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Biomedical subjects

J K White

Publications and source records attributed to J K White.

At least 19 recordsLinked to original sources
PubMed2002

Achronal generalized synchronization in mutually coupled semiconductor lasers.

Heil et al. [Phys. Rev. Lett. 86, 795 (2001)] recently discovered achronal synchronization of chaos in mutually coupled semiconductor lasers. This paper offers an analytic interpretation of their experiment using a simple rate equation model. Local eigenvalue analysis shows that isochronal synchronization is unstable; achronal synchronization, on the other hand, is stable if a generalized synchronization function is introduced. Single- and multimode simulations have substantiated this rate equation interpretation. Finally, there is a brief examination of "chaos pass filtering."

Journal Article↗
PubMed2000

Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice.

Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.

Animals↗
PubMed2000

The use of a novel tissue sealant as a hemostatic adjunct in cardiac surgery.

BACKGROUND: In spite of advances in the management of bleeding associated with cardiac surgery, hemorrhage remains a troublesome problem, particularly in complex cases and high risk patients. In minimally invasive cardiac surgery, limited exposure and tight quarters may make accurate suturing difficult, and increase the risk of surgical bleeding. A surgical sealant that effectively prevents suture line bleeding would be a valuable resource for cardiac surgeons and might help to facilitate minimal access cases. METHODS: We undertook acute canine studies with a new polyethylene glycol-based tissue sealant (FocalSeal, Focal, Inc., Lexington, MA) to determine its effectiveness in controlling bleeding from graduated needle punctures sites in the arteries of heparinized animals. For chronic canine studies, the sealant was applied to the suture line of a left internal mammary artery (LIMA) to left anterior descending (LAD) anastomoses. The anastomoses were then evaluated for patency and tissue reaction after a three-month recovery period. RESULTS: The sealant prevented bleeding from arterial puncture wounds up to 2.5 mm in diameter. Three months following the application of sealant to coronary anastomoses, no adverse tissue reaction was found on histologic examination. All anastomoses treated with the sealant remained patent. CONCLUSION: When applied as a hemostatic adjunct to sutures at a coronary anastomosis, the sealant appears to be an effective means of preventing bleeding without adverse tissue reaction or scarring.

Anastomosis, Surgical↗
PubMed1999

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse.

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.

Age Factors↗
PubMed1997

Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein. To elucidate the molecular basis of HD, we extended the polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an expanded human HD CAG repeat, creating mutant HdhneoQ50 and HdhQ50 alleles that express reduced and wild-type levels of altered huntingtin, respectively. Mice homozygous for reduced levels displayed characteristic aberrant brain development and perinatal lethality, indicating a critical function for Hdh in neurogenesis. However, mice with normal levels of mutant huntingtin did not display these abnormalities, indicating that the expanded CAG repeat does not eliminate or detectably impair huntingtin's neurogenic function. Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism.

Alleles↗
PubMed1995

Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism.

BACKGROUND: Murine Nramp is a candidate for the macrophage resistance gene Ity/Lsh/Bcg. Sequence analysis of human NRAMP was undertaken to determine its role in man. MATERIALS AND METHODS: A yeast artificial chromosome carrying NRAMP was subcloned and positive clones sequenced. The transcriptional start site was mapped using 5' RACE PCR. Polymorphic variants were amplified by PCR. Linkage analysis was used to map NRAMP. RESULTS: NRAMP spans 12kb and has 15 exons encoding a 550 amino acid protein showing 85% identity (92% similarity) with Nramp. Two conserved PKC sites occur in exon 2 encoding the Pro/Ser rich SH3 binding domain, and in exon 3. Striking sequence similarities (57 and 53%) were observed with yeast mitochondrial proteins, SMF1 and SMF2, especially within putative functional domains: exon 6 encoding the second transmembrane spanning domain, site of the murine susceptibility mutation; and exon 11 encoding a conserved transport motif. No mutations comparable to the murine susceptibility mutation were found. The transcriptional initiation site mapped 148 bp 5' of the translational initiation codon. 440bp of 5' flanking sequence contained putative promoter region elements: 6 interferon-gamma response elements, 3 W-elements, 3 NF kappa B binding sites and 1 AP-1 site. Nine purine-rich GGAA core motifs for the myeloid-specific PU.1 transcription factor were identified, two combining with imperfect AP1-like sites to create PEA3 motifs. TATA, GC and CCAAT boxes were absent. A possible enhancer element containing the Z-DNA forming dinucleotide repeat t(gt),ac(gt),ac(gt),g was polymorphic (4 alleles; n = 4,9,10,11), and was used to map NRAMP to 2q35. CONCLUSIONS: This analysis provides important resources to study the role of NRAMP in human disease.

Alleles↗
PubMed1994

Genetic and physical mapping of 2q35 in the region of the NRAMP and IL8R genes: identification of a polymorphic repeat in exon 2 of NRAMP.

Recent interest has focused on the region of conserved synteny between mouse chromosome 1 and human 2q33-q37, particularly over the region encoding the murine macrophage resistance gene Ity/Lsh/Bcg (candidate Nramp) and members of the Il8r interleukin-8 (IL8) receptor gene cluster. In this paper, identification of a restriction fragment length polymorphism in the IL8RB gene in 35 pedigrees previously typed for markers in the 2q33-q37 interval provided evidence (lod scores > 3) for linkage between IL8RB and the 2q34-q35 markers FN1, TNP1, VIL1, and DES. Physical mapping, using yeast artificial chromosomes isolated with VIL1, confirmed that IL8RA, IL8RB, and the IL8RB pseudogene map within the NRAMP-VIL1 interval, with the physical distance (155 kb) from 5' LSH to 3' VIL1 representing approximately 3-fold that observed in the mouse. Partial sequencing of NRAMP confirmed the presence of the N-terminal proline/serine-rich putative SH3 binding domain in exon 2 of the human gene. Further analysis of Brazilian leprosy and visceral leishmaniasis pedigrees identified a rare second allele varying in a 9-nucleotide repeat motif of the exon 2 sequence but segregating independently of the disease phenotype.

Animals↗
PubMed1994

NH2-terminal sequence of macrophage-expressed natural resistance-associated macrophage protein (Nramp) encodes a proline/serine-rich putative Src homology 3-binding domain.

The Lsh/Ity/Bcg locus on mouse chromosome 1 regulates macrophage (m phi) priming/activation for antimicrobial activity against intracellular pathogens. A candidate Bcg gene, designated natural resistance-associated m phi protein (Nramp), recently isolated from a pre-B cell cDNA library encodes a polytopic integral membrane protein with structural features common to prokaryotic and eukaryotic transporters. In the present study, an activated m phi cDNA library yielded new Nramp clones that differ in the 5' region from the published pre-B cell-derived clone sequence, resulting in addition of 64 amino acids at the NH2 terminus of the predicted protein. This new domain is rich in proline, serine, and basic amino acids, and includes three protein kinase C phosphorylation sites and a putative Src homology 3 binding domain. RNAs containing this domain are the only form found in the m phi. Hence, the protein encoded by this RNA is the candidate molecule mediating natural resistance to intra-m phi pathogens.

Amino Acid Sequence↗
PubMed1994

Genetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues.

A common basis to genetic regulation of leishmanial and mycobacterial infections is provided by the action of the murine Lsh/Ity/Bcg gene in controlling the priming/activation of macrophages for antimicrobial activity. This relies on the TNF-alpha-dependent sustained expression of the inducible nitric oxide synthase (iNOS) gene responsible for the generation of large amounts of toxic nitric oxide (NO). The Lsh/Ity/Bcg gene has many pleiotropic effects, including differential expression of the early response gene KC following stimulation of macrophages with bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM). The major signal transduction pathway involved in KC induction requires the generation of low levels of NO via constitutive nitric oxide synthase (cNOS) activity, leading to activation of guanylate cyclase and the cGMP-dependent kinase pathway. NO therefore appears to provide a common link between the early influence of Lsh in regulating the expression of genes which mediate many pleiotropic effects, and the later production of NO as the final effector mechanism for kill. The recently cloned candidate for Lsh/Ity/Bcg, designated Nramp for Natural resistance associated macrophage protein, encodes a polytopic integral membrane protein that has structural features common to prokaryotic and eukaryotic transporters and includes a conserved binding-protein-dependent transport motif which may be involved in interaction with peripheral ATP-binding subunits. The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function. (ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Chronotropic incompetence: a common and progressive finding in pacemaker patients.

Thirty-eight patients (ages 40 to 77 years, mean 63) followed in a pacemaker clinic underwent exercise treadmill tests to determine chronotropic incompetence. There were 28 men and 10 women. Twenty-seven patients had atrioventricular (AV) block and 11 patients had sick sinus syndrome. All patients were exercised to fatigue. None of the patients were receiving beta-blockers or other drugs that could reduce heart rate. Maximum heart rate (MHR) and percent predicted maximum heart rate (% PMHR) were used as an index of chronotropic incompetence. Chronotropic incompetence was defined as inability to achieve a % PMHR of greater than 80%. The overall incidence of chronotropic incompetence was 58% (22 of 38 patients). We examined the relationship between chronotropic incompetence and the time to pacemaker implantation. We found that in patients who had pacemakers for less than 2 years, the mean MHR was 125 +/- 21.6 beats/min compared with 111.9 +/- 23.6 beats/min for patients who had pacemakers implanted for longer than 4 years. Similarly, the mean % PMHR decreased from 76.5 +/- 12.5% to 68.7 +/- 15.4% in patients with pacemakers less than 2 years versus those with pacemakers for more than 4 years. Fifty-three percent of the patients with a pacemaker less than 2 years old were chronotropic incompetent versus 70% of the patients with a pacemaker more than 4 years old. These data suggest that chronotropic incompetence worsens with time after pacemaker implant. To further support this, eight patients with AV block underwent a second stress test an average of 2 years following the first.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

The potential utility of sensor-driven pacing in DDD pacemakers.

Sensor-driven pacemakers have clinically improved symptomatology over ventricular pacemakers. Adding rate responsiveness to DDD pacing would theoretically benefit patients with an inability to increase their atrial rate. We evaluated 20 patients who had long-term implanted DDD pacemakers as to the utility of an added effect of rate responsiveness. The pacemakers had been implanted for an average of 34 months. This patient group included 15 patients with atrioventricular (AV) block and five patients with sick sinus syndrome. All patients were exercised on the treadmill until they were fatigued and were monitored to determine their intrinsic heart rate response. A sensor-driven pacemaker was strapped to the patients and was connected to an ECG to measure its rate response. It was set to activity threshold of medium, with a rate response of 7. The 20 patients exercised for an average of 5.9 minutes, with a range of 1.7 to 10 minutes. The maximum intrinsic atrial response averaged 110 beats/min, ranging from 60 to 150 beats/min. The maximum achieved activity rate averaged 99 beats/min, ranging from 60 to 118 beats/min. In 7 of the 20 of patients (35%), the activity pacemaker reached a higher rate than the patient's intrinsic rate. Six had AV block and one had sick sinus syndrome. In these seven patients the peak activity rate response averaged 102 beats/min and their intrinsic activity averaged to 78 beats/min. There was an increase in rate by the addition of rate responsiveness in 35% of our DDD patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗