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Biomedical subjects

K Clark

Publications and source records attributed to K Clark.

At least 37 records · Page 2Linked to original sources
PubMed2001

A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia.

The recurrent translocation t(5;11)(q35;p15.5) associated with a 5q deletion, del(5q), has been reported in childhood acute myeloid leukemia (AML). We report the cloning of the translocation breakpoints in de novo childhood AML harboring a cryptic t(5;11)(q35;p15.5). Fluorescence in situ hybridization (FISH) analysis demonstrated that the nucleoporin gene (NUP98) at 11p15.5 was disrupted by this translocation. By using 3'--rapid amplification of complementary DNA ends (3'-RACE) polymerase chain reaction, we identified a chimeric messenger RNA that results in the in-frame fusion of NUP98 to a novel gene, NSD1. The NSD1 gene has 2596 amino acid residues and a 85% homology to the murine Nsd1 with the domain structure being conserved. The NSD1 gene was localized to 5q35 by FISH and is widely expressed. The reciprocal transcript, NSD1-NUP98, was also detected by reverse transcriptase--polymerase chain reaction. This is the first report in which the novel gene NSD1 has been implicated in human malignancy. (Blood. 2001;98:1264-1267)

Acute Disease↗
PubMed2001

IL-13 induces airways hyperreactivity independently of the IL-4R alpha chain in the allergic lung.

The potent spasmogenic properties of IL-13 have identified this molecule as a potential regulator of airways hyperreactivity (AHR) in asthma. Although IL-13 is thought to primarily signal through the IL-13Ralpha1-IL-4Ralpha complex, the cellular and molecular components employed by this cytokine to induce AHR in the allergic lung have not been identified. By transferring OVA-specific CD4(+) T cells that were wild type (IL-13(+/+) T cells) or deficient in IL-13 (IL-13(-/-) T cells) to nonsensitized mice that were then challenged with OVA aerosol, we show that T cell-derived IL-13 plays a key role in regulating AHR, mucus hypersecretion, eotaxin production, and eosinophilia in the allergic lung. Moreover, IL-13(+/+) T cells induce these features (except mucus production) of allergic disease independently of the IL-4Ralpha chain. By contrast, IL-13(+/+) T cells did not induce disease in STAT6-deficient mice. This shows that IL-13 employs a novel component of the IL-13 receptor signaling system that involves STAT6, independently of the IL-4Ralpha chain, to modulate pathogenesis. We show that this novel pathway for IL-13 signaling is dependent on T cell activation in the lung and is critically linked to downstream effector pathways regulated by eotaxin and STAT6.

Adoptive Transfer↗
PubMed2001

Schizotypy and the shift from dextrality: a study of handedness in a large non-clinical sample.

Numerous previous studies have reported associations between schizophrenia/schizotypy and atypical handedness. While there is broad agreement that schizophrenia/schizotypy is associated with a shift away from typical (strong right) handedness, it is not entirely clear what aspect of atypical handedness is implicated: 'ambiguous' handedness (the absence of hand preference for given actions) or 'mixed handedness' (different hand preferences for different actions). The present study used several indices of handedness (derived from the Annett scale) to address these questions in 3000 + (mostly) University student subjects recruited by electronic mail. It was found that positive schizotypy (indexed by a scale of 'unusual experiences') was associated with both aspects of atypical handedness. These findings are discussed in the light of various possible explanations of the association between handedness and schizophrenia/schizotypy.

Adolescent↗
PubMed2001

Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16.

We have sequenced 1949 kb from the terminal Giemsa light band of human chromosome 16p, enabling us to fully annotate the region extending from the telomeric repeats to the previously published tuberous sclerosis disease 2 (TSC2) and polycystic kidney disease 1 (PKD1) genes. This region can be subdivided into two GC-rich, Alu-rich domains and one GC-rich, Alu-poor domain. The entire region is extremely gene rich, containing 100 confirmed genes and 20 predicted genes. Many of the genes encode widely expressed proteins orchestrating basic cellular processes (e.g. DNA recombination, repair, transcription, RNA processing, signal transduction, intracellular signalling and mRNA translation). Others, such as the alpha globin genes (HBA1 and HBA2), PDIP and BAIAP3, are specialized tissue-restricted genes. Some of the genes have been previously implicated in the pathophysiology of important human genetic diseases (e.g. asthma, cataracts and the ATR-16 syndrome). Others are known disease genes for alpha thalassaemia, adult polycystic kidney disease and tuberous sclerosis. There is also linkage evidence for bipolar affective disorder, epilepsy and autism in this region. Sixty-three chromosomal deletions reported here and elsewhere allow us to interpret the results of removing progressively larger numbers of genes from this well defined human telomeric region.

Adolescent↗
PubMed2001

Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster.

We have cloned, sequenced and annotated segments of DNA spanning the mouse, chicken and pufferfish alpha globin gene clusters and compared them with the corresponding region in man. This has defined a small segment ( approximately 135-155 kb) of synteny and conserved gene order, which may contain all of the elements required to fully regulate alpha globin gene expression from its natural chromosomal environment. Comparing human and mouse sequences using previously described methods failed to identify the known regulatory elements. However, refining these methods by ranking identity scores of non-coding sequences, we found conserved sequences including the previously characterized alpha globin major regulatory element. In chicken and pufferfish, regions that may correspond to this element were found by analysing the distribution of transcription factor binding sites. Regions identified in this way act as strong enhancer elements in expression assays. In addition to delimiting the alpha globin chromosomal domain, this study has enabled us to develop a more sensitive and accurate routine for identifying regulatory elements in the human genome.

Animals↗
PubMed2001

Antiviral potential of chemokines.

In the past few years, a large number of new chemokines (chemotactic cytokines) and chemokine receptors have been discovered. The growth in knowledge about these molecules has been achieved largely through advances in bioinformatics and the expansion of expression sequence tag (EST) databases. It is now clear that chemokines are crucial in controlling both the development and functioning of leukocytes and that their role is not restricted to cell attraction, as originally assumed. In particular, recent findings provide strong support for the idea that chemokines and their receptors are especially important in the control of viral infection and replication. Thus, specific chemokines are now known to enhance the cytotoxic activity of infected cells, thus inhibiting further virus replication. In addition, some chemokines orchestrate the recruitment of activated leukocytes to foci of infection to aid viral clearance. Viruses, in turn, have evolved various defences against chemokines. These range from the production of proteins that inhibit biological activity of the host chemokine to the hijacking of the chemokine system, whereby certain viruses utilize chemokine receptors for their entry. The latter viral defence can itself be blocked by chemokines. Altogether, these findings illustrate the central role of chemokines in many different phases of the immune response, particularly those aspects involving antiviral defence, a variety and versatility that was not fully appreciated even a few years ago.

Animals↗
PubMed2001

Evidence for the neural crest origin of turtle plastron bones.

The migrating cranial neural crest cells of birds, fish, and mammals have been shown to form the membranous bones of the cranium and face. These findings have been extrapolated to suggest that all the dermal bones of the vertebrate exoskeleton are derived from the neural crest ectomesenchyme. However, only one group of extant animals, the Chelonians, has an extensive bony exoskeleton in the trunk. We have previously shown that the autapomorphic carapacial and plastron bones of the turtle shell arise from dermal intramembranous ossification. Here, we show that the bones of the plastron stain positively for HNK-1 and PDGFRalpha and are therefore most likely of neural crest origin. This extends the hypothesis of the neural crest origin of the exoskeleton to include the turtle plastron.

Animals↗
PubMed2001

Tamoxifen as systemic treatment of advanced breast cancer during pregnancy--case report and literature review.

BACKGROUND: When patients with metastatic breast cancer become pregnant, management is complicated by the potential harms of drug treatment to the fetus and by the potential effects of the pregnancy on the cancer. Chemotherapy is considered optimal systemic anti-cancer therapy from the second trimester, while tamoxifen has been considered inappropriate due to concerns over possible teratogenesis and lack of efficacy. CASE: We report a patient who became pregnant concurrent with the identification of metastatic breast cancer and who elected to continue her pregnancy with tamoxifen as sole systemic anti-cancer therapy. The pregnancy was difficult, but a normal child was delivered and the mother responded to subsequent hormone manipulation. The putative teratogenic effects of tamoxifen and the mechanisms underlying tamoxifen resistance in this setting are discussed. CONCLUSIONS: The use of tamoxifen in pregnancy is complex, but is not necessarily associated with fetal harm and may be considered a therapeutic option in selected cases.

Adult↗
PubMed2001

Relationship between 24-H blood pressure and sleep disordered breathing in a normotensive community sample.

Sleep disordered breathing (SDB) and hypertension are commonly associated. In this study, we assessed how longitudinal measures of SDB predict a 24-h ambulatory blood pressure monitoring (ABPM) profile. Participants (n = 82) were recruited from a community-based urban (26% African American) sample and included family members of patients with laboratory diagnosed SDB (cases) and family members of neighborhood control subjects evaluated at baseline and at 5 years. Nearly all participants were normotensive and were not receiving therapy for SDB. During both examinations, the respiratory distress index (RDI) was assessed with overnight in-home polysomnography. Seated blood pressure (BP) was assessed at a baseline examination (t,) and after a 5-year follow-up period (t5), when 24-h ABPM also was performed. The change in RDI (t5-t1) over 5 years was significantly associated with 24-h mean systolic blood pressure (SBP) (P = .04), 24-h maximum diastolic blood pressure (DBP) (P = .03), sleep mean SBP (P = .05), sleep mean DBP (P < .05), and sleep maximum SBP (P = .02). Regression analysis revealed that average 24-h mean arterial pressure (MAP) and mean 24-h DBP were each best predicted by change in RDI, explaining 5% of the variance in these 24-h BP readings, and by current smoking status. After accounting for these variables, BP was not predicted by any of the other potential confounders (all P > .10). Mean RDI (averaged between t5 and t1) was associated with mean MAP, mean SBP, and maximal SBP measured during sleep. This study documents for the first time the association between changes in sleep apnea activity and BP and in a community-based normotensive sample. Further long-term evaluation of the effects of these findings and the long-term consequences of hypertension are needed.

Adult↗
PubMed2001

Hypoxia induces the expression of the pro-apoptotic gene BNIP3.

It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene BNIP3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1alpha, but not p53, induces the expression of BNIP3. Overexpression of BNIP3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of BNIP3 may play a significant role during hypoxia-induced cell death.

Animals↗
PubMed2001

Validating risk-adjusted surgical outcomes: chart review of process of care.

OBJECTIVE: The primary purpose of this study was to validate risk-adjusted surgical outcomes as indicators of the quality of surgical care at US Department of Veterans Affairs (VA) hospitals. The secondary purpose was to validate the risk-adjustment models for screening cases for quality review. DESIGN: We compared quality of care, determined by structured implicit chart review, for patients from hospitals with higher and lower than expected operative mortality and morbidity (hospital-level tests) and between patients with high and low predicted risk of mortality and morbidity who died or developed complications (patient-level tests). SUBJECTS: 739 general, peripheral vascular and orthopedic surgery cases sampled from the 44 VA hospitals participating in the National VA Surgical Risk Study. MAIN OUTCOME MEASURES: A global rating of quality of care based on chart review. RESULTS: Ratings of overall quality of care did not differ significantly between patients from hospitals with higher and lower than expected mortality and morbidity. On some of the secondary measures, patient care was rated higher for hospitals with lower than expected operative mortality. At the patient level of analysis, those who died or developed complications and had a high predicted risk of mortality or morbidity were rated higher on quality of care than those with a low predicted risk of adverse outcome. CONCLUSIONS: The absence of a relationship between most of our measures of process of care and risk-adjusted outcomes may be due to an insensitivity of chart reviews to hospital-level differences in quality of care. Site visits to National VA Surgical Risk Study hospitals with high and low risk-adjusted mortality and morbidity have detected differences on a number of dimensions of quality. The patient-level findings suggest that the risk-adjustment models are useful for screening adverse outcome cases for quality of care review.

Data Interpretation, Statistical↗
PubMed2001

Spinal movement and performance of a standing reach task in participants with and without Parkinson disease.

BACKGROUND AND PURPOSE: Evidence suggests that individuals with early and mid-stage Parkinson disease (PD) have diminished range of motion (ROM). Spinal ROM influences the ability to function. In this investigation, the authors examined available spinal ROM, segmental excursions (the ROM used) during reaching, and their relationships in community-dwelling adults with and without PD. SUBJECTS: The subjects were 16 volunteers with PD (modified Hoehn and Yahr stages 1.5-3) and 32 participants without PD who were matched for age, body mass index, and sex. METHODS: Range of motion of the extremities was measured using a goniometer, and ROM of the spine was measured using the functional axial rotation (FAR) test, a measure of unrestricted cervico-thoracic-lumbar rotation in the seated position. Motion during reaching was determined using 3-dimensional motion analysis. Group differences were determined using multivariable analysis of variance followed by analysis of variance. Contributions to total reaching distance of segmental excursions (eg, thoracic rotation, thoracic lateral flexion) were determined using forward stepwise regression. RESULTS: Subjects with PD as compared with subjects without PD had less ROM (FAR of 98.2 degrees versus 110.3 degrees, shoulder flexion of 151.9 degrees versus 160.1 degrees) and less forward reaching (29.5 cm versus 34.0 cm). Lateral trunk flexion and total rotation relative to the ground contributed to reaching, with the regression model explaining 36% of the variance. DISCUSSION AND CONCLUSION: These results contribute to the growing body of evidence demonstrating that spinal ROM is impaired early in PD.

Adult↗
PubMed2001

American College of Sports Medicine position stand. Appropriate intervention strategies for weight loss and prevention of weight regain for adults.

In excess of 55% of adults in the United States are classified as either overweight (body mass index = 25-29.9 kg.m(-2)) or obese (body mass index > or = 30 kg.m(-2)). To address this significant public health problem, the American College of Sports Medicine recommends that the combination of reductions in energy intake and increases in energy expenditure, through structured exercise and other forms of physical activity, be a component of weight loss intervention programs. An energy deficit of 500-1000 kcal.d-1 achieved through reductions in total energy intake is recommended. Moreover, it appears that reducing dietary fat intake to <30% of total energy intake may facilitate weight loss by reducing total energy intake. Although there may be advantages to modifying protein and carbohydrate intake, the optimal doses of these macronutritents for weight loss have not been determined. Significant health benefits can be recognized with participation in a minimum of 150 min (2.5 h) of moderate intensity exercise per week, and overweight and obese adults should progressively increase to this initial exercise goal. However, there may be advantages to progressively increasing exercise to 200-300 min (3.3-5 h) of exercise per week, as recent scientific evidence indicates that this level of exercise facilitates the long-term maintenance of weight loss. The addition of resistance exercise to a weight loss intervention will increase strength and function but may not attenuate the loss of fat-free mass typically observed with reductions in total energy intake and loss of body weight. When medically indicated, pharmacotherapy may be used for weight loss, but pharmacotherapy appears to be most effective when used in combination with modifications of both eating and exercise behaviors. The American College of Sports Medicine recommends that the strategies outlined in this position paper be incorporated into interventions targeting weight loss and the prevention of weight regain for adults.

Adult↗
PubMed2001

Anesthetic efficacy of infiltrations in mandibular anterior teeth.

The purpose of this prospective, randomized, double-blind study was to measure the degree of anesthesia obtained with a labial infiltration of either 2% lidocaine with 1:50,000 or 2% lidocaine with 1:100,000 epinephrine in mandibular anterior teeth. Another objective was to measure the degree of anesthesia obtained with a lingual infiltration of 2% lidocaine with 1:100,000 epinephrine in mandibular anterior teeth. Through use of a repeated-measures design, 40 subjects randomly received a labial infiltration at the lateral incisor apex of either 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 2% lidocaine with 1:50,000 epinephrine at 2 separate appointments. An additional 40 subjects received a lingual infiltration at the lateral incisor apex of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. The mandibular anterior teeth were blindly pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive 80 readings were obtained. For the 3 infiltrations, success rates for the lateral incisor ranged from 43 to 50%. Adjacent teeth had success rates of 27 to 63%. There was no significant difference (P > 0.05) in success between the labial infiltration of 2% lidocaine with 1:100,000 epinephrine and 2% lidocaine with 1:50,000 epinephrine or the lingual infiltration of 2% lidocaine with 1:100,000 epinephrine when compared with the labial infiltration of 2% lidocaine with 1:100,000 epinephrine. Duration of pulpal anesthesia declined steadily for all solutions over the 60 minutes. In conclusion, the success rate of 43-50% and declining duration of pulpal anesthesia over an hour indicates that a labial infiltration of 1.8 mL of either 2% lidocaine with 1:100,000 epinephrine or 1: 50,000 epinephrine or a lingual infiltration of 2% lidocaine with 1:100,000 epinephrine over the lateral incisor apex cannot be recommended clinically to provide profound pulpal anesthesia.

Adult↗
PubMed2000

On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems. Evidence for a gamma-glutamyl carboxylase in Drosophila.

The vitamin K-dependent gamma-carboxylation of glutamate to gamma-carboxyglutamate was originally well characterized in the mammalian blood clotting cascade. gamma-Carboxyglutamate has also been found in a number of other mammalian proteins and in neuropeptides from the venoms of marine snails belonging to the genus Conus, suggesting wider prevalence of gamma-carboxylation. We demonstrate that an open reading frame from a Drosophila melanogaster cDNA clone encodes a protein with vitamin K-dependent gamma-carboxylase activity. The open reading frame, 670 amino acids in length, is truncated at the C-terminal end compared with mammalian gamma-carboxylase, which is 758 amino acids. The mammalian gene has 14 introns; in Drosophila there are two much shorter introns but in positions precisely homologous to two of the mammalian introns. In addition, a deletion of 6 nucleotides is observed when cDNA and genomic sequences are compared. In situ hybridization to fixed embryos indicated ubiquitous presence of carboxylase mRNA throughout embryogenesis. Northern blot analysis revealed increased mRNA levels in 12-24-h embryos. The continued presence of carboxylase mRNA suggests that it plays an important role during embryogenesis. Although the model substrate FLEEL is carboxylated by the enzyme, a substrate containing the propeptide of a Conus carboxylase substrate, conantokin G, is poorly carboxylated. Its occurrence in vertebrates, molluscan systems (i.e. Conus), and Drosophila and the apparently strong homology between the three systems suggest that this is a highly conserved and widely distributed post-translational modification in biological systems.

Amino Acid Sequence↗