Strategies for the design and delivery of antisense oligonucleotides in central nervous system.
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Animals↗
Biomedical subjects
S S Prabhu
Publications and source records attributed to S S Prabhu.
An in vivo rat model for visualizing glioma tumor cell invasion using stable persistent expression of the green fluorescent protein.
In our studies examining mechanisms of brain tumor cell migration/invasion into host tissue, the RT2 rat glioma cell line was stably transfected utilizing a green fluorescent protein (GFP) DNA construct. Stable transfected RT2 cells demonstrate high GFP expression at initial passages, maintain expression over 30 passages and have similar in vitro and in vivo growth patterns relative to controls. In rat brain tissue, individual tumor cells can be detected without any post-treatment. Using flow cytometry and cell sorting, we are able to retrieve and culture GFP positive cells from tumor core as well as adjacent tissue and contralateral hemisphere of tumor-bearing animals.
Animals↗
Distribution of macromolecular dyes in brain using positive pressure infusion: a model for direct controlled delivery of therapeutic agents.
BACKGROUND: Direct infusion of therapeutic agents into the brain is a novel technique that has the potential for bypassing the blood-brain barrier and delivering high concentrations of therapeutic agents into the brain parenchyma. We have developed a model to characterize the distribution of Evans Blue (MW 960) and Blue Dextran (MW 2 x 10(6)) in rat brain using a positive pressure infusion system. METHODS: Evans Blue and Blue Dextran were infused in volumes of 20, 40, 60, 100, 140, and 180 microL into the caudate putamen of female Fischer rats over a period of 2 h with rates of infusion varying between 0.167 microL and 1.5 microL/min. During the infusions, the pressure generated in the infusion system and intracranial pressure were measured using a fiberoptic pressure monitoring system. After infusions, the volumes of distribution of the dye molecules were measured from 3-mm thick sections using video microscopy and computer image analysis. Histologic changes during the infusion were studied using snap freezing and hematoxylin/eosin staining of cryosections. RESULTS: Volumes of distribution for Evans Blue were greater than those for Blue Dextran. There was extensive spread of each dye in the ipsilateral hemisphere and also across the corpus callosum to the opposite hemisphere. Infusion/interstitial pressures peaked during the first 5 min of the infusion period, after which pressures dropped to a plateau value that remained relatively constant during the remainder of the infusion. Histologic findings suggest that this phenomenon is an important transition process that is likely to play a role in the pattern of distribution of macromolecules infused by this technique. No marked changes in intracranial pressure were noted during the infusion procedure. CONCLUSIONS: Direct positive pressure infusion into the brain has great potential in the treatment of brain tumors and other central nervous system disorders using both high and low molecular weight compounds (immunotoxins, protein conjugates, pharmacologic agents, oligonucleotides, and viral vectors).
Animals↗
Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion.
OBJECT: High-flow microinfusion is a novel technique for delivery of compounds directly into brain parenchyma, bypassing the blood-brain barrier. The feasibility of this technique has been demonstrated with low-molecular-weight compounds, macromolecular dyes, and proteins. Delivery of antisense oligonucleotides into brain parenchyma represents an additional potential application of this technique not previously described. In this report the authors sought to examine the distribution and disposition of phosphorothioate oligodeoxynucleotide (PS-ODN) for this reason. METHODS: An 18-mer 35S-PS-ODN (Mr approximately 6000) was infused over 1 hour into the caudate putamen of Fischer 344 rats. At 1, 6, 12, 24, and 48 hours after beginning the infusion, the brains were extracted and analyzed using quantitative autoradiographic techniques. Cerebrospinal fluid (CSF) was also aspirated from the cisterna magna and was analyzed to determine the radioactivity and stability of the 35S-PS-ODN. At 1 hour, the infused ODN was uniformly distributed in brain tissue, with a maximum average concentration of 4806.5 +/- 210.5 nCi/g. This represents a tissue concentration of 19.2 +/- 0.84 microM. Extensive spread into surrounding parenchyma was observed over the ensuing 47 hours. The 35S-PS-ODN radioactivity peaked in the CSF at the end of the 1-hour infusion, containing 1% (50 +/- 20 nCi) of the infused radioactivity. Activity then decayed exponentially over 11 hours, but stabilized at a lower CSF content of 0.2% (1 +/- 0.1 nCi) thereafter. The volume of distribution was 105 +/- 7.9 mm3 at 1 hour, representing a volume of distribution/volume of infusion ratio of 5.2. The volume of distribution increased to 443 +/- 62.3 mm3 at the end of 48 hours, whereas the average minimum tissue concentration decreased from 15.2 microM to 3.2 microM. Undegraded 18-mer was observed throughout the 48-hour period by means of 20% polyacrylamide/7 M urea gel electrophoresis. The animals tolerated the infusion without evidence of toxicity and minimal structural changes in tissue were observed on histological investigation. CONCLUSIONS: The authors found that PS-ODNs can be safely delivered in high concentrations to wide areas of rat brain by using high-flow microinfusion and are stable even after 48 hours in situ.
Animals↗
Antiproliferative effect of c-myc antisense phosphorothioate oligodeoxynucleotides in malignant glioma cells.
OBJECTIVE: To improve the prognosis for primary malignant tumors of the central nervous system, new therapeutic strategies are needed. Antisense oligodeoxynucleotides (ODNs) offer the potential to block the expression of specific genes within cells. The proto-oncogene c-myc has long been implicated in the control of normal cell growth and its deregulation in the development of neoplasia. We therefore reasoned that a strategy using ODNs complementary to c-myc messenger ribonucleic acid would be a potent inhibitor of glioma cell proliferation. METHODS: A variety of antisense, sense, and scrambled (15-mer) phosphorothioate ODNs targeted to rat and human c-myc messenger ribonucleic acid were synthesized and added to the media of cultured RT-2 cells (a rat glioblastoma cell line). Cell growth was assessed by 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide dye assay 1 to 5 days after adding the ODNs. c-Myc protein expression was analyzed by Western blot analysis. The stability of the ODNs was confirmed by gel electrophoresis. RESULTS: Compared with cultures containing standard media, two of three antisense ODNs significantly inhibited the growth of glioma cells, whereas sense and scrambled sequence ODNs did not significantly affect cell growth at the concentrations tested. A human c-myc antisense sequence, which differed from the rat sequence by one base substitution, also had an inhibitory effect on RT-2 cells. Western blot analysis demonstrated that expression of immunoreactive c-Myc protein was also greatly reduced in the rat antisense ODN-treated cells (and not in sense-, scrambled-, or control-treated cells). The degree of reduction of c-Myc protein expression correlated well with the decrease in cell growth observed with several antisense ODNs. Phosphorothioate ODNs were stable in cell culture media for at least 5 days. CONCLUSION: These results suggest that c-Myc plays a critical role in glioma cell proliferation and demonstrate that antisense ODNs can suppress proto-oncogene expression and inhibit the proliferation of glioma cells. Our results indicate that the antiproliferative activity of these ODNs was mediated predominantly through sequence-specific antisense mechanisms, but that sequence-specific nonantisense effects may also contribute to the strongest effects demonstrated. These findings support a potential role for antisense strategies designed to inhibit c-myc expression in the treatment of malignant gliomas.
Animals↗
De novo development of saccular aneurysms: report of two cases.
The development of de novo aneurysms after previous successfully treated aneurysms is uncommon. If risk factors are not present the patient may be reassured that the risk of developing a further aneurysm following successful treatment is minimal. Two cases of second aneurysms developing six and eighteen years after successful treatment of a first aneurysm are reported. The risk factors associated with the formation of second aneurysms are emphasized.
Adult↗
A generalizable framework for information systems for physician recruitment/referral.
Hospital information systems have evolved from data processing systems for patient billing and payroll to decision-support systems which support decision making at the middle and upper management levels. With the advancements in the areas of database management, expert systems and networks, important hospital functions such as physician recruitment and referral which historically were performed using traditional procedures, are now performed using these computer-based technologies. Develops a generalizable framework for information systems for physician recruitment and referral using technologies of database management, expert systems and networks. This GIS-PRR system may be used by hospitals and other health-care providers to improve the efficiency and effectiveness of the physician recruitment/referral process.
Database Management Systems↗
Optochiasmal arachnoiditis induced by muslin wrapping of intracranial aneurysms. A report of two cases and a review of the literature.
Muslin wrapping of intracranial aneurysms has been used for many years, but muslin-induced optochiasmal arachnoiditis was first reported only in 1978, as a complication with catastrophic loss of vision. In this study of 54 cases wrapped with muslin over the last six years, two cases of optochiasmal arachnoiditis occurred. Three patients had early rebleeding among the 27 who had wrapping as the only treatment of the aneurysm.
Adult↗
Massive osteolysis--Gorham's syndrome.
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Child↗
Primary malignant non-Hodgkin's lymphoma of cranial vault: a case report.
Primary cranial vault non-Hodgkin's lymphomas are rare and only four such cases are described in the literature. A 65-year-old woman presented with focal neurological deficits and a subcutaneous scalp lump. Computed tomography (CT) scan showed a left parietal cranial vault lesion with soft tissue scalp swelling and underlying intracranial extra axial mass mimicking a meningioma. Histology showed features of a typical B-cell non-Hodgkin's lymphoma, there was no systemic involvement. The characteristic CT findings of this lesion are described and relevant literature is reviewed. We are reporting this case because of its rare occurrence. A diagnosis of primary lymphoma of the skull vault should always be considered in the differential diagnosis when such a lesion is encountered.
Aged↗
Intracranial meningeal melanocytoma: a report of two cases and a review of the literature.
Two rare cases of intracranial meningeal melanocytoma are reported with clinical, radiologic, and pathologic findings. In one of these the diagnosis was established by ultrastructural studies that showed premelanosomes and melanosomes in nonarachnoid-derived tumor cells. The other case was diagnosed retrospectively after a very long survival and is still alive 35 years after total excision and radiotherapy. The occurrence of these tumors in the cerebellopontine angle is rare as seen in our case.
Adult↗
Multifocal giant cell glioblastoma: case report.
Glioblastoma multiforme (GM) of the cerebellum is a rare tumour. A variant of GM, a multifocal giant cell glioblastoma, initially presenting in the cerebellum, has not previously been reported. A giant cell glioblastoma occurring in a 46-year-old man who presented initially with a cerebellar tumour is described. One month after excision of the tumour, the patient had a grand mal seizure. Computed tomography (CT) showed a low-density lesion in the left temporal lobe. Four months later he developed dysphasia and right-sided hemiparesis. Repeat CT scan revealed a large temporal lobe tumour which was excised, and histologically found to be a giant-cell glioblastoma with histopathological similarities to the original cerebellar tumour. The clinical course, computed tomographic and pathological features of this tumour are described and discussed.
Brain Neoplasms↗
Acute transient hydrocephalus in carbon monoxide poisoning: a case report.
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Ataxia↗
Ossification of the ligamentum flavum in a Caucasian: case report.
Ossification of the ligamenta flava (OLF) and posterior longitudinal ligament (OPLL) of the spine causing spinal cord compression is described mainly in Japanese patients and is often termed as 'Japanese disease'. We are reporting a case of OLF of the thoracic spine seen in a male Caucasian who presented with an intractable intercostal pain. This is the first case report of OLF in a Caucasian.
Adult↗
Primary cerebral lymphoma: report of 24 patients and review of the literature.
A retrospective study of 24 patients with primary non-Hodgkin's cerebral lymphoma (non-immunocompromised) is presented. All patients were seen at the Royal Preston Hospital, Lancashire between 1976 and 1991. Fifteen patients were over the age of 50 years (range 27-84). The commonest clinical presentation, seen in 16 patients was of an expanding space-occupying lesion. The diagnosis was suspected from the radiological findings but confirmation in every case was by histological examination of biopsy or necropsy material. The tumours were treated either by surgical excision or by biopsy and radiotherapy. Chemotherapy was given in two patients. Despite these measures the mean survival time was 3.6 months. The clinical radiological and pathological features of these tumours are highlighted with particular emphasis on the use of stereotactic biopsy, immunohistochemistry and chemotherapy in diagnosis and treatment.
Adult↗