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D Rigamonti

Publications and source records attributed to D Rigamonti.

At least 19 recordsLinked to original sources
PubMed2004

Apoptosome inactivation rescues proneural and neural cells from neurodegeneration.

Deficiency of the apoptosome component Apaf1 leads to accumulation of supernumerary brain cells in mouse embryos. We observed that neural precursor cells (NPCs) in Apaf1(-/-) embryos escape programmed cell death, proliferate and retain their potential to differentiate. To evaluate the circumstances of Apaf1(-/-) NPC survival and investigate their fate under neurodegenerative conditions, we established cell lines of embryonic origin (ETNA). We found that Apaf1(-/-) NPCs resist common apoptotic stimuli and neurodegenerative inducers such as amyloid-beta peptide (typical of Alzheimer's disease) and mutant G93A superoxide dismutase 1 (typical of familial amyotrophic lateral sclerosis). Similar results were obtained in Apaf1(-/-) primary cells. When death is prevented by Apaf1 deficiency, cytochrome c is released from mitochondria and rapidly degraded by the proteasome, but mitochondria remain intact. Under these conditions, neither activation by cleavage of initiator caspases nor release of alternative apoptotic inducers from mitochondria takes place. In addition, NPCs can still differentiate, as revealed by neurite outgrowth and expression of differentiation markers. Our findings imply that the mitochondrion/apoptosome pathway is the main route of proneural and neural cells to death and that its inhibition prevents them from dismantling in neurodegenerative conditions. Indeed, the ETNA cell model is ideally suited for exploring the potential of novel cell therapies for the treatment of human neurodegenerations.

Amyloid beta-Peptides↗
PubMed2004

Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache.

The aim of the present study was to report on the utility of continuous Pcsf monitoring in establishing the diagnosis of idiopathic intracranial hypertension without papilledema (IIHWOP) in chronic daily headache (CDH) patients. We report a series of patients (n = 10) with refractory headaches and suspected IIHWOP referred to us for continuous Pcsf monitoring between 1991 and 2000. Pcsf was measured via a lumbar catheter and analysed for mean, peak, highest pulse amplitude and abnormal waveforms. A 1-2 day trial of continuous controlled CSF drainage (10 cc/ h) followed Pcsf monitoring. Response to CSF drainage was defined as improvement in headache symptoms. Patients with abnormal waveforms underwent a ventriculoperitoneal (VPS) or lumboperitoneal (LPS) shunt insertion. All patients had normal resting Pcsf (8 +/- 1 mmHg) defined as ICP < 15 mmHg. During sleep, all patients had B-waves and 90% had plateau waves or near plateau waves. All patients underwent either a VPS or LPS procedure. All reported improvement of their headache after surgery. Demonstration of pathological Pcsf patterns by continuous Pcsf monitoring was essential in confirming the diagnosis of IIHWOP, and provided objective evidence to support the decision for shunt surgery. Increased Pcsf was seen mostly during sleep and was intermittent, suggesting that Pcsf elevation may be missed by a single spot-check LP measurement. The similarity between IIHWOP and CDH suggests that continuous Pcsf monitoring in CDH patients may have an important diagnostic role that should be further investigated.

Adult↗
PubMed2002

Low pressure hydrocephalus and ventriculomegaly: hysteresis, non-linear dynamics, and the benefits of CSF diversion.

Low pressure hydrocephalus (LPH) is a rare clinical condition. We report our experience with 10 patients treated at the Johns Hopkins Hospital. We reviewed the records of 10 patients (five men, five women; mean age 43 years) treated between 1996 and 2000. All underwent intracranial pressure (ICP) monitoring and subatmospheric cerebrospinal fluid (CSF) drainage with an intraventricular or lumbar catheter. All patients developed ventriculomegaly: five following aneurysmal subarachnoid haemorrhage; one after meningitis; one after intraventricular haemorrhage. Three patients presented with chronic aqueductal stenosis. Ventriculomegaly was clinically detected on average 12 days after presentation. Mean ICP was 4.8 mmHg (range 0-10). All patients improved only in the setting of negative pressure CSF drainage, and were subsequently treated with low pressure ventriculo- or lumboperitoneal shunts. At 1 year, eight patients (80%) showed good recovery to minimal disability; seven patients (70%) had resolving ventriculomegaly. The mechanism of low pressure hydrocephalus remains unclear. In our cohort, different aetiologies were responsible for the change in compliance/elastance of the brain parenchyma and subsequent development of ventriculomegaly. We propose that while ventriculomegaly (and therefore neuronal dysfunction) can be initiated in the setting of high ICP, the maintenance of ventriculomegaly at normal or low ICP is a physiological example of hysteresis. This behaviour, which has been characterized by the chaos theory of non-linear dynamics as a Hopf bifurcation, explains how a system can exhibit two different states (ventricular size) at a single parameter value (ICP). Most importantly, it helps to explain how lowering ICP in the setting of LPH can resolve ventriculomegaly and its neurologic sequelae.

Adult↗
PubMed2001

Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a common autosomal dominant disorder characterized by venous sinusoids that predispose to intracranial hemorrhage. CCM is genetically heterogeneous, with loci at 7q, 7p and 3q. Mutations in KRIT1 account for all cases linked to 7q (CCM1), but the pathogenesis of CCM is not understood. Krev Interaction Trapped 1 (krit1) was originally identified through its interaction with the Ras-family GTPase krev1/rap1a in a two-hybrid screen, inferring a role in GTPase signaling cascades. We demonstrated additional 5'-coding exons for krit1, extending the N-terminus by 207 amino acids compared to the previously reported protein. Remarkably, by two-hybrid analysis and co-immunoprecipitation, full-length krit1 fails to interact with krev1/rap1a but shows strong interaction with integrin cytoplasmic domain-associated protein-1 (icap1). Icap1 binds to a NPXY motif in the cytoplasmic domain of beta1 integrin and participates in beta1-mediated cell adhesion and migration. The novel N-terminus of krit1 contains a NPXY motif that it is required for icap1 interaction. Like beta1 integrin, krit1 interacts with the 200 amino acid isoform of icap1 (icap1alpha), but not a 150 amino acid form that results from alternative splicing (icap1beta). In a competition assay, induced expression of krit1 diminishes the interaction between icap1alpha and beta1 integrin. Taken together, these data suggest that beta1 integrin and krit1 compete for the same site on icap1alpha, perhaps constituting a regulatory mechanism. Loss-of-function KRIT1 mutations, as observed in CCM1, would shift the balance with predicted consequences for endothelial cell performance during integrin beta1-dependent angiogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.

Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD.

3T3 Cells↗
PubMed2001

Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing.

Huntington's Disease is an inherited neurodegenerative disease that affects the medium spiny neurons in the striatum. The disease is caused by the expansion of a polyglutamine sequence in the N terminus of Huntingtin (Htt), a widely expressed protein. Recently, we have found that Htt is an antiapoptotic protein in striatal cells and acts by preventing caspase-3 activity. Here we report that Htt overexpression in other CNS-derived cells can protect them from more than 20 days exposure to fatal stimuli. In particular, we found that cytochrome c continues to be released from mitochondria into the cytosol of cells that overexpress normal Htt. However, procaspase-9 is not processed, indicating that wild-type Htt (wtHtt) acts downstream of cytochrome c release. These data show that Htt inhibits neuronal cell death by interfering with the activity of the apoptosome complex.

Apoptosis↗
PubMed2001

ST14A cells have properties of a medium-size spiny neuron.

The ST14A cell line was previously derived from embryonic day 14 rat striatal primordia by retroviral transduction of the temperature-sensitive SV40 large T antigen. We showed that cell division and expression of nestin persists at 33 degrees C, the permissive temperature, whereas cell division ceases, nestin expression decreases, and MAP2 expression increases at the nonpermissive temperature of 39 degrees C. In this study, we further characterized the cells and found that they express other general and subtype-specific neuronal characteristics. ST14A cells express enolase and beta III-tubulin. Furthermore, they express the striatal marker DARPP-32, which is up-regulated upon differentiation of the cells by growth in serum-free medium. Stimulation with dopamine, the D2-dopamine receptor agonist quinpirole, or the D1-dopamine receptor agonist SKF82958 results in phosphorylation of CREB. Treatment of the cells with a mixture of reagents which stimulate the MAPK and adenylyl cyclase pathways radically changes the morphology of the ST14A cells. The cells develop numerous neurite-like appearing processes which stain with beta III-tubulin. Moreover, under these conditions, intracellular injection of rectangular depolarizing current stimuli elicits overshooting action potentials with a relatively fast depolarization rate when starting from a strongly hyperpolarized membrane potential. Taken together, these data imply that the ST14A cell line displays some of the characteristics of a medium-size spiny neuron subtype and provides a new tool to elucidate the pathways and molecules involved in medium-size spiny neuron differentiation and disease.

Action Potentials↗
PubMed2001

Loss of normal huntingtin function: new developments in Huntington's disease research.

Huntington's disease is characterized by a loss of brain striatal neurons that occurs as a consequence of an expansion of a CAG repeat in the huntingtin protein. The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the protein. Analysis of the mutant protein has attracted most of the research activity in the field, however re-examination of earlier data and new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology. Thus, complete elucidation of the physiological role(s) of huntingtin and its mode of action are essential and could lead to new therapeutic approaches.

Animals↗
PubMed2001

Shc signaling in differentiating neural progenitor cells.

Previously we found that the availability of ShcA adapter is maximal in neural stem cells but that it is absent in mature neurons. Here we report that ShcC, unlike ShcA, is not present in neural stem/progenitor cells, but is expressed after cessation of their division and becomes selectively enriched in mature neurons. Analyses of its activity in differentiating neural stem/progenitor cells revealed that ShcC positively affects their viability and neuronal maturation via recruitment of the PI3K-Akt-Bad pathway and persistent activation of the MAPK pathway. We suggest that the switch from ShcA to ShcC modifies the responsiveness of neural stem/progenitor cells to extracellular stimuli, generating proliferation (with ShcA) or survival/differentiation (with ShcC).

Adaptor Proteins, Signal Transducing↗
PubMed2001

Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease.

OBJECTIVE: The presentation, screening, management, and clinical outcomes of patients who presented to our institution from 1973 to 1999 with central nervous system (CNS) hemangioblastomas in von Hippel-Lindau (VHL) syndrome and sporadic disease were analyzed. METHODS: The surgical pathology database of our institution was searched to identify all patients with histologically verified CNS hemangioblastomas occurring from 1973 to 1999. The medical, radiological, surgical, pathological, and autopsy records from these patients were reviewed retrospectively and statistically analyzed. RESULTS: Forty patients (21 males and 19 females) presented with CNS hemangioblastomas. Twenty-five patients (62%) harbored sporadic hemangioblastomas. Fifteen patients (38%) had VHL syndrome. These 40 patients presented with 61 hemangioblastomas (8 patients had multiple lesions). Ten patients (25%) harbored spinal cord hemangioblastomas (5 patients had multiple lesions). Patients with VHL disease tended to present with neurological symptoms and signs at a younger age than patients with sporadic disease (P = 0.09), to present with multiple lesions (53%), and to develop new lesions (rate, 1 lesion/2.1 yr). Hemangioblastomas of the spinal cord were more prevalent in patients with VHL syndrome (P = 0.024). Neuroradiological screening of patients with VHL syndrome allowed identification of more than 75% of new lesions before they became symptomatic. Sixty-six surgical procedures were performed (12 patients required multiple operations). Six patients with VHL syndrome required surgery for new lesions. Surgical complications occurred in six patients (15%). Symptom resolution or arrest of progression at 1 year was documented in 88% of patients. Recurrence of symptoms from partially resected lesions occurred in eight patients (20%). No deaths associated with surgery occurred. One patient with sporadic disease and one patient with VHL syndrome (5%) died as a result of late medical complications from CNS hemangioblastomas. CONCLUSION: Surgical outcomes for patients with CNS hemangioblastomas are favorable. However, management of hemangioblastomas is a more difficult and prolonged endeavor for patients with VHL syndrome. In patients with VHL syndrome, neuroradiological screening allows identification of lesions before they become symptomatic. Because patients with VHL syndrome are at risk for development of new lesions, they require lifelong follow-up.

Adolescent↗
PubMed2001

Superficial siderosis associated with multiple cavernous malformations: report of three cases.

OBJECTIVE AND IMPORTANCE: Superficial siderosis is a rare but potentially devastating syndrome caused by recurrent subarachnoid hemorrhage. We present three cases of superficial siderosis associated with multiple cavernous malformations, and we review previous reports of superficial siderosis attributable to vascular malformations. CLINICAL PRESENTATION: Patients most commonly present with progressive sensorineural hearing loss, cerebellar ataxia, and pyramidal signs. Magnetic resonance imaging diagnosis may precede symptom development, however. In two of our cases, superficial siderosis was identified on magnetic resonance imaging scans in the absence of clinical symptoms. INTERVENTION: Magnetic resonance imaging studies revealed hemosiderin deposition, characteristic of superficial siderosis, and multiple cavernous malformations in all three cases. Surgical intervention was not pursued. CONCLUSION: We conclude that patients with multiple cavernous malformations and those with perisubarachnoid lesions are at risk for the development of superficial siderosis. Clinicians should recognize the radiographic appearance of superficial siderosis and its clinical presentation in patients with vascular malformations.

Adult↗
PubMed2001

The nature and fate of punctate (type IV) cavernous malformations.

OBJECTIVE: Four types of cavernous malformations (Types I-IV) have been described on the basis of their magnetic resonance imaging (MRI) appearance. The nature of the Type IV cavernous malformation is unclear. It has been suggested that these small lesions, which are well observed only on gradient echo MRI scans, are capillary telangiectasias. We sought to understand the relationship of Type IV cavernous malformations to the other cavernous malformation subtypes. METHODS: We examined serial MRI scans obtained between 1987 and 2000 from 68 patients with more than 228 cavernous malformations. Sixteen patients harbored Type IV cavernous malformations (total, >114 Type IV lesions). Spin echo T1-weighted, T2-weighted, proton density, and (when available) gradient echo MRI scans were reviewed. Cavernous malformations that met the Zabramski criteria for Type IV (poorly observed on T1- and T2-weighted images) were reviewed in serial scans from individual patients to characterize their radiographic behavior over time. RESULTS: Type IV cavernous malformations were best observed on gradient echo images and have an MRI appearance distinct from capillary telangiectasias. Proton density images demonstrate more Type IV lesions than T1- and T2-weighted images, but far fewer Type IV lesions than gradient echo images. When observed on T1- and T2-weighted images, Type IV cavernous malformations are generally punctate and hypointense. These lesions rarely enhance with gadolinium. Four of the Type IV cavernous malformations observed serially evolved into Type I and Type II cavernous malformations, for an approximate rate of progression of 0.05 per patient year. CONCLUSION: Although most Type IV cavernous malformations remain stable over time, a small subset of these lesions progress into Types I and II cavernous malformations.

Cavernous Sinus↗
PubMed2001

Blood clot resolution in human cerebrospinal fluid: evidence of first-order kinetics.

OBJECTIVE: To determine the kinetics of blood clot resolution in human cerebrospinal fluid. METHODS: Computed tomographic scans of 17 adult patients with intraventricular hemorrhages were analyzed. Intraventricular clot volume was determined and analyzed over time to determine both a standardized percentage rate and an absolute rate of clot resolution. Results were analyzed by use of regression for cross sectional time-series data. To determine the kinetics of intraventricular clot resolution, the effect of the clot volume on the percentage rate of clot resolution, clot half-life, and absolute rate of clot resolution was analyzed. The potential effect of age, sex, type of hemorrhage, and treatment with external ventricular drainage on the percentage rate of clot resolution was assessed. RESULTS: The percentage rate of clot resolution was 10.8% per day (95% confidence interval, 9.05-12.61 %), and it was independent of initial clot volume, age, sex, type of underlying hemorrhage, and use of external ventricular drainage. The absolute rate of clot resolution varied directly with the maximal clot volume (R2 = 0.88; P < 0.001). The percentage clot resolution data are consistent with events during the first 24 to 48 hours that antagonize clot resolution. CONCLUSION: These findings demonstrate that intraventricular blood clot resolution in patients with intraventricular hemorrhage follows first-order kinetics. The thrombolytic enzyme system responsible for intraventricular clot resolution seems to be saturated at 24 to 48 hours after the initial hemorrhage.

Adult↗
PubMed2001

The juxtaposition of a capillary telangiectasia, cavernous malformation, and developmental venous anomaly in the brainstem of a single patient: case report.

OBJECTIVE AND IMPORTANCE: Capillary telangiectasias, cavernous malformations, and developmental venous anomalies are all vascular malformations that occur on the capillary-venous side of the cerebral circulation. The associations of capillary telangiectasias with venous malformations, cavernous malformations with venous malformations, and capillary telangiectasias with cavernous malformations have all been described; however, the association of all three lesions in a single patient is extremely rare. CLINICAL PRESENTATION: A 52 year-old Caucasian woman presented to our clinic with an extended history of confusion, distorted visual perceptions, photophobia, neck pain, swallowing problems, and poor balance. The patient's examination was remarkable for difficulty concentrating, mild rotatory nystagmus, subtle decreased sensation over the left side of the face and body, and brisk reflexes. Review of the patient's magnetic resonance imaging examination demonstrated a cavernous malformation, a capillary telangiectasia, and a developmental venous anomaly located adjacent to one another in the brainstem. INTERVENTION: Given the patient's complex constellation of symptoms and relatively mild neurological findings, it was difficult to ascribe any one of them to a specific vascular malformation. Conservative management of this patient's vascular malformations was decided upon. CONCLUSION: Juxtaposition of these three different vascular lesions in the brainstem of an otherwise normal individual suggests a relationship among them. Although there are several theories that link similar associations through physiological mechanisms such as venous hypertension, we propose that a developmental event disrupting local capillary-venous pattern formation is a plausible alternative.

Brain Stem↗
PubMed2001

Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations.

OBJECTIVES: Cerebral cavernous malformations are linked to mutations of the KRIT1 gene at the CCM1 locus and to mutations at two other loci, CCM2 and CCM3, for which genes are not yet identified. There is little information regarding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiology. METHODS: Morphological analysis of cavernous malformations was extended to the ultrastructural level by examining lesions from two patients by immunocytochemistry and electron microscopy. RESULTS: The lesions consisted of endothelial lined vascular sinusoids embedded in a collagen matrix. Nuclei belonging to cells distinct from endothelial cells were rare. The basal lamina of the endothelial cells consisted focally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstrated apparent gaps between endothelial cell processes where basal lamina was exposed directly to the lumen of the sinusoids. Heavy hemosiderin deposits were found underlying the vascular channels within microns of the basal lamina without evidence of disrupted vessels. No astrocytic foot processes were seen within lesions. Glial fibrillary acidic protein immunocytochemistry confirmed that astrocyte processes stopped at the border of the lesions. CONCLUSIONS: The absence of blood-brain barrier components may lead to leakage of red blood cells into these lesions and the surrounding brain in the absence of major haemorrhage, thus accounting for the propensity of cavernous malformations to cause seizures. These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype.

Adult↗
PubMed2001

Ventriculopleural shunt obstruction and positive-pressure ventilation. Case report.

The authors report an unusual case of a patient with low-pressure hydrocephalus and a ventriculopleural shunt, in whom routine respiratory management performed using positive-pressure ventilation caused shunt obstruction and coma. While the patient received positive-pressure ventilation with external cerebrospinal fluid (CSF) drainage at subatmospheric pressure, the ventricles returned to normal size and the coma rapidly reversed. After the authors' recognition of the effect of positive-pressure ventilation on intrapleural pressure and ventriculopleural shunt function, and the subsequent removal of positive-pressure ventilation, CSF flow through the shunt resumed and the patient's coma resolved.

Cerebrospinal Fluid Shunts↗