Differenzialdiagnostische Bewertung neuropsychologischer Störungsprofile bei Basalganglien-Erkrankungen mit akinetisch-rigider Symptomatik

Parkinson, striatonigral degeneration, progressive supranuclear palsy, Steele-Richardson-Olszewski syndrome, multiple system atrophy, basal ganglia, neuropsychology, cognitive functions, group comparison

Hereditariedade da homeose

A preliminary account on the normal development of the imaginai discs in holometabolic Insects is made to serve as an introduction to the study of the hereditary homoeosis. Several facts and experimental data furnished specially by the students of Drosophila are brought here in searching for a more adequate explanation of this highly interesting phenomenon. The results obtained from the investigations of different homoeotic mutants are analysed in order to test Goldschmidt's theory of homoeosis. Critical examination of the basis on which this theory was elaborated are equally made. As a result from an extensive theoretical consideration of the matter and a long discussion of the most recent papers on this subject the present writer concludes that the Goldschmidt explanation of the homoeotic phenomena based on the action of diffusing substances produced by the genes, the "evocators", and on the alteration of the normal speed of maturation of the imaginai discs equally due to the activity of the genes, could not be proved and therefore should be abandoned. In the same situation is any other explanation like that of Waddington or Villee considered as fundamentally identical to that of Goldschmidt. In order to clear the problem of homoeosis in terms which seem to put the phenomenon in complete agreement with the known facts the present writer elaborated a theory first published a few years ago (1941) based entirely on the assumption that the imaginai discs are specifically determined by some kind of substances, probably of chemical nature, contained in the cytoplam of the cells entering in the consti- tution of each individual disc. These substances already present in the blastem of the egg in which they are distributed in a definite order, pass to different cells at the time the blastem is transformed into blastoderm. These substances according to their organogenic potentiality may be called antenal-substance, legsubstance, wing-substance, eye-substance, etc. The hipoderm of the embryo resulting from the multiplication of the blastoderm cells would be constituted by a series of cellular areas differing from each other in their particular organoformative capacity. Thus the hypoderm giving rise to the imaginai discs, it follows that each disc must have the same organogenic power of the hypodermal area it came from. Therefore the discs i*re determinated since their origin by substances enclosed in the cytoplasm of their cells and consequently can no longer alter their potentiality. When an antennal disc develops into a leg one can conclude that this disc in spite of its position in the body of the larva is not, properly speaking, an antennal disc but a true leg disc whose cells instead of having in their cytoplasm the antennal substance derived from the egg blastem have in its place the leg-substance. Now, if a disc produces a tarsus or an antenna or even a compound appendage partly tarsus-like, partly antenna-like, it follows tha,t both tarsal and antennal substances are present in it. The ultimate aspect of the compound structure depends upon the reaction of each kind of substance to the different causes influencing development. For instance, temperature may orient the direction of development either lowards arista or tarsus, stimulating, or opposing to the one or the other of these substances. Confering to the genes the faculty of altering the constitution of the substances containing in the cytoplasm forming the egg blastem or causing transposition of these substances from one area to another or promoting the substitution of a given substance by a different one, the hereditary homoeocis may be easily explained. However, in the opinion of the present writer cytoplasm takes the initiative in all developmental process, provoking the chromosomes to react specifically and proportionally. Accordingly, the mutations causing homoeotic phenomena may arise independently at different rime in the cytoplasm and in the chromosomes. To the part taken by the chromosomes in the manifestation of the homoeotic characters is due the mendalian ratio observed in homoeotic X normal crosses. Expression, in itself, is mainly due to the proportion of the different substances in the cells of the affected discs. Homoeotic phenomena not presenting mendelian ratio may appear as consequence of cytoplasmic mutation not accompanied by chromosomal mutation. The great variability in the morphology of the homoeotic characteres, some individual being changed towards an extreme expression of the mutant phenotype while others in spite of their homozigous constitution cannot be distinguished from the normal ones, strongly supports the interpretation based on the relative proportion of the determining substances in the discs. To the same interpretation point also asymetry and other particularities observed in the exteriorization of the phenomenon. In conformity with this new conception homoeosis should not prove homology of Insect appendages (Villee 1942) since a more replacement of substances may cause legs to develop in substitution of the wings, as it was already observed (requiring confirmation in the opinion of Bateson 1894, p. 184) and no one would conclude for the homology of these organs in the usual meaning of the term.

Anatomia, dos nectános de algumas espécies da flora apícola

This paper deals with anatomical descriptions of some types of nectaries in 27 species of honey plants of Piracicaba, S. P. The material studied was divides in two groups: a) Extra-floral nectaries; b) Floral nectaries. Euphorbia pulcherrima, Willd; showed to belonging to the first group: its nectaries tissue consist of an epidermal layer of cell without stomata and with true gland, with subepidermal cells diferentiated by the thickness of the wall. Among the plants with floral nectaries, the following types has been listed, according the location of the nectary in the flower: 1 - with true glands: a) in sepals, Hibiscus rosa sinensis, L.; Dombeya Wallichii, Bth. e Hk; b) in the stamens tube, Antigonum leptopus, Hook e Arn.; 2 - on the receptacle with nectariferous tissue in the epidermal cell with: a) thickness wall with stomata, Prunus persical, L.; b) thin wall without stomata, Crotalaria paulinia, Shranck; Caesal-pinia sepiaria, Roxb; Aberia caffra; 3 - with a disc located in the receptacle with: epidermal: a) with stomata, Coffea arábica, L. var. semper florens; Citrus aurantifolia, Swing; Cinchona sp.; Pryrostegia ignea, Presl.; b) without stomata and with thin wall, Leojurus sibiricus, L.; Bactocydia unguis, Mart., Ipomoea purpurea, L.; Greviüea Thelemanniana, Hueg.; Dolichos lablab, L.; Vernonia polyanthes, Less., Montanoa bipinatifida, C. Koch., Eruca sativa, L. Brassica Juncea, Co; Eucalyptus tereticomis, Smith.; Eucalyptus rostrata, Schleche; Salvia splendens, Selow.; 4 - in the basal tissues of the ovary, Budleia brasiliensis, Jacq F.; Petrea subserrata, Cham.; 5 - in the base of stamens, Per sea americana, Mill. On the anatomical point of view, most of the types of nectary studied has external nectariferous tissues, located on the epidermal cells with thin periclinal wall and without stomata. The sub-epidermal layer were rich in sugar. Short correlation was found between the structure of the nectary and the amount of nectar secretion. So, in the nectary with true glands, in those with thin wall and without stomata on epidermal cells and in those with stomata, the secretion was higher than in the other types listed.

The tadpole of Hypsiboas atlanticus (Anura, Hylidae) from northeastern Brazil

The tadpole of Hypsiboas atlanticus (Caramaschi & Velosa, 1996) is described from the municipality of Maceió, State of Alagoas, Brazil. At stage 36 the larvae have an overall elliptical body in lateral and dorsal views, oral disc anteroventral, spiracular tube sinistral, and labial tooth row formula 2(1,2)/3(1). The oral disc is surrounded, almost completely (anterior medial gap present) by a single row of marginal papillae. Described tadpoles of the H. punctatus species group can be differentiated by a combined disc oral features. Additional descriptions of H. punctatus (Schneider, 1799) tadpoles from populations throughout South America may be helpful in determining the status of these populations.

Estudo comparativo das inclusões do alastrim e da variola vera

Resulta das descripções e documentos examinados que as inclusões cytoplasmaticas da variola vera, no material humano examinado, apresentam caracteres geraes que poderão ser assim resumidos: 1. intensa coloração pela safranina nos preparados pelo methodo de Unna modificado (Fig. 42), mostrando a inclusão matiz semelhante ao dos nucleolos da mesma cellula. 2. reacção predominantemente acidophila nos preparados pela hematoxylina-eosina, traduzida pela tonalidade rosea ou vermelha de coloração (Figs. 27, 29, 30, 31 e 31). 3. frequente multiplicidade de inclusões de fórma e dimensões variadas na mesma cellula (Figs. 29 e 30), as maiores inclusões (Figs. 29 e 32), sendo menores que as grandes inclusões cytoplasmaticas solitarias do alastrim (Figs. 15, 16 e 18). É a regra, ainda, observar-se desapparecimento de qualquer estructura no cytoplasma das cellulas com inclusões em zona muito extensa, tornando-se difficil explicar tal aspecto unicamente pela retracção das inclusões no acto da fixação (Figs. 31 e 32). Quanto ás inclusões intranucleares, ellas se apresentam sob tres aspectos, dois dos quaes bem reconhecidos por Luger e Lauda (1926). Em um primeiro aspecto, o nucleo conserva, em parte, o reticulo de linina e encerra uma massa irregular (Fig. 35) ou, então, pequenas massas e granulos de dimensões variaveis (Figs. 33 e 34) constituidos por material acidophilo que ali não existe em condições normaes. A membrana nuclear tem espessura visinha do normal. Em um segundo aspecto, a inclusão occupa a totalidade do nucleoplasma (Fig. 3), apenas separado da membrana nuclear, em alguns casos (Fig. 38), por um estreito espaço claro (zona de retracção). Por vezes apresenta um aspecto homogeneo (Fig. 37); outras vezes a inclusão mostra pequenas areas chromophobas ( Fig. 38). A hyperchromatose da membrana nuclear é accentuada, tanto neste como no aspecto seguinte. No terceiro aspecto (aspecto corpuscular) (Figs. 39, 40, 48 e 50), a inclusão intranuiclear é formada por um ou mais corpusculos acidophilos, de contornos muito nitidos e fórma regular, ora ovoide, ora espherica. No interior de cada corpusculo, apparecem zonas chromophobas multiplas, sendo ordinariamente uma maior que as outras (Figs. 39, 40, 48 e 50). Fóra desses corpusculos, o nucleoplasma contem, por vezes material menos intensamente corado pelo eosina ou pela safranina (Figs. 40). O reticulo de linina, porém, acha-se completamente desapparecido, e não raro se observa, em torno dos corpusculos acidophilos, uma zona algum tanto extensa de nucleoplasma sem nenhuma estructura apparente (Fig. 48, á direita). Frisamos o modo peculiar de se comportar o nucleolo nas cellulas epidermicas com inclusões intranucleares da variola. Recalcado, a principio, de encontro á membrana nuclear (Fig. 36), elle em seguida é englobado pela propria membrana nuclear, parecendo incluso nessa estructura (Figs. 37, 35, 38 e 48, á direita). A « marginação » do nucleolo, e o seu englobamento ou inclusão na membrana nuclear, bem como o terceiro aspecto que descrevemos, de corpusculos intranucleares esphericos ou ovoides com zonas chromophobas, são caracteres que differenciam, de modo nitido, as inclusões intranucleares da variola vera da das demais inclusões das doenças de virus. Nem sempre, porém, os aspectos encontrados podem ser incluidos, com facilidade, em um dos tres grupos atraz mencionados, o que indica a existencia de phases de transição entre elles. Tal como assignalou Ewing, as cellulas epidermicas com inclusões intranucleares são geralmente as attingidas pela « ballonierende Degeneration ». Em geral taes elementos revestem o fundo da vesicula, ás vezes formando uma unica camada, e representando tudo o que resta da epiderme. Comtudo, em nosso material, conseguimos encontrar inclusões intranucleares em cellulas espinhosas do corpo mucoso de Malpighi que ainda conservaram relações normaes com os elementos contiguos e não eram attingidas pela « ballonierende Degeneration ». Em taes inclusões é que, de preferencia, observamos o aspecto de granulos mencionado no grupo I (Fig. 34). A hyperchromatose da membrana nuclear é, então, pouco notavel, constratando como o grau pronunciado que apresenta nos dois outros aspectos. Existiam, ellas em «lambeaux » epitheliaes, presos em certos pontos, por extreito pediculo, á camada basal, no fundo da vesicula.

Miocardite na forma aguda da doença de Chagas

The autopsy of a case of CHAGAS'S disease or American tryponosomiasis (a girl, 5 years old), dead in the 22nd day of illness is reported. The anatomic diagnosis was a follows: Acute diffuse chagasic nyocarditis. Chagasic encephalitis. Chagasic lymphadenitis of the right posterior auricular node. Tuberculosis of the bronchial and pulmonary nodes. Chronic passive hyperemia and atelectasia of the lungs. Chronic passive congestion and hemorrhages of the spleen. Serous hepatitis. Parotiditis. Edema of the right eyelids. Bilateral hydrothorax. Hydropericardium. Hydroperitoneum. The morphology of Schizotrypanum cruzi in the myocardium is considered. Besides agglomerates with typical small oval or round intracellular bodies, pre-flagellate and flagellate organisms, others are found in which the great amount of parasites and marked pressure exerted by them against each other render very difficult their identification; sometimes the similitude of such agglamerates to Toxoplasma is striking (Fig. 1 and 1 A). In such a case, the structure of the blepharoplast (Fig. 1 and IA), usually preserved, is profitable and allows the identification of the pre-flagellate and flagellate forms of Schizotrypanum cruzi. Most of the small sensitive nerves in the epicardium shows mononuclear infiltration of the perineurium (perineuritis, Figs. 12-14). Microscopically there is extensive Zenker's degeneration (Figs. 6-8) and parasitism of the heart muscle fibers, marked cellular infiltration of the interstitial connective tissue, which are found in the ordinary musculature of every chamber of the heart (Figs. 10-11) as well as in Tawara's node (Fig. 9), main bundle (Fig. 2) and right (Fig. 4) and left (Fig. 5) septal divisions of the bundle of His, and perineuritis. Those anatomic changes are associated to an abnormal electrocardiogram presenting some similitude to that of an anemic infarct of the anterior wall of the heart and which will be discussed elsewhere (unpublished paper by Dias, Nobrega & Laranja).

Sôbre a patogenia da Grangrena gasona

Since von Hibler gas grangrene has been considered a local infection with systemic symptoms. When we consider some of the symptoms of gas gangrene, those of the central nervous system are in evidence beeing similar to those observed in tetanus and botulism. It is likely therefore that gas gangrene intoxication and the disease caused by it are of neurotoxic nature. With Almeida Cardoso and Araujo Costa we were able to demonstrate lesions in the central nervous system of animals wich had been intoxicated during a short period of time as well in those with intoxication of longer duration. In acute intoxication, after intracreneal inoculation, severe alterations were seen within 20 to 30 minutes in the cells of the spinal cord, specially in motor cells and also in some cells of the posterior cord and spinal bulb. The changes consisted in chromatolysis and picnosis and were more marked in animals intoxicated with Clostridium histolyticum and Cl. perfringens toxines. Myelin sheet was unchanged. in delayed intoxication with greater and repeated dosis lesions of the central nervous system (brain, protuberance, medula ablongate and medula spinal) were observed. They consisted in hyperemia, perivascular hemorrages in white and grey substances, oedema, accumulation of glia cells with enlarged and hyperchromatic nuclei, fragmentation of the myelin sheet and balooning degeneration of the described by Spielmeyer. Such changes were found in the swollen and hemorragic zones and were generally similar to those found in the acute type of Spielmeyer 9acute swelling and liquefation). Other changes found sometimes were agglutination of Nissl's bodies, sinous appearence of the dendritic endings, shruncken cells of Spielmeyer and neuronophagy around "ghost" cells. In short the changes...

Transplantação de baço de coelho com mixoma infeccioso na câmara anterior do ôlho da cobaia: sôbre a degeneração mixomatosa: inclusões intranucleares

Heterotranplantability of myxoma of rabbits was formely demonstrated when grafts from subcutaneous tissue in skin were used (MARGARINOS TÔRRES & RITA CARDOSOS, 1949). Better results are reported in this paper when grafts from the spleen of infected rabbits were employed. While grafts from normal spleen are almost completely absorbed in sixteen days, those from infected rabbits give origin to full-grown and vascularised tissue in which typical myxoma cells are predominant elements. Progressive growth of heterotransplantated myxoma cells is another similarity between infectious myxoma and malignant tumors. Formation of clear areas of circular contour (interference of a diffusible substance?) associated to myxomatous degeneration is very conspicuous. Peculiar changes of the ground substance, reticular and collagenous fibers (globular swelling, rosary and bulb formation) apparently related to myxomatous degeneration are described. An unexpected finding was the presence of typical intranuclear inclusion bodies in five among forty-eight grafts examined in the sixth day.

Toxoplasmose congênita

We had the opportunity to study 6 cases of the congenital form of toxoplasmosis, found in a series of 1200 necropsies of fetuses and newborn babies, realized at 3 different hospitals in Rio de Janeiro, Brazil. Among the 6 cases, 4 were premature babies liveborn at the 6th-8th gestational month and 2 were stillborn (1 premature and 1 at term). In all those cases, the diagnosis was based in the detection of the parasite in tissues and in one case it was even isolated the Toxoplasma from the necrotic material found in the cranial cavity. This strain of Toxoplasma, pathogenic to pigeons, to guinea pigs and to mice, is preserved by successive transfers in mice. Some facts observed in those cases present an interest not only strictly anatomic but also have certain value for the better acknowlegment of the disease. First, we want to call the attention to the presence of a sudden high fever, during or just before pregnancy in the 4 cases in which the maternal anamnesis was perfectly studied; this fever that was preceded by a normal beginning of pregnancy, had relatively rapid remission, but in 2 cases was immediately followed by uterine bleeding and premature delivery, although the puerperium had been apparently normal. It is known that are normal the subsequent children of the mothers that delivered a baby with toxoplasmosis and that several women have normal babies before the toxoplasmotic one. We believe that the fever observed in our cases could be indicative of the beginning of maternal infection and those are the reasons why we emphasize the need of careful anamnesis, specially in the cases actually diagnosed as inapparent infection. Another fact to notice is that in 5 of our cases the event premature delivery happened always between the 6th and the 8th months of pregnancy, and the only term fetus was delivered in advanced stage of maceration. The above mentioned facts could agree with the opinion of FRENKEL (1949), when he declared that "primary infection of the pregnant mother appears more likely to be the commoner mode of fetal toxoplasmic infection", but they would disagree with WEINMAN (1952) who believes that the transmission of Toxoplasma to the fetus is more frequent through a pregnant woman with chronic disease and who says "that infection contracted during pregnancy may and probably does happen from time to time"...Still in connection with the transmission of toxoplasmosis, we want to note the verification of inflammatory lesions in the placental villi and in the umbilical cord in 3 of the 4 cases in which such organs were examined at the microscope. In the case n. 1, we found several pseudocysts of Toxoplasma in the placenta, and the fibroblasts of Wharton's jelly were particularly rich in isolated forms and in colonies of Toxoplasma; the easy multiplication of the parasite in that tissue calls the attention and even suggests its utilisation for Toxoplasma's cultivation. The confirmation of Toxoplasma in human placenta was made only recently by CRISTEN et al. (1951) and by NEGHME et al. (1952), in Chile; it is not frequent in the literature, what gives some value to our present verification. Another observation was that provided by the case n. 6. This baby, a premature one of the 6th month, was 14 days old and-died with signs of respiratory disease, the causa mortis have been pneumonia. At the necropsy, we found no gross change that suggested toxoplasmosis, except the presence of some small necrotic focuses in the cerebral nervous substance around the ventricles. As a matter of fact, there was no enlargement of spleen or liver and neither leptomeningitis nor hydrocephalus. Such focuses were attributed to possible anoxia and in fact they are extremely similar to anoxial softenings, even when they are examined at the microscope; its structure composed of a central necrotic zone, surrounded by proliferated neuroglia and by a variable deposit of calcium salts, closely simulated the anoxial softenings, when the microscopical examination is based in the common histological preparations (hematoxilin-eosin, etc.). But when we examine preparations by the Giemsa or by the periodic acid-Schiff methods, we will note the presence of Toxoplasma, with its typical aspect or a little changed by degeneration. When we describe this observation, we wish to evidence the need of the search of Toxoplasma and closed parasites, in the cases of supposed pure anoxial softenings of nervous substance, in children. The frequency with which the congenital toxoplasmosis was anatomically verified should be emphasized, although the disease had not been clinically suspected, and it should be borne in mind that the second case of toxoplasmosis reported in the world was observed in Brazil by MAGARINOS TORRES; this case was the first to be described of the generalized congenital form of the infection, i. e. with myocardial lesions and parasites in skeletal muscles and skin.

Stem Cell Transplantation for Retinal Degenerations

Within the last few years, several reports have revealed that cell transplantation can be an effective way to replace lost neurons in the central nervous system (CNS) of patients affected with neurodegenerative diseases. Concerning the retina, the concept that newborn photoreceptors can integrate the retina and restore some visual functions was univocally demonstrated recently in the mouse eye (MacLaren et al. 2006) and remains to be achieved in human. These results pave the way to a standard approach in regenerative medicine aiming to replace lost photoreceptors. With the discovery of stem cells a great hope has appeared towards elaborating protocols to generate adequate cells to restore visual function in different retinal degeneration processes. Retinal stem cells (RSCs) are good candidates to repair the retina and are present throughout the retina development, including adulthood. However, neonatal mouse RSCs derived from the radial glia population have a different potential to proliferate and differentiate in comparison to adult RSCs. Moreover, we observed that adult mouse RSCs, depending on the culture conditions, have a marked tendency to transform, whereas neonatal RSCs show subtle chromosome abnormalities only after extensive expansion. These characteristics should help to identify the optimal cell source and culture conditions for cell transplantation studies. These results will be discussed in light of other studies using RSCs as well as embryonic stem cells. Another important factor to consider is the host environment, which plays a crucial role for cell integration and which was poorly studied in the normal and the diseased retina. Nonetheless, important results were recently generated to reconsider cell transplantation strategy. Perspectives to enhance cell integration by manipulating the environment will also be presented.

Cells with neuronal characteristics differentiate and persist for one year in rat optic nerve explants cultures.

Evidence concerning the presence or absence of common neuronglia lineages in the postnatal mammalian central nervous system is still a matter of speculation. We address this problem using optic nerve explants, which show an extremely long survival in culture. Morphological, immunocytochemical and immunochemical methods were applied. The results obtained from in vitro tissue were compared with optic nerves (ONs) and whole-brain samples from animals of different ages. Newborn rat ONs represented the starting material of our tissue culture; they are composed of unmyelinated axons, astrocytes and progenitor cells but devoid of neuronal cell bodies. At this age, Western blots of ONs were positively stained by neurofilament and synapsin I specific antibodies. These bands increased in intensity during postnatal in situ development. In explant cultures, the glia cells reach a stage of functional differentiation and they maintain, together with undifferentiated cells, a complex histotypic organization. After 6 days in vitro, neurofilaments and synapsin I could not be detected on immunoblots, indicating that 1) axonal degeneration was completed, and 2) neuronal somata were absent at the time. Surprisingly, after about 4-5 weeks in culture, a new cell type appeared, which showed characteristics typical of neurons. After 406 days in vitro, neurofilaments and synapsin I were unequivocally detectable on Western blots. Furthermore, both immunocytochemical staining and light and electron microscopic examinations corroborated the presence of this earlier-observed cell type. These in vitro results clearly show the high developmental plasticity of ON progenitor cells, even late in development. The existence of a common neuron-glia precursor, which never gives rise to neurons in situ, is suggested.

Octopus Standard Automated Perimetry, Pulsar Perimetry, Moorfields Motion Displacement Test and Heidelberg Retinal Tomography in Glaucoma Detection - A Comparison of Diagnostic Accuracy

Purpose: To investigate the accuracy of 4 clinical instruments in the detection of glaucomatous damage. Methods: 102 eyes of 55 test subjects (Age mean = 66.5yrs, range = [39; 89]) underwent Heidelberg Retinal Tomography (HRTIII), (disc area<2.43); and standard automated perimetry (SAP) using Octopus (Dynamic); Pulsar (TOP); and Moorfields Motion Displacement Test (MDT) (ESTA strategy). Eyes were separated into three groups 1) Healthy (H): IOP<21mmHg and healthy discs (clinical examination), 39 subjects, 78 eyes; 2) Glaucoma suspect (GS): Suspicious discs (clinical examination), 12 subjects, 15 eyes; 3) Glaucoma (G): progressive structural or functional loss, 14 subjects, 20 eyes. Clinical diagnostic precision was examined using the cut-off associated with the p<5% normative limit of MD (Octopus/Pulsar), PTD (MDT) and MRA (HRT) analysis. The sensitivity, specificity and accuracy were calculated for each instrument. Results: See table Conclusions: Despite the advantage of defining glaucoma suspects using clinical optic disc examination, the HRT did not yield significantly higher accuracy than functional measures. HRT, MDT and Octopus SAP yielded higher accuracy than Pulsar perimetry, although results did not reach statistical significance. Further studies are required to investigate the structure-function correlations between these instruments.

Overexpression of mutant ataxin-3 in mouse cerebellum induces ataxia and cerebellar neuropathology.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a fatal, dominant neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Clinical manifestations include cerebellar ataxia and pyramidal signs culminating in severe neuronal degeneration. Currently, there is no therapy able to modify disease progression. In the present study, we aimed at investigating one of the most severely affected brain regions in the disorder-the cerebellum-and the behavioral defects associated with the neuropathology in this region. For this purpose, we injected lentiviral vectors encoding full-length human mutant ataxin-3 in the mouse cerebellum of 3-week-old C57/BL6 mice. We show that circumscribed expression of human mutant ataxin-3 in the cerebellum mediates within a short time frame-6 weeks, the development of a behavioral phenotype including reduced motor coordination, wide-based ataxic gait, and hyperactivity. Furthermore, the expression of mutant ataxin-3 resulted in the accumulation of intranuclear inclusions, neuropathological abnormalities, and neuronal death. These data show that lentiviral-based expression of mutant ataxin-3 in the mouse cerebellum induces localized neuropathology, which is sufficient to generate a behavioral ataxic phenotype. Moreover, this approach provides a physiologically relevant, cost-effective and time-effective animal model to gain further insights into the pathogenesis of MJD and for the evaluation of experimental therapeutics of MJD.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.