Biomedical subjects

Paul Gardner

Publications and source records attributed to Paul Gardner.

12 recordsLinked to original sources

PubMed2006

Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.

beta cell failure is a common denominator of diabetes. Susceptibility to stress-induced apoptosis may underlie beta cell failure and/or hamper islet transplantation therapy. The causal basis is not well understood. In efforts to identify important differences in gene expression in alpha vs. beta cells, a gene termed HIMP1 (Hypoglycemia/hypoxia Inducible Mitochondrial Protein, or HIG1) has been cloned from an alpha cell cDNA library. It is a member of a well conserved eukaryote protein family. In mice, its two alternatively spliced products each form a transmembrane loop, having an N(outside)-C(outside) orientation and are expressed highly in the mitochondrial inner membrane in several tissues including heart and pancreatic alpha cells, but not in beta cells. Ectopic expression of HIMP1 in MIN6 beta cells protects the cells from apoptosis induced by several stimuli and prolongs their survival. These results suggest an important role for HIMP1 in stress protective programs in mitochondria.

Animals↗

PubMed2005

Endoscopic endonasal surgery of the midline skull base: anatomical study and clinical considerations.

OBJECT: The midline skull base is an anatomical area that extends from the anterior limit of the cranial fossa down to the anterior border of the foramen magnum. Resection of lesions involving this area requires a variety of innovative skull base approaches. These include anterior, anterolateral, and posterolateral routes, performed either alone or in combination, and resection via these routes often requires extensive neurovascular manipulation. The goals in this study were to define the application of the endoscopic endonasal approach and to become more familiar with the views and skills associated with the technique by using cadaveric specimens. METHODS: To assess the feasibility of the endonasal route for the surgical management of lesions in the midline skull base, five fresh cadaver heads injected with colored latex were dissected using a modified endoscopic endonasal approach. Full access to the skull base and the cisternal space around it is possible with this route. From the crista galli to the spinomedullary junction, with incision of the dura mater, a complete visualization of the carotid and vertebrobasilar arterial systems and of all 12 of the cranial nerves is obtainable. CONCLUSIONS: The major potential advantage of the endoscopic endonasal approach to the skull base is that it provides a direct anatomical route to the lesion without traversing any major neurovascular structures, obviating brain retraction. Many tumors grow in a medial-to-lateral direction, displacing structures laterally as they expand, creating natural corridors for their resection via an anteromedial approach. Potential disadvantages of this procedure include the relatively restricted working space and the danger of an inadequate dural repair with cerebrospinal fluid (CSF) leakage and potential for meningitis resulting. These approaches often require a large opening of the dura mater over the tuberculum sellae and posterior planum sphenoidale, or retroclival space. In addition, they typically involve large intraoperative CSF leaks, which necessitate precise and effective dural closure.

Cadaver↗

PubMed2005

Expanded endonasal approach: the rostrocaudal axis. Part I. Crista galli to the sella turcica.

OBJECT: Transsphenoidal approaches have been used for a century for the resection of pituitary and other sellar tumors. More recently, the standard endonasal approach has been expanded to provide access to other, parasellar lesions. With the addition of the endoscope, this expansion carries significant potential for the resection of skull base lesions. METHODS: The anatomical landmarks and surgical techniques used in expanded (extended) endoscopic approaches to the rostral, anterior skull base are reviewed and presented, accompanied by case illustrations of each segment (or module) of approach. The rostral half of the anterior skull base is divided into modules of approach: sellar/parasellar, transplanum/transtuberculum, and transcribriform. Case illustrations of successful resections of lesions with each module are presented and discussed. CONCLUSIONS: Endoscopic, expanded endonasal approaches to rostral anterior skull base lesions are feasible and hold great potential for decreased morbidity. The effectiveness and appropriate use of these techniques must be evaluated by close examination of outcomes as case series expand.

Cranial Fossa, Posterior↗

PubMed2005

Expanded endonasal approach: the rostrocaudal axis. Part II. Posterior clinoids to the foramen magnum.

OBJECT: Transsphenoidal approaches have been used for a century for the resection of pituitary and other sellar tumors. Recently, however, the standard endonasal approach has been expanded to provide access to other parasellar lesions. With the addition of the endoscope, this expansion has significant potential for the resection of skull base lesions. METHODS: The anatomical landmarks and surgical techniques used in expanded (extended) endoscopic approaches to the clivus and cervicomedullary junction are reviewed and presented, accompanied by case illustrations of each segment (or module) of approach. The caudal portion of the midline anterior skull base and the cervicomedullary junction is divided into modules of approach: the middle third of the clivus, its lower third, and the cervicomedullary junction. Case illustrations of successful resections of lesions via each module of the approach are presented and discussed. CONCLUSIONS: Endoscopic expanded endonasal approaches to caudally located midline anterior skull base and cervicomedullary lesions are feasible and hold great potential for decreased morbidity. The effectiveness and appropriate use of these techniques must be evaluated by close examination of outcomes as case series expand.

Cranial Fossa, Posterior↗

PubMed2005

Extended endoscopic endonasal approach to the pterygopalatine fossa: anatomical study and clinical considerations.

OBJECT: The pterygopalatine fossa is an area located deep in the skull base. The microsurgical transmaxillary-transantral route is usually chosen to remove lesions in this region. The increasing use of the endoscope in sinonasal functional surgery has more recently led to the advent of the endoscope for the treatment of tumors located in the pterygopalatine fossa as well. METHODS: An anatomical dissection of three fresh cadaveric heads (six pterygopalatine fossas) and three dried skull base specimens was performed to evaluate the feasibility of the approach and to illustrate the surgical landmarks that are useful for operations in this complex region. The endoscopic endonasal approach allows a wide exposure of the pterygopalatine fossa. Furthermore, with the same access (that is, through the nostril) it is possible to expose regions contiguous with the pterygopalatine fossa, either to visualize more surgical landmarks or to accomplish a better lesion removal. CONCLUSIONS: In this anatomical study the endoscopic endonasal approach to the pterygopalatine fossa has been found to be a safe approach for the removal of lesions in this region. The approach could be proposed as an alternative to the standard microsurgical transmaxillary-transantral route.

Cranial Fossa, Anterior↗

PubMed2005

Expanded endonasal approach: fully endoscopic, completely transnasal approach to the middle third of the clivus, petrous bone, middle cranial fossa, and infratemporal fossa.

OBJECT: The middle third of the clivus and the region around the petrous internal carotid artery (ICA) is a difficult area of the skull base in terms of access. This is a deep area rich with critical neurovascular structures, which is often host to typical skull base diseases. Expanded endoscopic endonasal approaches offer a potential option for accessing this difficult region. The objective of this paper was to establish the clinical feasibility of gaining access to the paraclival space in the region of the middle third of the clivus, to provide a practical modular and clinically applicable classification, and to describe the relevant critical surgical anatomy for each module. METHODS: The anatomical organization of the region around the petrous ICA, cavernous sinus, and middle clivus is presented, with approaches divided into zones. In an accompanying paper in this issue by Cavallo, et al., the anatomy of the pterygopalatine fossa is presented; this was observed through cadaveric dissection for which an expanded endonasal approach was used. In the current paper the authors translate the aforementioned anatomical study to provide a clinically applicable categorization of the endonasal approach to the region around the petrous ICA. A series of zones inferior and superior to the petrous ICA are described, with an illustrative case presented for each region. CONCLUSIONS: The expanded endonasal approach is a feasible approach to the middle third of the clivus, petrous ICA, cavernous sinus, and medial infratemporal fossa in cases in which the lesion is located centrally, with neurovascular structures displaced laterally.

Cavernous Sinus↗

PubMed2005

Endoneurosurgical hemostasis techniques: lessons learned from 400 cases.

The increasing popularity of minimally invasive neurosurgery has led to the development of transnasal expanded approaches for the treatment of skull base lesions. One of the greatest challenges in safely accomplishing resection of tumors, particularly intradural lesions, is effective hemostasis. Over the past 7 years the authors have progressively developed an organized approach to address this challenge. This has required the development of new instrumentation as well as variations on standard techniques. In this report they present the technique that has evolved at their institution for endoneurosurgical hemostasis.

Bone Diseases↗

PubMed2005

Evolution of reconstructive techniques following endoscopic expanded endonasal approaches.

Harvey Cushing first popularized the transsphenoidal route to the sella turcica, and Jules Hardy subsequently refined it by adding the operating microscope. Over the ensuing decades, attempts at extending the application of this approach have been advanced by Edward Laws and others. With the evolution of endoscopic approaches, the natural expansion of their use to intradural lesions followed. For the expanded endonasal approach to become a viable option, the paramount concerns surrounding consistent reconstruction of the dura mater must be overcome. In this review the authors chronicle the evolution of the reconstruction technique they currently use after performing expanded endonasal approaches. They also report the use of a balloon stent to buttress the reconstruction and counter the effects of graft migration and cerebrospinal fluid fistula formation. The technique described in this report represents an important step forward in the reconstruction of defects resulting from expanded endonasal approaches.

Endoscopy↗

PubMed2005

The expanded endonasal approach: a fully endoscopic transnasal approach and resection of the odontoid process: technical case report.

The transoral approach to the odontoid process is considered the "gold standard" for resection of extradural lesions at this location. A completely transnasal endoscopic approach is feasible based on anatomic studies and our experience with the expanded endonasal approach for neoplasms of the cranial base. An illustrative case is presented to demonstrate the technical details of a fully transnasal completely endoscopic approach for the resection of the odontoid process. A 73-year-old woman with a long-standing history of rheumatoid arthritis presented with progressive cervicomedullary compression. Complete resection of the odontoid was achieved with no significant morbidity. This is the first reported case of a completely endoscopic resection of the odontoid using a fully transnasal route. The report demonstrates the feasibility of this approach and larger clinical series with long-term follow-up will be needed to determine the reproducibility and validation of any potential benefits.

Aged↗

PubMed2005

Predicting RNA structure using mutual information.

BACKGROUND: With the ever-increasing number of sequenced RNAs and the establishment of new RNA databases, such as the Comparative RNA Web Site and Rfam, there is a growing need for accurately and automatically predicting RNA structures from multiple alignments. Since RNA secondary structure is often conserved in evolution, the well known, but underused, mutual information measure for identifying covarying sites in an alignment can be useful for identifying structural elements. This article presents MIfold, a MATLAB toolbox that employs mutual information, or a related covariation measure, to display and predict conserved RNA secondary structure (including pseudoknots) from an alignment. RESULTS: We show that MIfold can be used to predict simple pseudoknots, and that the performance can be adjusted to make it either more sensitive or more selective. We also demonstrate that the overall performance of MIfold improves with the number of aligned sequences for certain types of RNA sequences. In addition, we show that, for these sequences, MIfold is more sensitive but less selective than the related RNAalifold structure prediction program and is comparable with the COVE structure prediction package. CONCLUSION: MIfold provides a useful supplementary tool to programs such as RNA Structure Logo, RNAalifold and COVE, and should be useful for automatically generating structural predictions for databases such as Rfam.

Algorithms↗

PubMed2003

Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1).

The subtilisin-like prohormone convertases (PCs) contain an essential downstream domain (P domain), which has been predicted to have a beta-barrel structure that interacts with and stabilizes the catalytic domain (CAT). To assess possible sites of hydrophobic interaction, a series of mutant PC3-enhanced GFP constructs were prepared in which selected nonpolar residues on the surface of CAT were substituted by the corresponding polar residues in subtilisin Carlsberg. To investigate the folding potential of the isolated P domain, signal peptide-P domain-enhanced GFP constructs with mutated andor truncated P domains were also made. All mutants were expressed in betaTC3 cells, and their subcellular localization and secretion were determined. The mutants fell into three main groups: (i) Golgisecreted, (ii) ERnonsecreted, and (iii) apoptosis inducing. The destabilizing CAT mutations indicate that the side chains of V292, T328, L351, Q408, H409, V412, and F441 and nonpolar fragments of the side chains of R405 and W413 form a hydrophobic patch on CAT that interacts with the P domain. We also have found that the P domain can fold independently, as indicated by its secretion. Interestingly, T594, which is near the P domain C terminus, was not essential for P domain secretion but is crucial for the stability of intact PC3. T594V produced a stable enzyme, but T594D did not, which suggests that T594 participates in important hydrophobic interactions within PC3. These findings support our conclusion that the catalytic and P domains contribute to the folding and thermodynamic stability of the convertases through reciprocal hydrophobic interactions.

Amino Acid Sequence↗

PubMed2002

Stereotactic radiosurgery for pilocytic astrocytomas when multimodal therapy is necessary.

OBJECT: The goal of this study was to examine the role of stereotactic radiosurgery in the treatment of patients with recurrent or unresectable pilocytic astrocytomas. METHODS: During a 13-year interval, 37 patients (median age 14 years) required multimodal treatment of recurrent or unresectable pilocytic astrocytomas. Tumors involved the brainstem in 18 patients, cerebellum in three, thalamus in five, temporal lobe in four, and parietal lobe in two, as well as the hypothalamus, optic tract, corpus callosum, insular cortex, and third ventricle in one patient each. Diagnosis was confirmed with the aid of stereotactic biopsy in 12 patients, open biopsy in five, partial resection in eight, and near-total resection in 12. Multimodal treatment included fractionated radiation therapy in 10 patients, stereotactic intracavitary irradiation of tumor in four, chemotherapy in two, cyst drainage in six, ventriculoperitoneal shunt placement in three, and additional cytoreductive surgery in four. Tumor volumes varied from 0.42 to 25 cm3. The median radiosurgical dose to the tumor margin was 15 Gy (range 9.6-22.5 Gy). After radiosurgery, serial imaging demonstrated complete tumor resolution in 10 patients, reduced tumor volume in eight, stable tumor volume in seven, and delayed tumor progression in 12. No procedure-related death was encountered. Thirty-three (89%) of 37 patients are alive at a median follow-up period of 28 months after radiosurgery and 59 months after diagnosis. Eight patients participated in follow-up review for more than 60 months. Three patients died of local tumor progression. CONCLUSIONS: Stereotactic radiosurgery is a valuable adjunctive strategy in the management of recurrent or unresectable pilocytic astrocytomas. Despite the favorable histological characteristics and prognosis usually associated with this neoplasm, an adverse location, recurrence, or progression of this disease requires alternative therapeutic approaches such as radiosurgery.

Adolescent↗