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Raj Murali

Publications and source records attributed to Raj Murali.

17 recordsLinked to original sources
PubMed2006

Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1.

The roles of the mitogen-activated kinase protein (MAPK) pathway, nuclear factor-kappa B (NF-kappaB), and activator protein-1 (AP-1) in cellular responses to growth factors and mitogen are well established. However, the manner by which these proliferative pathways are affected by the tumor suppressor protein p53 is not fully understood. We report here the results of an investigation of the status of p53 on two human melanoma cell lines with wild-type p53 (SK-Mel-186) or mutant p53 (SK-Mel-110). The basal levels of the activated extracellular-signal regulated kinases 1 and 2 (ERK1/2) were high in cells with wild-type p53, but low in cells with mutant p53. The 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of ERK1/2 through the phosphorylation of threonine and tyrosine at 202 and 204, respectively, was demonstrated in both cell lines, however, in a discrete manner. TPA-induced activation of ERK1/2 was sustained in wild-type p53 cells, while only a transient activation was seen in mutant p53 cells. Inhibition of MAPK kinase (MEK), an upstream kinase, by U0126, blocked TPA-induced activation of ERK1/2 in wild-type p53 cells and in mutant p53 cells. Treatment of wild-type p53 (SK-Mel 186) cells with small interfering RNA (siRNA) of p53 displayed a transient induction of activation of ERK1/2 following TPA treatment, indicating that p53 has a role in the regulation of the activation of ERK1/2. NF-kappaB activity decreased significantly in cells with wild-type p53, while enhanced NF-kappaB activity was evident in cells with mutant p53. The expression of either wild-type or mutant p53 had a similar effect on TPA-induced Jun N-terminal kinase (JNK) activation, indicating specificity for the ERK pathway. Similarly, AP-1 binding activity showed a transient variation in both cell lines after TPA treatment but with different kinetics. These observations suggest that both wild-type and mutant p53 can modulate the activation pathways for ERK1/2, and NF-kappaB distinctively, while modulating the pathways of JNK and AP-1 similarly. These differences may influence cellular processes such as proliferation, differentiation, and apoptosis.

Base Sequence↗
PubMed2006

Meningioangiomatosis associated with neurofibromatosis: report of 2 cases in a single family and review of the literature.

BACKGROUND: Meningioangiomatosis (MA) is a rare benign disorder. It may occur sporadically or in association with neurofibromatosis (NF). The sporadic type typically presents with seizures, whereas that associated with NF is often asymptomatic. Of the 100 cases reported, only 14 are associated with NF. We now report 2 additional cases of MA associated with neurofibromatosis 2 (NF2) in a single family, with one occurring in the cerebellum. The etiology, pathology, and imaging features of MA are presented. CASE DESCRIPTION: A 38-year-old woman (patient 1) presented with a 4-month history of ataxia. She had been diagnosed previously with NF2. Magnetic resonance imaging (MRI) scans of the brain revealed bilateral acoustic neuromas and multiple calcified intracranial lesions. Her 13-year-old daughter (patient 2) presented with complex partial seizures. MRI scans of the brain revealed bilateral acoustic neuromas and a right parietal mass. Patient 1 underwent a suboccipital craniotomy to resect the right-sided acoustic neuroma. A small portion of normal-appearing cerebellar cortex was resected to avoid undue retraction. Histopathologic examination showed the presence of a lesion consistent with MA. Patient 2 underwent a right temporal-parietal craniotomy to remove the enhancing epileptogenic right posterior temporoparietal lesion. Histopathologic analysis showed a lesion consistent with meningioma and MA. CONCLUSIONS: MA has been reported infrequently in association with NF2. We now report 2 cases of MA associated with NF2 in one family, and we add the cerebellum to possible locations of occurrence. MA should be considered in the differential diagnosis of cortical lesions, particularly in patients with NF2.

Adolescent↗
PubMed2006

Giant-cell tumors of the cervical spine: case report.

OBJECTIVE: Giant-cell tumors of bone are rare, benign neoplasms that occur infrequently in the spine above the sacrum, and their presence in the cervical vertebrae is even more exceptional. Although complete en bloc surgical resection is difficult in the cervical spine, treatment with adjuvant radiotherapy has been considered controversial because of a small risk of malignant transformation. The authors report two cases of giant-cell tumors in the cervical vertebrae that were treated successfully with surgical excision and postoperative radiation as well as long-term follow-up. CLINICAL PRESENTATION: Both patients presented with neck pain radiating into the upper extremities. In both cases, plain radiography, computed tomographic scanning, and magnetic resonance imaging revealed a large destructive process in the vertebral body. INTERVENTION: In one case, the tumor was treated by anterior resection, then by laminectomy and instrumented fusion, and finally by adjuvant postoperative radiotherapy. In the second case, treatment consisted of radical anterior and posterior resection with instrumented fusion. However, the tumor recurred, and, after several surgical procedures, external beam radiotherapy was administered. The patients have been followed for 17 and 11 years, respectively, with no evidence of tumor recurrence. CONCLUSION: Radical resection of giant-cell tumors is generally agreed to be the best treatment option. However, complete resection is often not a feasible option for tumors in the cervical spine because of involvement of critical neurovascular structures. In these cases, the benefits of radiotherapy to reduce the risk of local recurrence may well outweigh concerns about the treatment's theoretical risks.

Adult↗
PubMed2006

Hyponatremia and cerebrovascular spasm in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Hyponatremia develops in approximately a third of patients with aneurysmal subarachnoid hemorrhage (SAH). Studies have been conflicting about the association between hyponatremia and cerebrovascular spasm (CVS). AIMS: To investigate whether hyponatremia can signal the onset of CVS. SETTINGS AND DESIGN: Retrospective chart review of all patients with SAH treated at a tertiary-care university hospital from January to May 2002. MATERIALS AND METHODS: 106 patients were included in the study. Serum sodium levels were recorded from days 1 to 14 of hospitalization. Hyponatremia was defined as serum sodium level<135 meq/l and a fall in sodium level of >4 meq/l from the admission sodium level. The presence of CVS was determined by transcranial doppler sonography. Patients were assigned to one of four groups based on the presence or absence of CVS and hyponatremia. STATISTICAL ANALYSIS: Student's t-test was used for comparison of means. A logistical regression model was constructed and odds ratios (OR) were calculated. RESULTS: 41 patients developed hyponatremia and 44 developed CVS. Among the 41 with hyponatremia, 22 (54%) had evidence of CVS, whereas among the 65 patients without hyponatremia, 22 (34%) had evidence of CVS (P=0.023). Among those with hyponatremia, the mean sodium drop was 7.9 meq/L in those with CVS compared to 7.0 meq/L in those without CVS (P=0.068). More than half of those with hyponatremia and CVS (13/22) developed hyponatremia at least a day before CVS was diagnosed. CONCLUSION: In patients with SAH, hyponatremia is associated with a significantly greater risk of developing CVS and may precede CVS by at least one day.

Adolescent↗
PubMed2005

'Wristlock restraint' and physeal injuries of the distal radius.

Wristlock is a commonly used physical restraining manoeuvre to control aggressive and violent persons in penal and medical institutions. We report three cases of similar physeal injuries to the distal radius sustained consequent to a wristlock restraint. There may be a higher morbidity involved when wristlock restraint is used on those with an immature skeleton. We recommend that caution must be exercised whenever a wristlock restraint is used on individuals under 16 years of age.

Adolescent↗
PubMed2005

Hemifacial spasm in a patient with Marfan syndrome and Chiari I malformation. Case report.

Marfan syndrome, hemifacial spasm, and Chiari malformation are all relatively rare and seemingly separate entities. Marfan syndrome is caused by a defect in the gene that encodes fibrillin and leads to weakness of the artery wall. Hemifacial spasm results from compression of the facial nerve by an abnormal artery. Chiari malformation is characterized by a small posterior fossa. The authors report the case of a patient with Marfan syndrome who presented with hemifacial spasm and was also found to have a Chiari malformation Type I. The patient's Chiari malformation and hemifacial spasm were successfully treated by performing suboccipital and microvascular decompression surgeries, respectively. The pathophysiological characteristics of Marfan syndrome, hemifacial spasm, and Chiari malformation are discussed, and the authors propose a link between these conditions in this patient. The authors hypothesize that the patient's Marfan syndrome contributed to the abnormal shape of his vertebral artery and that, given the lack of space in his crowded posterior fossa due to the Chiari malformation, the artery caused compression of his facial nerve, resulting in hemifacial spasm.

Adult↗
PubMed2004

Aeromonas meningitis complicating medicinal leech therapy.

Medicinal leeches have an important and expanding role in medicine, but infection can complicate their use. We describe a unique case of Aeromonas meningitis associated with the use of leech therapy to salvage a skin flap after central nervous system surgery.

Adult↗
PubMed2004

History of instrumentation for stabilization of the subaxial cervical spine.

In the past several decades methods have been developed to stabilize the subaxial cervical spine both posteriorly and anteriorly. Methods of posterior stabilization have progressed from interspinous wiring, through facet wiring and sublaminar wiring, to the lateral mass screws with plates and rods that are in use today. Plates for anterior stabilization have evolved from rigid plates requiring bicortical screws through those used with unicortical locking screws, to dynamic load-sharing plates used with variable angle screws. The original description of spinous process wiring was published by Hadra in 1891. In 1942 Rogers described the interspinous wiring method used for trauma-induced cervical instability, which was modified by Bohlman in 1985 (triple wiring technique). Luque rods with sublaminar wires were introduced in the late 1970s to address multilevel and occipitocervical instability. Facet wiring was developed in 1977 by Callahan to address the problem of stabilization when laminae are not present. Wiring remained the method used until Roy-Camille introduced the lateral mass screw-plate construct in the 1980s. The first plate for anterior stabilization was designed by Orozco and Llovet in 1970 and was later refined by Caspar; this was a rigid plate with bicortical screws. Morscher devised unicortical locking screws in the 1980s. The latest concept of dynamic load-sharing plates with variable angle screws was developed in 2000. In this article historical landmarks in surgical methods for the stabilization of the subaxial cervical spine are reviewed.

Bone Plates↗
PubMed2004

Tempol, a nitroxide antioxidant, improves locomotor and histological outcomes after spinal cord contusion in rats.

We have determined whether the nitroxide antioxidant, tempol, can oppose tissue loss and improve recovery of locomotor function following contusion injury of the spinal cord. Contusion injury was produced in rats at the level of T10 with a weight-drop device and locomotor recovery was determined with the 21-point Basso, Beattie and Bresnahan (BBB) scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater in tempol-treated (275 mg/kg i.p., 20 min postinjury) compared to vehicle-treated rats (final BBB scores: 9.1 versus 6.4). Similarly enhanced locomotor recovery was observed with doses of tempol in the range of 138-550, but not 69 mg/kg, and with injection at 48 h postinjury indicating a therapeutic time-window of at least several days. The extent of recovery correlated with measurements of sparing of spinal cord white matter in a region several millimeters in length extending rostrally from the contusion epicenter. In contrast, loss of gray matter was unaffected by tempol treatment. Since tempol acts by scavenging reactive oxygen species (ROS) such as superoxide and hydroxyl radicals, the improved locomotor recovery and spared spinal cord tissue following contusion injury provides evidence of a direct role of ROS-mediated neurodegeneration in spinal cord injury.

Animals↗
PubMed2004

Large anterior skull base lesions in patients presenting with obstructive sleep apnea. Report of two cases and review of the literature.

Patients with sleep apnea often are treated by sleep disorder specialists and are studied in a sleep laboratory. The authors present two such patients who ultimately were found to harbor large benign anterior skull base lesions that caused their obstructive sleep apnea (OSA). The first patient had a massive pituitary tumor and had undergone a tracheostomy before the lesion was diagnosed. The second patient had a large frontoethmoidal encephalocele that was diagnosed at the same time as a recommendation for continuous positive airway pressure therapy was being considered. Such therapy in the presence of an encephalocele can be dangerous and even fatal. Although there are case reports of tumors causing OSA, nearly all of these lesions have been large pharyngeal lipomas (some of which were palpable in the neck during physical examination) or growth hormone-secreting pituitary adenomas. The patients reported here were completely unaware of the presence of these large lesions until imaging studies and/or nasal endoscopy were performed. These cases illustrate the need to perform nasopharyngeal endoscopy and also to obtain magnetic resonance images of the head before prescribing therapy for OSA. Neurosurgeons must be aware that large skull base lesions sometimes present only with OSA.

Adenoma↗
PubMed2003

Widespread central nervous system cavernous malformations associated with café-au-lait skin lesions. Case report.

The simultaneous presence of cavernous malformations in the brain and spinal cord is a very rare finding and is typically associated with familial cavernous malformations. Although they are uncommon, various skin lesions can manifest in patients with familial cavernous malformations. The authors report on a 60-year-old man in whom more than 100 lesions consistent in appearance with cavernous malformations, including several intramedullary spinal cord lesions, were found throughout the neuraxis. This patient also displayed prominent café-au-lait skin lesions, but had no additional signs of neurofibromatosis or other neurocutaneous disorders. Analysis of his DNA revealed a novel mutation in the KRIT1/CCM1 gene, thereby confirming the diagnosis of familial cavernous malformation. The presence of these lesions in every major compartment of this patient's central nervous system underscores their indiscriminate nature and the need to screen throughout the neuraxis in patients in whom familial cavernous malformations are suspected. The findings in this case add to the growing list of skin lesions associated with genetically confirmed familial cavernous malformations. In patients presenting with seizures, focal neurological deficits, or hemorrhagic stroke, the presence of unusual skin lesions should prompt consideration of familial cavernous malformations, and appropriate screening should be performed.

Brain↗
PubMed2002

Tunneled lumbar drain. Technical note.

The authors report a simple and rapid procedure for tunneling a lumbar drain subcutaneously to facilitate chronic cerebrospinal fluid (CSF) drainage. A standard lumbar puncture (LP) is performed with a large-bore Tuohy needle (14- to 16-gauge), the drainage catheter is advanced into the subarachnoid space, and the needle is removed. The free Tuohy needle is then passed from a lateral position and brought out through the initial LP site. The free catheter is fed through the needle, and the needle is removed. The drain is attached to an external drainage bag in the usual manner. The authors have found this method particularly useful in some skull base and spinal surgical applications in which longer term continuous CSF drainage is desired.

Brain Diseases↗
PubMed2002

Treatment of an anterior communicating artery aneurysm through an anomalous anastomosis from the cavernous internal carotid artery.

Cavernous internal carotid artery (ICA)-anterior cerebral artery (ACA) anastomoses are unusual anomalies in which a duplicated A, segment of the ACA arises from the infraoptic ICA. The authors report on a 30-year-old woman who presented with subarachnoid hemorrhage from an anterior communicating artery (ACoA) aneurysm associated with an extremely rare variant of this anastomosis. The extra A, segment emerged from the ICA within the cavernous sinus rather than at or above the level of the ophthalmic artery. The presence of the anomalous vessel provided a straightforward endovascular approach to the ACoA and allowed the use of coil placement rather than surgical clipping to treat the aneurysm successfully.

Adult↗
PubMedDate not supplied

The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway.

BACKGROUND: The tumor suppressor gene PTEN, mutated in 40-50% of patients with brain tumors, especially those with glioblastomas, maps to chromosome 10q23.3 and encodes a dual-specificity phosphatase. PTEN exerts its effects partly via inhibition of protein tyrosine kinase B (Akt/Protein Kinase B), which is involved in the phosphatidylinositol (PtdIns) 3-kinase (PI3K)-mediated cell-survival pathway. The naturally occurring bioflavonoid Quercetin (Qu) shares structural homology with the commercially available selective PI3K inhibitor, LY 294002 (LY). Here, the effects of Qu on the Akt/PKB pathway were evaluated. MATERIALS AND METHODS: The human breast carcinoma cell lines, HCC1937, with homozygous deletion of the PTEN gene, and T47D, with intact PTEN, were time-treated with Qu or LY and analyzed for activated levels of Akt by measuring phospho-Akt (p-Akt) levels using immunoblotting analysis. To detect p-Akt, the T47D cells were treated with EGF prior to treatment with or without Qu or LY Cell proliferation after 24-h treatment with Qu or LY was quantified by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Treatment with Qu (25 microM) for 0.5, 1 and 3 h completely suppressed constitutively activated Akt/PKB phosphorylation at Ser-473 in HCC1937 cells. Pre-exposing T47D cells to Qu (25 microM) or LY (10 microM) abrogated EGF-induced Akt/PKB phosphorylation at Ser-473. Both Qu (100 microM) and LY (50 microM) treatments for 24 h significantly decreased cell proliferation, as shown by the MTT assay. CONCLUSION: Pharmacologically safe doses of the naturally occurring bioflavonoid Qu inhibit the PI3K-Akt/PKB pathway, in a manner similar to that of the commercially available LY. Overall, our results indicated that Qu inhibited the constitutively activated-Akt/PKB pathway in PTEN-null cancer cells, and suggest that this compound may have therapeutic benefit against tumorigenesis and cancer progression.

Antineoplastic Agents↗
PubMedDate not supplied

Revisiting the role of p53 in primary and secondary glioblastomas.

Glioblastoma multiforme (GBM) develops from astrocytes and is the most aggressive primary cancer in humans. Invading cells grow rapidly and form their own blood vessels making them difficult to surgically remove or treat. GBM may develop de novo (primary) or through progression from a low-grade or anaplastic astrocytoma (secondary). Mutational inactivation of the p53 gene and presence of aberrant p53 expression are reported in GBM, suggesting that p53 has a role in tumor progression. This study of seven de novo GBM and four secondary GBM patients, indicated that nine out of eleven (82%) had overexpression of p53. Our histopathological analysis showed that the expression of p53 in three out of four (75%) secondary GBM was confined to the nucleus and the p53 positive cells were randomly distributed throughout the tumor. The expression of p53 in four out of seven (57%) de novo GBM was cytoplasmic, diffusive, and confined to the perivascular region of the tumor. In two (29%) de novo samples both nuclear as well as cytoplasmic staining that was not confined to the perivascular area was observed. The results suggest that cytoplasmic p53 may contribute to the formation and maintenance of de novo GBM by virtue of its control of the vasculature of tumors. Furthermore, cytoplasmic p53 may reflect an association of p53 with Cullin 7, PARC, or with the sequestering partner of p53, mortalin. These results underscore the significance of p53 in the tumorigenesis of de novo GBM.

Adult↗