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Biomedical subjects

P Dean

Publications and source records attributed to P Dean.

At least 19 recordsLinked to original sources
PubMed2006

Using magnetic forces to enhance non-viral gene transfer to airway epithelium in vivo.

We have assessed whether magnetic forces (magnetofection) can enhance non-viral gene transfer to the airways. TransMAG(PEI), a superparamagnetic particle was coupled to Lipofectamine 2000 or cationic lipid 67 (GL67)/plasmid DNA (pDNA) liposome complexes. In vitro transfection with these formulations resulted in approximately 300- and 30-fold increase in reporter gene expression, respectively, after exposure to a magnetic field, but only at suboptimal pDNA concentrations. Because GL67 has been formulated for in vivo use, we next assessed TransMAG(PEI) in the murine nasal epithelium in vivo, and compared this to naked pDNA. At the concentrations required for in vivo experiments, precipitation of magnetic complexes was seen. After extensive optimization, addition of non-precipitated magnetic particles resulted in approximately seven- and 90-fold decrease in gene expression for naked pDNA and GL67/pDNA liposome complexes, respectively, compared to non-magnetic particles. Thus, whereas exposure to a magnetic field improved in vitro transfection efficiency, translation to the in vivo setting remains difficult.

Animals↗
PubMed2005

Long time-constant behavior of the oculomotor plant in barbiturate-anesthetized primate.

The mechanics of the extraocular muscles and orbital tissue ("oculomotor plant") can be approximated by a small number of viscoelastic (Voigt) elements in series. Recent analysis of the eye's return from displacement in lightly anesthetized rhesus monkeys has suggested a four-element plant model with time constants (TCs) of approximately 0.01, 0.1, 1, and 10 s. To demonstrate directly the presence of long (1,10 s) TC elements and to assess their contribution quantitatively, horizontal eye displacement was induced in Cynomolgus monkeys under deep barbiturate anesthesia that prevented interference from spontaneous eye movements. The displacement was maintained for either a prolonged (30 s) or brief (0.2 s) period before release. Return to resting position took 20-30 s after prolonged displacement but only 1-2 s after brief displacement, consistent with the presence of long TC elements that would only be substantially stretched in the former condition. Quantitative fitting of the release curves after prolonged displacement indicated that the two long TC elements contribute a substantial proportion (approximately 30%) of the total plant compliance. A model based on the estimated compliance values is shown to account quantitatively both for our release data and for Goldstein and Robinson's data on hysteresis of ocular motoneuron firing rates measured after centripetal saccades following prolonged eccentric fixation. Long time-constant elements in the plant thus make a substantial contribution to some types of eye movement, and their inclusion in plant models can help interpret the firing patterns of single units in the oculomotor system.

Animals↗
PubMed2005

Depth-resolved holographic imaging through scattering media by use of a photorefractive polymer composite device in the near infrared.

We report full-field depth-resolved holographic imaging through scattering media by use of a photorefractive polymer device in the near infrared. Real-time images through seven scattering mean free paths are acquired in a few seconds with a broadband superluminescent diode at 794 nm. A depth resolution of 15 microm and a transverse resolution of better than 42 microm are achieved. The photorefractive devices used are based on a poly(N-vinylcarbazole):2,4,7-trinitro-9-fluorenone dimalenitrile charge-transport network doped with the electro-optic chromophore 1-(2'-ethylhexyloxy)-2,5-dimethyl-4-(4"-nitrophenylazo)benzene.

Journal Article↗
PubMed2005

Distinct clinicopathologic subtypes of cortical dysplasia of Taylor.

BACKGROUND: Two pathologic subtypes based on the presence or absence of balloon cells have been described in cortical dysplasia of Taylor (CDT). OBJECTIVE: To determine whether the pathologic subtype has any distinct clinical or MRI features that are relevant to management. METHODS: The histopathologic, clinical, and MRI features of 34 children with CDT who underwent epilepsy surgery at Miami Children's Hospital from 1990 to 2001 were investigated. RESULTS: Bizarre neuronal cytomegaly was the primary pathologic feature of 15 patients with the dysplasia-only subtype, and 19 cases showed additional characteristics including balloon cells and marked white matter abnormalities. Both groups presented with severe intractable epilepsy of very-early-onset, multiple daily seizures, cognitive disability, and focal neurologic deficits. The dysplasia-only subtype had higher rates of neonatal onset, hemiparesis, and severe mental retardation (p < 0.05). The MRI features of focal cortical thickening with associated cortical T2 signal change showed excellent sensitivity (94%) and reasonable specificity (73%) for the diagnosis of the balloon cell subtype. The overall surgical outcome was 59% seizure freedom at 2 years. CONCLUSIONS: Children with cortical dysplasia of Taylor type have in common a very-early-onset, severe epilepsy with neurologic co-morbidity. Patients with the non-balloon cell pathologic subtype have a more severe phenotype. A trend toward a better outcome in the balloon cell group suggests that preoperative identification of these subtypes may impact surgical planning.

Adolescent↗
PubMed2004

Hyperphagocytic haemocytes in Manduca sexta.

We have discovered a new type of haemocyte in the larval stage of the tobacco hornworm moth Manduca sexta that has extreme phagocytic ability; each cell can engulf up to 500 bacteria. This level of phagocytosis may be unprecedented among animal cells. Although these hyperphagocytic cells (HP) only represent about 1% of the circulating haemocytes, they are responsible for sequestering the majority of the bacteria by circulating haemocytes when non-pathogenic, heat-killed Escherichia coli are injected into the haemolymph. Extreme phagocytosis by HP is not limited to Gram-negative bacteria since heat-killed Staphylococcus aureus as well as positively and negatively charged microspheres are also highly phagocytosed. Evidence is presented to show that phagocytosis by HP is involved in the early stages of nodule formation in infected insects. In addition, HP are also present in non-infected insects, characterised by their distinctive spreading morphology, which becomes impaired following hyperphagocytosis of bacteria. This is the first time that a dedicated "professional" phagocytic class of haemocyte has been reported for an invertebrate. The importance of these specialised cell types in the M. sexta immune response and their role in nodule formation is discussed.

Animals↗
PubMed2004

Effect of the insect pathogenic bacterium Photorhabdus on insect phagocytes.

Photorhabdus are insect pathogenic bacteria that replicate within the insect haemocoel following release from their entomopathogenic nematode symbionts. To investigate how they escape the cellular immune response we examined the effects of two strains of Photorhabdus, W14 and K122, on Manduca sexta phagocytes (haemocytes), in vitro and in vivo. Following injection of Esherichia coli into Manduca larvae, these non-pathogenic bacteria are rapidly cleared from the haemolymph and the number of free haemocytes transiently increases. In contrast, following injection of either strain of pathogenic Photorhabdus, the bacteria grow rapidly while the number of haemocytes decreases dramatically. In vitro incubation of haemocytes with either Photorhabdus supernatant reduced haemocyte viability, and the W14 supernatant caused distinct changes in the actin cytoskeleton morphology of different haemocyte cell types. In phagocytosis assays both Photorhabdus strains can inhibit their own phagocytosis whether the bacterial cells are alive or dead. Further, the supernatant of W14 also contains a factor capable of inhibiting the phagocytosis of labelled E. coli. Together these results suggest that Photorhabdus evades the cellular immune response by killing haemocytes and suppressing phagocytosis by mechanisms that differ between strains.

Actin Cytoskeleton↗
PubMed2003

Eicosanoid involvement in the regulation of behavioral fever in the desert locust, Schistocerca gregaria.

The desert locust Schistocerca gregaria behaviorally thermoregulates in order to try and maintain a favoured "set point" body temperature. Locusts infected with the deuteromycete fungal pathogen Metarhizium anisopliae var acridumchoose a significantly elevated temperature. This "behavioral fever" greatly delays the progress of mycosis. We have confirmed this phenomenon and shown that desert locusts also fever when infected with the bacterial pathogen Serratia marcescens. Elevation in the prefered environmental temperature occurs also upon injection with laminarin and lipopolysaccharide (microbial cell wall components). Since such treatments also stimulate the immune system it would appear that "behavioral fever" is probably a feature of the immune response. The eicosanoid biosynthesis inhibitor dexamethasone prevented laminarin invoked fever. This effect was reversable by arachidonic acid. Therefore in common with the febrile response in mammals behavioral fever in insects may be mediated locally by circulating eicosanoids.

Animals↗
PubMed2002

Estimation of premotor synaptic drives to simulated abducens motoneurons for control of eye position.

The firing rate of an abducens motoneuron (AbMN) is linearly related to eye position with slope K, above recruitment threshold theta. Within the AbMN population K increases as theta increases. It is possible that these properties depend on the synaptic drives generated by the major premotor inputs to AbMNs, namely position-vestibular-pause (PVP) cells and eye and head velocity (EHV) cells in the medial vestibular nucleus, and eye-position and burst-position cells in the nucleus prepositus hypoglossi (NPH). Premotor inputs to AbMNs were therefore modelled by a two-layer net, in which the output nodes represented the AbMNs (with fixed intrinsic properties) and the input nodes the three classes of premotor units ( n=20/class). Conjugate eye-position commands were used to generate the firing rates in premotor units found experimentally. The output of the net was compared with observed AbMN firing rates, and the resultant error used to adjust the magnitude and sign of the connection weights between premotor units and AbMNs. To provide additional constraints on permitted weights, the net was also trained under simulated smooth pursuit, cancellation of the vestibular-ocular reflex, and the vestibulo-ocular reflex itself (all at 0.5 Hz). Since the projections of EHV cells have not been clearly characterized, two versions of the model were trained, corresponding to different assumptions about these projections. In both versions, position-related AbMN firing rates were derived mainly from an excitatory drive from PVP cells and an inhibitory drive from NPH cells with the opposite ON direction. Variation in AbMN threshold theta and position sensitivity K depended on the strength of the drive from the NPH: the stronger the drive, the higher both K and theta. This arrangement was observed in six variants of the basic model with different parameter values, and in a simplified form (constant PVP drive and varying NPH drive) was able to generate qualitatively the observed relationship between K and theta even in the absence of input from EHV cells. It appears to be a robust mechanism for producing the experimentally observed variation in position-related firing of AbMNs, even without a contribution from their intrinsic properties, and predicts that local blocking of the inhibitory drive from cells in the NPH should lower both the position threshold and sensitivity of an individual AbMN. The model also indicates that if EHV cells have ipsilateral inhibitory projections, as has been proposed on the basis of their similarity with cells receiving input from the flocculus, then their role in eye-position control would reinforce that of cells in the NPH.

Abducens Nerve↗
PubMed2001

Developmental dyslexia: the cerebellar deficit hypothesis.

Surprisingly, the problems faced by many dyslexic children are by no means confined to reading and spelling. There appears to be a general impairment in the ability to perform skills automatically, an ability thought to be dependent upon the cerebellum. Specific behavioural and neuroimaging tests reviewed here indicate that dyslexia is indeed associated with cerebellar impairment in about 80% of cases. We propose that disorders of cerebellar development can in fact cause the impairments in reading and writing characteristic of dyslexia, a view consistent with the recently appreciated role of the cerebellum in language-related skills. This proposal has implications for early remedial treatment.

Animals↗
PubMed2001

Site-specific molecular design and its relevance to pharmacogenomics and chemical biology.

The emergence of the new discipline of pharmacogenomics reflects the growing convergence of chemical and genomic space. The massive information-driven growth in both computational chemistry and structural biology is leading to unprecedented opportunities in both chemical and biological design. In this paper we relate current opinion in structural biology to recent developments in computational drug design. Sequence information now permits protein structure prediction and, together with experimental protein structure determination, a complete database of ligand-binding sites and protein-protein interactions can be assembled. When aligned with site exploration and virtual screening, this information provides a foundation for structure-based pharmacogenomics. In association with chemical genomics, structure-based design will allow major new insights into a compound's biological and pharmaceutical properties.

Binding Sites↗
PubMed2001

Audit in general practice: how much and how complete? Frequency of audit in general practice.

The aim of this study was to determine the frequency of audit and the proportion completed in a group of practices. Data obtained by interviewing a member of each practice and inspecting practice records were independently coded by researchers. Practices initiated an average of 3.5 (range 1-7) audits in 2 years, of which an average of 0.9 (range 0-3) were completed. Ten of 16 completed audits were externally funded or facilitated. Few audits are completed in general practice and practices require continuing support for audit.

Abstracting and Indexing↗
PubMed2000

Acid phosphatases in the haemolymph of the desert locust, Schistocerca gregaria, infected with the entomopathogenic fungus Metarhizium anisopliae.

A comparison has been made between the effects of wounding, chemical stimulation of the immune system and fungal infection on acid phosphatase (AcP) activity in the haemolymph of the desert locust, Schistocerca gregaria. Untreated control locusts had constitutive levels of AcP. As a lysosomal enzyme, AcP may have a role in autophagy and cell turn over as well as defence. Injection of saline and beta-1,3-glucan caused significant increases in haemocyte and plasma AcP. AcP activity also increased in the haemolymph on the 3rd day after inoculation with the entomopathogenic fungus M. anisopliae var acridum. This coincided with a decline in the total haemocyte count and a marked reduction in the proportion of plasmatocytes and coagulocytes that stained positive for AcP. Therefore a priori it seemed unlikely that the extra AcP in infected insects came from the host. A fungal origin for the enzyme was suggested by the identification of AcP isoforms from haemolymph of different treatments. Control inoculated (oil only) insects had an AcP at a pI of 4.3 that was stimulated further by the injection of laminarin. Additional isoforms appeared at around 7.3-7.5 in the laminarin treatment. However, the 4.3 isoform appeared to be suppressed in the insects infected with M. anisopliae var acridum. The band intensity was more like that of the control than the laminarin-injected insects. Two new isoforms appeared later on in infection. These enzymes had pIs that corresponded to some of the AcPs produced in vitro by the fungus. The results are discussed in the light of the possible benefits of secreted fungal acid phosphatases to the pathogen.

Journal Article↗
PubMed2000

Predictors of outcome in pediatric epilepsy surgery.

OBJECTIVE: To determine the correlation between pre- and perioperative variables on the outcome of children undergoing focal resections for medically intractable partial epilepsy. METHODS: Retrospective analysis of pre- and perioperative variables in a cohort of 75 patients younger than 12 years of age who underwent excisional surgery and had at least 1 year of follow-up. Outcome, measured by postoperative seizure frequency, was analyzed as a function of age at seizure onset, duration of epilepsy, presence of cognitive impairment, lobe of seizure origin, presence of a lesion, histopathology, and completeness of resection. Completeness of resection was defined on the basis of excising both the entire structural lesion if present and the region revealing prominent interictal and ictal abnormalities on intracranial EEG. RESULTS: Seventy-seven percent of patients had good outcomes (class 1 or 2), and 59% were seizure-free. Lesional status, site of resection, and pathologic diagnoses were not significant predictors of outcome except for in multilobar resection, for which overall outcome was relatively poor (44% class 3 or 4; 22% seizure-free). Completeness of resection was the only significant predictor of good outcome (p < 0.001), with 92% of patients who underwent complete resection of the epileptogenic zone achieving good outcome compared with 50% of patients who had incomplete resections. CONCLUSION: In this series of pediatric patients, complete resection of the lesion and the electrographically abnormal region was the main determinant of outcome after focal resections. Except for multilobar resections, other factors examined in this study did not significantly influence postoperative seizure prognosis and should not influence candidate selection for the surgical process.

Child↗
PubMed2000

A simple control law generates Listing's positions in a detailed model of the extraocular muscle system.

The neural commands for maintaining static Listing's positions were identified using a detailed model of extraocular muscle based on Miller and Shamaeva (Orbit 1.5 gaze mechanics simulation 1995). The commands were approximately separable, suggesting a simple control law whereby independent horizontal and vertical commands are combined to generate tertiary positions. Tests showed that this control law (i) generated Listing' s positions to reasonable accuracy over+/-30 deg, provided pulleys were represented in the model; (ii) if driven by retinal coordinates, produced errors close to the theoretical minimum for a commutative system. The proposed commands appear consistent with electrophysiological evidence.

Biomechanical Phenomena↗
PubMed2000

Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome.

PURPOSE: Children with tuberous sclerosis complex (TSC) benefit from excisional surgery if seizures can be localized to a single tuber. We evaluated the role of noninvasive studies to localize the epileptogenic tuber/region (ET/R) and the outcome of focal resection. METHODS: We identified 21 children with TSC, ages 3 months to 15 years (mean 4.8 years). All had video-(electroencephalogram) EEG and magnetic resonance imaging (MRI) scans, and 18 also had ictal single photon emission-computed tomography (SPECT) studies. An ET/R was localized in 17 patients. Thirteen patients underwent resection guided by intraoperative electrocorticography (n = 7) or subdural monitoring (n = 6). RESULTS: Interictal EEG revealed a principal spike focus (PSF) that corresponded to the ET/R in 14 children. In seven, PSFs occurred in rhythmic runs. PSFs were not observed remote from the ET/R. Focal polymorphic slowing and attenuation occurred in the region of the PSF in 11 patients. Sixteen patients demonstrated an ictal focus corresponding to the ET/R. Ictal SPECT revealed focal hyperperfusion correlating with the ET/R in 10 patients. Although the MRIs in all children revealed multiple tubers, the ET/R corresponded to a large discrete tuber in 8 patients and a calcified tuber in 13 patients. Patchy calcified tubers were also seen elsewhere in six patients. At a mean follow-up of 26 months, 9 of the 13 children who underwent surgery were seizure-free, one had greater than 75% reduction in seizures, two were unchanged, and one was lost to follow-up. New seizures developed in one child from a contralateral tuber. CONCLUSIONS: Surgical resection of an ET/R alleviates seizures in most children with TSC and intractable epilepsy. The scalp EEG and MRI help define the ET/R and improve case selection when ictal SPECT is nonlocalizing.

Adolescent↗