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Biomedical subjects

J Chandler

Publications and source records attributed to J Chandler.

At least 19 recordsLinked to original sources
PubMed1997

Multidisciplinary approach to the treatment of pediatric pancreaticobiliary disorders.

A multidisciplinary approach using traditional open surgery, endoscopic retrograde cholangiopancreatography (ERCP) and laparoscopic surgery has revolutionized the care of the adult with pancreaticobiliary disease. This study focuses on a similar collaborative effort to diagnose and treat children with pancreaticobiliary disorders. Charts of all patients treated on the pediatric surgery service between June 1990 and May 1995, who also underwent ERCP, were abstracted for disease process, presenting symptoms, laboratory evaluation, surgical or endoscopic procedures, and eventual outcome. Twenty-six children were identified, ranging from 6 months to 19 years of age. Pancreaticobiliary disorders included pancreas divisum (n = 1), choledochal cyst (n = 4), pancreaticobiliary trauma (n = 4), cholelithiasis and choledocholithiasis (n = 17). The pancreaticobiliary tree was successfully visualized by ERCP in 25 of 26 (96%) patients. Fifteen of these patients also underwent attempted therapeutic endoscopic procedures, with 13 (87%) performed successfully. Three patients with choledochal cyst had stents placed preoperatively for cholangitis, all of whom have undergone successful choledochal cyst excision. Two trauma patients underwent attempted stenting of a bile leak and bile duct stricture, respectively, both of which were unsuccessful, necessitating surgical correction. Seventeen patients with cholelithiasis underwent ERCP to rule out choledocholithiasis. Ten patients were found to have common duct stones, and all stones were endoscopically extracted, including those in a 6-month-old child. Overall survival rate was 96% (25 of 26), with the one death occurring in a trauma patient unrelated to his pancreaticobiliary disorder. A multidisciplinary approach using traditional open surgery, ERCP and laparoscopic surgery can successfully treat even young children with pancreaticobiliary disorders. In experienced hands, diagnostic ERCP and therapeutic endoscopic intervention can be performed successfully in most pediatric patients, greatly simplifying the surgical management of these potentially complex problems.

Adolescent↗
PubMed1997

Save the child's esophagus, Part II: Colic patch repair.

PURPOSE: In a previous report, the authors documented the procedures necessary to regain esophageal continuity in infants who had massive disruption of the suture line following esophagoplasty. As a corollary, this study shows the feasibility of preserving the esophagus in older children by using an esophageal patch. METHODS: Fifteen children ranging in age from 8 months to 16 years at the time of surgery had repair of esophageal strictures or tracheoesophageal fistulae by the use of a vascularized patch rather than esophageal resection and interposition with colon or stomach. The technique of "colonic-patch oesophagoplasty" was described by Hecker and Hollman in 1975. From 1976 to 1995, the authors have used a modification of their procedure in 14 children, and in one patient an intercostal muscle flap was interposed. The technique consists of esophagotomy through the area of stricture with application of a vascularized patch of colon to the resulting defect. RESULTS: Ten of the patients were boys and four were girls with an additional girl considered for the procedure at 8 months of age. However, during surgery, an intercostal muscle flap interposition was used. Eight children had esophageal stricture caused by lye ingestion; two from anastomotic stricture; two from gastroesophageal reflux; two from recurrent tracheoesophageal fistula; and one from long-term nasogastric intubation. Follow-up showed excellent results in nine patients who had the colic patch operation. All had good swallowing. A tenth patient, the child with the vascularized intercostal muscle flap, is currently eating a regular diet but it has only been 4 months since the operation. However, one of these excellent patients continues to have a small focus of Barrett's esophagus and another one was killed in an automobile accident one year after operation. Three children have good results but with occasional difficulty in swallowing boluses of meat or with continuing reflux. Two patients had poor results and both have undergone reoperation. In one of these children with Down's syndrome and diabetes, the colic patch worked well for 6 years but because of continuing reflux, distal esophageal scarring and obstruction eventually ensued. After reoperation for distal esophageal resection and colic interposition, the patient died of pulmonary failure. The second child with poor results has recently undergone reoperation to extend the esophagotomy through the distal scarred esophagus and to revise the colic patch. CONCLUSION: The use of a vascular colic patch for treatment of severe esophageal strictures is a viable alternative to esophageal resection and interposition. However, patients with continuing reflux or Barrett's esophagus, or both, may progress with distal esophageal scarring and obstruction and subsequent dilation of the patch. Those patients will require reoperation.

Adolescent↗
PubMed1997

IL2 fused to lectin-deficient ricin is toxic to human leukemia cells expressing the IL2 receptor.

Interleukin-2 (IL2) fused to ricin B chain (RTB) with modifications of amino acid residues in each of three galactose-binding subdomains (1alpha, 1beta and 2gamma) was expressed in insect cells, purified by immunoaffinity chromatography and reassociated with ricin A chain (RTA). The fusion toxin-bound human leukemic cells with IL2 receptors and the binding was competed with IL2 but not asialofetuin. In contrast, binding was not observed with receptor negative human cell lines, and the fusion molecule very weakly bound asialofetuin (Kd= 10(-6)M), indicating lectin-deficient RTB. The IL2-lectin-deficient RTB-RTA intoxicated IL2 receptor bearing cells as well as ricin or IL2-wild-type RTB-RTA. While ricin and IL2-wild-type RTB-RTA were equally toxic to receptor negative cell lines, the IL2-lectin-deficient RTB-RTA was two-two and one half logs less cytotoxic to these cell lines. The sensitivity of receptor-positive cells to the lectin-deficient fusion protein suggests that high avidity intracellular galactose binding may not be required for ricin intoxication, at least in the case of IL2 receptor-targeted molecules. Furthermore, the potent selective cytotoxicity of the fusion protein suggests that the IL2-lectin-deficient RTB-RTA and similar ricin fusion molecules directed against other leukemic cell surface receptors provide a novel class of fusion toxins for therapy of human leukemias.

Antibodies, Monoclonal↗
PubMed1997

Reliability of impairment and physical performance measures for persons with Parkinson's disease.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is characterized by rigidity, postural instability, bradykinesia, and tremor, as well as other musculoskeletal impairments and functional limitations. The purpose of this investigation was to determine the reliability and stability of measures of impairments and physical performance for people in the early and middle stages of PD, Subjects. Thirteen men and 2 women in Hoehn and Yahr stages 2 and 3 of PD participated. Their mean age was 74.5 years (SD = 5.7, range = 64-84). METHODS: Thirteen impairment-level variables and 8 physical performance variables were measured. Measurements were taken on two consecutive days and again a week later on the corresponding two consecutive days. Reliability and stability were assessed using analysis of variance and intraclass correlation coefficients (ICCs). RESULTS: Test-retest reliability (ICCs) of variables ranged from .69 (hamstring muscle length) to .97 (lumbar flexion). Intraclass correlation coefficients were .85 or greater for 10 of the variables. CONCLUSIONS AND DISCUSSION: The results suggest that in the early and middle stages of PD, many of the measures of impairment and physical performance are relatively stable.

Activities of Daily Living↗
PubMed1996

Ricin toxin contains at least three galactose-binding sites located in B chain subdomains 1 alpha, 1 beta, and 2 gamma.

Ricin toxin, the heterodimeric 65 kDa glycoprotein synthesized in castor bean seeds, consists of a cell binding lectin subunit (RTB) disulfide linked to an rRNA N-glycosidase protein synthesis inactivating subunit (RTA). While X-ray crystallography and equilibrium dialysis suggested two sugar-combining sites located in subdomains 1 alpha and 2 gamma, biochemical and mutational analyses suggested the existence of a third lectin site. We performed oligonucleotide-directed mutagenesis on RTB cDNA to create mutants with modifications in subdomains 1 alpha, 2 gamma, and either 1 beta or 2 alpha. The triple-site mutant RTBs were expressed in insect cells. Partially purified recombinant proteins obtained from infected cell extracts and cell supernatants were characterized for asialofetuin and cell binding, immunoreactivites, ability to reassociate with RTA, and recombinant heterodimer cell cytotoxicity. Yields of both triple-site mutants were similar to the parent double-site mutant. Both mutants showed immunoreactivity with a panel of anti-RTB monoclonal and polyclonal antibodies. The triple-site mutant with modification of amino acid residues in subdomains 1 alpha, 2 alpha, and 2 gamma bound asialofetuin and cells similarly to the parent 1 alpha, 2 gamma, subdomain mutant. In contrast, the 1 alpha, 1 beta, 2 gamma subdomain triple-site mutant had a one and one-half log decrease in asialofetuin and cell binding relative to the parent double-site mutant. The 1 alpha, 2 alpha, 2 gamma triple-site mutant and 1 alpha, 2 gamma parent protein had sugar binding which was inhibited by 3-27-fold by lactose and asialofetuin. Both triple-site mutants reassociated well with RTA. The 1 alpha, 2 alpha, 2 gamma triple-site mutant-RTA was equally cytotoxic to mammalian cells as the double-site mutant-RTA heterodimer. In contrast, the 1 alpha, 1 beta, 2 gamma triple-site mutant-RTA was 25 times less toxic than the double mutant and 20 times more toxic than RTA alone. These data support a model for at least three lectin-binding subdomains in RTB.

Animals↗
PubMed1996

Preproricin expressed in Nicotiana tabacum cells in vitro is fully processed and biologically active.

Ricin, the highly toxic glycoprotein expressed in the endosperm of castor seeds, is composed of a galactose-binding lectin B chain (RTB) disulfide linked to a RNA N-glycosidase A chain (RTA). Chemically modified ricin has been conjugated to monoclonal antibodies and used for targeted therapy of cancer and autoimmune diseases. Replacement of chemically coupled molecules with a genetically engineered targeted ricin would improve homogeneity and yield and permit structural changes in the fusion toxin to be introduced readily by oligonucleotide-directed mutagenesis. Previous methods of expression of ricin fusion proteins have been limited to expression of RTA or RTB moieties alone or expression of incompletely processed toxin in Xenopus laevis oocytes. In the present study, we introduced the cDNA encoding preproricin into cultured tobacco cells via Agrobacterium tumefaciens-mediated gene transfer. Yields of ricin in soluble cell extracts were 1 microg/g in cells or, approximately, 0.1% of the total soluble protein. The ricin was partially purified by P2 monoclonal antibody anti-RTB affinity chromatography. The RTA and RTB immunoreactive material migrated on SDS-PAGE at 65 kDa under nonreducing conditions and at 32-35 kDa under reducing conditions. The tobacco ricin bound to immobilized asialofetuin as avidly as castor bean ricin, suggesting intact sugar binding. Tobacco ricin inhibited rabbit reticulocyte lysate protein translation similar to castor bean ricin (IC50 of 3 x 10(-12) M for tobacco ricin and 1 x 10(-11) M for castor bean ricin). The human cutaneous T cell lymphoma cell line HUT102 showed similar sensitivity to tobacco ricin when compared to castor bean ricin (IC50 = 9 x 10(-13) and 2 x 10(-12) M, respectively). The efficiency of gene transfer, reasonable levels of expression, and full post-translational processing indicate that this expression system is suitable for production of ricin fusion toxins for therapeutic applications.

Agrobacterium tumefaciens↗
PubMed1996

Pregnancy outcomes and health care use: effects of abuse.

OBJECTIVE: Our purpose was to determine whether pregnancy and neonatal outcomes differed between abused and nonabused women. STUDY DESIGN: Women (N=1014) who completed an abuse questionnaire during pregnancy were followed up after delivery. The 242 women reporting past abuse and the 59 women reporting abuse in pregnancy were grouped in terms of recency and severity of domestic abuse, and their pregnancy and birth outcomes were compared with those of nonabused women with the chi-square test, analysis of variance, and multivariate logistic regression techniques. RESULTS: Abused women smoked more cigarettes (p<0.0001) and took more prescription drugs (p<0.03) and antidepressants (p>0.05) than nonabused women; they were more likely to have epilepsy (p=0.0002) and asthma (p=0.0018), and also they used social work services more often (p>0.0001). Obstetric histories revealed a higher incidence of miscarriage (p=0.0014), two or more pregnancy terminations (p>0.0001), and neonatal death (p=0.0503) among the abused group. Although abused women delivered infants whose mean birth weight was 132 gm lower than that of nonabused women, the difference was not significant after adjustments were made. Mildly and moderately abused women were admitted to the hospital more frequently during pregnancy (p=0.0067). CONCLUSION: Domestic abuse adds significantly to the cost of health care during pregnancy and is associated with poor maternal and fetal outcomes.

Abortion, Induced↗
PubMed1996

Save the child's esophagus: management of major disruption after repair of esophageal atresia.

PURPOSE: Given the bias that the native esophagus is the best conduit between the oropharynx and the stomach, the authors report a "conservative" approach to massive esophageal leak, which may be considered "radical" by others. Major disruption of the anastomosis after primary repair of esophageal atresia is a recognized and feared complication. Historically, management has been the performance of cervical esophagostomy and gastrostomy. The aim of this report is to describe the authors' approach to this difficult and serious complication. METHODS: A 15-year retrospective analysis was performed of all patients having esophageal atresia. Data collection focused on the management of all patients with clinically significant esophageal disruption. Radiographically detected (clinically asymptomatic) leaks were managed by continuation of drainage by thoracostomy tubes already in place and are not included. Reoperative thoracotomies were performed, which included primary repair (2), placement of pleural patch alone (2), pleural patch with intercostal muscle flap buttress (2), and operative debridement and drainage alone (1). RESULTS: It was noted that seven patients had clinically significant esophageal disruption requiring reoperation, with circumferential disruptions ranging from 15% to 85%. Presentation included persistent pleural collection (4) and pneumothorax (3). Both patients who underwent primary repair had no evidence of leakage on follow-up esophagograms, neither did one with a pleural patch alone and one with an intercostal muscle flap. Five of the seven patients were tolerating oral feedings at the time of follow-up (range, 6 months to 8 years). One of the two others (both currently inpatients), has a recurrent leak associated with mediastinitis, and the other (who had primary repair) has a presumed neurological impairment of eating. CONCLUSION: Clinically significant disruption of primary esophageal repair should not warrant a cervical esophagostomy and placement of a gastrostomy tube, thus precluding eventual use of the native esophagus. The authors have shown that management by reoperation with primary repair, intercostal muscle flap with or without pleural patch, and/or drainage allows the patient to maintain the native esophagus and yields a generally good outcome after a prolonged healing time.

Esophageal Atresia↗
PubMed1996

Arabidopsis mutants showing an altered response to vernalization.

Flowering in many plant species is accelerated by a long period of cold temperature, known as a vernalization period. This research investigates how this cold temperature signal is perceived by plant cells and the mechanism by which it influences the transition to flowering. Mutagenesis of the late-flowering, vernalization-responsive, Arabidopsis mutant, fca, has yielded five independent mutations (termed vrn mutations) conferring an altered vernalization response. Allelism tests showed that these mutations fall into at least three complementation groups defining three loci named VRN 1, 2 and 3. The vrn1 and vrn2 mutations did not affect the acclimation response as judged by expression of cold-induced transcripts and freezing tolerance assays. vrn1-1 affected the short-day vernalization response of Landsberg erecta and reduced the vernalization response of other late-flowering Arabidopsis mutants. The acceleration of flowering by GA3 was not affected by vrn1-1. The VRN 1 locus was mapped to chromosome 3.

Acclimatization↗
PubMed1996

Characterization of a ricin fusion toxin targeted to the interleukin-2 receptor.

Fusion toxins are hybrid proteins consisting of peptide ligands linked through amide bonds to polypeptide toxins. The ligand directs the molecule to the surface of target cells and the toxin enters the cytosol and induces cell death. Ricin is an excellent candidate for use in fusion toxins because of its extreme potency, the extensive knowledge of its atomic structure and the lack of prior immunological exposure in patients. We synthesized a baculovirus transfer vector with the polyhedrin promoter followed sequentially from the 5' end with DNA encoding the gp67A leader sequence, the tripeptide ADP, IL-2 (interleukin-2), another ADP tripeptide and RTB (ricin toxin B chain) with lectin-site mutations W37S and Y248H. Recombinant baculovirus was generated in Sf9 insect cells and used to infect Sf9 cells. Recombinant IL-2-RTB[W37S/Y248H] protein (fusion protein of IL-2 with modifications W37S and Y248H) was recovered at high yields from day 6 insect cell supernatants, partially purified by affinity chromatography and reassociated with RTA (ricin toxin A chain). The fusion toxin was soluble, immunoreactive with antibodies to RTB, IL-2 and RTA and had a molecular weight of 80 kDa by SDS-PAGE. The molecule reacted poorly with asialofetuin, but bound strongly to IL-2 receptor based on selective cytotoxicity to IL-2 receptor bearing cells. The specific cytotoxicity could be blocked with IL-2 but not lactose. Thus, we report a novel targeted fusion toxin protein with full biological activity.

Animals↗
PubMed1996

Double-site ricin B chain mutants retain galactose binding.

Three distinct double-site and two single-site ricin B chain (RTB) mutants were expressed in Spodoptera frugiperda insect cells and purified from infected cell supernatants. The yields of recombinant proteins were 0.01-0.2 mg/l. The purity after monoclonal antibody affinity chromatography was 1-20%. The mutant proteins were soluble, immunoreactive with monoclonal antibodies and polyclonal antibodies to RTB and demonstrated molecular weights of 32 kDa, similar to plant RTB. All three double-site and both single-site mutants bound asialofetuin and mammalian cell surfaces based on an asialofetuin ELISA and cell binding immunofluorescence assay. While one double-site mutant, W37S/Y248S, had a 1 log drop in sugar binding, the other two double-site mutants W37S/Y248H and D22E/D234E had 2 log reductions in sugar binding. Each mutant reassociated efficiently (25-75%) with plant ricin A chain (RTA) to form cytotoxic heterodimers. The concentration of protein required to reduce protein synthesis 50% (ID50) was 1 log higher than plant ricin for W37S/Y248S-RTA and the single-site mutant heterodimers, Q35N-RTA and D22E-RTA and 2 logs higher than plant ricin for the other two double-site mutant heterodimers. The results suggest amino acid residues in both the 1 alpha and 2 gamma subdomains of RTB participate in sugar binding. However, other subdomains must contribute to the avidity of ricin for cell surface oligosaccharides.

Animals↗
PubMed1996

Relationships between mobility of axial structures and physical performance.

BACKGROUND AND PURPOSE: Many day-to-day activities require bending and twisting motions of the spine (axial mobility). Because little is known about the relationship between axial mobility and physical performance, this investigation explored these relationships. SUBJECTS: Thirty-one men and 26 women, aged 20 to 91 years (chi=58.4, SD=24.4), participated. METHODS: Subjects were assigned to one of three age groups: 20 to 40 years, 60 to 74 years, or 75 years and older. Five sets of variables were identified and measured: cervical, lumbar, sagittal configuration (ie, kyphosis, lordosis), combined spinal motion, and physical performance. RESULTS: A multivariate analysis of variance revealed age effects for all sets of variables; a post hoc analysis of variance revealed age effects for all variables within the sets. Canonical correlations, controlling for age, demonstrated associations between the cervical and combined spinal motion sets of variables and between the combined spinal motion and physical performance sets of variables. CONCLUSION AND DISCUSSION: This investigation demonstrated an age effect for selected measures of axial mobility, sagittal configuration, and physical performance thought to depend on axial motion. Controlling for age, the results also demonstrated associations between measures of axial mobility and physical performance.

Adult↗
PubMed1996

Cytotoxicity of KDEL-terminated ricin toxins correlates with distribution of the KDEL receptor in the Golgi.

DNAs encoding ricin toxin A chain (RTA), with or without a C-terminal endoplasmic reticulum retention signal KDEL, were subcloned into pGEX2T bacterial expression plasmid. After transformation of JM105 E. coli cells and induction with isopropylthio-beta-galactoside (IPTG), fusion proteins were bound to an immobilized glutathione matrix and recombinant ricin A chains released with thrombin. Both recombinant wild-type RTA and RTA with KDEL had immunological reactivity and catalytic activity indistinguishable from plant RTA. The bacterial RTA products reassociated with plant ricin B chain (RTB) similarly to plant RTA. Cell cytotoxicities were measured on seven cell lines for each A-chain and heterodimer. Although KDEL sequences enhanced cytotoxicity in most cases, significant variability was observed. In each case, addition of KDEL enhanced A-chain cytotoxicity more than holotoxin cytotoxicity. Three cell lines showed reduced KDEL enhancement of both RTA and ricin cytotoxicity. The concentration of KDEL receptor was examined on each cell line by immunofluorescence microscopy with an antireceptor monoclonal antibody. Differences in sensitivity to KDEL-containing toxins correlated with altered distribution of KDEL receptor between endoplasmic reticulum (ER) and Golgi compartments.

Amino Acid Sequence↗
PubMed1995

Sensory interaction and descriptions of fabric hand.

82 subjects who viewed and felt fabrics (sensory interaction group) used different categories of terms to describe fabric hand than did 38 subjects who only felt the fabrics. Therefore, the methods used to measure fabric hand that isolate the senses may not accurately assess the way in which subjects describe fabric hand in nonlaboratory settings.

Adult↗
PubMed1994

Predicting falls: the role of mobility and nonphysical factors.

OBJECTIVE: Our purpose was to test a four-domain predictive model of recurrent falls developed for this study. In this model, limited mobility is considered a necessary but not sufficient element in risk of recurrent falls. Three other domains, attitudinal, social, and environmental, are proposed to influence fall risk only in persons with impaired mobility. DESIGN: Prospective cohort study. SETTING: Veterans Affairs Ambulatory Care Service serving rural and urban central North Carolina. SUBJECTS: Male Veterans aged 70 or older (n = 306) were monitored prospectively for falls. At baseline, 159 screened as high-risk mobility status and 147 as low-risk mobility status. MEASUREMENTS: The primary outcome was recurrent falls. The mobility screen used for risk assignment defined immobile as unable to sit without support for 60 seconds, mobile and stable as meeting criteria for normal ambulation and stair climbing, and mobile but unstable as those who met neither of the above criteria. The high-risk subjects were further assessed in their homes for mobility in more detail, attitude toward risk, social supports, and environmental status. Other data included demographics, functional status, diagnoses, and medications. RESULTS: Recurrent falls occurred in 37 (23.3%) high-risk subjects and seven (4.8%) low-risk subjects (relative risk = 4.8, confidence interval 2.5 to 9.6, P < 0.001). Within the high-risk group, the probability of recurrent falls was significantly affected by degree of impaired mobility (P < 0.001), attitude toward risk (P = 0.005), and environment score (P = 0.03). CONCLUSIONS: A simple mobility screen can identify elders at increased risk for recurrent falls. Risk within this group is further modified by risk-taking behavior and environment.

Accidental Falls↗
PubMed1993

Magnetic resonance imaging morphometric analysis of cerebral volume loss in human immunodeficiency virus infection. The HNRC Group.

Magnetic resonance imaging was used to compare male subjects seropositive for antibody to human immunodeficiency virus type 1 (HIV positive), with and without medical symptoms, with two groups of men who were seronegative (HIV negative). The control subjects included men at high risk for exposure to HIV-1 and those at low risk. None of the HIV-positive subjects met criteria for HIV-associated dementia or had detectable opportunistic brain disease. Quantitative image-analytic techniques were used to estimate volumes of ventricular and cortical cerebrospinal fluid, cerebral white matter, and cortical and subcortical gray matter structures. Relative to low-risk group control subjects and asymptomatic HIV-positive subjects, nondemented but medically symptomatic HIV-positive subjects showed significant increases in cerebrospinal fluid, reduced volume of cerebral white matter, and reduced cerebral gray matter volumes. Unexpectedly, however, some cerebrospinal fluid increases and gray matter volume decreases were present in the seronegative high-risk control subjects as well.

Adult↗