Family cluster of Chagas disease among Bolivian immigrants in Italy: High rate of maternal-fetal transmission.

BACKGROUND: Chagas disease (CD) or American trypanosomiasis is a neglected anthropozoonosis caused by Trypanosoma cruzi that affects 6-8 million people worldwide (mainly in Latin America), 30-40% of whom develop cardiac or digestive complications. Once confined to endemic areas of Latin America, CD has more recently become a global disease as a result of migration flows from endemic to non-endemic regions, particularly in northern America and Europe. Congenital transmission is a particular challenge as it may be sustained for multiple generations and perpetuate the infection even in non-endemic countries. METHODS: Subjects were identified during a cross-sectional survey of CD among Latin American people living in Milan, Italy. Serology was carried out using tests based on either a lysate and a recombinant antigen of Trypanosoma cruzi. They were also tested by a conventional Polymerase Chain Reaction (PCR) targeting the 330 bp variable region of the T. cruzi kinetoplast minicircle genome and a commercial real-time PCR. RESULTS: We here describe a Bolivian family cluster with seven affected people with at least two autochthonous congenital T. cruzi infection which was identified during the course of a CD screening programme. We also review the epidemiology, diagnosis and control of congenital CD, with particular emphasis on the challenges facing the control and management of such a complex and still largely hidden disease. CONCLUSIONS: Our experience confirms the need to screen for CD all family members once a case is diagnosed and shows the possible high rate of congenital CD also in non-endemic areas.

White matter damage in Alzheimer disease and its relationship to gray matter atrophy.

PURPOSE: To explore the regional patterns of white matter (WM) tract damage in (a) patients with probable Alzheimer disease (AD) and (b) patients with amnestic mild cognitive impairment (aMCI) and at least one abnormal biomarker and to investigate whether WM damage is related to gray matter (GM) atrophy. MATERIALS AND METHODS: This study was approved by the institutional review board, and written informed consent was obtained from each participant. Twenty-three patients with AD, 15 patients with aMCI, and 15 healthy control subjects underwent diffusion tensor magnetic resonance imaging. WM tract damage was investigated by using tract-based spatial statistics, and GM atrophy was measured by using voxel-based morphometry. RESULTS: Compared with control subjects, patients with AD had an increase in mean diffusivity in all major WM tracts studied, including the limbic, cortico-cortical, interhemispheric, and corticospinal tracts. Conversely, fractional anisotropy decreased only in the parahippocampal tract, fornix, and small, inferior parietal regions. In addition, patients with AD showed a widespread increase in axial and radial diffusivity compared with control subjects. Patients with aMCI showed an increase in axial diffusivity only in tracts projecting to the frontal cortex and splenium of the corpus callosum. Significant and anatomically congruent correlations between WM changes and regional GM atrophy were found in patients with AD. Conversely, damage to most WM tracts in patients with aMCI did not correlate with GM atrophy. CONCLUSION: In AD, the observed patterns of WM abnormalities may reflect the advanced phase of a secondary degenerative process and an association, especially in the early phases of the disease, with primary WM tract damage over and above GM abnormalities.

Rapid semi-automatic segmentation of the spinal cord from magnetic resonance images: application in multiple sclerosis.

A new semi-automatic method for segmenting the spinal cord from MR images is presented. The method is based on an active surface (AS) model of the cord surface, with intrinsic smoothness constraints. The model is initialized by the user marking the approximate cord center-line on a few representative slices, and the compact surface parametrization results in a rapid segmentation, taking on the order of 1 min. Using 3-D acquired T(1)-weighted images of the cervical spine from human controls and patients with multiple sclerosis, the intra- and inter-observer reproducibilities were evaluated, and compared favorably with an existing cord segmentation method. While the AS method overestimated the cord area by approximately 14% compared to manual outlining, correlations between cord cross-sectional area and clinical disability scores confirmed the relevance of the new method in measuring cord atrophy in multiple sclerosis. Segmentation of the cord from 2-D multi-slice T(2)-weighted images is also demonstrated over the cervical and thoracic region. Since the cord center-line is an intrinsic parameter extracted as part of the segmentation process, the image can be resampled such that the center-line forms one coordinate axis of a new image, allowing simple visualization of the cord structure and pathology; this could find wider application in standard radiological practice.

Assessment of white matter tract damage in mild cognitive impairment and Alzheimer's disease.

Diffusion tensor MRI-based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico-cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto-occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimer's disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas-based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto-occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico-cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico-cortical association pathways in aMCI and AD patients.

Primary progressive multiple sclerosis: tactile-associated functional MR activity in the cervical spinal cord.

PURPOSE: To assess the extent of tactile-associated cervical spinal cord activation in patients with primary progressive (PP) multiple sclerosis (MS) and to investigate the relationship between spinal cord functional activation and the severity of cervical spinal cord and brain structural damage by using magnetic resonance (MR) images. MATERIALS AND METHODS: The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Cervical spinal cord functional MR images were obtained in 23 patients with PP MS and 18 healthy control subjects during tactile stimulation of the right hand. Conventional and diffusion-tensor MR images of the brain and spinal cord were also acquired. Mean stimulus-related signal intensity change for all activated voxels and the distribution of functional MR activity at each spinal cord level were obtained. Univariate analysis was used to compare MR findings between groups. Between-group differences in topographic distribution of functional MR activity were evaluated by using random-effects logistic regression models. RESULTS: Patients with PP MS had higher mean spinal cord activity on functional MR images than did controls. A higher occurrence of functional MR activation in the right versus left side of the spinal cord and in the posterior versus anterior section of the spinal cord was found in both control subjects and patients with PP MS. Patients who were mildly disabled had a pattern of functional MR activity distribution similar to that of controls, but patients who were more severely disabled did not show differential activation between the right and left sides of the spinal cord. A higher occurrence of functional MR activity in the anterior section of the right side of the spinal cord at the level of the C6-7 intervertebral disk (P = .05) and the left side of the spinal cord at the level of the C7-T1 intervertebral disk (P = .03) was found in patients with PP MS than in control subjects. Mean spinal cord functional MR imaging signal intensity change correlated with spinal cord fractional anisotropy. CONCLUSION: Patients with PP MS showed tactile-associated cervical spinal cord overactivation. Spinal cord functional changes, possibly owing to injured interneurons, likely contribute to the complex process that leads to the accumulation of irreversible disability in patients with PP MS.

Longitudinal assessment of grey matter contraction in amyotrophic lateral sclerosis: A tensor based morphometry study.

Our objective was to investigate grey matter (GM) contraction in patients with amyotrophic lateral sclerosis (ALS) using tensor based morphometry (TBM). Using a 1.5 Tesla scanner, T1-weighted MRI scans were obtained at baseline and at follow-up (mean interval, 9 months) from 16 ALS and 10 controls. Standard TBM procedures in Statistical Parametric Mapping (SPM2) were used for image processing and statistical analyses. The frontotemporal cortex and basal ganglia were considered areas of interest, based on pathological studies. Eight patients showed rapid clinical progression of ALS during the follow-up period. Compared to controls, all ALS patients showed progression of GM atrophy in left premotor cortex and right basal ganglia. Patients with rapidly progressing ALS showed GM atrophy changes in a larger motor cortical-subcortical area and in extramotor frontal regions compared to both controls and to non-rapidly progressing cases. Thus, TBM detected longitudinal atrophy changes in the motor network in ALS occurring over less than one year. The faster the clinical progression, the greater was the GM loss in motor and prefrontal areas. Further advances in tracking longitudinal changes in cortical and subcortical regions in ALS may provide an objective marker for monitoring disease progression, and the disease-modifying effect of potential treatments.

Mucopolysaccharidosis VI: the Italian experience.

The current paper describes the natural history and management of mucopolysaccharidosis VI (MPS VI) in all patients currently diagnosed with the disease in Italy. Nine patients (5.5-14.4 years) were included in the data review in March 2008. Gestational and perinatal data were normal for all patients. Median age at diagnosis was 1.9 years. During the course of the disease, all patients developed coarsened facial features, short stature, heart valve disease, eye problems, musculoskeletal problems, hepatosplenomegaly and neurological abnormalities. All patients received rhASB enzyme replacement therapy (ERT) and showed improvement or stabilisation in clinical manifestations after onset of therapy. The most frequently reported improvements were increased joint mobility and reduced hepatosplenomegaly. No relevant safety issues of ERT were reported. In conclusion, patients in Italy with MPS VI are diagnosed early in life. All patients have access to ERT and appear to benefit from this therapy.

Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. METHODS: JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. RESULTS: The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. CONCLUSIONS: Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease.

The urokinase plasminogen activator (uPA) and its receptor (uPAR) play important physiological functions in extracellular proteolysis, as well as cell adhesion and migration. Through dysregulation of these functions, the uPA/uPAR system might be involved in the pathogenesis of AIDS dementia complex (ADC), and, in fact, uPAR has been found to be overexpressed in the cerebrospinal fluid (CSF) and brain tissues of patients with ADC. On the other hand, its ligand uPA has been shown to down-regulate HIV replication in vitro. In this study, we examined uPAR and uPA expression in the brain of HIV-related lesions, as well as CSF levels of soluble uPAR (suPAR), uPA, and complexes between these two molecules (suPAR/uPA) in patients with HIV infection with or without ADC. uPAR was highly expressed by macrophages in both HIV encephalitis (HIV-E) or leukoencephalopathy (HIV-LE), with a distribution exceeding that of HIV p24 antigen. In contrast, uPA was detected only on rare cells in most of the cases. Both uPA and suPAR/uPA complex concentrations were significantly correlated with CSF suPAR levels, and CSF concentrations of both markers were higher in ADC patients than controls. However, uPA levels were substantially lower than corresponding suPAR levels. Although these findings remain correlative, they add support to the hypothesis that uPAR might be an important participant in the events leading to ADC. Additionally, these findings are consistent with a model in which overexpression of uPAR and overproduction of its soluble form may promote HIV replication via binding and removal of uPA from cell surface.

Microstructural changes and atrophy in brain white matter tracts with aging.

Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography was used to investigate microstructural and volumetric abnormalities of the major brain white matter (WM) tracts with aging in 84 healthy subjects. Linear relationships were found between age and mean diffusivity (MD) increase and fractional anisotropy (FA) decrease in all WM tracts, except the right cingulum and bilateral uncinate, where a linear correlation with age was found for FA only. Quadratic model fitted better MD and FA values of several tracts, including the corpus callosum, limbic pathways, and bilateral association, and corticospinal tracts. Age-related MD and FA abnormalities were associated with radial diffusivity increase in all WM tracts, while axial diffusivity changes were characterized by a considerable variation from a tract to another. A linear negative relationship with age was found for the volumes of the left cingulum and fornix, while the quadratic model fitted better age-related volume loss of corpus callosum and right inferior fronto-occipital fasciculus. Diffusion tensor magnetic resonance imaging may shed light into the complex pathological substrates of WM changes with aging.

Unexpected dramatic increase in CD4+ cell count in a patient with AIDS after enfuvirtide treatment despite persistent viremia and resistance mutations.

An unexpected dramatic immune recovery was observed in a patient with full-blown AIDS receiving enfuvirtide-based antiretroviral therapy after multiple treatment failures. A complex interplay of viral and host factors, including the control of X4 viruses and proviral burden, may favor immune restoration with HIV neutralizing activity, despite persistent viremia.

Evidence for cervical cord tissue disorganisation with aging by diffusion tensor MRI.

This study investigated the influence of normal aging on cervical cord volumetry and diffusivity changes and assessed whether magnetic resonance imaging (MRI) abnormalities of the aging cervical cord and brain are associated. Conventional and diffusion tensor (DT) MRI of the brain and cervical cord were acquired from 96 healthy subjects (age range=13-70 years). Cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA) of the cervical cord were measured. Volumetry and diffusivity metrics were also obtained for the brain white matter (WM) and grey matter (GM) (overall and cortical). No cervical cord lesions were seen on conventional MR images from all subjects. Degenerative vertebral column changes (not associated to cord compression) were found in 41 subjects (43%). Average FA of the cervical cord, but not average MD and cross-sectional area, was correlated with age (r=-0.70, p<0.001). Additionally, T2 brain lesion volume, normalised brain volume (NBV), normalised global and cortical brain GM volumes and average MD of the brain GM and WM also correlated with age (r values ranging from -0.83 to 0.62). Only brain WM average FA was weakly correlated with cervical cord average FA (r=0.25, p=0.02). The final multivariate model retained cord average FA (r=-0.37, p<0.001), normalised cortical GM volume (r=-0.56, p<0.001) and NBV (r=-0.22, p=0.04) as independent correlates of age (r2=0.76). Cervical cord is vulnerable to aging. The decrease of FA, in the absence of atrophy and MD changes, suggests gliosis as the most likely pathological feature of the aging cord.