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Biomedical subjects

C D Smith

Publications and source records attributed to C D Smith.

At least 37 records · Page 2Linked to original sources
PubMed2003

Comparative results of endoluminal gastroplasty and laparoscopic antireflux surgery for the treatment of GERD.

BACKGROUND: Transoral endoluminal gastroplasty (EG) by the Bard Endocinch device is available for the treatment of gastroesophageal reflux disease (GERD). This study assessed the early (<or=12 months) outcomes in patients undergoing EG performed by one gastroenterologist compared with another set of patients referred by the same gastroenterologist for laparoscopic antireflux surgery (LAS) at a foregut surgery center. METHODS: From June 2000 to July 2002, 87 consecutive patients cared for by a single gastroenterologist were diagnosed with refractory GERD and underwent either EG (n = 47) or referral for LAS (n = 40). Preoperative evaluation included symptom assessment, pH studies, and motility studies. Outcomes were assessed by symptomatic improvement and dependence on anti-acid medications. Data analyzed by chi-square or Mann-Whitney tests are reported as mean +/- SEM. RESULTS: Preoperative symptom duration, Johnson-DeMeester (JD) score, % time pH < 4, and reflux episodes were statistically similar in both treatment groups. The follow-up times for EG and LAS groups were 7.3 +/- 0.9 and 8 +/- 0.4 months, respectively. Of EG patients, 94% were available for follow-up, and all LAS patients had follow-up data. Overall, 66% of patients were satisfied with EG as compared to 93% after LAS (p = 0.1). Postoperative PPI/motility agent use was 32% for EG and 13% for LAS (p = 0.03). Identifiable causes of EG failure were premature procedure termination due to hypoxia or bleeding (three patients), intractable vomiting (two patients), and delayed gastric emptying (five patients). Three EG patients subsequently had LAS within 6 months of the procedure. CONCLUSIONS: LAS offers greater reduction in medication use than EG, as well as more durable patient satisfaction. Benefits of EG may include short-term symptomatic improvement while considering definitive surgical management.

Adult↗
PubMed2003

Preoperative factors predictive of complicated postoperative management after Roux-en-Y gastric bypass for morbid obesity.

INTRODUCTION: This study was undertaken to determine preoperative predictive factors of complicated postoperative management after Roux-en-Y gastric bypass (RYGB) for morbid obesity. METHODS: Between January 1999 and January 2002, 158 patients who underwent a RYGB received a standardized preoperative evaluation and data were collected prospectively. Complicated postoperative management was defined as patients requiring postoperative ICU admission for > or =48 h, or those needing transfer from the floor to the ICU. Patients with complicated management were compared with those in whom ICU admission was not necessary. RESULTS: Twenty-three patients (14.5%) required prolonged ICU admission (mean stay of 6.3 +/- 1.7 days). After multivariate analysis, body mass index (BMI) >50 kg/m2, forced expiratory volume (FEV1) <80% predicted, previous abdominal surgeries, and abnormal EKG were found to be independently associated with an increased likelihood of complicated postoperative care. CONCLUSION: BMI >50 kg/m2, FEV1 <80% predicted, previous abdominal surgeries, and abnormal EKG increase the likelihood of complicated postoperative management after RYGB for morbid obesity.

Adult↗
PubMed2003

Can current technology be integrated to facilitate laparoscopic living donor hepatectomy?

BACKGROUND: Living donor hepatectomy (LDH) is a technically demanding procedure that is an alternative for providing livers for transplantation. Unlike liver resections for other pathology, LDH requires preservation of the major vessels and biliary tree. This study was performed to determine if current technology can be integrated to perform laparoscopic LDH. METHODS: Six adult sheep underwent laparoscopic LDH of the left lateral segment under general anesthesia. Instruments utilized included standard dissecting instruments, ultrasound, ultrasonic dissectors, CUSA, the TissueLink Floating Ball, and endoscopic staplers. RESULTS: LDH-harvested liver grafts were 44% of whole liver weight. Estimated blood loss was 300 cc. Warm ischemia time was 5-7 min. Grafts were delivered through 18-cm abdominal wounds. Major vessels and biliary anatomy were positively identified in the grafts. CONCLUSIONS: Laparoscopic LDH can be performed with available technology. Theoretical advantages include reduced liver manipulation and smaller wound size.

Animals↗
PubMed2003

Telomeric protein distributions and remodeling through the cell cycle in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, telomeric DNA is protected by a nonnucleosomal protein complex, tethered by the protein Rap1. Rif and Sir proteins, which interact with Rap1p, are thought to have further interactions with conventional nucleosomic chromatin to create a repressive structure that protects the chromosome end. We showed by microarray analysis that Rif1p association with the chromosome ends extends to subtelomeric regions many kilobases internal to the terminal telomeric repeats and correlates strongly with the previously determined genomic footprints of Rap1p and the Sir2-4 proteins in these regions. Although the end-protection function of telomeres is essential for genomic stability, telomeric DNA must also be copied by the conventional DNA replication machinery and replenished by telomerase, suggesting that transient remodeling of the telomeric chromatin might result in distinct protein complexes at different stages of the cell cycle. Using chromatin immunoprecipitation, we monitored the association of Rap1p, Rif1p, Rif2p, and the protein component of telomerase, Est2p, with telomeric DNA through the cell cycle. We provide evidence for dynamic remodeling of these components at telomeres.

Blotting, Southern↗
PubMed2002

An integrated computational pipeline and database to support whole-genome sequence annotation.

We describe here our experience in annotating the Drosophila melanogaster genome sequence, in the course of which we developed several new open-source software tools and a database schema to support large-scale genome annotation. We have developed these into an integrated and reusable software system for whole-genome annotation. The key contributions to overall annotation quality are the marshalling of high-quality sequences for alignments and the design of a system with an adaptable and expandable flexible architecture.

Animals↗
PubMed2002

Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. METHODS: Postmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. RESULTS: Hippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). CONCLUSION: Volumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

Aged↗
PubMed2002

Women at risk for AD show increased parietal activation during a fluency task.

BACKGROUND: Imaging studies have shown disparities in resting metabolism and in functional activation between cognitively normal individuals at high and low risk for AD. A recent study has shown increased parietal activation in high-risk subjects during a paired associates recall task, which the authors postulated might overlap activation typically observed in verbal fluency. OBJECTIVE: To determine whether parietal activation is altered in a letter fluency task in cognitively normal individuals at high risk for AD. METHODS: fMRI was used to compare cortical activation between two groups of cognitively normal women differing in their risk for developing AD. A letter fluency task was used, which activates left frontal and parietal regions. The risk groups differed in family history of AD and APOE allele status but were matched in age, education, and measures of cognitive performance. Average age of the study participants was 53 years. RESULTS: The regional patterns of brain activation were similar between groups and similar to patterns observed by other investigators. However, the high-risk group showed significantly increased activation in the left parietal region despite identical letter fluency performance between risk groups. CONCLUSIONS: Cognitively normal individuals at high risk for AD show increased brain activation in the left parietal region with letter fluency, a region adjacent to that observed by others using a recall task. This convergence of results indicates disruption of functional circuits involving the left parietal lobe in asymptomatic individuals at increased risk for AD.

Alzheimer Disease↗
PubMed2002

Long-term outcome of laparoscopic repair of paraesophageal hernia.

BACKGROUND: It has been reported that the laparoscopic repair of paraesophageal hernias is associated with higher complication and recurrence rates than the open methods of repair. METHODS: We identified 136 consecutive patients who underwent laparoscopic repair of a paraesophageal hernia between 1993 and 1999. Patient demographics and symptom scores for regurgitation, heartburn, chest pain, and dysphagia at presentation and at last follow-up were recorded (0 = none, 1 = mild, 2 = moderate, 3 = severe). The operative records were reviewed, and early and late complications were noted. Only patients with a follow-up of >1 were included in the analysis. RESULTS: The median age was 64 years, and there was a female preponderance (1.8:1). Most patients had some medical comorbidity; the American Society of Anesthesiologists (ASA) scores were <2 in eight patients and ?2 in 117 patients. Three laparoscopic operations were converted to open procedures. There were nine intraoperative complications, five early complications, and three related deaths (morbidity and mortality rates of 10.2% and 2.2%, respectively). Follow-up data were available for 83 patients (66%), and the mean follow-up time was 40 months (range, 12-82). The percentage of patients experiencing chest pain, dysphagia, heartburn, and regurgitation in the moderate to severe range dropped from a range of 34-47% to 5-7% (p <0.05). Three patients underwent repeat laparoscopic repair for symptomatic recurrence. CONCLUSION: The laparoscopic repair of paraesophageal hernias provides excellent long-term symptomatic relief in the majority of patients and has a low rate of symptomatic recurrence. The complication and death rates may be related in part to the higher incidence of comorbidities in this somewhat elderly patient population.

Female↗
PubMed2002

Frequency of postoperative nausea and vomiting in patients undergoing laparoscopic foregut surgery.

BACKGROUND: Wrap disruption or intrathoracic herniation of a fundoplication is a dreaded complication of laparoscopic foregut surgery. This problem may often be related to postoperative nausea and vomiting (PONV). This study aimed to investigate the occurrence of PONV and its management in patients undergoing laparoscopic foregut procedures. METHODS: Between January 31 and May 23, 2000, 104 patients undergoing laparoscopic foregut procedures (fundoplication, myotomy, or paraesophageal hernia repair) were followed prospectively. Their postoperative course was documented along with the occurrence and management of PONV. All laparoscopic foregut surgery patients are managed postoperatively with a uniform clinical pathway, and their care is focused on a nursing unit with skill and experience in postoperative management. RESULTS: Nausea was documented in the postanesthesia care unit (PACU) for 30.1% of the patients, and for 59.6% of the patients during their nursing unit stay. Antiemetics were given to all the patients with documented nausea. Emesis was noted in 1.9% of the patients in the PACU, as compared with 3.8% of the patients on the floor. In one of the patients with nursing unit emesis, an acute wrap herniation into the chest occurred, necessitating a return to the operating room for correction. The patients with a history of postoperative nausea did not have a higher rate of PONV than in those with no history of postoperative nausea. The use of preoperative or intraoperative antiemetics did not appear to alter the occurrence of PONV. Postoperative nausea occurred in 60% of the patients administered preoperative antiemetic, as compared with 64% of the patients who received no preoperative antiemetic. The average length of hospital stay was longer in those with PONV than in those with no PONV (2.6 vs 1.8 days). CONCLUSION: Nausea after laparoscopic foregut procedures is common, occurring twice as often on the nursing unit as in the PACU. The occurrence of PONV leads to a longer hospital stay, and can result in significant sequelae requiring reoperation. The use of preoperative or intraoperative antiemetics does not alter the frequency of postoperative nausea, suggesting the need to develop effective preemptive regimens for patients undergoing laparoscopic foregut procedures. The high rate of PONV and its potential risk of damage to a fundoplication and hiatal hernia repair should lead surgeons to consider whether laparoscopic foregut procedures should ever be performed on an outpatient basis.

Antiemetics↗
PubMed2002

Success factors and hurdles in quality improvement in a children's hospital.

A set of nurse/respiratory therapist-driven algorithms developed by a multidisciplinary team with the goal of "liberating" mechanically ventilated pediatric patients more rapidly from the ventilator resulted in sustained improvement over a 47-month period. The difference between expected and observed billed ventilator hour totals was over 22,000 hours (475 hours per month), a 17.5% reduction, which was significant at the P =.03 level by multiple linear regression analysis. Length of stay and mortality rate were unchanged. This difference represents a measure of the unrecognized cost of a nonstandardized approach to the weaning process. This reports reviews this team's success factors and hurdles and offers practical suggestions for pediatric surgeons interested in leading quality improvement initiatives.

Adolescent↗
PubMed2001

Cellular pharmacology of cerulenin analogs that inhibit protein palmitoylation.

S-palmitoylation is a dynamic post-translational modification of certain proteins, which helps determine membrane association and may function to enhance the interactions of signaling molecules with their activated receptors and effector systems. Unlike enzymes that catalyze other protein lipidation reactions, e.g. farnesylation and N-myristoylation, protein palmitoyltransferase is virtually uncharacterized biochemically. We have described previously the synthesis of cerulenin analogs including cis-2,3-epoxy-4-oxononadecanamide (16C) and cis-2,3-epoxy-4-oxododecanamide (9C) that inhibit protein palmitoylation (Lawrence et al., J Med Chem 1999;42:4932-41), most likely through covalent alkylation of protein palmitoyltransferase. [3H]9C and [3H]16C were prepared by catalytic incorporation of 3H2 into unsaturated precursors for further study of their cellular pharmacology. After 4 hr, T24 bladder carcinoma cells in the absence of serum accumulated a 4-fold higher intracellular level of [3H]16C than of [3H]9C. Uptake of [3H]9C and [3H]16C was reduced by the presence of serum in the medium, suggesting their binding to serum proteins. [3H]9C and [3H]16C alkylated unique patterns of proteins in T24 cells, with proteins of approximately 80 and 31 kDa being labeled by each compound. A panel of human tumor cell lines demonstrated half-maximal proliferation inhibition at concentrations of 7-30, 4-16, and 8-36 microM, for cerulenin, 9C, and 16C, respectively, indicating that the cell lines have approximately equal sensitivity to these compounds. Different cell lines have similar patterns of protein alkylation by [3H]9C or [3H]16C, with labeling intensity related to cytotoxicity of the compounds. Since both 9C and 16C inhibit palmitoylation, the commonly labeled proteins are candidates for human protein palmitoyltransferase.

Alkylation↗
PubMed2001

Resection and advancement of esophageal mucosa. A potential therapy for Barrett's esophagus.

BACKGROUND: Barrett's esophagus affects 5-10% of patients with gastroesophageal reflux disease (GERD) and is associated with a 40-fold increased risk of malignant transformation. Ablative therapies may lead to esophageal perforation or stricture formation if applied too liberally and residual glandular tissue and persistent cancer risk if utilized too sparingly. METHODS: Ten pigs underwent gastrotomy. Mucosa below the gastroesophageal (GE) junction was elevated by saline injections, circumferentially incised, and secured to an orogastric tube. By traction, the distal esophageal mucosa was inverted 10 cm proximally, then returned to the gastric lumen. In group A (n = 4), the mucosa (5 cm) was resected and the remnant was allowed to retract. In group B (n = 4), the mucosa was simply sutured back into its native position. In group C (n = 2), the mucosa (5 cm) was resected and the proximal segment was advanced and sutured to the gastric mucosa. At 6 weeks, or sooner if stricture developed, the animals were killed. Stricture formation was determined by ex vivo barium esophagram and gross assessment. The extent of fibrosis and epithelial healing were established histologically. RESULTS: Group A (mucosa resected) developed weight loss and anorexia within 4 weeks. Pathology revealed dense fibrotic stricture without reepithelialization. Group B (mucosa elevated/replaced) gained weight after the operation. Histology demonstrated mucosal healing without significant stricture or fibrosis. Group C (mucosa resected/advanced) also thrived postoperatively. Histology confirmed mucosal healing without evidence of retraction or dense stricture. CONCLUSIONS: Exposure of submucosal tissues causes esophageal stricture. Mucosal coverage minimizes submucosal fibrosis after injury. Mucosal resection and advancement allows healing without stricture and may have therapeutic potential for patients with Barrett's esophagus.

Anastomosis, Surgical↗
PubMed2001

Recursive partitioning analysis of locoregional recurrence patterns following mastectomy: implications for adjuvant irradiation.

PURPOSE: Postmastectomy irradiation improves overall survival for breast cancer patients at high risk for locoregional recurrence (LRR). The objective of this study was to use recursive partitioning analysis (RPA) to define patient subgroups at high risk for LRR following mastectomy. PATIENTS AND METHODS: A cohort of 1031 patients treated on prospective trials with mastectomy and doxorubicin-based chemotherapy without irradiation was analyzed. The variables considered in the RPA were tumor size, number of involved nodes, number of nodes examined, and percentage of nodes involved (nodes involved/nodes examined). The endpoint was LRR +/- distant metastasis. Only patients with complete data were analyzed (n = 913). Median follow-up was 8 years (range, 0.7-22 years). RESULTS: Involvement of 20% or more of the lymph nodes examined was the most significant variable predicting LRR. Three risk categories were defined. Patients with 20% or more involved nodes and tumors of 3.5 cm or more were at greatest risk for LRR (41% at 8 years). An intermediate-risk group included patients with 20% or more involved nodes and tumors of less than 3.5 cm as well as those with less than 20% involved nodes and tumor size of 5 cm or greater (18% at 8 years). Patients with less than 20% involved nodes and tumor size of less than 5 cm were at lowest risk for LRR (10% at 8 years). CONCLUSION: Tumor size and extent of nodal involvement play interrelated roles in predicting LRR following mastectomy and systemic therapy. Patients with 20% or greater involved nodes and those with less than 20% nodes and tumors of 5.0 cm or greater are at significant risk of LRR and should be considered for postoperative irradiation.

Adult↗
PubMed2001

A hypothalamic stroke producing recurrent hemihyperhidrosis.

A 40-year-old man awoke with exuberant sustained sweating of the entire left side of the body, which became intermittent over the next few days. MRI indicated a single linear hyperintensity in the right posterior hypothalamus, diminishing on a repeat scan. He continues to have episodes of left unilateral sweating precipitated by exercise or minor infection.

Adult↗
PubMed2001

Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance.

Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either of the transport proteins, P-glycoprotein or MRP1. Because of this activity, methods for the synthesis of analogues of this oxazole- and thiazole-containing cyclic peptide have been developed, and the total synthesis of 1 has been completed. Highlights of the synthetic strategy are as follows: (1) a dicyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction with Burgess reagent and DBU-assisted oxidation to form D-Ala-oxazole; (2) formation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reactions; and (3) use of molecular modeling to select the preferred precursor for the final cyclization of the peptide analogue. Synthetic 1 demonstrated spectral properties identical to those of the natural product and reversed P-glycoprotein-mediated drug resistance more effectively than MRP1-mediated resistance. Certain of the synthetic precursors had biological activity, indicating that cell permeability and peptide cyclization are necessary for optimal activity. Thus, the structure and the biological activities of the natural product are confirmed, and methods for the synthesis of analogues for further structure-activity explorations are defined.

Antineoplastic Agents↗
PubMed2001

Outcomes of laparoscopic fundoplication for gastroesophageal reflux disease and paraesophageal hernia.

BACKGROUND: Laparoscopic fundoplication has become the standard for operative treatment of gastroesophageal reflux disease (GERD). METHODS: We reviewed our experience with 1,000 consecutive patients receiving laparoscopic fundoplication for GERD (n = 882) or paraesophageal hernia (n = 118) between October 1991 and July 1999. Patients with achalasia and failed fundoplication were excluded from analysis. All the patients were evaluated preoperatively by upper endoscopy, esophageal manometry, and barium swallow. After 1994, 24-h pH monitoring was performed selectively in patients with extraesophageal symptoms and/or those without erosive esophagitis. There were 490 men 510 women in this review. Their mean age was 49 years. Procedures performed were 360 degrees floppy fundoplication (n = 879), 360 degrees fundoplication without fundus mobilization (Rossetti) (n = 22), 270 degrees posterior fundoplication (n = 96), and anterior fundoplication (n = 2). Esophageal lengthening procedure (Collis gastroplasty) was performed in combination with fundoplication in 15 patients. In seven patients the treatment was converted to open fundoplication. OUTCOMES: The average length of hospitalization was 2.2 days, and 136 patients stayed longer than 2 days. Major complications occurred in 21 patients: esophageal perforation (n= 10), acute paraesophageal herniation (n = 4), splenic bleeding (n = 2), cardiac arrest (n = 1), pneumonia (n = 3), and testicular abscess (n = 1). Additional operations were required to manage the complications in 14 patients (70%): Four of these procedures were performed emergently, and 10 patients underwent reoperation between 6 h and 10 days. There were three deaths, all of which involved elderly patients with paraesophageal hernia. There were 35 late failures requiring reoperation for recurrence of GERD or development of new symptoms: The treatment of 32 patients was revised laparoscopically, and 4 patients required laparotomy. Beyond 1 year (median follow-up period, 27 months), 94% of the reviewed patients were satisfied with their surgical outcome.

Aged↗
PubMed2001

Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists.

A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.

ATP Binding Cassette Transporter, Subfamily B, Mem↗