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R Kay

Publications and source records attributed to R Kay.

At least 55 records · Page 3Linked to original sources
PubMed1999

The Dbl-related protein, Lfc, localizes to microtubules and mediates the activation of Rac signaling pathways in cells.

The possibility that the Dbl family member Lfc can activate Rac1 in cells is investigated in this study. Previously, we demonstrated that both Lfc and Lsc, like their closest relative Lbc, can act catalytically in stimulating the guanine nucleotide exchange activity of RhoA in vitro. Neither Lfc nor Lsc stimulated the in vitro exchange activity of Cdc42 or Rac1; however, Lfc was capable of forming a tight complex with Rac1 in vitro. We show here that Lfc stimulates c-Jun kinase (JNK) activity in COS-7 cells. This stimulation was blocked by a dominant negative mutant of Rac1 and somewhat less effectively by dominant negative RhoA, but not by dominant negative Cdc42. Overexpression of Lfc in NIH 3T3 cells induced the formation of actin stress fibers and membrane ruffles, consistent with the activation of both RhoA and Rac1 signaling pathways, whereas overexpression of Lsc led exclusively to well developed stress fibers. Using a recently developed assay for measuring the cellular activation of Rac, we did not find that expression of Lfc increased the levels of GTP-bound Rac1. However, an examination of the cellular localization of Lfc showed that it was localized to microtubules, similar to what has been reported for activated Rac1, the mixed lineage kinase (MLK) and JNK. Moreover, we have found that the Pleckstrin homology (PH) domain of Lfc specifically associates with tubulin. Taken together, these findings suggest a model where the PH domain-mediated localization of Lfc to microtubules enables the recruitment of Rac to a site proximal to its signaling targets, resulting in JNK activation and actin cytoskeletal changes.

3T3 Cells↗
PubMed1999

Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis.

OBJECTIVE: To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. METHODS: Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. RESULTS: Patients with arthritis involving >4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to <4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P = 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P < 0.02). CONCLUSION: The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis.

Arthritis, Juvenile↗
PubMed1999

Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a Chinese population.

Parkinson's disease (PD) is a neurodegenerative disease caused by a multitude of environmental, neurochemical, and genetic factors. The gene for human dopamine D4 receptor (DRD4) has been considered as a plausible candidate for the pathogenesis of PD. Different dopamine D4 receptor allelic forms have variable affinity toward certain neuroleptics such as clozapine, suggesting a role for dopamine D4 receptors in neurologic disorders. To test the hypothesis that the DRD4 polymorphism is associated with the susceptibility to Parkinson's disease, we have examined differences in allele frequencies of different DRD4 polymorphisms in 101 Chinese patients with PD and in 105 age-matched control subjects in Hong Kong. The DRD4 gene was analyzed by a non-radioactive polymerase chain reaction-based Southern hybridization with chemiluminescence detection. The number of polymorphic 48 base pair tandem repeats in exon 3 was identified in each study subject. The DRD4 alleles with high frequencies in the control subjects are 4-repeat allele (72.4%), 2-repeat allele (21.4%), and 7-repeat allele (3.8%) which accounted for over 97% of the total alleles in the elderly Chinese population. The most prevalent genotype in the control subjects is the 4/4 (47.6%), followed by 4/2 (38.6), 4/7 (7.6%), and 2/2 (3.0%). None of the variable number tandem repeat polymorphism showed evidence for genetic association with Parkinson's disease.

Aged↗
PubMed1999

Risk of contralateral hydrocele or hernia after unilateral hydrocele repair in children.

PURPOSE: Recent laparoscopic studies indicate a high incidence of a contralateral open internal ring in children undergoing unilateral hydrocele or hernia repair, raising the question of whether routine contralateral exploration should be done. Data on the long-term risk of clinical contralateral hernia or hydrocele after unilateral hydrocele repair are limited. To address this question we performed long-term followup in patients who underwent unilateral hydrocele repair. MATERIALS AND METHODS: We followed patients who previously underwent unilateral hydrocele repair performed by one of us before 1997. Patients were interviewed by telephone and encouraged to return to one of us or their pediatrician for evaluation. RESULTS: Of the 101 patients who fulfilled study inclusion criteria 85 who were 5 to 107 months old (median age 37) at the original surgery were successfully contacted, including 45 examined by one of us or a pediatrician and 40 followed by telephone interview only. Contralateral hydrocele or hernia developed in 6 of the 89 patients (7%) 6 to 15 months (median 12) postoperatively. The remaining 79 patients have been recurrence-free for 6 to 153 months (mean 44, median 37). Of the patients 5 of 32 are (15%) and 1 of 53 (2%) who underwent left and right hydrocele repair, respectively, had contralateral recurrence. CONCLUSIONS: The risk of a clinically evident contralateral hydrocele or hernia after unilateral hydrocele repair is approximately 7%. We do not recommend routine contralateral exploration in children undergoing unilateral hydrocele repair.

Child↗
PubMed1999

Comparison of direct hospital costs and length of stay for radical nephrectomy versus nephron-sparing surgery in the management of localized renal cell carcinoma.

OBJECTIVES: Recent work has demonstrated comparable surgical results and 5-year cancer-specific survival rates between radical nephrectomy and nephron-sparing surgery (NSS) in the treatment of patients with small (4 cm or smaller) solitary renal cell carcinomas (RCCs). However, differences exist in the intraoperative management and postoperative care of patients undergoing NSS versus radical nephrectomy, and we sought to compare direct hospital costs and length of stay (LOS) between these two groups to determine whether either treatment imparts a specific cost advantage. METHODS: Data were retrieved from medical records and administrative data sets containing billing encounters for all costs incurred during hospitalization at the Cleveland Clinic Foundation. Individual costs were grouped together using nine cost center categories encompassing every aspect of direct hospital care, including anesthesiology, laboratory, radiology, nursing, pharmaceutical, and emergency services, and medical care, surgical care, and miscellaneous costs. Each cost center was further subdivided, and a total of 52 cost subcategories were assessed. The total direct costs of hospitalization were compared using a multivariate regression model in which patient demographics and tumor characteristics, type and year of surgery, LOS, and cost center categories were assessed as single and interactive factors. Postoperative complication and cancer-specific survival rates were also compared to identify any potential therapeutic differences between the two groups. RESULTS: Between 1991 and 1995, 80 patients underwent surgery at the Cleveland Clinic Foundation for solitary RCCs 4 cm or smaller, including 52 partial and 28 radical nephrectomies. We found no difference in the postoperative complication rate or cancer-specific survival rate between the two surgical groups. Total direct hospital costs and LOS were not statistically different between the NSS and radical nephrectomy groups (P >0.05). This was further supported by our multivariate model, which accounted for 61% of the observed variance in the total costs (F = 12.11, P = 0.0001). The type of surgery was not associated with total cost when controlling for all other factors, including age, sex, year of surgery, tumor size, grade, and stage, and postoperative complications (P = 0.7). There was no significant interaction between the type of surgery and the LOS (P = 0.5). CONCLUSIONS: This study demonstrated that elective NSS can be performed with equivalent direct hospital costs and LOS when compared with patients undergoing radical nephrectomy for small solitary RCCs. These data have significant economic implications for the comparison of competing surgical treatment strategies for localized RCC.

Aged↗
PubMed1999

Taking the plunge. Terminal differentiation in Dictyostelium.

During the last stage of Dictyostelium development a motile, cylindrical slug transforms into an immotile, stalked fruiting body and the constituent cells change from amoebae to either refractile spores or vacuolated stalk cells. Analysis of this process using genetics and simple culture techniques is becoming a powerful way of investigating a number of conserved signal transduction processes. A common pathway activating cAMP-dependent protein kinase (PKA) triggers the maturation of spore cells and those stalk cells forming the stalk. It uses a eukaryotic version of the 'bacterial' two-component phospho-relay system to control cAMP breakdown. A second pathway, inhibiting the GSK3 protein kinase, might control the maturation of a distinct set of stalk cells at the base of the fruiting body.

Animals↗
PubMed1999

Dependence of Dbl and Dbs transformation on MEK and NF-kappaB activation.

Dbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (>20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-kappaB transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-kappaB, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-kappaB-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation.

3T3 Cells↗
PubMed1999

Surgical considerations for patients with Wilms' tumor.

Despite the advances in multimodal treatment of Wilms' tumor, surgical staging and tumor resection remain a central component of therapy. Although standard approaches are available through multicenter studies, such as the NWTS and SIOP, controversy exists regarding several aspects of surgical management. Recent data call into question the need for contralateral exploration in the era of modern imaging. Various methods are available for managing caval tumor thrombus. Bilateral Wilms' tumor requires a special surgical strategy. The surgeon plays a key role in determining whether preoperative chemotherapy should be used to facilitate surgical resection. The role of partial nephrectomy is still being defined. And finally, surgery plays an important role in the management of tumor recurrence. Surgeons must be fully aware of the data and philosophical issues that pertain to these areas if they are to fulfill their role in the multidisciplinary team caring for children with Wilms' tumor.

Child↗
PubMed1999

Outcome of hamstring lengthening and distal rectus femoris transfer surgery.

To evaluate the outcome of hamstring lengthening and distal rectus femoris transfer, a retrospective study was performed comparing preoperative and postoperative gait analysis data from 16 children with neurologic involvement. Postoperatively, the timing of peak knee flexion during swing and the total arc of knee motion significantly improved. Hamstring range of motion and knee extension at terminal swing significantly improved, but stride length and gait velocity did not for the overall population. Patients who used braces postoperatively showed an improvement in stride length and velocity when wearing orthoses. This suggests that postoperative bracing may be needed in some patients to maximize the surgical outcome.

Adolescent↗
PubMed1999

Effect of beta-blockade on baroreceptor and autonomic function in heart failure.

Although beta-adrenoreceptor antagonists appear to be beneficial in chronic heart failure there is little information on their effects on autonomic and baroreceptor function which may have important prognostic implications. We sought to determine first whether beta-adrenoreceptor blockade will improve baroreceptor function and vagal tone in chronic heart failure, and second whether there were any differences between standard therapy with metoprolol and the second-generation vasodilating beta-blocker celiprolol. In this double-blind randomized placebo-controlled study 50 patients with stable chronic heart failure received either celiprolol 200 mg daily, metoprolol 50 mg twice daily or placebo for 12 weeks after a 4-week dose titration period. Thirty-five healthy normal subjects were also studied. Baroreceptor gain was assessed non-invasively by cross-spectral analysis of R-R and systolic blood pressure low- and high-frequency components (the alpha angle) during controlled respiration. High-frequency power was used as a measure of vagal modulation. Satisfactory recordings for analysis were obtained in 31 patients with heart failure. The results showed that at baseline baroreceptor gain (alphaHF) was significantly depressed in patients with heart failure compared with the normal control group (4.95+/-0. 55 versus 11.73+/-1.32 ms/mmHg, P<0.0001). After 12 weeks of treatment with metoprolol baroreceptor gain improved significantly whether measured while supine (P=0.03) or standing (P=0.009), and this was associated with a significant increase in R-R HF power (P=0. 008). There were no significant changes after treatment with celiprolol or placebo. We conclude that metoprolol but not celiprolol therapy restores baroreceptor gain towards normal and increases vagal tone in chronic heart failure. The ancillary properties of celiprolol do not appear to provide any advantages over metoprolol for the restoration of autonomic and baroreceptor function in heart failure.

Adrenergic beta-Antagonists↗
PubMed1998

Rarity of debrisoquine hydroxylase gene polymorphism in Chinese patients with Parkinson's disease.

Impaired debrisoquine metabolism resulting from defects in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene has been shown to be associated with the development of Parkinson's disease (PD). We studied two polymorphisms in this gene in 207 Chinese PD patients and 227 control subjects by polymerase chain reaction and restriction analysis. The G to A substitution at position 1934 in the junction of intron 3/exon 4 was detected in one sporadic PD patient and two control subjects, all of whom were heterozygous. The single base deletion at position 2637 in exon 5 was not detected in any of the study subjects. Such rarity of CYP2D6 polymorphism indicates PD in the Chinese population is associated with some other gene defects.

Aged↗
PubMed1998

Ureteropelvic junction obstruction in children. Unique considerations for open operative intervention.

The treatment of UPJ obstruction in children should be approached in a fashion that recognizes the differences between children and adults. Radiographic definition of the urinary tract is different in children than in adults because of the size of the child and technical difficulties with instrumentation. Retrograde pyelography, in general, is not necessary in children, although this decision must be individualized. The surgical incision should be chosen based on the size of the child and the unique considerations of individual renal anatomy and pathology, as well as the surgeon's experience. In children, tubeless surgery may be performed with excellent results, however, diversion with nephrostomies and stents may be necessary in selected cases. With attention to technical details and the unique considerations in children, the results of repair of the UPJ should be excellent and reproducible.

Child↗
PubMed1998

Ureteropelvic junction obstruction in anomalous kidneys.

UPJ obstructions occurring in anomalous kidneys require special consideration. Many anomalous kidneys are dysmorphic with extrarenal pelves, making the distinction between obstructed and nonobstructed hydronephrosis crucial. The radiographic evaluation must be thorough because there are often other associated anomalies of the ipsilateral or contralateral kidney. Operative intervention must be tailored to the specifics of the case. Although most UPJ obstructions in anomalous kidneys can be reconstructed successfully with dismembered pyeloplasty or treated with newer minimally invasive techniques, issues regarding access, operative detail, and adjunct procedures make these cases challenging for the urologic surgeon.

Adolescent↗