Biomedical subjects

Seth Love

Publications and source records attributed to Seth Love.

27 records · Page 2Linked to original sources

PubMed2003

Retrograde reactions of Clarke's nucleus neurons after human spinal cord injury.

Successful axon regeneration depends on the expression of regeneration-associated genes by axotomized neurons. Here, we demonstrate, for the first time to our knowledge, the expression of regeneration-associated genes by axotomized human CNS neurons. In situ hybridization and immunohistochemistry showed a transient induction of GAP-43 and c-jun in Clarke's nucleus neurons caudal to traumatic human spinal cord injury. These results support experimental data that nonregenerating central nervous system neurons can temporarily upregulate regeneration-associated genes, reflecting a transient regenerative capacity that fails over time.

Caspase 3↗

PubMed2003

Apoptosis and brain ischaemia.

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.

Animals↗

PubMed2003

Unilateral subthalamotomy in the treatment of Parkinson's disease.

Hyperactivity in the subthalamic nucleus (STN) is seen in animal models of Parkinson's disease, and lesioning of the STN dramatically relieves the animal's parkinsonism. Deep brain stimulation (DBS) of the STN is an effective treatment for patients with advanced Parkinson's disease. We have studied the effects of a unilateral lesion placed in the STN in predominantly hemi-parkinsonian patients. Twenty-one patients with advanced idiopathic Parkinson's disease were studied. Seventeen had asymmetrical tremor-dominant Parkinson's disease and four had bilateral disease. All patients underwent radiofrequency lesioning of the dorsolateral part of the STN under stereotactic guidance. The four patients with bilateral disease had, in addition, an electrode implanted contralaterally in the STN. Twenty-one patients have been followed for a minimum of 12 months. Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgery. Post-operative high-resolution MRI was performed in each patient to confirm lesion location, and this was correlated with clinical outcome. There was improvement in contralateral tremor, rigidity and bradykinesia in all patients followed for 6, 12 and 24 months, with the effect on tremor being greatest. L-dopa equivalent daily intake was approximately halved, and this resulted in a significant reduction in dyskinesia. Psychometric test scores were mostly unchanged or improved. All lesions were successfully located in the dorsolateral STN. Nineteen of the 21 lesions extended beyond the STN to involve pallidofugal fibres (H2 field of Forel) and the zona incerta (ZI). Lesion-induced dyskinesias were not a management problem except in one patient, whose lesion was confined to the STN. This patient was successfully treated with deep brain stimulator placement in the region of H2/ZI. Unilateral STN lesions can be made safely and are an effective alternative to thalamotomy, pallidotomy and unilateral STN DBS for the treatment of asymmetrical tremor-dominant advanced Parkinson's disease. Com bined lesioning of the dorsolateral STN and H2/ZI is particularly effective.

Antiparkinson Agents↗

PubMed2003

Posthemorrhagic ventricular dilation in the neonate: development and characterization of a rat model.

Intraventricular hemorrhage is a common complication of prematurity. Posthemorrhagic ventricular dilation (PHVD) has a high rate of disability and no safe and effective treatment. Its pathogenesis is poorly understood, largely because of the lack of a satisfactory animal model. We have developed a model of neonatal PHVD in the rat. Seven-day-old (P7) Wistar rat pups were given 80-microl injections of citrated rat blood or artificial cerebrospinal fluid (CSF) into alternate lateral ventricles on P7 and P8. Intracranial pressure was monitored and increased briefly by over 8-fold. Some rats received further 10-microl intraventricular injections of India ink on P21. Animals were weighed daily and simple neurologic tests performed. On P21 (or P22 if India ink had been injected), the rats were perfusion-fixed and blocks processed for paraffin histology. Sixty-five percent of pups injected with blood and 50% injected with artificial CSF developed dilated lateral ventricles, with patchy loss of ependyma, marked astrocytic gliosis, and rarefaction of periventricular white matter. India ink injection revealed slow transit of CSF from the dilated lateral ventricles but eventual passage into the subarachnoid space. Pups that had received intraventricular injections but did not develop ventricular dilation nonetheless had lighter brains than littermate controls (p < 0.001). Body weights were not significantly different from controls. Hydrocephalic animals had reduced motor performance as assessed by a grip traction test (p = 0.0002). This model is well suited to studying the pathogenesis of PHVD.

Animals↗

PubMed2003

Familial idiopathic brain calcification--a new and familial alpha-synucleinopathy?

Familial idiopathic brain calcification (FIBC) is a rare disorder characterised by autosomal dominant transmission, adult onset cerebellar and/or extrapyramidal features and idiopathic calcification of the brain. We present a family with FIBC where pathological studies showed that the proband had alpha-synuclein-immunopositive glial and neuronal cytoplasmic inclusions in oligodendrocytes in the putamen, midbrain and pons. This may represent a new and familial alpha-synuclein disorder causing a predominantly extrapyramidal picture similar to multisystem atrophy.

Adolescent↗

PubMed2003

Expression of mos in ependymal gliomas.

The c-mos gene and its protein product mos, components of the mitogen-activated protein kinase transduction pathway, are known to be involved in the control of meiosis and mitosis. Apart from our previous studies on lung carcinomas and astrocytic gliomas, little has been published about its role in human neoplasia. The aim of this study was to investigate the expression of mos in ependymal neoplasms and to correlate it with tumor grade, proliferative fraction, and clinical behavior. We studied mos expression in biopsy specimens from 34 patients with ependymomas. Intracytoplasmic immunopositivity for mos was found in 16 (47%) and was associated significantly with tumor grade: 5 (24%) of 21 grade II ependymomas; 11 (85%) of 13 grade III anaplastic ependymomas (P < .01). Tumors with an MIB-1 labeling index of more than 4% were significantly more likely than those with a lower proliferative fraction to be immunopositive for mos (P = .012). Expression of mos showed a significant negative association with recurrence-free interval (P = .05) but not with overall survival. Our results suggest that overexpression of mos identifies a biologically aggressive subgroup of ependymal tumors and may be involved in their neoplastic progression.

Adolescent↗

PubMed2002

Expression of mos in astrocytic tumors and its potential role in neoplastic progression.

The c-mos gene and its protein product mos, components of the mitogen-activated protein kinase transduction pathway, are known to be involved in the control of meiosis and mitosis. Apart from a study on lung carcinomas, there is little information about its role in human neoplasia. The aim of this study was to investigate expression of mos in astrocytic tumors and to correlate it with accumulation of p53. We studied expression of mos in 62 cases of supratentorial astrocytic tumor. Intracytoplasmic immunostaining for mos was found in 28 (45%) cases: 3 of 20 (15%) grade 2 astrocytomas, 9 of 20 (45%) grade 3 anaplastic astrocytomas, and 16 of 22 (73%) glioblastomas. Immunopositivity for mos correlated significantly (P < 0.01) with tumor grade but not with p53 expression. In contrast to the findings in relation to lung tumors, immunopositivity for mos in astrocytic tumors did not predict recurrence-free or overall survival time. Cytoplasmic immunostaining was observed in scattered large cortical neurons adjacent to tumors, possibly due to stress-induced abortive entry into the cell cycle. The correlation of mos immunopositivity with tumor grade may reflect the expansion of more malignant mos-positive clones. This study provides evidence that mos may be involved in the neoplastic progression of a proportion of astrocytic tumors.

Adolescent↗

PubMed2002

Evaluation of molecular markers in low-grade diffuse astrocytomas: loss of p16 and retinoblastoma protein expression is associated with short survival.

Diffuse astrocytomas have a median survival of 6-8 years. However, in a minority of cases that are histologically low grade, progression is rapid, leading to death within 2 years. Loss of p16, retinoblastoma protein, and deleted-in-colon-carcinoma protein expression, and monosomy of chromosome 10 have been shown to occur in malignant astrocytic tumors. We have investigated the prognostic value of expression of these markers, using techniques applicable in many histopathology laboratories, in diffuse astrocytomas that are histologically low grade. Paraffin sections from 71 diffuse, supratentorial, low-grade astrocytomas, from patients with at least 8-year survival data, were immunostained with antibodies to p16, deleted-in-colon-carcinoma protein, p53, Ki67, and retinoblastoma protein. In situ hybridization with a digoxigenin-labeled probe to chromosome 10 was used to assess chromosomal loss. In most cases there was immunostaining of virtually all tumor cell nuclei with antibodies to p16 and retinoblastoma protein. Three of the 68 tumors in which assessment of p16 was possible included discrete foci with lack of detectable immunoreactivity in tumor cells. The three patients concerned had a significantly shortened median survival (1.1 years vs 4.4 years in those without loss of p16; p <0.01). In six of the 61 cases where assessment of retinoblastoma protein was possible, <70% of tumor cell nuclei showed immunoreactivity. These six patients had a shorter survival (4.0 years) than had the remaining patients (5.4 years), although this difference was not statistically significant. The tumor from one of these patients included areas where only 36% of tumor cells showed retinoblastoma protein immunoreactivity, and this patient survived only 1.5 years. Tumors showing loss of both p16 and retinoblastoma were not seen. p53 and deleted-in-colon-carcinoma protein expression was highly variable and did not correlate with survival. Tumors with monosomy for chromosome 10 were not identified. Both polyploidy and the Ki67 labeling index were significantly associated with the p53 labeling index but not with survival. Focal loss of p16 or retinoblastoma protein is demonstrable in approximately 5% and 10% of diffuse low-grade diffuse astrocytomas, respectively. Tumors with focal loss of immunoreactivity for these proteins are associated with shorter survival than those without, suggesting that immunohistochemistry for p16 and retinoblastoma protein may be a useful adjunct to other methods for assessing the prognosis of astrocytomas.

Astrocytoma↗

PubMed2002

MRI-directed subthalamic nucleus surgery for Parkinson's disease.

The subthalamic nucleus (STN) is now regarded as the optimal surgical target for the treatment of medically refractory idiopathic Parkinson's disease. In our center, a predominantly MRI-directed method has been developed for targeting the STN. The STN is localized on T2-weighted images from a 1.5-T MRI scanner. Long acquisition, high-resolution images are acquired in both the axial and coronal planes under strict stereotactic conditions with the patient under general anesthesia. The boundary of STN is co-registered in both planes to give optimal 3-dimensional target definition. Stereotactic coordinates of the dorsolateral STN are recorded and the trajectory is planned down the axis of the nucleus in the coronal plane. Initially, per-operative macrostimulation was used for adjustment at the target prior to unilateral subthalamotomy in 26 patients. Five patients were lost to follow-up. Assessments of the lesions in post-operative images confirmed successful localisation of the lesions within the dorsolateral STN in all of the remaining 21 cases. In a subsequent series of 19 patients treated by deep brain stimulation (DBS), unilateral in 1 patient and bilateral in 18, the STN was targeted using the same MRI-directed method, guide tubes and radio-opaque stylettes were implanted, and target verification was entirely MRI-based. Following implantation of the guide tubes and stylettes, assessments of the per-operative MRI images for the 37 STN targetings confirmed a mean target error, between the stylette and the desired target in the axial plane, of 0.3 mm mediolaterally (SD = 0.4) and 0.4 mm anteroposteriorly (SD = 0.4), with median errors of 0.5 mm. This study demonstrates that MRI-directed targeting of the STN through guide tubes is accurate, and allows direct verification and corrections as necessary. Cumulative frequencies predict that the majority of DBS electrodes placed in this manner will be within 0.5 mm of the planned target. Because physiological methods are not required, the whole procedure can be performed under general anesthesia. We feel that planning with reference to a standard atlas is unreliable and not significantly helped by the addition of microelectrode recording, the accuracy of which in the axial plane is dependent upon the distance between the recording trajectories, which is typically 2 mm.

Electric Stimulation Therapy↗