety concerns exist with herbal products including lack of safety data, absence of quality-control requirements for potency and purity, and lenient labeling standards.
Bell's Palsy in an Older Patient with Uncontrolled Hypertension Due to Medication Nonadherence
Authors: Ellis Samuel L , Carter Barry L , Leehey Maureen A , Conry Colleen M
Published: March 2004

OBJECTIVE:

To describe and inform pharmacists of a rarely reported occurrence of facial palsy in an elderly patient with uncontrolled hypertension resulting from nonadherence to blood pressure medications.

CASE SUMMARY:

A 62-year-old Hispanic woman presented to the hypertension clinic with left facial weakness, mild eyelid lag, and auricular pain for two days. The patient self-discontinued fosinopril and minoxidil six days and two days prior to developing these symptoms, respectively. A diagnosis of idiopathic peripheral VII cranial nerve lesion was made after ruling out other possible causes. Corticosteroids were not initiated because of this patient's labile hypertension. Palliative therapy was initiated and the left facial paralysis continuously improved during the six months after discharge.

DISCUSSION:

Patients have rarely presented with facial paralysis as the initial feature of severe hypertension. The relationship between facial paralysis and hypertension has been reported in a small number of cases, including several reports of recurrence of paralysis during acute exacerbations of hypertension. A variety of physiologic theories to explain the relationship between facial paralysis and hypertension have been published, including small hemorrhages into the facial canal which have been confirmed by two autopsies. However, the true etiology remains unknown.

CONCLUSIONS:

The possible relationship between facial paralysis and uncontrolled hypertension has not been reported in pharmacy literature and has been reported only twice in subspecialty medical journals since 1990. Pharmacists should be aware of the complications of hypertension and should question patients about signs and symptoms at each visit. While Bell's palsy complicating hypertension does not appear to be a serious complication, pharmacists must appreciate that the patient should be immediately evaluated to rule out a more serious neurologic event.
Accuracy of Measured Vancomycin Serum Concentrations in Patients with End-Stage Renal Disease
Authors: Smith Patrick F , Morse Gene D
Published: March 2004

OBJECTIVE:

TO review information related to the accuracy of vancomycin serum drug concentrations in patients with end-stage renal disease, focusing on available assays and mechanisms of cross-reactivity.

DATA SOURCES:

Primary and review articles identified from a MEDLINE search (January 1980-June 1999) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified were evaluated, and all relevant information was included in this review.

DATA SYNTHESIS:

Falsely elevated vancomycin serum concentrations may occur in patients with renal dysfunction. The underlying mechanism is due to the formation and accumulation of a pseudo-metabolite, the vancomycin crystalline degradation product (CDP). Vancomycin is converted to CDP when exposed to heat, including normal body temperature. Because the molecular structures of CDP and vancomycin are similar, both molecules are detected by polyclonal immunoassay systems used in clinical laboratories. This cross-reactivity leads to falsely elevated serum vancomycin concentrations in excess of 50–70%. Such large assay inaccuracies may result in improper dosage adjustments and therapeutic failures. A monoclonal immunoassay system has been developed that does not significantly cross-react with CDP.

CONCLUSIONS:

TO appropriately interpret laboratory results, it is essential for clinicians to be aware of the vancomycin-CDP cross-reactivity problem and to be familiar with the specific assay used to measure vancomycin concentrations in patients with renal dysfunction.
The Vagus Nerve is One Route of Transneural Invasion for Intranasally Inoculated Influenza A Virus in Mice
Authors: Matsuda K. , Park C. H. , Sunden Y. , Kimura T. , Ochiai K. , Kida H. , Umemura T.
Published: March 2004

Intranasally inoculated neurotropic influenza viruses in mice infect not only the respiratory tract but also the central nervous system (CNS), mainly the brain stem. 26 , 34 Previous studies suggested that the route of invasion of virus into the CNS was via the peripheral nervous system, especially the vagus nerve. To evaluate the transvagal transmission of the virus, we intranasally inoculated unilaterally vagectomized mice with a virulent influenza virus (strain 24a5b) and examined the distribution of the viral protein and genome by immunohistochemistry and in situ hybridization over time. An asymmetric distribution of viral antigens was observed between vagal (nodose) ganglia: viral antigen was detected in the vagal ganglion of the vagectomized side 2 days later than in the vagal ganglion of the intact side. The virus was apparently transported from the respiratory mucosa to the CNS directly and decussately via the vagus nerve and centrifugally to the vagal ganglion of the vagectomized side. The results of this study, thus, demonstrate that neurotropic influenza virus travels to the CNS mainly via the vagus nerve.
Cyclooxygenase-2 Expression in the Cornea of Dogs with Keratitis
Authors: Sellers R. S. , Silverman L. , Khan K. N. M.
Published: March 2004

Cyclooxygenase-2 (COX-2) can be overexpressed at inflammatory sites, leading to the generation of proinflammatory prostanoids. Selective inhibitors of COX-2 have potential use in treating inflammatory conditions including ophthalmic diseases in veterinary medicine. Keratitis is considered the most common inflammatory eye disease in dogs. In this study we evaluated the expression of COX-2 in normal dog eyes and in dog eyes with keratitis by immunohistochemistry using isoform-specific antibodies. In the normal eye ( n = 4), no COX-2 immunoreactivity was observed in the cornea. In keratitis, COX-2 ( n = 12) expression was observed in all corneal layers (epithelium, stromal cells, and endothelium). COX-2 immunoreactivity was also noted in the stromal and epithelial cells of the iris and the stromal cells of the trabecular meshwork. These data indicate that COX-2 may play a pathophysiologic role in keratitis and suggest potential therapeutic implications of prostaglandin modulation in inflammatory eye diseases.
Granulomatous Uveitis Associated with Vaccination in the Atlantic Salmon
Authors: Koppang E. O. , Haugarvoll E. , Hordvik I. , Poppe T. T. , Bjerkås I.
Published: March 2004

This study addressed histologic and immunopathologic changes in ocular tissues and investigated the distribution of major histocompatibility class II (MHC class II)-positive cells in Atlantic salmon ( Salmo salar) suffering from severe postvaccination disease. Twenty-nine fish with generalized inflammation, probably a result of vaccination, were investigated. One individual that had escaped vaccination was included in the study. Material was investigated by cultivation methods for fungi and bacteria. Histology using conventional staining procedures and immunohistochemistry with antisera against MHC class II β chain were performed. No growth was observed from the cultivation investigations. Histology revealed occlusion of the lumen in the larger choroid vessels and in the choriocapillaris, inflammatory infiltrations and loss of structure in the choroid rete, and, in some cases, aggregations of multinucleated giant cells (MGC) and Splendore-Hoeppli material. Immunohistochemistry demonstrated massive MHC class II+ cellular infiltrations in the uveal tract. Such infiltrations were also seen in the ventral ciliary cleft, a condition that is associated with glaucoma. Immunoreactive cells included dendritelike cells, epithelioid cells, and MGCs. The endothelia of smaller vessels were frequently MHC class II+, and immunoreactive infiltrations were seen in the optic nerve in several individuals. No pathologic changes were detected in the unvaccinated individual. In conclusion, generalized inflammatory reactions in fish may lead to severe ocular inflammation, occlusion of uveal vessels, and perivascular changes with MHC class II+ upregulation in cells in the uveal tract and optic nerve.
Canine Prostate Carcinomas Express Markers of Urothelial and Prostatic Differentiation
Authors: Leroy B. E. , Nadella M. V. P. , Toribio R. E. , Leav I. , Rosol T. J.
Published: March 2004

Prostate carcinoma and transitional cell carcinoma (TCC) occur in the prostate gland of older dogs and have morphologic similarities when evaluated by light microscopy. The dog is a commonly used animal model for studying human prostate carcinoma; therefore, it is important to accurately differentiate canine prostate carcinomas from TCCs. We investigated whether keratin 7 (K7) and arginine esterase (AE) would aid differentiation of canine prostate carcinoma from TCC. K7 expression was evaluated in normal and neoplastic canine prostate and bladder tissues using immunohistochemistry. The expression of AE messenger ribonucleic acid (mRNA) in normal and neoplastic canine prostate and bladder was detected using northern blots and reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, AE enzyme activity was measured in normal and neoplastic canine prostate and bladder tissues. We found marked similarities in K7 expression in prostate carcinomas and TCCs. AE mRNA was present in high levels in normal prostatic tissue but was reduced in prostate carcinoma by northern blot assay. Nested RT-PCR detected AE mRNA both in TCCs (13 of 15) and in prostate carcinomas (13 of 13). Enzymatic activity of AE was high in normal prostate gland and in some prostate carcinomas, whereas normal bladder and TCCs produced lower levels of AE. In conclusion, K7 and AE cannot be used to differentiate TCC from prostate carcinoma in dogs.
Characterization of Lymphocytes in Canine Gastrointestinal Lymphoma
Authors: Coyle K. A. , Steinberg H.
Published: March 2004

Primary canine gastrointestinal lymphoma has been believed to be of B-cell origin based on the morphology and behavior of the neoplastic cells and the evidence from the human medical field. However, the neoplasms have not to date been characterized as to the origin of the cell population. Forty-four cases diagnosed as canine gastrointestinal lymphoma were retrieved from the records of the Veterinary Teaching Hospitals at the University of Minnesota and the University of Wisconsin-Madison. Four of the cases have been previously identified as epitheliotropic T-cell gastrointestinal lymphoma. Twenty-three of the dogs were female, with 11 intact and 12 neutered, and 21 of the dogs were male, with 12 intact and nine neutered. Sixteen breeds as well as individuals of mixed breeding were represented. The Boxer and the sharpei were the most commonly represented breeds with six individuals each. The age range of the dogs was 1.5–14.66 years, with two dogs identified as adult and two of unknown age. Archived tissue blocks of gastrointestinal samples were sectioned in duplicate and prepared for immunohistochemical staining with CD3 (T-cell marker) and CD20 (B-cell marker). In 75% of the cases examined under light microscopy, 50–95% of the neoplastic cells stained positively with CD3 and exhibited marked epitheliotropic behavior. In three of the cases, from 10% up to 50% of the neoplastic cells stained positively with CD20, with widely scattered CD3(+) cells. In the remainder of the cases, few to none of the neoplastic cells stained with either of the markers. This retrospective study shows that canine primary gastrointestinal lymphoma is more commonly of T-cell origin, rather than B-cell origin.
Hepatic Lesions in Cetaceans Stranded in the Canary Islands
Authors: Jaber J. R. , Pérez J. , Arbelo M. , Andrada M. , Hidalgo M. , Gómez-Villamandos J. C. , Van Den Ingh T. , Fernández A.
Published: March 2004

This article describes the gross, histopathologic, and ultrastructural findings of the livers of cetaceans stranded on the coast of the Canary Islands between 1992 and 2000. A total of 135 cetaceans were included in the study, among which 25 were common dolphins ( Delphinus delphis), 23 Atlantic spotted dolphins ( Stenella frontalis), 19 striped dolphins ( Stenella coeruleoalba), and 15 other species of dolphins and whales. The most common lesion observed in these animals was a nonspecific chronic reactive hepatitis (47/135), followed by hyaline intracytoplasmic inclusions in hepatocytes (33/135). Parasitic cholangitis was detected in 8/135 animals, whereas hepatic lipidosis was presented in 7/135 animals. The ultrastructure of hyaline hepatocytic cytoplasmic inclusions is described, and possible causes of these inclusions are discussed.
Abomasal Emptying Defect of Sheep may be an Acquired Form of Dysautonomia
Authors: Pruden S. J. , Mcallister M. M. , Schultheiss P. C. , O'Toole D. , Christensen D. E.
Published: March 2004

Abomasal emptying defect (AED) is a disease syndrome that primarily affects Suffolk sheep and is characterized by distension and impaction of the abomasum. No histologic lesion has been consistently associated with this condition. There is no known etiology. In this study, nine cases of AED were identified by necropsy, including three rams and six ewes between 2 and 6 years of age. Four of the cases occurred sporadically, and five ewes were submitted on the same day from a single flock. Histologic examination of celiacomesenteric ganglia from six of the affected sheep revealed scattered chromatolytic or necrotic neurons, without inflammation. Chromatolytic neurons were observed more frequently in AED-affected sheep than in seven healthy Suffolk sheep ( P < 0.08, weak statistical support). Neuronal necrosis was not observed in any of the healthy sheep. Lineage records of the flock that suffered an outbreak were incompatible with the possibility of a simple inheritance pattern for this disease; furthermore, the very occurrence of AED in outbreak form is inconsistent with transmission solely by inheritance. Only one of the six tested sheep showed concurrent immunohistochemical evidence of scrapie. The lesion pattern in celiacomesenteric ganglia is suggestive of a neurotoxicosis. Neuronal lesions of AED resemble dysautonomic diseases of humans and other animals.
Solitary Retinal Astrocytoma in a Dog
Authors: Meyerholz D. K. , Haynes J. S.
Published: March 2004

An intraocular mass from a 13-year old Husky-mix dog was diagnosed as retinal astrocytoma. The mass arose from the ganglion layer of the retina and occupied 50% of the vitreous space. The mass was immunoreactive for neuron-specific enolase, S-100, vimentin, and glial fibrillary acidic protein. The neoplasm had characteristics similar to solitary retinal astrocytomas of humans but lacked the marked vascularity.
Cystic Endometrial Hyperplasia in Elephants
Authors: Agnew D. W. , Munson L. , Ramsay E. C.
Published: March 2004

Most captive female elephants are nulliparous and aged and many have endometrial disease, factors that may hinder fertility. This study characterized the pathologic features and demographic distribution of endometrial lesions from 27 captive Asian ( Elephas maximus) and 13 African elephants ( Loxodonta africanus), 12- to 57-years of age. The principal lesion was marked cystic and polypoid endometrial hyperplasia (CEH), present in 67% of Asian and 15% of African elephants ranging from 26 to 57 years. The lower prevalence in African elephants likely reflects their younger age range in this study. Fourteen of 15 affected elephants with breeding information were nulliparous. These results suggest that CEH and polyps are common in aged nulliparous elephants, and the severity of these lesions may impair fertility. These findings will be useful in the interpretation of ultrasonographic findings during reproductive examinations of potential breeding cows. Also, breeding programs should focus on younger animals.
Malignant Ameloblastic Fibro-odontoma in a Dog
Authors: Ueki H. , Sumi A. , Takaishi H. , Ito H. , Oyamada T. , Yoshikawa H.
Published: March 2004

An 11-year-old male Collie was presented with a swelling of the face caused by tumor masses arising from the gingiva. Postmortem examination revealed metastases to the lymph nodes, lung, liver, and orbital cavity. Histologically, the tumor represented a combination of fibrosarcomatous proliferation, pulpal mesenchyme, and undifferentiated odontogenic epithelium, with a follicular or plexiform growth pattern. In addition, the follicular areas of the tumor showed a biphasic character, and there were numerous apoptotic cells in plexiform areas. Furthermore, acidophilic material resembling dysplastic dentine or enamel matrix was observed in the metastatic lesion in the lung. Based on the histological characters, the present case was diagnosed as malignant ameloblastic fibro-odontoma. This study is the first known description of a possible malignant ameloblastic fibro-odontoma in a dog with metastasis to distant organs.
Pathologic and Immunohistochemical Findings in a Feline Aortic Body Tumor
Authors: Paltrinieri S. , Riccaboni P. , Rondena M. , Giudice C.
Published: March 2004

The presence of a heart-base tumor was diagnosed by ultrasound imaging in a 10-year-old, female, domestic shorthaired cat presenting with dyspnea and pleural effusion because of the presence of a modified transudate. Hematology and clinical chemistry were unremarkable. The owner elected euthanasia. At necropsy, a locally extensive, firm, multilobulated nodule surrounded the pulmonary vein. The tumor was composed of lobules of large polygonal cells separated by a fine fibrovascular stroma. Tumor cells infiltrated the myocardium, and neoplastic emboli were present, but no metastases were macroscopically detectable. Tumor cells were immunohistochemically positive for chromogranin A, for synaptophysin and, faintly, for neuron-specific enolase and negative for vimentin, cytokeratin, a smooth muscle actin, glial fibrillary acidic protein, thyreoglobulin, and calcitonin. Based on histologic and immunohistochemical findings, the diagnosis of chemodectoma was made.
Raising and lowering movement
Authors: Belkacemi Cemi
Published: March 2004

This article looks at the recent approaches taken vis-à-vis the sentence structure of English and French. It looks at the different movements operating at D-structure and the possible reasons that lead to the verb in French raising to T and the English verb remaining in [spec,
VP] triggering the lowering of T. These movements, we explain convincingly we hope, by arguing that they are triggered by AGR. In French AGR is strong and allows verb movements from V to T and to C. In English, on the other hand, AGR is weak and as a result, the verb remains unable to raise
to T. This inability to move leads to the lowering of T to V level for support. This reasoning is backed up by evidence which demonstrates that English AGR weakness is observed in its reliance on the ‘do-support’ for its interrogatives. Further evidence is also supplied through
the study of modal and auxiliary verbs.
Henri Lopes and the postcolonial riddle of métis identity
Authors: Onyeoziri Gloria Nne
Published: March 2004

This study explores recent discussions surrounding the concept of métissage as a term which, though it may no longer be appropriate to describe the cultural hybridity of the postmodern or postmodern context, still carries significant traces of historical practices of oppression,
psychological disturbances, sexual exploitation and struggles for the survival of cultural identities. An examination of some of the ideological, mythical and symbolic structures of métissage allows us to envisage ways in which these traces may translate into literary forms. Two novels
of Henri Lopes - Le Chercheur d’Afriques and Le Lys et le Flamboyant - are themselves explorations of métissage that playfully interrupt our perceptions of racial and cultural identity without ever giving up on their métis characters’ desire for cultural belonging.
The results are both aesthetically challenging and suggestive of a continuing malaise in postcolonial African literatures.
Ethnography, improvisation, and the Archimedean fulcrum:
Authors: Prieto Eric
Published: March 2004

Michel Leiris’s ongoing fascination with jazz music is instructive for several reasons. His initial encounters with jazz played an important catalytic role for his ethnographic project, sparking the interest in ‘l’art nègre’ that would eventually lead
him to Africa, and setting him on a search for an Archimedean vantage point: one able to gain insight into different forms of cultural production by attempting to place itself outside of all existing cultures. This Archimedean ideal enabled him to apply lessons learned from jazz to his own
literary project - not by engaging in merely imitative practices, but by rethinking the surrealist theories of inspiration, subjectivity, and expression in terms of improvisation and vocal performance. Accordingly, this essay attempts to show how jazz influenced Leiris’s literary and
anthropological projects by looking below the surface, emphasizing the music’s influence on the semiotic functioning of his autobiographical texts.
Le Dialogue des cultures and the Ninth Sommet de la Francophonie
Authors: Brown Peter
Published: March 2004

The Ninth Summit of Heads of State and Government of countries having the French language en partage took place in Beirut, Lebanon, last October, with 40 heads of state and representatives of 16 other members of la Francophonie in attendance. Originally scheduled for October 2001, the
gathering had to be postponed for a year, following the attacks of September 11 (i.e. the previous month). The theme chosen for the Summit, ‘le dialogue des cultures’, promoted as one of the francophone movement’s goals in the first article of its charter, thus took on a
much greater significance in Beirut than it might have otherwise done, particularly given the fact that this was the first francophone summit to be held on Arab soil.
The woman in Portuguese fado-singing
Authors: Cook Manuela
Published: March 2004

This article argues that the way in which women are portrayed in Portuguese fado-singing can be shown to bear a significant relation to some important aspects of twentieth-century Portuguese cultural and political history. These include the reports that the Virgin Mary appeared before
three children near the village of Fátima in Portugal and the ensuing development of a great Catholic pilgrimage centre at that location. Also to be considered is the establishment of the Estado Novo, the ‘New State’, the regime that, mainly under the leadership of
Salazar, would govern Portugal for over forty years, during which time there were good Church-State relations. Fado became a regime-encouraged entertainment and was elevated to Portugal’s national song. This article seeks to explain a particular image of woman that occurs in fado lyrics,
in the context of the devotion to Our Lady of Fátima and theEstado Novo’s general policy.
Book Reviews
Authors: Godsland Shelley , Jaspe Alvaro , Longhurst Alex , Magone José M. , Cannon Jackie
Published: March 2004

The Companion to Hispanic Studies, Catherine Davies (ed.) (2002) London: Arnold, viii+198 pp., ISBN 0-340-76298-5 (paperback), ISBN 0-340-76297-7 (hardback)

Don Juan de Borbón, Julio Aróstegui, (2002) Madrid: Arlanza Ediciones, 191 pp., ISBN
84-95503-33-6 (paperback)

The Battle over Spanish between 1800 and 2000: Language Ideologies and Hispanic Intellectuals, José del Valle and Luis Gabriel-Stheeman (eds.), (2002) London and New York: Routledge, xiv + 237 pp., ISBN 0-415-25256-3 (hardback)

Política
Externa e Política de Defesa do Portugal Democrático, José Medeiros Ferreira (ed.) (2001) Lisbon: Edições Colibri, 232 pp., ISBN 972-772-221-0 (paperback)

Te Toca, Richard Pym and Mark Allison (2002) London: Arnold, viii + 285 pp.,
ISBN 0-3440-74073-6 (paperback)
Loss-of-Function Analysis of EphA Receptors in Retinotectal Mapping
Authors: Feldheim David A. , Nakamoto Masaru , Osterfield Miriam , Gale Nicholas W. , DeChiara Thomas M. , Rohatgi Rajat , Yancopoulos George D. , Flanagan John G.
Published: March 2004

EphA tyrosine kinases are thought to act as topographically specific receptors in the well-characterized projection map from the retina to the tectum. Here, we describe a loss-of-function analysis of EphA receptors in retinotectal mapping. Expressing patches of a cytoplasmically truncated EphA3 receptor in chick retina caused temporal axons to have reduced responsiveness to posterior tectal repellent activityin vitroand to shift more posteriorly within the mapin vivo. A gene disruption of mouse EphA5, replacing the intracellular domain with β-galactosidase, reducedin vitroresponsiveness of temporal axons to posterior target membranes. It also caused map abnormalitiesin vivo, with temporal axons shifted posteriorly and nasal axons anteriorly, but with the entire target still filled by retinal axons. The anterior shift of nasal axons was not accompanied by increased responsiveness to tectal repellent activity, in contrast to the comparable anterior shift in ephrin-A knock-outs, helping to resolve a previous ambiguity in interpreting the ephrin gene knock-outs. The results show the functional requirement for endogenous EphA receptors in retinotectal mapping, show that the receptor intracellular domain is required for a forward signaling response to topographic cues, and provide new evidence for a role of axon competition in topographic mapping.
Oscillating Purkinje Neuron Activity Causing Involuntary Eye Movement in a Mutant Mouse Deficient in the Glutamate Receptor δ2 Subunit
Authors: Yoshida Takashi , Katoh Akira , Ohtsuki Gen , Mishina Masayoshi , Hirano Tomoo
Published: March 2004

How failures in regulation of synaptic transmission in the mammalian CNS affect neuronal activity and disturb motor coordination is addressed. The mutant mouse deficient in the glutamate receptor δ2 subunit, specifically expressed in cerebellar Purkinje neurons, has defects in synaptic regulations such as synaptic plasticity, stabilization, and elimination of synaptic connections and shows failures in motor coordination and learning. In this study, the cause of motor discoordination of the δ2 mutant mouse was analyzed by comparing its motor control ability with those of the wild-type mouse and thelurchermutant mouse, which loses all Purkinje neurons, the sole output neurons in the cerebellar cortex. Unexpectedly, the δ2 mutant mouse showed severer motor discoordination than thelurchermouse without any cerebellar cortical outputs. The δ2 mutant mouse showed involuntary spontaneous eye movement with characteristic 10 Hz oscillation, which disappeared by ablation of the cerebellar flocculus, suggesting that the δ2 mutant cerebellar cortex outputs an abnormal signal.In vivoextracellular recordings of neuronal activity revealed that Purkinje neurons tended to fire clustered action potentials and complex spikes at ∼10 Hz in the δ2 mutant mouse. A whole-cell patch-clamp recording from Purkinje neurons in cerebellar slices indicated that the clustered action potentials could be induced by climbing fiber activation. Taken together, our results suggest that the δ2 subunit deficiency produces the oscillating activity in Purkinje neurons by enhancing climbing fiber inputs, causing surplus movement and affecting motor control worse than no signal at all.
Neuronal Integration of Synaptic Input in the Fluctuation-Driven Regime
Authors: Kuhn Alexandre , Aertsen Ad , Rotter Stefan
Published: March 2004

During sensory stimulation, visual cortical neurons undergo massive synaptic bombardment. This increases their input conductance, and action potentials mainly result from membrane potential fluctuations. To understand the response properties of neurons operating in this regime, we studied a model neuron with synaptic inputs represented by transient membrane conductance changes. We show that with a simultaneous increase of excitation and inhibition, the firing rate first increases, reaches a maximum, and then decreases at higher input rates. Comodulation of excitation and inhibition, therefore, does not provide a straightforward way of controlling the neuronal firing rate, in contrast to coding mechanisms postulated previously. The synaptically induced conductance increase plays a key role in this effect: it decreases firing rate by shunting membrane potential fluctuations, and increases it by reducing the membrane time constant, allowing for faster membrane potential transients. These findings do not depend on details of the model and, hence, are relevant to cells of other cortical areas as well.
The Processing of Visual Shape in the Cerebral Cortex of Human and Nonhuman Primates: A Functional Magnetic Resonance Imaging Study
Authors: Denys Katrien , Vanduffel Wim , Fize Denis , Nelissen Koen , Peuskens Hendrik , Van Essen David , Orban Guy A.
Published: March 2004

We compared neural substrates of two-dimensional shape processing in human and nonhuman primates using functional magnetic resonance (MR) imaging in awake subjects. The comparison of MR activity evoked by viewing intact and scrambled images of objects revealed shape-sensitive regions in occipital, temporal, and parietal cortex of both humans and macaques. Intraparietal cortex in monkeys was relatively more two-dimensional shape sensitive than that of humans. In both species, there was an interaction between scrambling and type of stimuli (grayscale images and drawings), but the effect of stimulus type was much stronger in monkeys than in humans. Shape- and motion-sensitive regions overlapped to some degree. However, this overlap was much more marked in humans than in monkeys. The shape-sensitive regions can be used to constrain the warping of monkey to human cortex and suggest a large expansion of lateral parietal and superior temporal cortex in humans compared with monkeys.
Altered Synapse Formation in the Adult Somatosensory Cortex of Brain-Derived Neurotrophic Factor Heterozygote Mice
Authors: Genoud Christel , Knott Graham W. , Sakata Kazuko , Lu Bai , Welker Egbert
Published: March 2004

Increased sensory stimulation in the adult whisker-to-barrel pathway induces the expression of BDNF as well as synapse formation in cortical layer IV. Here, we investigated whether BDNF plays a role in the alterations of connectivity between neurons by analyzing the ultrastructure of the BDNF heterozygote mouse, characterized by a reduced level of BDNF expression. Using serial section electron microscopy, we measured synapse density, spine morphology, and synaptic vesicle distribution to show that mice with a reduced level of BDNF have a barrel neuropil that is indistinguishable from wild-type controls. After 24 hr of whisker stimulation, however, there is no indication of synapse formation in the heterozygous mouse. Whereas the balance between excitatory and inhibitory synapses is modified in the controls, it remains constant in the heterozygotes. The distribution of synaptic vesicles in excitatory synapses is the same in heterozygous and wild-type mice and is not influenced by the stimulation paradigm. Spine volume, however, is unchanged by stimulation in the wild-type animals, but does increase significantly in the heterozygous animal. These results provide evidence that,in vivo, BDNF plays an important role in the structural rearrangement of adult cortical circuitry as a consequence of an increased sensory input.
Efficient Isolation and Gene Expression Profiling of Small Numbers of Neural Crest Stem Cells and Developing Schwann Cells
Authors: Buchstaller Johanna , Sommer Lukas , Bodmer Matthias , Hoffmann Reinhard , Suter Ueli , Mantei Ned
Published: March 2004

Schwann cells develop from multipotent neural crest stem cells and are important for neuronal survival, maintenance of axonal integrity, and myelination. We used transgenic mice expressing green fluorescent protein in a tissue-specific manner to isolate viable, pure populations of neural crest stem cells and developing Schwann cells, which are not readily accessible by microdissection. Starting with the minute amounts of RNA obtained, a two-round amplification procedure was used to achieve reproducible DNA array hybridizations. We validated our screening procedure by comparisons with the literature and byin situhybridization. Stage-to-stage comparisons and hierarchical clustering for neural crest and five stages of Schwann cell development suggest a wealth of candidates for genes involved in stem cell regulation and in early Schwann cell development. The combination of methods applied in this study should be generally useful for isolating and profiling other stem cell and difficult to isolate cell populations.
The Two Regulatory Subunits ofAplysiacAMP-Dependent Protein Kinase Mediate Distinct Functions in Producing Synaptic Plasticity
Authors: Liu Jinming , Hu Jiang-Yuan , Schacher Samuel , Schwartz James H.
Published: March 2004

Activation of the cAMP-dependent protein kinase (PKA) is critical for both short- and long-term facilitation inAplysiasensory neurons. There are two types of the kinase, I and II, differing in their regulatory (R) subunits. We clonedAplysiaRII; RI was cloned previously. Type I PKA is mostly soluble in the cell body whereas type II is enriched at nerve endings where it is bound to two prominent A kinase-anchoring-proteins (AKAPs). Disruption of the binding of RII to AKAPs by Ht31, an inhibitory peptide derived from a human thyroid AKAP, prevents both the short- and the long-term facilitation produced by serotonin (5-HT). During long-term facilitation, RII is transcriptionally upregulated; in contrast, the amount of RI subunits decreases, and previous studies have indicated that the decrease is through ubiquitin-proteosome-mediated proteolysis. Experiments with antisense oligonucleotides injected into the sensory neuron cell body show that the increase in RII protein is essential for the production of long-term facilitation. Using synaptosomes, we found that 5-HT treatment causes RII protein to increase at nerve endings. In addition, using reverse transcription-PCR, we found that RII mRNA is transported from the cell body to nerve terminals. Our results suggest that type I operates in the nucleus to maintain cAMP response element-binding protein-dependent gene expression, and type II PKA acts at sensory neuron synapses phosphorylating proteins to enhance release of neurotransmitter. Thus, the two types of the kinase have distinct but complementary functions in the production of facilitation at synapses of an identified neuron.
Styrylbenzoxazole Derivatives forIn VivoImaging of Amyloid Plaques in the Brain
Authors: Okamura Nobuyuki , Suemoto Takahiro , Shimadzu Hiroshi , Suzuki Masako , Shiomitsu Tsuyoshi , Akatsu Hiroyasu , Yamamoto Takayuki , Staufenbiel Matthias , Yanai Kazuhiko , Arai Hiroyuki , Sasaki Hidetada , Kudo Yukitsuka , Sawada Tohru
Published: March 2004

Progressive deposition of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's disease (AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early detection of AD patients. For imaging SPs in the living brain, we have developed a series of styrylbenzoxazole derivatives that achieve high binding affinity for amyloid-β (Aβ) fibrils. One of these compounds, 6-(2-Fluoroethoxy)-2-[2-(4-methylaminophenil) ethenyl]benzoxazole (BF-168), selectively binds SPs in AD brain sections and recognizes Aβ1-42-positive diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specificin vivolabeling to both compact and diffuse amyloid deposits in the brain. In addition,18F-radiolabeled BF-168 demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t1/2= 24.7 min) after intravenous administration in normal mice. Furthermore, autoradiograms of brain sections from APP23 transgenic mice at 180 min after intravenous injection of [18F]BF-168 showed selective labeling of brain amyloid deposits with little nonspecific binding. These findings strongly suggest that styrylbenzoxazole derivatives are promising candidate probes for positron emission tomography and single-photon emission computed tomography imaging for early detection of amyloid plaque formation.
Noradrenaline and Dopamine Efflux in the Prefrontal Cortex in Relation to Appetitive Classical Conditioning
Authors: Mingote Susana , de Bruin Jan P. C. , Feenstra Matthijs G. P.
Published: March 2004

We trained rats to learn that an auditory stimulus predicted delivery of reward pellets in the Skinner box. After 2 d of training, we measured changes in efflux of noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex using microdialysis on the third day. Animals were subjected to a normal rewarded session and an extinction session, in which the auditory stimulus was presented alone. In the rewarded session, both NA and DA efflux were increased, but in extinction, only NA was activated. The data suggest that NA has a role in the reaction to reward-predicting stimuli, which complements that of DA.
Direct Impact of T Cells on Neurons Revealed by Two-Photon Microscopy in Living Brain Tissue
Authors: Nitsch Robert , Pohl Elena E. , Smorodchenko Alina , Infante-Duarte Carmen , Aktas Orhan , Zipp Frauke
Published: March 2004

Encephalitogenic T cells invade the brain during neuroinflammation such as multiple sclerosis (MS), inducing damage to myelin sheaths and oligodendrocytes. Only recently, neuronal structures were reported to be a crucial target in the disease. Here, two-photon microscopy using ion-sensitive dyes revealed that within the complex cellular network of living brain tissue, proteolipid protein (PLP)-specific T cells and T cells recognizing the nonmurine antigen ovalbumin (OVA) directly and independently of the major histocompatibility complex (MHC) contact neurons in which they induce calcium oscillations. T cell contact finally resulted in a lethal increase in neuronal calcium levels. This could be prevented by blocking both perforin and glutamate receptors. For the first time, our data provide direct insight into the activity of T cells in the living brain and their detrimental impact on neurons.
Subunit Composition and Alternative Splicing Regulate Membrane Delivery of Kainate Receptors
Authors: Jaskolski Frédéric , Coussen Françoise , Nagarajan Naveen , Normand Elisabeth , Rosenmund Christian , Mulle Christophe
Published: March 2004

Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors (GluRs) that play various roles in the regulation of synaptic transmission. The KAR subunits GluR5 and GluR6 exist under different splice variant isoforms in the C-terminal domain (GluR5a, GluR5b, GluR5c, GluR6a, GluR6b). The differential role of KAR subunit splice variants is presently unknown. In transfected COS-7 cells and neurons from wild-type and GluR5 × GluR6 mice, we have found that the subcellular localization and membrane delivery differed between these splice variants. GluR6a was highly expressed at the plasma membrane. GluR6b, GluR5a, and GluR5b were detected at lower levels in the plasma membrane and mainly colocalized with calreticulin in the endoplasmic reticulum (ER). GluR5c was strongly retained in the ER by an RXR motif. GluR6a acted as a key subunit splice variant promoting surface expression of ER-retained subunit splice variants when assembled in heteromeric KARs. Surface expression of GluR6a was independent of its PDZ (postsynaptic density-95/discs large/zona occludens-1) binding motif and was promoted by a stretch of four basic amino acid residues at its C terminus. Overall, splice variants and subunit composition of KARs regulate receptor trafficking from the endoplasmic reticulum to the plasma membrane.
Targeted Microlesions Reveal Novel Organization of the Hamster Suprachiasmatic Nucleus
Authors: Kriegsfeld Lance J. , LeSauter Joseph , Silver Rae
Published: March 2004

The role of the suprachiasmatic nuclei (SCN) in generating circadian rhythms in physiology and behavior is well established. Recent evidence based on clock gene expression indicates that the rodent SCN are composed of at least two functional subdivisions. In Syrian hamsters (Mesocricetus auratus), cells in a subregion of the caudal SCN marked by calbindin-D28K(CalB) express light-induced, but not rhythmic, clock genes (Per1, Per2, andPer3). In the SCN region marked by vasopressinergic cells and fibers, clock gene expression is rhythmic. Importantly, lesions of the CalB subregion that spare a significant portion of the SCN abolish rhythms in locomotor behavior. One possibility is that the CalB subregion is required to maintain SCN function necessary to support all behavioral and physiological rhythms. Alternatively, this subregion may control circadian rhythms in locomotor behavior, whereas other circadian responses in physiology and behavior are sustained by different SCN compartments. The present study sought to distinguish between these possibilities by examining the role of the CalB subregion in a battery of rhythms within an individual animal. The results indicate that lesions of the CalB subregion of the SCN abolish circadian rhythms in behavior (locomotion, drinking, gnawing), physiology (body temperature, heart rate), and hormone secretion (melatonin, cortisol), even when other SCN compartments are spared. Together, these findings suggest a novel fundamental property of SCN organization, with a subset of cells being critical for the maintenance of SCN function manifest in circadian rhythms in physiology and behavior.
Novel Dominant Rhodopsin Mutation Triggers Two Mechanisms of Retinal Degeneration and Photoreceptor Desensitization
Authors: Iakhine Roustem , Chorna-Ornan Irit , Zars Troy , Elia Natalie , Cheng Yan , Selinger Zvi , Minke Baruch , Hyde David R.
Published: March 2004

A variety of rod opsin mutations result in autosomal dominant retinitis pigmentosa and congenital night blindness in humans. One subset of these mutations encodes constitutively active forms of the rod opsin protein. Some of these dominant rod opsin mutant proteins, which desensitize transgenicXenopusrods, provide an animal model for congenital night blindness. In a genetic screen to identify retinal degeneration mutants inDrosophila, we identified a dominant mutation in theninaEgene (NinaEpp100) that encodes the rhodopsin that is expressed in photoreceptors R1-R6. Deep pseudopupil analysis and histology showed that the degeneration was attributable to a light-independent apoptosis. Whole-cell recordings revealed that theNinaEpp100mutant photoreceptor cells were strongly desensitized, which partially masked their constitutive activity. This desensitization primarily resulted from both the persistent binding of arrestin (ARR2) to the NINAEpp100mutant opsin and the constitutive activity of the phototransduction cascade. Whereas mutations in severalDrosophilagenes other thanninaEwere shown to induce photoreceptor cell apoptosis by stabilizing a rhodopsin-arrestin complex,NinaEpp100represented the first rhodopsin mutation that stabilized this protein complex. Additionally, theNinaEpp100mutation led to elevated levels of Gqα in the cytosol, which mediated a novel retinal degeneration pathway. Eliminating both Gqα and arrestin completely rescued theNinaEpp100-dependent photoreceptor cell death, which indicated that the degeneration is entirely dependent on both Gqα and arrestin. Such a combination of multiple pathological pathways resulting from a single mutation may underlie several dominant retinal diseases in humans.