The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. ...Development of this structure from neural crest begins
in utero
and continues into early adulthood. However, the anatomy of the murine inner ear has only been well-characterized from early embryogenesis to post-natal day 6. Inner ear and skull base development continue into the post-natal period in mice and early adulthood in humans. Traditional methods used to evaluate the inner ear in animal models, such as histologic sectioning or paint-fill and corrosion, cannot visualize this complex anatomy
in situ
. Further, as the petrous bone ossifies in the postnatal period, these traditional techniques become increasingly difficult. Advances in modern imaging, including high resolution Micro-CT and MRI, now allow for 3D visualization of the
in situ
anatomy of organs such as the inner ear. Here, we present a longitudinal atlas of the murine inner ear using high resolution
ex vivo
Micro-CT and MRI.
Non-Islet Origin of Pancreatic Islet Cell Tumors Vortmeyer, Alexander O; Huang, Steve; Lubensky, Irina ...
The journal of clinical endocrinology and metabolism,
2004-April, Letnik:
89, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The histogenesis of pancreatic islet cell tumors was investigated by morphological identification of putative precursor lesions in pancreatic tissue from patients with multiple endocrine neoplasia ...type 1 (MEN1), tissue microdissection, and genetic analysis. MEN1 mutation and absence of the MEN1 wild-type allele in different precursor lesions strongly suggest that pancreatic islet cell tumors are derived from the ductal/acinar system but not from pancreatic islet tissue. Pluripotent cells within the exocrine pancreas appear capable of formation into small atypical accumulations of MEN1-deficient cells with both exocrine and endocrine phenotype. The findings suggest presence of multiple developmental aberrations in MEN1 pancreas that potentially serve as precursor material for neuroendocrine tumors.
High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind ...anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.
Stroke is among the three leading causes of death worldwide and the most frequent cause of permanent disability. Brain ischemia induces an inflammatory response involving activated complement ...fragments. Here we show that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivation resulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis; both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke.
Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood-brain barrier (BBB). These ...features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine.
Dose-escalation toxicity studies were performed by perfusing the striatum (10 microl, 24 rats) and brainstem (10 microl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 microl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy. Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01).
The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.
Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not ...been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases.
This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure.
Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival.
Clinicaltrials.gov identifier: NCT03398694 (registration date: January 12, 2018).
Human herpesvirus-6 (HHV-6) is a beta-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active ...infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive-the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.
Brainstem pathology in spasmodic dysphonia Simonyan, Kristina; Ludlow, Christy L.; Vortmeyer, Alexander O.
The Laryngoscope,
01/2010, Letnik:
120, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Spasmodic dysphonia (SD) is a primary focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speech production. We examined two rare cases of ...postmortem brainstem tissue from SD patients compared to four controls. In the SD patients, small clusters of inflammation were found in the reticular formation surrounding solitary tract, spinal trigeminal, and ambigual nuclei, inferior olive, and pyramids. Mild neuronal degeneration and depigmentation were observed in the substantia nigra and locus coeruleus. No abnormal protein accumulations and no demyelination or axonal degeneration were found. These neuropathological findings may provide insights into the pathophysiology of SD. Laryngoscope, 2010
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological ...studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions. Ann Neurol 2005;57:687–694
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