The data project: a shared approach between stakeholders of the healthcare system in definition of a therapeutic algorithm for inflammatory arthritis.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

Step by step procedure for stereological counts of catecholamine neurons in the mouse brainstem.

This work represents a detailed methodological description of automated stereology dedicated to all brainstem catecholamine nuclei. Each tyrosine-hydroxylase-containing nucleus was analyzed to count the following features: i) nuclear volume; ii) neuron number per nucleus; iii) neuron area per each nucleus.A number of reports described catecholamine-containing neurons within brainstem of a variety of animal species. In a recently published work, we reported a simultaneous quantitative analysis of tyrosine hydroxylase-positive neurons in the whole brainstem. Here we report the detailed step by step stereological procedure which allowed to perform a morphometric assessment of each catecholamine nucleus. This protocol provides the method chance to analyze simultaneously various morphological features in the same experimental setting to avoid variability when single nuclei are analyzed in different experiments. This improves the reliability of comparisons between brainstem catecholamine nuclei within the reticular formation to increase our insight about the key functional roles played by these cells in the mammalian brain. In fact, despite being a discrete number of neurons scattered in a small brain area, these cells provide remarkable axonal collateralization which allows the modulation of neuronal activity in the entire CNS. The step by step description of brainstem stereology provided here is reported in order to share these methods and enhance quantitative studies about these fascinating nuclei. At the same time we aim to provide a tool to be used routinely when analyzing the morphology and physiology of brainstem catecholamine cells.

Methamphetamine increases Prion Protein and induces dopamine-dependent expression of protease resistant PrPsc.

The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein (PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions.Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune- histochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons which do not produce DA. In the latter cells exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA-dependent mechanism by a drug of abuse.

High-intensity exercise training induces morphological and biochemical changes in skeletal muscles.

IN THE PRESENT STUDY WE INVESTIGATED THE EFFECT OF TWO DIFFERENT EXERCISE PROTOCOLS ON FIBRE COMPOSITION AND METABOLISM OF TWO SPECIFIC MUSCLES OF MICE: the quadriceps and the gastrocnemius. Mice were run daily on a motorized treadmill, at a velocity corresponding to 60% or 90% of the maximal running velocity. Blood lactate and body weight were measured during exercise training. We found that at the end of training the body weight significantly increased in high-intensity exercise mice compared to the control group (P=0.0268), whereas it decreased in low-intensity exercise mice compared to controls (P=0.30). In contrast, the food intake was greater in both trained mice compared to controls (P < 0.0001 and P < 0.0001 for low-intensity and high-intensity exercise mice, respectively). These effects were accompanied by a progressive reduction in blood lactate levels at the end of training in both the exercised mice compared with controls (P=0.03 and P < 0.0001 for low-intensity and high-intensity exercise mice, respectively); in particular, blood lactate levels after high-intensity exercise were significantly lower than those measured in low-intensity exercise mice (P=0.0044). Immunoblotting analysis demonstrated that high-intensity exercise training produced a significant increase in the expression of mitochondrial enzymes contained within gastrocnemius and quadriceps muscles. These changes were associated with an increase in the amount of slow fibres in both these muscles of high-intensity exercise mice, as revealed by the counts of slow fibres stained with specific antibodies (P < 0.0001 for the gastrocnemius; P=0.0002 for the quadriceps). Our results demonstrate that high-intensity exercise, in addition to metabolic changes consisting of a decrease in blood lactate and body weight, induces an increase in the mitochondrial enzymes and slow fibres in different skeletal muscles of mice, which indicates an exercise-induced increase in the aerobic metabolism.

Karyotype evolution and phylogenetic analyses in the genus Cardiospermum L. (Paullinieae, Sapindaceae).

Cardiospermum L. belongs to the Paullinieae tribe (Sapindaceae) and comprises 16 species. Of these, 12 species are present in South America and all occur in Brazil. Cardiospermum shows the most variable chromosome number of the tribe. Phylogenetic relationships within the genus Cardiospermum, especially with other species of the tribe, are poorly understood. This research focuses on characterisation of the karyotypic features of Cardiospermum using conventional cytogenetic methods, CMA/DAPI chromosome banding and fluorescence in situ hybridisation (FISH). To elucidate the phylogeny of the genus, the nuclear markers ITS1 and ITS2 were sequenced and analysed using maximum parsimony and Bayesian inference. Cardiospermum shows important diversity in basic numbers, with x = 7, 9, 10, 11 and 12. All species studied have metacentric and submetacentric chromosomes, some species have subtelocentric chromosomes, while telocentric chromosomes are absent. The interphase nuclei differentiate the Cardiospermum species into two groups. The CMA(3) /DAPI chromosome banding revealed the presence of an AT-rich terminal region in C. corindum, C. grandiflorum and C. urvilleoides, whereas GC-rich regions were found in C. grandiflorum, C. halicacabum var. halicacabum, C. halicacabum var. microcarpum, C. heringeri and C. integerrimum. FISH revealed syntenic and non-syntenic distribution of the 18-5.8-26S and 5S rDNA. The syntenic distribution always occurred in the short arms of the same chromosome in all of the species. The phylogenetic relationships reveal, in part, the taxonomic arrangement of the genus Cardiospermum.

High-intensity exercise training produces morphological and biochemical changes in adrenal gland of mice.

The effects of training are dependent on complex, adaptive changes which are induced by acute physical exercise at different levels. In particular, evidence shows that the hypothalamus-pituitary-adrenocortical axis, as well as the sympatho-adrenomedullary system, is mainly involved in mediating the physiological effects of physical exercise. The aim of the present study was to investigate, through a morphological and biochemical approach, the effects of training on the adrenal gland of mice, following two different protocols consisting of either low- or high-intensity training. Mice were run daily on a motorised treadmill for 8 weeks, at a velocity corresponding to 60% (low-intensity exercise) or 90% (high-intensity exercise) of the maximal running velocity previously determined by an incremental exercise test. We found that physical exercise produced an increase in the adrenal gland size compared with the control (sedentary) mice. The increase was 31.04% for mice that underwent high-intensity exercise and 10.08% for mice that underwent low intensity exercise, and this appeared to be the result of an increase in the area of both the adrenal cortex and adrenal medulla. Morphological analysis of the adrenal cortex showed that both types of exercise produced an increase in cytoplasmic vacuoles in steroidogenic cells, appearing more abundant after high-intensity exercise. No change was found in the reticulate zone. In the adrenal medulla, despite the absence of morphological changes, immunohistochemistry for tyrosine hydroxylase, dopamine ß-hydroxylase and phenyl-ethanolamine-N-methyltransferase demonstrated an increased immunopositivity for these cathecolamine-synthesizing enzymes after intense exercise. These results were confirmed by immunoblot accompanied by densitometric analysis.

Prevalencia de papilomavirus humano (HPV) tipo 6, 11, 16 y 18 en la ciudad de Buenos Aires: implicancias en la implementación de vacunas profilácticas / Prevalence of human papillomavirus (HPV-6-11, -16 and -18) in the city of Buenos Aires: epidemiology and vaccination

Introducción: el cáncer cervical es uno de los cáncer más comunes que afectan mujeres en países en desarrollo. Es provocado por la infección persistente del Papilomavirus Humano (HPV). En los últimos años se ha lanzado al mercado una vacuna cuadrivalente contra los HPV de bajo y alto riesgo (HPV-6, 11, 16 y 18), otra vacuna, bivalente para HPV-16 y 18, también ha sido introducida al mercado. En el presente trabajo se evaluó si los tipos de HPV cubiertos por las vacunas profilácticas son los más prevalentes en nuestro país, así como la utilidad de los métodos de detección viral por ADN como herramienta para el diagnóstico en mujeres asintomáticas. Materiales y métodos: éste protocolo se encuentra aprobado por el Comité de Docencia e Investigación (CODEI) del Hospital Gral. de Agudos "C.G. Durand" y por el consejo de Etica de la USAL. Todos los participantes dieron consentimiento escrito voluntario antes de participar del mismo. Se analizaron biopsias cervicales obtenidas en el Servicio de Tocoginecología de dicho Hospital, las cuales fueron agrupadas en 4 categorías: Grupo Control (ctrl.) n= 27, Grupo de lesiones de bajo grado (CIN I) n = 22, Grupo de lesiones de mediano y alto grado (CIN II/III) n = 30, Grupo de carcinomas cervicales (CC) n = 35. El ADN fue extraído por métodos estándar. La determinación de presencia de HPV se realizó mediante PCR específica con cebadores MY09/MY11. La tipificación de ADN específico de HPV-6, -11, -16 y -18 se realizó con PCR multiplex específica. Resultados y conclusiones: hemos observado una alta incidencia de la infección con HPV-16 en todos los grupos analizados (52% p< 0,0001), y varias muestras mostraron coinfección entre HPVs de alto riesgo, y entre HPVs de bajo y alto riesgo (6,85%, p< 0,001 vs. HPV16). Estos resultados, sumados al hecho que el 17,8 % de las muestras no mostró infección con los citados tipos de HPV, sugieren que la prevalencia de los tipos virales cubiertos por las vacunas es menor a la esperada...

Introductions: Cervical cancer is one of the most frequent cancers that affect women in developing countries. It is caused by persistent infection with Human Papillomavirus (HPV). In the last years a cuadrivalent vaccine against High-risk HPVs (HPV-6, -11, -16 and -18) has been launched into the market; another vaccine, bivalent for HPV-16 and -18, has also been introduced intro the market. In the present work we evaluated if HPV types covered by these vaccines are actually the most prevalent in our country, as well as the utility of DNA-based viral detection essays as a diagnosis tool in asymptomatic women. Materials and Methods: this protocol has been approved by the Hospital Durand's Teaching and Ethics committee (CODEI) and by the Ethics committee of USAL. All pariticipants gave voluntary informed consent before being included in the study. we analyzed cervical biopsies obtained in Gynecology Service of Hospital Durand, which were grouped into 4 categories: Control group (ctrl.) n = 27, low grade cervical lesions group (CIN I) n = 22, high grade cervical lesions group (CIN II/III) n = 30, cervical carcinomas (CC) n = 35. DNA was extracted by standard methods. Viral HPV presence was evaluated by specific PCR with MY09/MY11 primers. Viral-specific DNA determination of HPV-6, -11, -16 and -18 was evaluated by specific multiplex PCR. Results and conclusions: We observed a high incidence of and several samples showd co-infection between High-risk HPVs, and between high and low-risk HPVs (6.85%, p< 0.001 vs. HPV16). These results, plus the fact that almost 17.8% of the samples shown no expression of HPV types covered by the vaccines, suggest that the prevalence of HPV-6,-11, -16 and -18 is lower than expected in Buenos Aires city.

Methamphetamine induces ectopic expression of tyrosine hydroxylase and increases noradrenaline levels within the cerebellar cortex.

Methamphetamine produces locomotor activation and typical stereotyped motor patterns, which are commonly related with increased catecholamine activity within the basal ganglia, including the dorsal and ventral striatum. Since the cerebellum is critical for movement control, and for learning of motor patterns, we hypothesized that cerebellar catecholamines might be a target of methamphetamine. To test this experimental hypothesis we injected methamphetamine into C57 Black mice at the doses of 5 mg/kg two or three times, 2 h apart. This dosing regimen is known to be toxic for striatal dopamine terminals. However, we found that in the cerebellum, methamphetamine increased the expression of the primary transcript of the tyrosine hydroxylase (TH) gene, followed by an increased expression of the TH protein. Increased TH was localized within Purkinje cells, where methamphetamine increased the number of TH-immunogold particles, and produced a change in the distribution of the enzyme by increasing the cytoplasmic percentage. Increased TH expression was accompanied by a slight increase in noradrenaline content. This effect was highly site-specific for the cortex of posterior vermal lobules, while only slight effects were detectable in the hemispheres. The present data indicate that the cerebellum does represent a target of methamphetamine, which produces specific and fine alterations of the catecholamine system involving synthesis, amount, and compartmentalization of TH as well as increased noradrenaline levels. This may be relevant for motor alterations induced by methamphetamine. In line with this, inherited cerebellar movement disorders in various animal species including humans are associated with increased TH immunoreactivity within intrinsic neurons of the same lobules of the cerebellar cortex.

[Response to anti-TNF-alpha treatment for secondary renal amyloidosis in a patient with ankylosing spondylitis]. / Effetto della terapia con anti-TNF-alpha in un paziente con amiloidosi renale secondaria a spondilite anchilosante.

Renal amyloidosis is a complication of ankylosing spondylitis. A possible pathogenetic role is due to TNF-alpha, with a direct action on glomerular receptors TNFR2 and renal injury, secondary to deposition of amyloid fibrils. The most frequent clinical manifestation is proteinuria or nephrotic syndrome. Etanercept, a soluble receptor of TNF-alpha, binds this circulant cytokine with a progressive improvement of renal function and reduction of deposits of amyloid. Transient leukopenia, observed during ankylosing spondylitis, should not be considered a controindication to the use of Etanercept, but it requires a constant monitoring. The benefit observed in our patient can represent an indication to the use of Etanercept for the management of amyloidosis.

Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: severe deterioration and morphological correlates following the loss of locus coeruleus neurons.

Parkinsonian patients are treated with dopamine replacement therapy (typically, intermittent administration of the dopamine precursor L-DOPA); however, this is associated with the onset of abnormal involuntary movements, which seriously impair the quality of life. The molecular mechanisms underlying abnormal involuntary movements represent an intense field of investigation in the area of neurobiology of disease, although their aetiology remains unclear. Apart from the fine cellular mechanisms, the pathways responsible for the generation of abnormal involuntary movements may involve changes in neurotransmitter systems. A potential candidate is noradrenaline, since a severe loss of this neurotransmitter characterizes Parkinson's disease, and noradrenergic drugs produce a symptomatic relief of L-DOPA-induced dyskinesia. In previous studies we found that pulsatile dopamine release, in the absence of the physiological noradrenaline innervation, produces motor alterations and ultrastructural changes within striatal neurons. In the present study we demonstrate that a unilateral damage to the noradrenaline system anticipates the onset and worsens the severity of L-DOPA-induced contralateral abnormal involuntary movements in hemi-parkinsonian rats. Similarly, ubiquitin-positive striatal ultrastructural changes occur in unilaterally dopamine-depleted, noradrenaline-deficient rats following chronic L-DOPA administration. This study confirms a significant impact of the noradrenergic system in the natural history of Parkinson's disease and extends its role to the behavioural and morphological effects taking place during pulsatile dopamine replacement therapy.

A hypothesis on prion disorders: are infectious, inherited, and sporadic causes so distinct?

Prion diseases include a group of either sporadic, inherited or infectious disorders characterized by spongiform neurodegeneration and reactive glyosis in several brain regions. Whatever the origin, the neuropathological hallmark of prion diseases is the presence of brain aggregates containing an altered isoform of a cellular protein, named prion protein. Recent findings show the potential toxicity of the normal cellular prion protein, which occurs when its physiological metabolism is altered. In particular, several studies demonstrate that accumulation of the prion protein in the cytosol can be a consequence of an increased amount of misfolded prion proteins, a derangement of the correct protein trafficking or a reduced activity of the ubiquitin-proteasome system. The same effects can be a consequence of a mutation in the gene coding for the prion protein. In all these conditions, one assists to accumulation and self-replication of insoluble prion proteins which leads to a severe disease resembling what observed following typical "prion infections". This article provides an opinion aimed at reconciling the classic Prusiner's theory concerning the "prion concepts" with the present knowledge arising from experimental studies on neurodegenerative disorders, suggesting a few overlapping steps in the pathogenesis of these diseases.

Previous exposure to (+/-) 3,4-methylenedioxymethamphetamine produces long-lasting alteration in limbic brain excitability measured by electroencephalogram spectrum analysis, brain metabolism and seizure susceptibility.

Seizures represent the most common neurological emergency in ecstasy abusers; however, no study addressed whether (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") per se might produce long-lasting alterations in brain excitability related to a pro-convulsant effect. C57 Black mice were treated with three regimens of (+/-) 3,4-methylenedioxymethamphetamine (5mg/kg x 2 for 1, 2 or three consecutive days). Following the last dose of (+/-) 3,4-methylenedioxymethamphetamine, during a time interval of 8 weeks, the following procedures were carried out: 1) cortical electroencephalographic recordings, including power-spectrum analysis; 2) administration of sub-threshold doses of kainate; 3) measurement of regional [(14)C]2-deoxyglucose uptake; 4) monoamine assay. We demonstrate that all mice pre-treated with (+/-) 3,4-methylenedioxymethamphetamine showed long-lasting encephalographic changes with frequencies peaking at 3-4.5 Hz at the power-spectrum analysis. This is concomitant with latent brain hyperexcitability within selected limbic brain regions, as shown by seizure facilitation and long-lasting latent metabolic hyperactivity which can be unraveled by phasic glutamate stimulation. This study sheds new light into the brain targets of (+/-) 3,4-methylenedioxymethamphetamine and discloses the occurrence of (+/-) 3,4-methylenedioxymethamphetamine-induced latent hyperexcitability within limbic areas, while it might provide a model to study in controlled experimental conditions limbic seizures and status epilepticus in C57 Black mice. Persistent changes produced by (+/-) 3,4-methylenedioxymethamphetamine in limbic brain excitability might be responsible for seizures and limbic-related disorders in chronic (+/-) 3,4-methylenedioxymethamphetamine abusers.

Similarities between methamphetamine toxicity and proteasome inhibition.

The monoamine neurotoxin methamphetamine (METH) is commonly used as an experimental model for Parkinson's disease (PD). In fact, METH-induced striatal dopamine (DA) loss is accompanied by damage to striatal nerve endings arising from the substantia nigra. On the other hand, PD is characterized by neuronal inclusions within nigral DA neurons. These inclusions contain alpha-synuclein, ubiquitin, and various components of a metabolic pathway named the ubiquitin-proteasome (UP) system, while mutation of genes coding for various components of the UP system is responsible for inherited forms of PD. In this presentation we demonstrate for the first time the occurrence of neuronal inclusions in vivo in the nigrostriatal system of the mouse following administration of METH. We analyzed, in vivo and in vitro, the shape and the fine structure of these neuronal bodies by using transmission electron microscopy. Immunocytochemical investigation showed that these METH-induced cytosolic inclusions stain for ubiquitin, alpha-synuclein, and UP-related molecules, thus sharing similar components with Lewy bodies occurring in PD, with an emphasis on enzymes belonging to the UP system. In line with this, blockade of this multicatalytic pathway by the selective inhibitor epoxomycin produced cell inclusions with similar features. Moreover, using a multifaceted pharmacological approach, we could demonstrate the need for endogenous DA in order to form neuronal inclusions.

Effects of repeated low doses of MDMA on EEG activity and fluoro-jade B histochemistry.

The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine derivative that is widely abused. In previous studies, depending on the animal species, neurotoxicity has been demonstrated for either serotonin (5-HT) or/and dopamine (DA) nerve endings. These studies focused on the basal ganglia circuitry; however, in humans chronic abuse of MDMA often results in neurological symptoms that last after MDMA withdrawal and are not related to the extrapyramidal system such as electroencephalographic (EEG) abnormalities and cognitive impairment. These alterations might be due to the concomitant intake of other illicit compounds, the consequence of MDMA-induced hyperthermia, or to a primary neurotoxicity directed to extrastriatal regions. These observations call for a more in-depth analysis on the potential involvement of brain areas outside the basal ganglia in the toxic effects induced primarily by MDMA. In the present study, we treated C57Black mice chronically (25 days) with daily injections of MDMA (2.5 mg/kg). During treatments, mice were monitored in order to detect behavioral modifications, and epidural electrodes were installed to perform EEG recording. Behavioral data showed a sensitization as measured by locomotor activity, which related to progressive and long-lasting EEG changes and neuronal degeneration within the hippocampus.

DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy).

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. Previous reports, carried out in rodents and non-human primates, demonstrated neurotoxicity to monoamine axon terminals, although no study has analyzed nigral and striatal cell bodies at the sub-cellular level. OBJECTIVE: In this study, we examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate whether, in mice, MDMA might affect nigral and striatal cell bodies. METHODS: After administering MDMA, we analyzed effects induced in vivo and in vitro using high-performance liquid chromatography (HPLC) analysis, light- and electron microscopy with immunocytochemistry, and DNA comet assay. RESULTS: We found that MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal neurons consisting of multi-layer ubiquitin-positive whorls extending to the nucleus of the cell. These fine morphological changes are associated with clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin filaments. In the same experimental conditions, we could detect oxidation of DNA bases followed by DNA damage. The nature of inclusions was further investigated using PC12 cell cultures. CONCLUSIONS: The present findings lead to re-consideration of the neurotoxic consequences of MDMA administration. In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity.

Presence of beta-arrestin in cellular inclusions in metamphetamine-treated PC12 cells.

Cellular inclusions containing ubiquitin and alpha-synuclein were observed in PC12 cells treated with metamphetamine (MA). To study the possible involvement of beta-arrestin in inclusion formation, we treated PC12 cells with MA for different times and analyzed the ubiquitin proteosome pathway (UPP). We found that beta-arrestin is ubiquitinated in the MA-treated PC12 cell line. The involvement of beta-arrestin in UPP was further supported by electron microscopy and by confocal microscopy, which documented the presence of beta-arrestin in these Lewy body-like inclusions. Our experiments reveal an interesting and previously unappreciated connection between beta-arrestin and ubiquitination and suggest that beta-arrestin could be involved in the development of the inclusion bodies.

Amphetamines induce ubiquitin-positive inclusions within striatal cells.

The present study explores whether effects induced by amphetamine derivatives on striatal GABA cells might be connected with effects on dopamine (DA) metabolism. Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were administered to C57Black mice following a dosage regimen in which various doses of both drugs were injected i.p. at 2-h intervals. Neuronal inclusions produced under these experimental conditions were examined under electron microscopy. Drugs reducing DA availability prevented inclusion formation; conversely we observed that increasing DA synthesis or impairing physiological DA degradation enhanced the number of inclusions. The present study indicates that the presence of extracellular striatal DA is essential for the production of subcellular alterations induced by amphetamine derivatives. This is in line with a recent hypothesis connecting striatal DA release with degeneration of striatal GABA neurons.

Systemic sclerosis could mask the presentation of psoriasis in a patient with symptomatic and bilateral sacroiliitis.

Psoriasis is rarely associated with systemic sclerosis (SSc), and sacroiliitis associated to Connective Tissue Diseases is also rather rare. In this report we describe a case of a young woman with SSc who developed symptomatic and bilateral sacroiliitis. The clinical pattern of sacroiliac involvement of this patient resembles that of psoriatic sacroiliitis. HLA typing was compatible with both SSc and psoriasis. Psoriatic sacroiliitis could not be diagnosed, but, on the basis of these observations, the patient described could represent a case of PsA without psoriasis. and psoriatic cutaneous involvement masked by the presence of SSc.

Recent knowledge on molecular components of Lewy bodies discloses future therapeutic strategies in Parkinson's disease.

Lewy bodies (LB) were first described by Lewy in 1912 [1] as neuronal pale eosinophilic inclusions which became a pathological hallmark of Parkinson s disease (PD). In his original study, Lewy defined these inclusions as pale eosinophilic cytoplasmic structures, and studies since then have revealed LB to be ubiquitin-, alpha-synuclein-, and parkin-containing inclusions. This suggests that knowledge of the biochemical steps involved in the genesis of LB might disclose a final common pathway which might be responsible for different types of inherited and sporadic parkinsonism. This would lead to the identification of new therapeutic targets for interfering with disease progression. Although LB were originally described solely in PD, in the last decade these inclusions were described in a spectrum of degenerative disorders ranging from pure movement disorders to dementia. This suggests that common biochemical alterations leading to the formation of intracellular inclusions might underlie various pathological conditions. Consequently, the knowledge of the biochemical steps involved in the formation of neuronal inclusions could represent a key to develop new therapeutic strategies. In recent years it has been possible to develop both in vitro and in vivo neuronal inclusions resembling Lewy bodies. These experimental approaches have ranged from the use of alpha-synuclein transgenic mice to the continuous exposure to a mitochondrial complex I inhibitor. The aim of the present paper is to review briefly, recent advances on Lewy body research to achieve new insight into the etiology of PD and the molecular events leading to neurodegeneration.