Peter H. King

Elective Stenting of the Extracranial Carotid Arteries

OBJECTIVES In symptomatic and asymptomatic patients with significant carotid artery stenosis, surgical endarterectomy has been shown to be beneficial when compared with medical management. Carotid stenting is evolving as an alternative technique for treating such patients. This prospective study was designed to assess the feasibility and safety of carotid angioplasty and stenting. METHODS Fourteen patients (15 carotid arteries) with significant carotid artery stenosis were enrolled. These patients were in the age range 46 to 84 years (mean 60.9 +/- 7 years) and there were 12 males (86%). All of these patients were symptomatic with either TIA (n = 8) or stroke (n = 6). Wallstents were used in all the cases to stent the carotid arteries. One patient underwent bilateral carotid artery stenting. RESULTS Carotid angioplasty and stenting was successful in 13 out of 14 (92.8%) patients and 14 out of 15 (93.3%) carotid arteries, with reduction in mean (+/- SD) stenosis from 86 +/- 6% to 3 +/- 3%. There was one episode of minor stroke, no major stroke or death during the initial hospitalization. Another patient had a minor stroke with patent ipsilateral carotid artery (on repeat angiography) during the first 30 days after the procedure. This patient was also found to have asymptomatic thrombus formation in the contralateral carotid stent which resolved with intravenous anticoagulation. During a mean follow up of 6 +/- 2 months there has been no recurrence of symptoms. CONCLUSIONS Based upon our limited experience we believe that percutaneous carotid angioplasty with stenting is feasible with low periprocedural complication rate.

Angioplasty and Stenting for Restenosis After Carotid Endarterectomy Initial Experience

BACKGROUND AND PURPOSE Endarterectomy for recurrent carotid stenosis after endarterectomy has a significantly higher complication rate than the original operation. Angioplasty and stenting may offer a useful alternative treatment for these patients. METHODS Between September 1994 and April 1996, 22 patients had 25 carotid arteries treated with angioplasty and stenting for postendarterectomy restenosis. All patients had an independent neurological examination and National Institutes of Health Stroke Scale evaluation before and after the procedure. Patients were treated with aspirin and ticlopidine. All patients were requested to return at 6 months for follow-up angiography. The mean patient age was 69 +/- 7 years, and the mean elapsed time from endarterectomy was 73 +/- 69 months. Seventy-seven percent of the patients were symptomatic. RESULTS Mean stenosis was reduced from 79 +/- 13% before the procedure to 1.8 +/- 3.6% after stenting. One patient had a minor stroke, for a complication rate of 4% per treated artery. In the eight patients who returned for 6-month angiography, mean stenosis was 19.4 +/- 4.4% and restenosis (> or = 50% stenosis) did not occur. CONCLUSIONS In a small series, angioplasty and stenting appear to be safe and well tolerated for the treatment of postendarterectomy restenosis.

Stepping and Stretching HOW KINESIN USES INTERNAL STRAIN TO WALK PROCESSIVELY

The ability of kinesin to travel long distances on its microtubule track without dissociating has led to a variety of models to explain how this remarkable degree of processivity is maintained. All of these require that the two motor domains remain enzymatically “out of phase,” a behavior that would ensure that, at any given time, one motor is strongly attached to the microtubule. The maintenance of this coordination over many mechanochemical cycles has never been explained, because key steps in the cycle could not be directly observed. We have addressed this issue by applying several novel spectroscopic approaches to monitor motor dissociation, phosphate release, and nucleotide binding during processive movement by a dimeric kinesin construct. Our data argue that the major effect of the internal strain generated when both motor domains of kinesin bind the microtubule is to block ATP from binding to the leading motor. This effect guarantees the two motor domains remain out of phase for many mechanochemical cycles and provides an efficient and adaptable mechanism for the maintenance of processive movement.

MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria

A 20-year-old woman had an attack of acute intermittent porphyria (AIP) with seizures and hallucinations. MRI revealed multiple lesions in both hemispheres. Both the cerebral clinical abnormalities and the MRI lesions resolved following treatment. These findings suggest that a vascular mechanism may underlie the pathogenesis of cerebral dysfunction in AIP.

Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study

OBJECTIVE The objective is to report the clinical, electrophysiological, and histopathological features of 16 patients with anti-Hu antibody neuropathy. METHODS Clinical and electrophysiological data in 16 patients (11 females and 5 males) with positive anti-Hu antibody and nerve biopsy data in 9 cases were analyzed. RESULTS Cancer was detected in 11 patients, including 9 with small-cell lung cancer. Classical paraneoplastic subacute sensory neuronopathy (SSN) and/or encephalomyelitis (EM) was observed in 7 patients (44%), including 5 with SSN. The most common clinical feature was sensory-motor neuropathy (SMN), accounting for 50% of cases. Though sensory nerve conduction abnormality was the prominent feature in 14 (88%) cases, sensory and motor nerve conduction was abnormal in all cases. Motor nerve conduction findings were typical of axonal degeneration. The most common nerve conduction pattern was that of SMN, with a sensory neuronopathy pattern being observed in only 3 cases. Sural nerve biopsy in 9 patients showed axonal degeneration in all cases and inflammatory cells in 4 cases. CONCLUSIONS Classical sensory neuronopathy is rarer than expected, both clinically and electrophysiologically. Motor involvement is not uncommon and motor nerve conduction abnormality is frequently seen. A diverse clinical and electrophysiological, and histopathological spectrum was observed in this neuropathy. SIGNIFICANCE New guidelines for the selection of patients for anti-Hu antibody test are recommended.

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Abstract Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

Alterations in RNA-binding activities of IRES-regulatory proteins as a mechanism for physiological variability and pathological dysregulation of IGF-IR translational control in human breast tumor cells

The type I insulin‐like growth factor receptor (IGF‐IR) is integrally involved in the control of cellular proliferation and survival. An internal ribosomal entry site (IRES) within the 1,038 nucleotide 5′‐untranslated region of the human IGF‐IR mRNA helps to provide the tight control of IGF‐IR expression necessary for maintenance of normal cellular and tissue homeostasis. The IRES maps to a discrete sequence of 85 nucleotides positioned just upstream of the IGF‐IR initiation codon, allowing the ribosome to bypass the highly structured regions of the 5′‐UTR as well as the upstream open reading frame. The authenticity of the IGF‐IR IRES has been confirmed by its sensitivity to deletion of the promoter from a bicistronic reporter construct, and its resistance in a monocistronic reporter construct to co‐expression of a viral 2A protease. We previously characterized HuR as a potent repressor of IGF‐IR translation. Here we demonstrate that hnRNP C competes with HuR for binding the IGF‐IR 5′‐UTR and enhances IRES‐mediated translation initiation in a concentration‐dependent manner. We observed changes in binding of hnRNP C versus HuR to the IGF‐IR 5′‐UTR in response to physiological alterations in cellular environment or proliferative status. Furthermore, we have found distinct alterations in the pattern of protein binding to the IGF‐IR 5′‐UTR in human breast tumor cells in which IGF‐IR IRES activity and relative translational efficiency are aberrantly increased. These results suggest that dysregulation of the IGF‐IR IRES through changes in the activities of RNA‐binding translation‐regulatory proteins could be responsible for IGF‐IR overexpression in a proportion of human breast tumors. J. Cell. Physiol. 217: 172–183, 2008.

Phosphoregulation of the RNA-binding Protein Hu Antigen R (HuR) by Cdk5 Affects Centrosome Function

Background: Regulation of protein function by phosphorylation is an important mechanism to control many cellular processes. Results: We found that the mRNA-binding protein HuR is phosphorylated by Cdk5 at the serine 202 residue. Conclusion: The aberrant phosphorylation of HuR at Ser-202 affects centrosome function and induces arrest of cell cycle progression. Significance: This work emphasizes HuR phosphorylation as a novel molecular target in cancer. Hu antigen R (HuR) is an mRNA-binding protein belonging to the ELAV family. It is highly expressed in cancer and involved in cell survival and proliferation. The impact of post-translational regulation of HuR and resulting cellular effects are poorly understood. In the current report, we describe a direct interaction between HuR and Cdk5 in glioma. We determined that Cdk5 specifically phosphorylates HuR at the serine 202 residue in the unique hinge region. The molecular consequences of this interaction are an altered HuR ability to bind, stabilize, and promote translation of mRNAs. At the cellular level, the anomalous HuR phosphorylation at this site evokes robust defects in centrosome duplication and cohesion as well as arrest of cell cycle progression. Subcellular fractionation and immunofluorescence technique confirm a direct integration of HuR and Cdk5 with centrosomes. We propose that HuR stores mRNA in the centrosome and that HuR phosphorylation by Cdk5 controls de novo protein synthesis in near proximity to centrosomes and, thus, impacts centrosome function.

Differential expression of the neuroendocrine genes Hel‐N1 and HuD in small‐cell lung carcinoma: Evidence for down‐regulation of HuD in the variant phenotype

Hel‐N1 and HuD belong to the elav gene family and have gained recent attention as potential neuroendocrine markers for small‐cell lung carcinoma (SCLC). Members of this conserved family normally appear at different stages of neuronal maturation, raising the possibility that their expression patterns in SCLC reflect the degree of neuroendocrine differentiation. I have utilized a ribonuclease protection assay to analyze Hel‐N1 and HuD expression in cultured SCLC cells with high (classic phenotype) and low (variant phenotype) levels of neuroendocrine differentiation. Hel‐N1 was detected in both classic and variant SCLC. Although HuD was detected consistently in classic SCLC, it was low to absent in variant SCLC, indicating a significant down‐regulation in that phenotype. The expression patterns of Hel‐N1 and HuD also were analyzed in 9 primary SCLC and 10 non‐SCLC lung‐tumor samples. In the majority of SCLC samples, either Hel‐N1 or HuD was detected exclusively or predominantly, indicating a pattern of variable gene expression similar to cultured SCLC. Neither transcript could be detected in the non‐SCLC samples. These data indicate that (i) HuD mRNA expression is associated with a higher level of neuroendocrine differentiation in SCLC, (ii) Hel‐N1and HuD expressions are variable in both primary and cultured SCLC and (iii) HuD and Hel‐N1, in combination, are neurogenetic markers for SCLC. Int. J. Cancer 74:378–382, 1997.

Porphyria presenting with bilateral radial motor neuropathy: Evidence of a novel gene mutation

The authors identified a novel mutation of the porphobilinogen deaminase (PBG-D) gene in a patient with acute intermittent porphyria presenting with severe and bilateral axonal radial motor neuropathy. Electrophysiologic studies revealed prominent involvement of distal radial nerves in the setting of mild polyneuropathy. Analysis of the PBG-D gene revealed a single base-pair insertion (887insA) in exon 14.