Biomedical subjects

J L Jensen

Publications and source records attributed to J L Jensen.

At least 19 recordsLinked to original sources

PubMed2005

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

Adenocarcinoma↗

PubMed2003

PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.

BACKGROUND: Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified. METHODS: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS. RESULTS: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP(2)-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males. CONCLUSIONS: The novel mutations corresponding to residues involved in Kir2.1 channel-PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.

Abnormalities, Multiple↗

PubMed2003

Idiopathic priapism in a young boy.

We report a case of recurrent priapism in a boy. There were no recurrences during or after oral treatment with Bricanyl (terbutaline).

Adolescent↗

PubMed2002

Submillimeter-wave phonon modes in DNA macromolecules.

A detailed investigation of phonon modes in DNA macromolecules is presented. This work presents experimental evidence to confirm the presence of multiple dielectric resonances in the submillimeter-wave spectra (i.e., approximately 0.01-10 THz) obtained from DNA samples. These long-wave (i.e., approximately 1-30 cm(-1)) absorption features are shown to be intrinsic properties of the particular DNA sequence under study. Most importantly, a direct comparison of spectra between different DNA samples reveals a large number of modes and a reasonable level of sequence-specific uniqueness. This work establishes the initial foundation for the future use of submillimeter-wave spectroscopy in the identification and characterization of DNA macromolecules.

Biophysics↗

PubMed2001

How do non-muscular torques contribute to the kinetics of postural recovery following a support surface translation?

The common platform translation paradigm used in balance control studies employs a disturbance event that applies non-muscular forces to the body for the duration of the disturbance. Previous research has explored the process of constructing the balance recovery by considering these perturbations to be trigger events, not events with an ongoing force application timeline. The purpose of this study was to quantify the effect of muscular and non-muscular torques on post-perturbation balance with particular interest in the role of the external perturbation in balance recovery. Five young adult males experienced backward translations of the support surface at three different speeds. Integration intervals were defined for each segment and angular impulses were calculated for a period of increasing angular momentum (destabilization), and a period of decreasing angular momentum (restabilization). Destabilization of distal segments was primarily due to impulse generated by the motion of the support surface. For the trunk, however, muscle and motion-dependent sources contributed most to increasing momentum. Restabilization of distal segments was achieved by muscle and platform impulses while trunk restabilization was achieved by muscle and motion-dependent terms in opposition to gravity. Increased platform speed resulted in increased muscular contribution only in the control of the trunk, while demand on distal musculature decreased with change in platform speed as the platform contribution to restabilization increased in these segments. Therefore, impulses from non-muscular sources, including the perturbation itself, are significant modifiers of the response to balance disturbances and must be accounted for in balance research.

Adult↗

PubMed2001

A dynamical systems investigation of lower extremity coordination during running over obstacles.

OBJECTIVE: To investigate intralimb coordination during running over a level surface and over obstacles of three different heights. DESIGN: The phasing relationships between the foot and leg motions in the frontal plane, and the shank and thigh motions in the sagittal plane were used to compare patterns of coordination. BACKGROUND: The coordinated actions of lower extremity segments are necessary to absorb the impact forces generated during running. The behavioral patterns of these segments can be studied under changing task demands using analysis techniques from the Dynamical Systems Theory. METHODS: Ten subjects ran at their self-selected pace under four conditions: over a level surface and over obstacles of different heights (5%, 10%, 15% of their standing height). A force platform was used to record impact forces during landing after obstacle clearance, while kinematics were collected using a two-camera system. RESULTS: The increases in obstacle height resulted in significant changes in impact forces (34% increase between the two extreme conditions) and more in-phase relationships between the segments during early stance. No changes were observed in the variability of the phasing relationships. CONCLUSIONS: The coordination changes observed might be compensatory strategies aimed to reduce forces and potential injury. However, since the impact forces still increased significantly, it is also possible that the observed changes might be at-risk movement patterns predisposing runners to injury.

Adult↗

PubMed2001

Intralimb coordination following obstacle clearance during running: the effect of obstacle height.

The purpose of this study was to investigate the different coordination strategies used following obstacle clearance during running. Ten subjects ran over a level surface and over obstacles of six different heights (10, 12.5, 15, 17.5, 20 and 22.5% of their standing height). Analysis based upon the dynamical systems theory (DST) was used and the phasing relationships between lower extremity segments were examined. The results demonstrated that the increasing obstacle height elicited behavioral changes. The foot and the leg became more independent in their actions, while the leg and the thigh strengthened their already stable relationship. The 15% obstacle height seems to be a critical height for the observed changes.

Adult↗

PubMed2001

The translating platform paradigm: perturbation displacement waveform alters the postural response.

The translating platform paradigm is widely used to investigate the regulation of upright standing and locomotion. This study investigated how the displacement waveform characteristics underlying the translating platform perturbation are revealed in the resulting postural response. Eight participants experienced a series of backward-directed perturbations using a hydraulically driven forceplate. Two ranges of platform displacement (5 and 15 cm) in combination with two peak velocities (40 and 60 cm/s) were achieved using three distinct waveforms for platform displacement: (a) RAMP: ramp onset and ramp offset, (b) Ramp-to-Parabola (R-P): ramp onset with parabolic offset and (c) SINE: sine-wave onset with sine wave offset. Our findings indicated that the unique and distinctive acceleration and deceleration characteristics that result from the three different platform displacement waveforms significantly altered the postural response to the perturbation.

Adult↗

PubMed2001

Molecularly imprinted polymer sensors for pesticide and insecticide detection in water.

Antibodies, peptides, and enzymes are often used as molecular recognition elements in chemical and biological sensors. However, their lack of stability and signal transduction mechanisms limits their use as sensing devices. Recent advances in the field of molecularly imprinted polymers (MIPs) have created synthetic materials that can mimic the function of biological receptors but with less stability constraints. These polymers can provide high sensitivity and selectivity while maintaining excellent thermal and mechanical stability. To further enhance the advantages of the traditional imprinted polymer approach, an additional fluorescent component has been introduced into these polymers. Such a component provides enhanced chemical affinity as well as a method for signal transduction. In this type of imprinted polymer, binding of the target analyte invokes a specific spectral signature from the reporter molecule. Previous work has provided molecularly imprinted polymers that are selective for the hydrolysis products of organophosphorus species such as the nerve agents sarin and soman. (A. L. Jenkins, O. M. Uy and G. M. Murray, Anal. Chem., 1999, 71, 373). In this paper the direct imprinting of non-hydrolyzed organophosphates including pesticides and insecticides is described. Detection limits for these newly developed MIP sensors are less than 10 parts per trillion (ppt) with long linear dynamic ranges (ppt to ppm) and response times of less than 15 min.

Insecticides↗

PubMed2001

Development of lower extremity kinetics for balance control in infants and young children.

Developmental changes in the kinematics and kinetics underlying balance control were studied in 61 children, 9 months to 10 years of age. The children were classified according to developmental milestones as standers; new, intermediate, and advanced walkers; runners-jumpers; hoppers; gallopers; and skippers. The children experienced support-surface translations of varying size and speed. Children with greater locomotor experience withstood larger balance threats without collapsing or stepping. Analyses of scaled trials (perturbations normalized in size to foot length and center of gravity height) revealed that improvement in balance was not related to initial configuration parameters surrounding the task (degree of crouch or lean). Children with advanced locomotor skills had faster recovery times and relatively larger muscle torques than children with less experience. Relative torque-time histories of the more experienced children began to match the adult response to similar perturbations. With increased experience and changing muscle torque regulatory abilities, balance skills became more robust.

Child↗

PubMed2001

A dependent-rates model and an MCMC-based methodology for the maximum-likelihood analysis of sequences with overlapping reading frames.

We present a model and methodology for the maximum-likelihood analysis of pairwise alignments of DNA sequences in which two genes are encoded in overlapping reading frames. In the model for the substitution process, the instantaneous rates of substitution are allowed to depend on the nucleotides occupying the sites in a neighborhood of the site subject to substitution at the instant of the substitution. By defining the neighborhood of a site to extend over all sites in the codons in both reading frames to which a site belongs, constraints imposed by the genetic code in both reading frames can be taken into account. Due to the dependency of the instantaneous rates of substitution on the states at neighboring sites, the transition probability between sequences does not factorize and therefore cannot be obtained directly. We present a Markov chain Monte Carlo procedure for obtaining the ratio of two transition probabilities between two sequences under the model considered, and we describe how maximum-likelihood parameter estimation and likelihood ratio tests can be performed using the procedure. We describe how the expected numbers of different types of substitutions in the shared history of two sequences can be calculated, and we use the described model and methodology in an analysis of a pairwise alignment of two hepatitis B sequences in which two genes are encoded in overlapping frames. Finally, we present an extended model, together with a simpler approximate estimation procedure, and use this to test the adequacy of the former model.

Base Sequence↗

PubMed2001

Basal cell carcinoma of the buccal mucosa.

True basal cell carcinoma (BCC) involving the oral mucous membranes is extraordinarily rare. Most of those described as occurring in the oral cavity usually involve the gingiva and are not true BCCs but peripheral ameloblastomas. A true BCC, which arose on the buccal mucosa of a 69-year old man, is reported. It presented as a 1.3 cm ulcerated plaque without gingival connection. Histologically, the lesion exhibited classic features of BCC with palisading and retraction spaces, and focally communicated with the overlying squamous epithelium. Although it is possible that this lesion also arose from a heterotopic odontogenic rest, the anatomical location, focal squamous (metatypical) features, and positive staining for Ber-EP4 support an origin from the basal cell layer of stratified squamous mucosa.

Aged↗

PubMed2001

Oligodontia is associated with extra-oral ectodermal symptoms and low whole salivary flow rates.

INTRODUCTION: Ectodermal dysplasias (EDs) involve abnormal development of hair, teeth, nails, and sweat glands. OBJECTIVES: (1) To investigate the frequency of extraoral ectodermal symptoms in persons with oligodontia (>6 congenitally missing teeth). (2) To examine whole salivary flow rates in oligodontia patients, with special emphasis on persons with EDs. SURVEY GROUP AND METHODS: Sixty-eight persons with oligodontia and 39 healthy control persons were included. All participants underwent an interview, general and oral examinations, and whole salivary secretory tests. RESULTS: Thirty-nine (57%) of the oligodontia patients had disturbances in either hair, nails and/or sweat production in addition to teeth and were classified as the ED group. The remaining 29 oligodontia patients had no obvious signs of EDs (non-ED group). The prevalences of dry skin, asthma and eczema were higher, and whole salivary secretory rates lower, in the ED group as compared to the control group. Intermediate values were observed in the non-ED group. Incisors, canines and molars were more frequently missing in the ED group than in the non-ED group, whereas no differences were observed in the frequency of missing premolars. Negative correlations between the number of missing teeth and unstimulated and chewing stimulated whole salivary secretory rates were found.

Adolescent↗

PubMed2000

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Aneuploidy↗

PubMed2000

Spatial mixture modeling of fMRI data.

Recently, Everitt and Bullmore [1999] proposed a mixture model for a test statistic for activation in fMRI data. The distribution of the statistic was divided into two components; one for nonactivated voxels and one for activated voxels. In this framework one can calculate a posterior probability for a voxel being activated, which provides a more natural basis for thresholding the statistic image, than that based on P-values. In this article, we extend the method of Everitt and Bullmore to account for spatial coherency of activated regions. We achieve this by formulating a model for the activation in a small region of voxels and using this spatial structure when calculating the posterior probability of a voxel being activated. We have investigated several choices of spatial models but find that they all work equally well for brain imaging data. We applied the model to synthetic data from statistical image analysis, a synthetic fMRI data set and to visual stimulation data. Our conclusion is that the method improves the estimation of the activation pattern significantly, compared to the nonspatial model and to smoothing the data with a kernel of FWHM 3 voxels. The difference between FWHM 2 smoothing and our method were more modest.

Brain↗

PubMed2000

Metal-catalyzed oxidation of brain-derived neurotrophic factor (BDNF): analytical challenges for the identification of modified sites.

PURPOSE: We examined the metal-catalyzed oxidation of brain-derived neurotrophic factor (BDNF) using the Cu(II)/ascorbate/O2 model oxidative system. METHODS: Electrospray ionization mass spectrometry, peptide mapping and amino acid analysis were utilized to determine the nature of the covalent modification induced by the metal-catalyzed oxidative system. Additionally, analytical ultracentrifugation, the Bradford assay, circular dichroism and ANSA dye-binding were used to determine the nature of any conformational changes induced by the oxidation. RESULTS: Exposure of BDNF to the Cu(II)/ascorbate/O2 system led to the modification of ca. 35% of Met92 to its sulfoxide, and to subsequent conformational changes. The proteolytic digestion procedure was sensitive to this conformational change, and was unable to detect the modification. Chemical digestion with CNBr, however, was not sensitive to this change, and allowed for the identification of the site of modification. CONCLUSIONS: The modification of Met92 to its sulfoxide rendered the oxidized BDNF inaccessible to proteolytic digestion, due to conformational changes associated with the oxidation.

Amino Acid Sequence↗

PubMed2000

The development of compensatory stepping skills in children.

The development of the ability to use the step for balance recovery was studied among twenty-five 9- to 19-month-old children. The children were grouped according to walking experience (4 levels) and exposed to backward support surface translations, 8 cm in amplitude, under 3 velocity conditions: 15, 20, and 25 cm/s. New walkers (up to 2 weeks' walking experience) used the step infrequently and ineffectively in response to threats to balance. Intermediate walkers (1-3 months' walking experience) showed an increasing use of the step and significant improvement in step execution compared with new walkers. Advanced walkers (>3; months' walking experience) experienced no falls throughout the protocol, capturing balance with feet-in-place or step responses under all perturbation conditions. A significant developmental transition in the emergence of the compensatory step occurred between the new walker and the intermediate walker experience levels, that is, within the first 3 months of walking experience. Three to 6 months' experience was required for the development of an effective stepping response. A concomitant change in mediolateral stability paralleled the emergence of compensatory stepping.

Child Development↗

PubMed2000

Metal-catalyzed oxidation of brain-derived neurotrophic factor (BDNF): selectivity and conformational consequences of histidine modification.

We have studied the metal-catalyzed oxidation (MCO) of brain-derived neurotrophic factor (BDNF) with regard to target sites and potential conformational changes of the protein. The exposure of BDNF to three different levels of ascorbate/Cu(II)/O2 [20 microM Cu(II), 2 mM ascorbate (level 1); 20 microM Cu(II), 4 mM ascorbate (level 2); 40 microM Cu(II), 4 mM ascorbate (level 3)], chosen based on the extent of chemical modification of Met and His, respectively, resulted in the exclusive oxidation of a buried Met residue, Met92, at level 1 but in the predominant oxidation of His at level 3. His modification had a significant impact on the structure of BDNF, as quantified by CD and ANSA fluorescence measurements, while Met oxidation had not, also assessed through complementary oxidation of BDNF through hydrogen peroxide. Our ultimate objective was the correlation of the surface exposure of an oxidized His residue in a protein with potential effects on the conformational integrity of the oxidized protein. In a series of three proteins, human growth hormone (hGH), human relaxin (hR1x), and BDNF, we have now observed that His oxidation is paralleled by significant conformational changes when the target His residue is more surface exposed (hR1x, BDNF) while conformational consequences of His modification are less significant when the target His residues are more buried in the interior of the protein (hGH).

Amino Acid Sequence↗