[Autoimmune chronic meningitis secondary to pneumococcal meningitis. Report of one case]. / Meningitis crónica autoinmune secundaria a meningitis aguda por neumococo. Caso clínico.

Pneumococcal meningitis produces several inflammatory disorders in susceptible subjects. A worsening of meningitis can occur on the fourth day of evolution in relation with the withdrawal of steroids. Other complications include the development of inflammatory signs in the post-acute stage of infection associated with disseminated vasculitis of the cerebral blood vessels and, even later, an autoimmune chronic meningitis. All these inflammatory complications are well controlled with the use of steroids. We report a 53-year-old woman with pneumococcal meningitis that had a good response to treatment with antibiotics and steroids. On the four day, after the steroids were discontinued, she complained of headache, became confused, and had an abnormal cerebrospinal fluid (CSF), report CT angiography showed signs of arteritis. She improved when the steroids were re-started. She was discharged in good condition but after slow tapering of the steroids over a four-month period she had a relapse of all her symptoms and had a gait disturbance. On readmission, she had an inflammatory CSF, there were no signs of infection and the cerebral MRI showed meningeal thickening with ventricular space enlargement. She improved again with steroids and she is now well on high-dose steroids but deteriorates each time the steroids are stopped. She experienced both acute and sub-acute inflammatory responses and finally developed a chronic meningitis responsive, and is dependent on steroids.

[O6-methylguanine-DNA-methyltransferase (MGMT) expression in patients with glioblastoma multiforme]. / Expresión de O6-metilguanina-ADN-metiltransferasa (MGMT) en pacientes chilenos con glioblastoma multiforme.

BACKGROUND: Patients with Glioblastoma multiforme (GBM) have a five years survival of less than 5%, but the response to chemotherapy with alkylating agents can vary depending on the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT). Genetic testing has limitations for routine use, while immunohistochemistry (IHC) offers a fast and affordable technique but with heterogeneous results in the literature. AIM: To evaluate MGMT expression by IHC in tumor tissue of Chilean patients with GBM. MATERIAL AND METHODS: Tumor samples of 29 patients with a pathological diagnosis of GBM were studied. We performed IHC staining and manual analysis of positive and negative cells for MGMT expression. A cut-off of at least 10% of cells expressing MGMT was used. Demographic and clinical features of patients were obtained from clinical records. RESULTS: The median number of cells counted per case was 692 (interquartile range [IQR] 492-928). Fifteen cases (52%) were positive for MGMT expression. Median overall survival was 5.3 months (IQR 3.4-12-8). The effect of MGMT expression on the therapeutic response was not studied since only 3 patients received chemotherapy. CONCLUSIONS: Our results are similar to international reports, but we were not able to determine the association between MGMT expression and therapeutic response.

O6-methylguanine-DNA-methyltransferase immunostaining intensity in glioblastoma.

Immunohistochemistry (IHC) for O6-methylguanine-DNA-methyltransferase (MGMT) has shown heterogeneous results. Cell staining intensity has not been included as a quantifiable variable in IHC analyses. We performed MGMT IHC in 29 patients diagnosed as glioblastoma classifying cells into three categories based on nuclear staining intensity compared with adjacent endothelium. The median proportions of strong-moderate, weak and no staining cells were 10%, 16% and 71%, respectively. The proportion of positive cases for MGMT expression varies from 38% to 52% depending on the classification of weakly stained cells. This letter challenges previous studies that have not included intensity as a variable for IHC analysis.

Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.

UNLABELLED: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. IMPORTANCE: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear. Here, we show that the viral transactivator Tax increases activated leukocyte cell adhesion molecule (ALCAM/CD166) expression. This molecule facilitates the migration of lymphocytes across the BBB endothelium. Targeting this molecule could be of interest in preventing or reducing the development of HAM/TSP.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.

Human T-Lymphotropic Virus Type 1 and 2 Seroprevalence among first-time blood donors in Chile, 2011-2013.

Infection with human T-lymphotropic virus type 1/2 (HTLV-1/2) is a major health problem. HTLV-1/2 infection is endemic in Chile but representative donor prevalence data are lacking. Data on all blood donors in a large network of Chilean blood centers were examined during 2011-2013. Screening of HTLV-1/2 antibodies were measured by enzyme immunoassay (EIA) at all blood banks. Blood samples with anticoagulants from initially reactive blood donors were analyzed by serological confirmation tests (immunofluorescence or recombinant immunoblot) at the HTLV National Reference Laboratory of the Public Health Institute of Chile. Additionally, detection of HTLV-1 and HTLV-2 provirus in peripheral blood mononuclear cells (PBMCs) was performed in all blood donors as confirmatory test. Prevalence rates were calculated. Among 694,016 donors, 706 were seropositive for HTLV-1 (prevalence, 1.02 cases per 1,000; 95% confidence interval [CI], 0.94-1.09), and 97 were seropositive for HTLV-2 (prevalence, 0.14 cases per 1,000; 95%CI, 0.11-0.17). Prevalence of HTLV-1 differed considerably by region, from 0.51 to 1.69 per 1,000. Prevalence of HTLV-2 was similar across the country (0.12-0.16). HTLV-1 prevalence was associated with female sex, older age, and residence in the north of Chile. HTVL-2 prevalence was associated with older age. The HTLV-1 prevalence among Chilean blood donors was relatively high and could be reduced by improving donor recruitment and selection in high prevalence areas. Blood center data may contribute to surveillance for HTLV-1 and HTLV-2 infections.

Tax secretion from peripheral blood mononuclear cells and Tax detection in plasma of patients with human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis and asymptomatic carriers.

Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested that extracellular Tax might involve cytokine-like extracellular effects. We evaluated Tax secretion in 18 h-ex vivo peripheral blood mononuclear cells (PBMCs) cultures from 15 HAM/TSP patients and 15 asymptomatic carriers. Futhermore, Tax plasma level was evaluated from other 12 HAM/TSP patients and 10 asymptomatic carriers. Proviral load and mRNA encoding Tax were quantified by PCR and real-time RT-PCR, respectively. Intracellular Tax in CD4(+)CD25(+) cells occurred in 100% and 86.7% of HAM/TSP patients and asymptomatic carriers, respectively. Percentage of CD4(+)CD25(+) Tax+, proviral load and mRNA encoding Tax were significantly higher in HAM/TSP patients. Western blot analyses showed higher secretion levels of ubiquitinated Tax in HAM/TSP patients than in asymptomatic carriers. In HTLV-1-infected subjects, Western blot of plasma Tax showed higher levels in HAM/TSP patients than in asymptomatic carriers, whereas no Tax was found in non-infected subjects. Immunoprecipitated plasma Tax resolved on SDS-PAGE gave two major bands of 57 and 48 kDa allowing identification of Tax and Ubiquitin peptides by mass spectrometry. Relative percentage of either CD4(+)CD25(+) Tax+ cells, or Tax protein released from PBMCs, or plasma Tax, correlates neither with tax mRNA nor with proviral load. This fact could be explained by a complex regulation of Tax expression. Tax secreted from PBMCs or present in plasma could potentially become a biomarker to distinguish between HAM/TSP patients and asymptomatic carriers.

[Pontine reversible leucopathy in an AIDS patient associated with highly active antiretroviral therapy (HAART): Report of one case]. / Leucopatía reversible de la protuberancia: en paciente con SIDA y tratamiento retroviral.

Posterior reversible encephalopathy (PRES) is a condition characterized by T2 and FLAIR hyperintensities in magnetic resonance imaging (MRI) studies, localized preferentially in the occipital-parietal white matter regions. Pathological MRI images located in midbrain, pons, medulla and spinal cord, that could be asymptomatic, were recently included in this entity. These images are interpreted as vasogenic edema, which is caused by arterial hypertension or eclampsia, neurotoxicity related to immunosuppressive agents or chemotherapy, among other causes. We report a 25 years old asymptomatic male with AIDS, with normal blood pressure who after initiating highly active antiretroviral therapy (HAART) reported vertigo. The MRI showed a central pontine T2 hyperintensity with diffusion restriction, which was interpreted as a central pontine myelinolysis (CPM), but the lack of motor symptoms made improbable a real demyelination of the pons. The follow-up MRI revealed complete regression of the images. To our knowledge, this case could be the second report of a reversible leucopathy of the pons in a patient with AIDS, were the MRI images also simulated a CPM. This report extends the knowledge around the variability of the pathogenic interpretation of CPM images and their association with HAART.

[Meningitis-retention syndrome. Report of one case]. / Síndrome de meningitis y retención urinaria.

The Meningitis-Retention Syndrome associates aseptic meningitis and neurogenic bladder, with a vesical dysfunction that outlasts meningitis widely. Urodynamic assessment shows a detrusor palsy with normal function of the external sphincter. We report a 24-year-old male admitted for headache, fever, myalgias and acute urinary retention, which was diagnosed as a urinary tract infection. Worsening of symptoms and slight meningeal signs prompted for a lumbar puncture that yielded a cerebrospinal fluid with 94 lymphocytes, in which etiological evaluation was inconclusive. Meningeal syndrome and myalgia subsided by the fifth day, while urinary retention persisted. A magnetic resonance imaging of the brain and spinal cord done at the fifth day, showed high intensity signals in basal ganglia and central spinal cord, not altered by contrast. These images disappeared in the imaging control performed two months later. Bladder dysfunction lasted at least until the second month of follow up.

[Bifrontal cerebritis and brain abscess caused by Sreptococcus anginosus group: report of one case]. / Cerebritis bifrontal y absceso cerebral por Streptococcus del grupo anginosus, en paciente previamente sano: Caso clínico.

The etiology of brain abscesses is mostly polymicrobial. Streptococci and anaerobic bacteria are the most commonly isolated pathogens. We report a previously healthy female without predisposing factors, presenting with a bifrontal cerebritis caused by a Streptococcus anginosus group infection. The patient developed a brain abscess and a subdural collection with severe intracranial hypertension of fatal evolution. The etiologic diagnosis was made culturing the material obtained from the subdural collection. It is presumed that, within the Streptococcus anginosus group, Streptococus intermedius could have been the causing bacteria, given its central nervous system tissue tropism and its predisposition to form brain abscesses.

[Limbic encephalitis with positive anti-N-methyl-D-aspartate antibodies. Report of one case]. / Encefalitis autoinmune reversible y anticuerpos anti-receptores de N-metil-D-aspartato.

BACKGROUND: Limbic encephalitis is a subacute syndrome characterized by memory impairment, confusion, seizures, hypothalamic dysfunction and psychiatric symptoms. It has been associated to tumors located outside of the central nervous system. In 2007, anti-N-methyl-D-aspartate receptors (NMDAr) antibodies were found in serum and CSF of patients with this particular type of encephalitis. We report a 25-year-old female who, following upper respiratory tract symptoms, developed serious behavioral and consciousness impairment that progressed to coma. Cerebrospinal fluid (CSF) analysis showed a lymphocyte pleocytosis, the electroencephalogram was altered with a slow encephalopathic rhythm and a brain magnetic resonance imaging was normal. Infectious etiologies were ruled out. CSF and serum anti NMDA receptors antibodies were positive.

[Clinical and pathologic identification of different forms of Creutzfeldt Jakob disease in Chile]. / Identificación clínica y patológica de las diversas formas de la enfermedad de Creutzfeldt Jakob en Chile.

BACKGROUND: The identification of clinical and pathological forms of Creutzfeldt Jakob Disease (CJD) started with the first cases of the disease. Genetic and biomolecular prion status assessment are allowing now a better classification. AIM: To identify the clinical forms of the disease that exist in Chile, based on clinical and neuropathological data. PATIENTS AND METHODS: Review of records of 40 patients with CJD in whom a complete history, clinical details and neuropathological studies were available. Clinical aspects were grouped into five categories: behavioral and cognitive changes, sleep and alertness, visual impairment, motor disturbances, myoclonus and epilepsy. The neuropathological examination in each case allowed us to evaluate the damage of 13 areas of the central nervous system. RESULTS: Five forms of CJD were identified. The classic form was present in 28 patients (70%), the Heidenhain form was present in five (12.5%), the ataxic form in four (10%), the form with Kuru plaques in two (5%) and the Vacuolar was present in one patient (2.5%). CONCLUSIONS: The variety and forms of CJD in Chile do not differ substantially from those found abroad.

Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-ß prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes.

Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-ß (GSK3-ß) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-ß and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-ß active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in ß-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-ß. Thus, GSK3-ß seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection.

Molecular and clinical effects of betamethasone in human T-cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.

There is no effective therapy for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Glucocorticoids are effective to reduce the motor disability in these patients, but its role as anti-spastic drugs is unknown. Here it is reported the use of corticosteroids in HAM/TSP. The goal was to find reliable molecular markers linked to treatment effectiveness. The clinical efficacy of corticosteroids was studied in 22 HAM/TSP. The treatment was a single dose of 7.0 mg of systemic betamethasone. Pre-treatment samples were obtained immediately before steroid administration and post-treatment samples were collected after 5 days. Neurological disability was evaluated by the Osame's Motor Disability Scales. Relative levels of Tax, Foxp3, IL-10, TGF-ß, CTLA-4, and GITR mRNA were measured and the percentage of CD4(+) Foxp3(+) and CD4(+) Tax(+) populations was quantified in PBMCs by real-time PCR and flow cytometry, respectively. The same parameters were studied in eight untreated carriers. Betamethasone treatment showed neurological improvement in 21 HAM/TSP patients, with one patient without response to treatment. This therapy was associated with a decrease in Tax mRNA load and CD4(+) Tax(+) T cells in HAM/TSP. Simultaneously, an increase in Foxp3 mRNA and CD4(+) Foxp3(+) T cell was detected in these patients. The other markers studied had no significant changes after treatment. Clinical improvement in betamethasone-treated HAM/TSP was associated with an inverse relationship between a decrease in Tax and an increase in Foxp3 at the mRNA and protein levels. These results suggest that both Tax and Foxp3 may represent potential biomarkers for drug treatment assessments in HAM/TSP.

Alteration of blood-brain barrier integrity by retroviral infection.

The blood-brain barrier (BBB), which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans), both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

Dynamin 2 mutations associated with human diseases impair clathrin-mediated receptor endocytosis.

Dynamin 2 (DNM2) is a large GTPase involved in the release of nascent vesicles during endocytosis and intracellular membrane trafficking. Distinct DNM2 mutations, affecting the middle domain (MD) and the Pleckstrin homology domain (PH), have been identified in autosomal dominant centronuclear myopathy (CNM) and in the intermediate and axonal forms of the Charcot-Marie-Tooth peripheral neuropathy (CMT). We report here the first CNM mutation (c.1948G>A, p.E650 K) in the DNM2 GTPase effector domain (GED), leading to a slowly progressive moderate myopathy. COS7 cells transfected with DNM2 constructs harboring a disease-associated mutation in MD, PH, or GED show a reduced uptake of transferrin and low-density lipoprotein (LDL) complex, two markers of clathrin-mediated receptor endocytosis. A decrease in clathrin-mediated endocytosis was also identified in skin fibroblasts from one CNM patient. We studied the impact of DNM2 mutant overexpression on epidermal growth factor (EGF)-induced extracellular signal-regulated kinase 1 (ERK1) and ERK2 activation, known to be an endocytosis- and DNM2-dependent process. Activation of ERK1/2 was impaired for all the transfected mutants in COS7 cells, but not in CNM fibroblasts. Our results indicate that impairment of clathrin-mediated endocytosis may play a role in the pathophysiological mechanisms leading to DNM2-related diseases, but the tissue-specific impact of DNM2 mutations in both diseases remains unclear.

Microtubule proteins and their post-translational forms in the cerebrospinal fluid of patients with paraparesis associated with HTLV-I infection and in SH-SY5Y cells: an in vitro model of HTLV-I-induced disease.

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by axonal degeneration of the corticospinal tracts. The specific requirements for transport of proteins and organelles to the distal part of the long axon are crucial in the corticospinal tracts. Microtubule dysfunction could be involved in this disease, configuring an axonal transport disease. We measured tubulin and its post-translational modified forms (acetylated and tyrosinated) in CSF of patients and controls, as well as tau and its phosphorylated forms. There were no significant differences in the contents of tubulin and acetyl-tubulin between patients and controls; tyrosyl-tubulin was not detected. In HAM/TSP, tau levels were significantly reduced, while the ratio of pT181/total tau was higher in patients than in controls, this being completely different from what is reported in other neurodegenerative diseases. Phosphorylation at T181 was also confirmed by Mass Spectrometry analysis. Western Blotting with monospecific polyclonal antibodies against pS199, pT205, pT231, pS262, pS356, pS396, pS404 and pS422 did not show differences in phosphorylation in these residues between patients and controls. Treating human SH-SY5Y neuroblastoma cells, a well-known in vitro neurite retraction model, with culture supernatant of MT-2 cells (HTLV-I infected cell line that secretes the viral Tax protein) we observed neurite retraction and an increase in tau phosphorylation at T181. A disruption of normal phosphorylation of tau protein in T181 could result in its dysfunction, contributing to axonal damage.

Trophic factors in cerebrospinal fluid and spinal cord of patients with tropical spastic paraparesis, HIV, and Creutzfeldt-Jakob disease.

HTLV-1-associated myelopathy/tropical spastic paraparesis (TSP/HAM) is a chronic CNS disease characterized by axomyelinic degeneration of the long axons of corticospinal tracts. Levels of NGF, NT-3, NT-4/5, BDNF, GDNF, CNTF, and FGF-2 were measured in the cerebrospinal fluid (CSF) of 21 TSP/HAM patients and 20 controls. NGF, BDNF, and FGF-2 levels were also determined in 19 patients with HIV motor cognitive motor syndrome, and in 21 subjects diagnosed with Creutzfeldt Jakob disease (CJD). No significant differences were detected in the concentrations of NGF, BDNF, NT-3, NT-4/5, GDNF, and CNTF in the CSF between TSP/HAM patients and controls. FGF-2 was significantly lower in the CSF of the three groups of patients compared with controls; the HIV group exhibited the lowest values. HIV patients differed from TSP/HAM in their significantly higher levels of NGF and lower levels of BDNF and FGF-2, whereas CJD patients differed only in their higher levels of NGF. Immunohistochemical studies were done of trophic factors (NGF and FGF-2) and neurotrophin receptors (trkA and p75) in spinal cord and motor cortical areas from anatomopathological cases of TSP/HAM. Results indicated that NGF is expressed in motoneurons and oligodendrocytes of the posterior column of the spinal cord. FGF-2 was detected in motoneurons and spinal cord vessels. p75 receptor was detected in cortical neurons. The absence of a significant change in the trophic factor levels in TSP/HAM may be attributed to a selective axonal lesion in a slow process.

Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth.

Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4(+) T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4(+) T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser(522). The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4(+)Tax(+) T cells with a high CRMP-2 pSer(522) content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.

[Frontotemporal dementia non familial and generalized epilepsy]. / Demencia frontotemporal no familiar y epilepsia generalizada.

UNLABELLED: A 62 year-old patient is presented, without family antecedents of dementia who begins with 45 years of age with sudden crisis of dyspnea, blurred vision, fall to the floor and repetitive jerks of arms. Tried by epilepsy with phenytoin and valproate repeats similar crisis sporadically. Four years ago their relatives began to notice changes of personality, irritability and obsessive behaviors. Later on, are added episodes of disorientation of days of duration, some with auditory hallucinations and also convulsive manifestations. Finally appear polymorphic crisis, some with continue alteration of consciousness, catatonic states and sphincteric incontinence. Physical and neurological examination without abnormalities. Neuropsychological evaluation evidenced consistent defects in frontal functions. EEG showed widespread slowness and sporadic irritative activity in frontotemporal regions. Anterior cortical atrophy in CT scan and bilateral frontotemporal hypoperfusion in SPECT. Labs exams and CSF were normal. CONCLUSION: The association of FTD and epilepsy, in non-family form, suggests a different neurodegenerative cortical syndrome.