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Biomedical subjects

C Garner

Publications and source records attributed to C Garner.

At least 19 recordsLinked to original sources
PubMed2002

The role of bicarbonate in regulatory volume decrease (RVD) in the epithelial-derived human breast cancer cell line ZR-75-1.

This study investigates the mechanisms involved in the regulatory volume decrease (RVD) in ZR-75-1 epithelial-derived human breast cancer cells. Cell volume changes were measured during osmotic shock using video imaging. In HEPES-buffered hypotonic solutions no RVD was observed; however, RVD was observed in HCO(3)(-)-buffered hypotonic solutions. Inhibition of RVD by 10 microM tamoxifen and 100 microM DIDS (inhibitors of volume-regulated anion channels; VRAC) and 2 mM TEA(+) (inhibitor of K(+) channels) indicates a role for these channels. In HCO(3)(-)-buffered Cl(-)-free solutions RVD was partially abolished indicating that HCO(3)(-) efflux can support RVD but also may have another role. Further experiments investigated whether HCO(3)(-) assists in the accumulation of Cl(-) via Cl(-)-HCO(3)(-) exchange. Regulatory volume increase (RVI) was also HCO(3)(-)-dependent and was inhibited by 500 microM DIDS and 10 microM 5-( N, N-dimethyl)-amiloride (DMA) indicating a role for coupled Cl(-)-HCO(3)(-) and Na(+)-H(+) exchange. Finally, in the presence of 10 microM DMA, RVD was partially inhibited providing further evidence for a role of Cl(-)-HCO(3)(-) exchange. Thus RVD in ZR-75-1 cells involves the activation of VRAC and K(+) channels. RVD is HCO(3)(-)-dependent and HCO(3)(-) efflux through VRAC appears to contribute directly to RVD. HCO(3)(-), however, also has another role in facilitating Cl(-) accumulation via Cl(-)-HCO(3)(-) exchange.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method.

Recently developed algorithms permit nonparametric linkage analysis of large, complex pedigrees with multiple inbreeding loops. We have used one such algorithm, implemented in the package SimWalk2, to reanalyze previously published genome-screen data from a Costa Rican kindred segregating for severe bipolar disorder. Our results are consistent with previous linkage findings on chromosome 18 and suggest a new locus on chromosome 5 that was not identified using traditional linkage analysis.

Algorithms↗
PubMed2000

Modulation of tau phosphorylation and intracellular localization by cellular stress.

Tau is a microtubule-associated protein that is functionally modulated by phosphorylation and hyperphosphorylated in several neurodegenerative diseases. Because phosphorylation regulates both normal and pathological tau functioning, it is of great interest to identify the signalling pathways and enzymes capable of modulating tau phosphorylation in vivo. The present study examined changes in tau phosphorylation and localization in response to osmotic stress, which activates the stress-activated protein kinases (SAPKs), a family of proline-directed protein kinases shown to phosphorylate tau in vitro and hypothesized to phosphorylate tau in Alzheimer's disease. Immunoblot analysis with phosphorylation-dependent antibodies revealed that osmotic stress increased tau phosphorylation at the non-Ser/Thr-Pro sites Ser-262/356, within the microtubule-binding domain, as well as Ser/Thr-Pro sites outside of tau's microtubule-binding domain. Although all SAPKs examined were activated by osmotic stress, none of the endogenous SAPKs mediated the increase in tau phosphorylation. However, when transfected into SH-SY5Y cells, SAPK3, but not the other SAPKs examined, phosphorylated tau in situ in response to activation by osmotic stress. Osmotic-stress-induced tau phosphorylation correlated with a decrease in the amount of tau associated with the cytoskeleton and an increase in the amount of soluble tau. This stress-induced alteration in tau localization was only partially due to phosphorylation at Ser-262/356 by a staurosporine-sensitive, non-proline-directed, protein kinase. Taken together, these results suggest that osmotic stress activates at least two tau-directed protein kinases, one proline-directed and one non-proline-directed, that SAPK3 can phosphorylate tau on Ser/Thr-Pro residues in situ, and that Ser-262/356 phosphorylation only partially regulates tau localization in the cell.

Anisomycin↗
PubMed2000

Genetic influences on F cells and other hematologic variables: a twin heritability study.

To assess the relative contribution of genetic factors in the variation of F cells (FC) and other hematologic variables, we conducted a classical twin study in unselected twins. The sample included 264 identical (monozygotic [MZ]) twin pairs and 511 nonidentical (dizygotic [DZ]) same-sex twin pairs (aged 20 to 80 years) from the St. Thomas' UK Adult Twin Register. The FC values were distributed continuously and positively skewed, with values ranging from 0.6% to 22%. FC values were higher in women than in men and decreased with age, with the variables accounting for 2% of the total FC variance. The intraclass correlations of FC values were higher in MZ (rMZ = 0.89) than in DZ (rDZ = 0.49) twins. The XmnI-(G)gamma polymorphism in the beta-globin gene cluster had a significant effect on FC levels, accounting for approximately 13% of the total FC variance. Variance components analysis showed that the FC values were accounted for predominantly by additive genetic and nonshared environmental influences, with an estimate of heritability of 0.89. Hemoglobin levels and red blood cell, white blood cell, and platelet numbers were also substantially heritable, with heritability estimates of 0.37, 0.42, 0.62, and 0.57, respectively. Previously, studies of sib pairs with sickle cell disease and isolated family studies showed that high levels of Hb F and FC tend to be inherited. Here, our classical twin study demonstrated that the variance of FC levels in healthy adults is largely genetically determined. (Blood. 2000;95:342-346)

Adult↗
PubMed2000

Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the hairless gene by mutation analysis.

Marie-Unna hypotrichosis (MU) is a rare autosomal dominant congenital alopecia characterised by progressive hair loss starting in early childhood, often aggravated at puberty and leading to scarring alopecia of variable severity. We have studied three multigeneration families of Belgian, British and French descent. The human genome was screened with microsatellite markers spaced at 10-cM intervals and significant evidence for linkage to the disease was observed on chromosome 8p21, with a maximum two-point lod score of 8.26 for D8S1786 at a recombination fraction of 0. Recombinants narrowed the region of interest to a genetic interval of about 12 cM flanked by markers D8S280 and D8S1839. This interval contains the hairless gene which is mutated in autosomal recessive congenital atrichia. Sequencing of the entire coding region and intronic splice sites of the hairless gene in these three families and in two unrelated familial cases revealed several polymorphic changes but failed to identify causative mutations. Nine other genes located within this region and expressed in skin were also excluded by mutation analysis. Together with a recent linkage study performed in a Dutch and a British family by van Steensel et al these results provide evidence for the presence of a gene distinct from hairless in chromosomal region 8p21 playing an important role in hair follicle biology.

Alopecia↗
PubMed2000

Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping.

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.

Adolescent↗
PubMed2000

Genetic and environmental influences on left ventricular mass. A family study.

The relations between left ventricular mass (LVM) with age, gender, body size, and blood pressure were investigated in healthy adults and children from 149 nuclear families. LVM was strongly correlated with overall weight, especially in the children. Genetic analysis indicated that the segregation of LVM was compatible with an additive polygenic model, with a heritability estimate of 34% before adjustment for weight and 28% after adjustment for weight. Genetic and/or familial environmental factors played a strong role in the correlation of LVM and weight; they accounted for all of the correlation between the 2 traits in adults and 59% of the correlation in children. Spouses exhibited a strong correlation in their weight, which suggested that common family environment may contribute to the family correlations and to the observed heritability of the trait. LVM was strongly correlated with blood pressure before adjustment for weight, but this correlation could be attributed to nonfamilial environment rather than genetic factors. After adjustment for weight, the intertrait correlations between LVM and blood pressure were nonsignificant. Thus, adjustment for weight accounts for all common determinants of LVM and blood pressure.

Adolescent↗
PubMed2000

Prospects for reducing and refining the use of dogs in the regulatory toxicity testing of pharmaceuticals.

A workshop was held to critically discuss the need for a nonrodent species and the role of the dog in regulatory toxicity testing of pharmaceuticals; to discuss opportunities to reduce and refine the use of dogs in preclinical toxicology; and to identify a number of specific recommendations which could be feasibly achieved to move the process forward. To facilitate a preliminary evaluation of the contribution of dog studies to the risk assessment process, anonymised, unpublished data were provided from fully evaluated, repeat-dose toxicity studies in the rat and dog. Results of the International Life Sciences Institute (ILSI) Human Toxicity Project were also presented and discussed. Analysis of the data demonstrated that the dog can provide additional toxicity information, which, in some cases, was shown to be predictive for humans. Discussions indicated that there is potential for achieving a reduction in dog use and several possible approaches were identified. To further the progress of this initiative, there is a need to collate the results of pharmacology, toxicology, and clinical studies to address some of the proposed approaches. One of the outcomes of the workshop will be the establishment of a steering group to co-ordinate data collation for further analysis.

Animal Testing Alternatives↗
PubMed2000

Evidence for a major gene for bone mineral density in idiopathic osteoporotic families.

Although there have been a number of studies indicating a heritable component for osteoporosis in middle to late adulthood, the etiology of osteoporosis in young people is uncertain. The present study aims to evaluate the extent to which genetic factors influence familial resemblance for bone mineral density (BMD) in families ascertained on the basis of young osteoporotic probands. The sample comprises eight families (74 total individuals) that were identified through a proband under the age of 35 years with a history of two or more fractures and a spinal bone density of at least 2.5 SDs below the mean for age and sex (Z score). Secondary causes of osteoporosis were excluded in the probands. In total, 27% (18/66) of the probands' relatives had osteoporosis and an additional 30% (20/66) had osteopenia. Classical segregation analysis was performed to evaluate the extent to which a genetic etiology could account for familial resemblance in these families. The results indicate a major gene of codominant inheritance for spinal BMD. Model-fitting comparisons revealed no support for environmental effects or for polygenic inheritance.

Adolescent↗
PubMed1999

Pseudo-occlusion and/or pseudo-stenosis of the intracranial internal carotid artery.

This report summarizes our recent experience with two patients who presented with symptoms ipsilateral to a severe carotid stenosis at the bifurcation, with one having a severe stenosis at the siphon and the other an occlusion of the internal carotid artery in its intracranial portion. These lesions were documented on preoperative angiography. In both instances, persistence of symptoms, despite maximal medical therapy, led us to proceed with carotid endarterectomy. In both cases, intraoperative angiography confirmed a normal intracranial internal carotid artery, contrary to what had been seen on preoperative angiography. Carotid endarterectomy was performed, with resolution of clinical symptoms in both cases. This experience suggests that the appearance of the intracranial portion of the carotid artery can be significantly affected by the presence of a proximal lesion at the bifurcation. Stenosis and/or occlusion of the intracranial portion of the carotid artery may appear on preoperative angiography secondary to flow alterations as a result of the more proximal lesion. This, in part, may explain why many patients with combined extracranial and intracranial arterial disease improve after carotid endarterectomy and suggests that, in the presence of a severe extracranial lesion, further evaluation be undertaken to exclude the possibility of pseudo-stenosis or pseudo-occlusion of the intracranial carotid artery.

Aged↗
PubMed1999

Endovascular, transperitoneal, and retroperitoneal abdominal aortic aneurysm repair: results and costs.

PURPOSE: Contemporary treatment of abdominal aortic aneurysms (AAA) includes transabdominal (TA), retroperitoneal (RP), and endovascular (EV) repair. This study compares the cost and early (30-day) results of a consecutive series of AAA repair by means of these three methods in a single institution. METHODS: A total of 125 consecutive AAA repairs between February 1993 and August 1997 were reviewed. Risk factors, 30-day morbidity and mortality rates, and hospital stay and cost were analyzed according to method of repair (TA, RP, EV). Cost was normalized by means of a conversion factor to maintain confidentiality. Cost analysis includes conversion to TA repair (intent to treat) in the EV group. RESULTS: One hundred twenty-five AAA repairs were performed with the TA (n = 40), RP (n = 24), or EV (n = 61) approach. Risk factors among the groups (age, coronary artery disease, hypertension, diabetes, chronic obstructive pulmonary disease, and cigarette smoking) were not statistically different, and thus the groups were comparable. The average estimated blood loss was significantly lower for EV (300 mL) than for RP (700 mL) and TA (786 mL; P>.05). Statistically significant higher cost for TA and RP for pharmacy and clinical laboratories (likely related to increased length of stay [LOS]) and significantly higher cost for EV in supplies and radiology (significantly reducing cost savings in LOS) were revealed by means of an itemized cost analysis. Operating room cost was similar for EV, TA, and RP. There were six perigraft leaks (9.6%) and six conversions to TA (9.6%) in the EV group. CONCLUSION: There were no statistically significant differences in mortality rates among TA, RP, and EV. Respiratory failure was significantly more common after TA repair, compared with RP or EV, whereas wound complications were more common after RP. Overall cost was significantly higher for TA repair, with no significant difference in cost between EV and RP. EV repair significantly shortened hospital stay and intensive care unit (ICU) use and had a lower morbidity rate. Cost savings in LOS were significantly reduced in the EV group by the increased cost of supplies and radiology, accounting for a similar cost between EV and RP. Considering the increased resource use preoperatively and during follow-up for EV patients, the difference in cost between TA and EV may be insignificant. EV repair is unlikely to save money for the health care system; its use is likely to be driven by patient and physician preference, in view of a significant decrease in the morbidity rate and length of hospital stay.

Aortic Aneurysm, Abdominal↗
PubMed1999

Executive function and theory of mind performance of boys with fragile-X syndrome.

Fragile-X syndrome is the most common genetically inherited cause of intellectual disability. People with this syndrome typically show a behavioural profile of abnormal social interactions which are similar in some ways to those seen in people with autism. The present study investigated whether cognitive processes which have been hypothesized to underlie social abnormalities associated with autism are also impaired in boys with fragile-X syndrome without autistic spectrum disorders. Eight boys with fragile-X syndrome and eight with intellectual disability of unknown aetiology, matched on receptive verbal ability, age and with no diagnosis of autism, were tested on a battery of theory of mind and executive function tasks. Significantly more boys with fragile-X syndrome failed the simplest theory of mind task. However, this could be attributed to overall level of ability rather than group membership. No differences were found between the groups on any other measures used. A proportion of both groups failed first- and second-order false belief tasks. The performance of both groups on the executive function measure was at the floor of the test. At low levels of overall ability, the performance of boys with fragile-X syndrome and boys with intellectual disability of unknown aetiology may be more similar than they are different The implication of this result for clinical interventions is discussed.

Adolescent↗
PubMed1999

American Academy of Pediatrics. Committee on Children With Disabilities. Care coordination: integrating health and related systems of care for children with special health care needs.

Care coordination is a process that links children with special health care needs and their families to services and resources in a coordinated effort to maximize the potential of the children and provide them with optimal health care. Care coordination often is complicated because there is no single entry point to multiple systems of care, and complex criteria determine the availability of funding and services among public and private payers. Economic and sociocultural barriers to coordination of care exist and affect families and health care professionals. In their important role of providing a medical home for all children, primary care pediatricians have a vital role in the process of care coordination, in concert with the family.

Case Management↗
PubMed1998

Aspirin-like molecules that covalently inactivate cyclooxygenase-2.

Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.

Acetylation↗
PubMed1998

[The status of neurologic intensive care in Germany. Current data].

In 1994 this journal published the results of a survey undertaken on behalf of the Working Association for Neurological Intensive Care Medicine (ANIM) in the winter of 1992/93. In the winter of 1996/97 a continuation of this analysis was performed. With the help of a questionnaire the data of 62 intensive care units with a total of 420 beds were established. This is 11 intensive care units and 83 beds more than 1992/93. The intensive care units were again classified into three groups (ventilation units, monitoring units, interdisciplinary units) relating to their equipment and structure. The questions concerned structural organisation, such as the number of beds, type of clinic, number and training of physicians and nurses, technical equipment and availability of large and high-tech apparatus or access to other facilities, such as neurosurgery. Of great interest were data about whether and to what extent special measures of intensive medicine can be taken on the one hand and performance parameter data e.g. days of ventilation and duration of in-patient treatment on the other hand. Detailed data were provided concerning the frequency of each diagnosis of patients treated in those intensive care units. Evaluating the data a positive development in the last four years of the neurological intensive care can be found in most of the areas investigated. It has also been found that neurological intensive care in the new lander has reached equal standard both in quality and quantity. Now a single physician is responsible for 2,3 beds compared to 3,6. Today 78 per cent of the beds in ventilation units are equipped with a ventilator. The overall time of ventilation increased to 48 per cent. Overall there are, however, considerable differences between individual units as well as regions. The data presented can serve as a means to monitor the quality of neurological intensive care.

Equipment and Supplies, Hospital↗