Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.

M. Santos, G. Gold, E. Kövari, F. R. Herrmann, P. R. Hof, C. Bouras and P. Giannakopoulos (2010) Neuropathology and Applied Neurobiology36, 661-672
Neuropathological analysis of lacunes and microvascular lesions in late-onset depression Aims: Previous neuropathological studies documented that small vascular and microvascular pathology is associated with cognitive decline. More recently, we showed that thalamic and basal ganglia lacunes are associated with post-stroke depression and may affect emotional regulation. The present study examines whether this is also the case for late-onset depression. Methods: We performed a detailed analysis of small macrovascular and microvascular pathology in the post mortem brains of 38 patients with late-onset major depression (LOD) and 29 healthy elderly controls. A clinical diagnosis of LOD was established while the subjects were alive using the DSM-IV criteria. Additionally, we retrospectively reviewed all charts for the presence of clinical criteria of vascular depression. Neuropathological evaluation included bilateral semi-quantitative assessment of lacunes, deep white matter and periventricular demyelination, cortical microinfarcts and both focal and diffuse gliosis. The association between vascular burden and LOD was investigated using Fisher's exact test and univariate and multivariate logistic regression models. Results: Neither the existence of lacunes nor the presence of microvascular ischaemic lesions was related to occurrence of LOD. Similarly, there was no relationship between vascular lesion scores and LOD. This was also the case within the subgroup of LOD patients fulfilling the clinical criteria for vascular depression. Conclusions: Our results challenge the vascular depression hypothesis by showing that neither deep white matter nor periventricular demyelination is associated with LOD. In conjunction with our previous observations in stroke patients, they also imply that the impact of lacunes on mood may be significant solely in the presence of acute brain compromise.

Monitoring natural hazards

Few subjects have caught the attention of the entire world as much as those dealing with natural hazards. The first decade of this new millennium provides a litany of tragic examples of various hazards that turned into disasters affecting millions of individuals around the globe. The human losses (some 225,000 people) associated with the 2004 Indian Ocean earthquake and tsunami, the economic costs (approximately 200 billion USD) of the 2011 Tohoku Japan earthquake, tsunami and reactor event, and the collective social impacts of human tragedies experienced during Hurricane Katrina in 2005 all provide repetitive reminders that we humans are temporary guests occupying a very active and angry planet. Any examples may have been cited here to stress the point that natural events on Earth may, and often do, lead to disasters and catastrophes when humans place themselves into situations of high risk. Few subjects share the true interdisciplinary dependency that characterizes the field of natural hazards. From geology and geophysics to engineering and emergency response to social psychology and economics, the study of natural hazards draws input from an impressive suite of unique and previously independent specializations. Natural hazards provide a common platform to reduce disciplinary boundaries and facilitate a beneficial synergy in the provision of timely and useful information and action on this critical subject matter. As social norms change regarding the concept of acceptable risk and human migration leads to an explosion in the number of megacities, coastal over-crowding and unmanaged habitation in precarious environments such as mountainous slopes, the vulnerability of people and their susceptibility to natural hazards increases dramatically. Coupled with the concerns of changing climates, escalating recovery costs, a growing divergence between more developed and less developed countries, the subject of natural hazards remains on the forefront of issues that affect all people, nations, and environments all the time.This treatise provides a compendium of critical, timely and very detailed information and essential facts regarding the basic attributes of natural hazards and concomitant disasters. The Encyclopedia of Natural Hazards effectively captures and integrates contributions from an international portfolio of almost 300 specialists whose range of expertise addresses over 330 topics pertinent to the field of natural hazards. Disciplinary barriers are overcome in this comprehensive treatment of the subject matter. Clear illustrations and numerous color images enhance the primary aim to communicate and educate. The inclusion of a series of unique ?classic case study? events interspersed throughout the volume provides tangible examples linking concepts, issues, outcomes and solutions. These case studies illustrate different but notable recent, historic and prehistoric events that have shaped the world as we now know it. They provide excellent focal points linking the remaining terms in the volume to the primary field of study. This Encyclopedia of Natural Hazards will remain a standard reference of choice for many years.

Microvascular burden and Alzheimer-type lesions across the age spectrum.

The occurrence of microvascular and small macrovascular lesions and Alzheimer's disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still a matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden.

Infection of the central nervous system caused by varicella zoster virus reactivation: a retrospective case series study.

BACKGROUND: Recent data suggest that varicella zoster virus (VZV)-associated complications of the central nervous system (CNS) are more common and diverse than previously thought. The main purpose of this article is to describe the clinical characteristics and the outcome of patients suffering from meningitis and encephalitis caused by VZV reactivation. METHODS: A retrospective case study of adult patients (≥16 years old) diagnosed with a VZV reactivation in the CNS was performed. The cases were identified by a qualitative PCR DNA assay of the cerebrospinal fluid (CSF) at the Regional Hospital of Lugano between January 1, 2003 and July 31, 2010. RESULTS: Eleven out of 519 CSF samples (2.1%), submitted from patients with a clinical diagnosis of viral meningitis or encephalitis, were positive for VZV. A vesiculo-pustular skin eruption was observed in only five patients (45%). In six cases (55%), a systemic inflammatory syndrome was absent. The clinical outcome was favorable in eight patients (73%). Only one out of 11 patients (9%) died. The four patients with encephalitis had a less favorable prognosis: one patient recovered without residual neurological sequelae; two had a chronic neuropsychological handicap, speech difficulties, facial nerve palsy, and focal seizures; one patient died. We estimated an annual incidence rate of VZV infection of the CNS of 1.02/100 000 inhabitants for southern Switzerland. CONCLUSIONS: Screening of CSF for VZV by PCR is recommended for all patients with encephalitis and for those with viral meningitis of unclear origin in order to better target antiviral treatment.

Increased carotid intima-media thickness in the absence of atherosclerotic plaques in an adult population with Fabry disease.

AIM: Fabry disease is considered primarily as a progressive small vessel disease, with ischaemic degenerative lesions involving the kidneys, brain and heart. Macrovascular involvement in male patients includes an accelerated wall hypertrophy of the radial artery and a thickening of the intima-media of the common carotid artery. The aim of this study is to evaluate the prevalence and severity of carotid artery atherosclerosis in hemizygous and heterozygous patients with Fabry disease, compared with a matched control population. METHODS: The common carotid artery intima-media thickness (IMT) of 53 patients with Fabry disease (24 men, 29 women) was measured by high-definition ultrasonography, and the presence or absence of atherosclerotic plaques reported. Results were compared with those of 120 age-matched healthy individuals (83 men, 37 women). RESULTS: The common carotid artery IMT was increased to the same extent in male and female patients with Fabry disease (706+/-211 microm and 749+/-395 microm, respectively) compared with that of the control population (614+/-113 microm). In the Fabry population, IMT did not correlate with either systolic blood pressure or with renal function (plasma creatinine). In the control population, only systolic blood pressure was positively and significantly correlated with IMT. Atherosclerotic plaques in the common carotid artery were not observed in any patient with Fabry disease, whereas 34% of the control population had carotid artery plaques, as evidenced by focal non-homogeneous intima-media thickening greater than 1.2 mm. CONCLUSION: This study presents evidence of a major increase in common carotid artery IMT, both in hemizygous and heterozygous patients with Fabry disease, in the absence of focal atherosclerotic plaques. These results suggest that the conduit arteries may be protected from atherosclerosis in Fabry disease.

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

3D virtual rendering before laparoscopic partial splenectomy in children.

INTRODUCTION: Partial splenectomy in children is a good surgical option for hematological diseases and focal splenic tumors because it allows the preservation of the spleen's immunological function. Furthermore, it can be performed by laparoscopy in children as it is a safe procedure, offering the benefits of a minimally invasive approach. MATERIALS AND METHODS: The software VR-render LE version 0.81 is a system that enables the visualization of bidimentional 3D images with magnification of anatomical details. We have applied this system to five cases of non-parasitic splenic cysts before laparoscopic partial splenectomy. RESULTS: The images obtained with VR rendering software permitted the preoperative reconstruction of the vascularization of the splenic hilum, allowing the surgeon safe vessel control during laparoscopic procedures. All five partial splenectomies were carried out with no complications or major blood loss. CONCLUSIONS: Laparoscopic partial splenectomy should be a first choice procedure because it is feasible, reproducible, and safe for children; furthermore, it preserves enough splenic tissue thereby preventing post-splenectomy infections. Volume rendering provides high anatomical resolution and can be useful in guiding the surgical procedure.

Factors influencing emergency delays in acute stroke management.

Early admission to hospital with minimum delay is a prerequisite for successful management of acute stroke. We sought to determine our local pre- and in-hospital factors influencing this delay. Time from onset of symptoms to admission (admission time) was prospectively documented during a 6-month period (December 2004 to May 2005) in patients consecutively admitted for an acute focal neurological deficit presented at arrival and of presumed vascular origin. Mode of transportation, patient's knowledge and correct recognition of stroke symptoms were assessed. Physicians contacted by the patients or their relatives were interviewed. The influence of referral patterns on in-hospital delays was further evaluated. Overall, 331 patients were included, 249 had an ischaemic and 37 a haemorrhagic stroke. Forty-five patients had a TIA with neurological symptoms subsiding within the first hours after admission. Median admission time was 3 hours 20 minutes. Transportation by ambulance significantly shortened admission delays in comparison with the patient's own means (HR 2.4, 95% CI 1.6-3.7). The only other factor associated with reduced delays was awareness of stroke (HR 1.9, 95% CI 1.3-2.9). Early in-hospital delays, specifically time to request CT-scan and time to call the neurologist, were shorter when the patient was referred by his family or to a lesser extent by an emergency physician than by the family physician (p < 0.04 and p < 0.01, respectively) and were shorter when he was transported by ambulance than by his own means (p < 0.01). Transportation by ambulance and referral by the patient or family significantly improved admission delays and early in-hospital management. Correct recognition of stroke symptoms further contributed to significant shortening of admission time. Educational programmes should take these findings into account.

Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) affects vascular barrier function and thus increases vessel permeability. This phenomenon may be exploited to facilitate targeted drug delivery and may lead to a new clinical application of photodynamic therapy. Here, we investigate the role of leukocyte recruitment for PDT-induced vascular permeabilization. STUDY DESIGN/MATERIAL AND METHODS: Fluorescein isothiocyanate dextran (FITC-D, 2,000 kDa) was injected intravenously 120 minutes after focal PDT on striated muscle in nude mice bearing dorsal skinfold chambers (Visudyne® 800 µg/kg, fluence rate 300 mW/cm2 , light dose of 200 J/cm2). Leukocyte interaction with endothelial cells was inhibited by antibodies functionally blocking adhesion molecules ("MABS-PDT" group, n = 5); control animals had PDT but no antibody injection (group "PDT", n = 7). By intravital microscopy, we monitored leukocyte rolling and sticking in real-time before, 90 and 180 minutes after PDT. The extravasation of FITC-D from striated muscle vessels into the interstitial space was determined in vivo during 45 minutes to assess treatment-induced alterations of vascular permeability. RESULTS: PDT significantly increased the recruitment of leukocytes and enhanced the leakage of FITC-D. Neutralization of adhesion molecules before PDT suppressed the rolling of leukocytes along the venular endothelium and significantly reduced the extravasation of FITC-D as compared to control animals (156 ± 27 vs. 11 ± 2 (mean ± SEM, number of WBC/30 seconds mm vessel circumference; P < 0.05) at 90 minutes after PDT and 194 ± 21 vs. 14 ± 4 at 180 minutes after PDT). In contrast, leukocyte sticking was not downregulated by the antibody treatment. CONCLUSION: Leukocyte recruitment plays an essential role in the permeability-enhancing effect of PDT.

An unusual uterine tumour with signet ring cell features

Objective: Lymphomas with signet ring cell features are rare, as is uterine dissemination of lymphomas. We report an exceptional case of a uterine tumor combining these two characteristics. Method: A 61-year-old female was diagnosed in 2004 with localized nodal grade 2 follicular lymphoma (stage IA). She received local radiation therapy, experienced total remission, and did well until 2009 when a systematic CT scan evidenced a pelvic anterior-lateral mass. Total enlarged hysterectomy was performed. Results: The anterior uterine wall contained a 4.8-cm fish flesh well-delineated mass corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells with extensive signet ring cell changes. Tumor cells were CD20-, CD10-, Bcl2-, and Bcl6-positive with a low proliferation rate (<10-15%); CD21 underlined a focal follicular architecture. The vacuoles were PAS-negative and did not stain for immunoglobulin; ultrastructural analysis revealed nonspecific degenerative vacuoles. No lymph nodes were identified isolated from the surgical specimen. The tumor was considered as a secondary localization of the systemic follicular lymphoma, though no signet ring cells were evidenced in the cervical lymph node biopsy (reviewed). Follow-up showed retroperitoneal tissue infiltration (PET-CT) and normal medullar biopsy. She recently started R-CHOP chemotherapy. Conclusion: This case illustrates both an unusual site of dissemination and challenging cytological characteristics in a follicular lymphoma. The signet ring cell changes challenged the adequate classification of this lymphoma as either a large B cell or a follicular B cell lymphoma.

Patterns of extraocular muscle weakness in vasculopathic pupil-sparing, incomplete third nerve palsy.

OBJECTIVE: To determine the pattern of extraocular muscle (EOM) paresis in incomplete vasculopathic third nerve palsies (3NP) that have normal pupillary function. METHODS: A retrospective study in a private practice and academic neuro-ophthalmic practice. Patients diagnosed with vasculopathic 3NP within 4 weeks of symptom onset were identified. The chart of each patient was reviewed to determine pupillary function and the pattern and degree of EOM and levator palpebrae paresis at the time of presentation. RESULTS: Of 55 patients with vasculopathic 3NP, 42 (76%) had normal pupillary function. Of these 42, 23 (55%) demonstrated an incomplete EOM palsy, defined as partially reduced ductions affecting all third nerve-innervated EOMs and levator (diffuse pattern) or partially reduced ductions that involved only some third nerve-innervated EOMs and levator (focal pattern). Twenty (87%) of these 23 patients showed a diffuse pattern of paresis; only three (13%) showed a focal pattern of paresis, one that affected only the superior rectus and levator muscles (superior division weakness). CONCLUSIONS: Based on our series, most patients with EOM/levator involvement in pupil-sparing, incomplete 3NP of vasculopathic origin have a diffuse pattern of paresis. In contrast, our review of the literature suggests that pupil-sparing 3NP of aneurysmal origin usually have a focal pattern of paresis. We propose that distinguishing these two patterns of EOM paresis may be helpful in differentiating between vasculopathic and aneurysmal 3NP. Future studies will be needed to confirm the clinical utility of this hypothesis.

Cerebral vasculitis complicating postoperative meningitis: the role of steroids revisited.

Meningitis due to Streptococcus pneumoniae is a rare complication of trans-sphenoidal surgery. We present the case of a patient who developed pneumococcal meningitis with associated bacteraemia after elective endoscopic trans-sphenoidal resection of a pituitary macro-adenoma. After initial treatment with ceftriaxone and dexamethasone, the patient made a good recovery and dexamethasone was discontinued. Two days later the patient's condition deteriorated rapidly, presenting focal and diffuse neurological deficits. Cerebral MRI revealed widespread punctate ischaemic-type lesions affecting both anterior and posterior vascular territories bilaterally and involving features consistent with cerebral vasculitis. Antibiotic treatment was broadened to include meropenem and dexamethasone was restarted, but the patient remained in a comatose state and died 14 days later. Steroid treatment may play a dual role in this poorly characterised infectious complication of trans-sphenoidal pituitary surgery. This possibility is discussed and the options for prophylaxis are reviewed.

The small RNA PhrS stimulates synthesis of the Pseudomonas aeruginosa quinolone signal.

Quorum sensing, a cell-to-cell communication system based on small signal molecules, is employed by the human pathogen Pseudomonas aeruginosa to regulate virulence and biofilm development. Moreover, regulation by small trans-encoded RNAs has become a focal issue in studies of virulence gene expression of bacterial pathogens. In this study, we have identified the small RNA PhrS as an activator of PqsR synthesis, one of the key quorum-sensing regulators in P. aeruginosa. Genetic studies revealed a novel mode of regulation by a sRNA, whereby PhrS uses a base-pairing mechanism to activate a short upstream open reading frame to which the pqsR gene is translationally coupled. Expression of phrS requires the oxygen-responsive regulator ANR. Thus, PhrS is the first bacterial sRNA that provides a regulatory link between oxygen availability and quorum sensing, which may impact on oxygen-limited growth in P. aeruginosa biofilms.

The diagnostic dilemma of hyperintense fetal lung on prenatal MRI : 12.03

Purpose: In the last years, MRI appears as a complementary diagnostic method to US in the diagnosis of congenital lung lesions. Focal homogeneous pulmonary hyperintensity on T2-WI constitutes a frequent pattern observed. Our purpose is to determine if this finding is associated with a characteristic pulmonary lesion. Materials and methods: Between 01.01.00 and 31.12.07, a total of 50 prenatal MRI in fetuses with echographic diagnosis of thoracic pathology were performed in our institution, including 12 cases of suspected congenital pulmonary lesions. Prenatal images were correlated with post-natal diagnosis. Results: In 12 cases, fetal MRI detected congenital pulmonary lesions. In 8 patients, typical signs (cystic lesions, septations, anomalous vasculature) clearly suggested a specific pathology. In 4 cases, MRI showed a focal homogeneous increase of the signal intensity (SI) on T2-WI of the pathologic lung related to the normal one. The final diagnosis of these fetuses included 1 patient with congenital cystic adenomatoid malformation type III, 1 patient with segmental emphysema and 2 cases of bronchial atresia. In all 4 cases, a significant post-natal reduction of the lesion size related to prenatal MRI studies was observed. Conclusion: Our study suggests that a focal increment of the SI of the lung on T2-WI is a non specific sign of congenital lung disease, present in different pathologies. Therefore, a prospective diagnosis is not possible.

Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor.

TAT-RasGAP317-326, a peptide corresponding to the 317-326 sequence of p120 RasGAP coupled with a cell-permeable TAT-derived peptide, sensitizes the death response of various tumor cells to several anticancer treatments. We now report that this peptide is also able to increase cell adherence, prevent cell migration and inhibit matrix invasion. This is accompanied by a marked modification of the actin cytoskeleton and focal adhesion redistribution. Interestingly, integrins and the small Rho GTP-binding protein, which are well-characterized proteins modulating actin fibers, adhesion and migration, do not appear to be required for the pro-adhesive properties of TAT-RasGAP317-326. In contrast, deleted in liver cancer-1, a tumor suppressor protein, the expression of which is often deregulated in cancer cells, was found to be required for TAT-RasGAP317-326 to promote cell adherence and inhibit migration. These results show that TAT-RasGAP317-326, besides its ability to favor tumor cell death, hampers cell migration and invasion.