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Biomedical subjects

David M Williams

Publications and source records attributed to David M Williams.

11 recordsLinked to original sources
PubMed2003

Recognition of base-pairing by DNA polymerases during nucleotide incorporation: the properties of the mutagenic nucleotide dPTP alphaS.

The highly mutagenic nucleoside dP (6-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one) is a bicyclic analogue of N4-methoxy-2'-deoxycytidine. It exists as a mixture of its imino and amino tautomers in solution with a ratio of about 10:1 based on its tautomeric constant. The bicyclic nature of the heterocycle P restrains the amino substituent in an anti conformation and permits effective Watson-Crick base-pairing using either tautomer. The specificity of incorporation of dP by the 3'-5'-exonuclease-free Klenow fragment of DNA polymerase I (exo-free Klenow) has been studied using the 5'-(1-thio)triphosphate dPTP alphaS in combination with phosphorothioate-specific sequencing of the DNA products. The method provides a convenient qualitative assay for studying nucleotide incorporation and reveals for the first time a potential role for the minor tautomeric forms of the natural DNA bases in base misinsertion (substitution mutagenesis) during replication.

Base Pairing↗
PubMed2003

The effect of tautomeric constant on the specificity of nucleotide incorporation during DNA replication: support for the rare tautomer hypothesis of substitution mutagenesis.

The nucleoside analogue dP (6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one) displays ambivalent hydrogen bonding characteristics whereby the imino tautomer of P can base-pair with adenine and its amino tautomer can base-pair with guanine. Fixed imino and amino tautomers of 6-methyl-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one (N-methyl P) have been synthesised and their structures obtained by X-ray crystallography. The tautomeric constant of N-methyl P has been calculated from pK(a) values of the fixed tautomers and the kinetic parameters for the incorporation of its 5'-triphosphate (dPTP) by exonuclease-free Klenow fragment of DNA polymerase I have been determined. A strong correlation between the tautomeric constant and the incorporation specificity of dPTP is found. These results lend support to the proposal that the minor tautomeric forms of the natural bases may play an important role in substitution mutagenesis during DNA replication. Furthermore, they imply that DNA polymerases impose specific steric requirements on the base-pair during nucleotide incorporation.

Adenine↗
PubMed2003

Gadolinium as a nonnephrotoxic contrast agent for catheter-based arteriographic evaluation of renal arteries in patients with azotemia.

OBJECTIVE: This study was undertaken to determine the effect of gadolinium arteriography on renal function and its diagnostic accuracy in patients with azotemia with suspected renovascular disease. METHODS: Catheter-based digital subtraction arteriographic studies with gadolinium as the contrast agent were performed on 25 occasions in 21 consecutive patients with azotemia to evaluate renal arterial circulation. Gadolinium (gadodiamide, 287 mg/mL) was the only contrast used in these studies. Quantities of gadolinium administered ranged from 40 to 264 mL (mean +/- standard deviation, 124 +/- 74 mL). Serial determinations of renal function were performed in all patients. Arteriography was undertaken 20 times after prior renal revascularizations: seven times as a routine postoperative follow-up study, nine for increasing azotemia, three for worsening hypertension, and once for evaluation of a known renal artery stenosis in patient with an abdominal aortic aneurysm. Three additional arteriograms were performed as part of an evaluation for suspected renovascular hypertension. The two remaining arteriograms were performed in patients with known aortic aneurysms in whom renal artery stenosis was suspected. RESULTS: No adverse changes in renal function followed gadolinium arteriography. Prearteriography serum creatinine values ranged from 1.6 to 9.1 mg/dL (3.0 +/- 1.4 mg/dL), compared with postangiography values that ranged from 1.2 to 8.4 mg/dL (2.9 +/- 1.3 mg/dL). Comparable blood urea nitrogen values ranged from 23 to 71 mg/dL (40.1 +/- 13.5 mg/dL) before arteriography and from 21 to 68 mg/dL (36.5 +/- 13.3 mg/dL) after arteriography. All 38 renal arteries evaluated were adequately imaged. First-order and second-order branchings were well visualized on selective renal studies. Twenty-one renal arteries showed no abnormalities, including six of seven reconstructed arteries subjected to early postoperative evaluation. Twelve renal arteries manifested significant disease, including seven with stenoses and five that had become occluded. Among five additional renal arteries studied, two exhibited obstructing thrombus, two had dissections, and one had a kinked aortorenal bypass graft. CONCLUSION: Catheter-based arteriography in patients with azotemia with gadolinium as a contrast agent is a safe and effective means to evaluate the renal arterial circulation. The preferential use of gadolinium in lieu of nephrotoxic iodinated contrast agents for catheter-based arteriography in patients with azotemia is supported by this experience.

Adult↗
PubMed2003

Endovascular treatment of aortic aneurysms in patients with renal transplants.

Endovascular treatment of an abdominal aortic aneurysm was undertaken in two orthotopic renal transplant recipients with US Food and Drug Administration-approved aortic stents without specific measures taken to protect the transplanted kidney. Renal function remained unchanged in both patients. Follow-up imaging studies showed successful aneurysm exclusion. Endovascular abdominal aortic aneurysm treatment in renal transplant recipients does not appear to place the transplanted kidney at undue ischemic risk and may be the preferred approach in select patients.

Aged↗
PubMed2003

Aortic intimal tears: detection with spiral computed tomography.

PURPOSE: To determine the frequency, locations, and sizes of aortic intimal tears detected using spiral computed tomography (CT). METHODS: CT scans (26 single detector and 26 multidetector studies) from 52 patients with an unoperated aortic dissection and a patent false lumen were evaluated on a workstation. The number, location, and size of aortic tears were recorded and compared between the following groups: acute and chronic dissection, type A and type B, and single detector and multidetector studies. RESULTS: In 52 patients, 129 tears were identified (mean 2.48 per patient, median 2, range 1-7). There were no significant differences in the number or size of tears between the acute and chronic, the type A and type B, or the single detector and multidetector groups (p>0.05). The most common locations for tears were the descending aorta (57, 44%) and the juxtarenal region (26, 20%). Within the type B category, there was no significant difference in tear locations between the acute and chronic groups (p>0.05). The majority of tears (88, 68%) were < or =1 cm in each dimension. Tears in the thoracic aorta were significantly larger than abdominal aortic tears (p<0.05). CONCLUSIONS: All patients with an aortic dissection and a patent false lumen demonstrated one or more aortic intimal tears using spiral CT. Although most tears were small (</=1 cm), they were usually easily visualized.

Acute Disease↗
PubMed2002

Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May-Thurner) syndrome.

Intravascular ultrasound (IVUS) imaging and venography of the left common femoral and iliac veins were performed in 16 patients. The studies were evaluated for the anatomic cause of obstruction and how IVUS influenced endovascular management. IVUS demonstrated the cause of vessel compression in all 16 patients. Other findings, such as associated thrombus and guide wire localization within the residual vessel lumen, can modify the approach to intervention in as many as 50% of patients. IVUS is a useful adjunct in the diagnosis and endovascular management of iliac vein compression syndrome.

Adolescent↗
PubMed2002

Endovascular treatment of abdominal aortic aneurysm is associated with a low incidence of deep venous thrombosis.

OBJECTIVE: This study was performed to define the incidence of acute deep venous thrombosis (DVT) after endovascular treatment of abdominal aortic aneurysms (AAAs). Because aortic endograft placement requires prolonged femoral vessel instrumentation, it may be hypothesized that these patients are at increased risk for development of an acute DVT. PATIENTS AND METHODS: Fifty consecutive patients (42 men, eight women) ranging in age from 48 to 85 years (mean, 72 years) underwent endovascular treatment of an AAA from January 2000 to August 2001. Clinical examination and bilateral lower extremity duplex ultrasonography for DVT were performed on the first postoperative day and at the 1-month follow-up visit. No patient had a prior DVT or identifiable hypercoagulable state. Seven patients (14%) had concurrent malignant disease. Preoperative antiplatelet agents were administered in 26 patients (52%), and nine (18%) were on warfarin sodium therapy before surgery. No new DVT prophylaxis was initiated perioperatively. Epidural anesthesia was used in 60% of the patients, with general endotracheal anesthesia used in the remainder. Risk factors for DVT were evaluated with univariate statistical analysis. RESULTS: Three patients (6%) had an acute postoperative DVT develop. Two occurred in the femoral veins, and one occurred in the popliteal vein. Of these patients, one had been continued on perioperative anticoagulation therapy, and the remaining two were started on low-molecular weight heparin and warfarin sodium therapy on recognition of the DVT. One patient had an intraoperative injury of the affected common femoral vein, and this individual was the only one to have clinical signs of a DVT. The mean follow-up period was 8 +/- 0.8 months. In this experience, factors that may have placed patients at increased risk for an acute DVT were not identified. CONCLUSION: Six percent of patients undergoing endovascular repair of AAAs had postoperative DVT develop. These patients had a number of risk factors for the development of a DVT; however, no specific factor was identified that predisposed to DVT.

Aged↗
PubMed2002

Nuclear targeting of Porphyromonas gingivalis W50 protease in epithelial cells.

Porphyromonas gingivalis is an important pathogen associated with destructive periodontal disease and is able to invade the epithelial cell barrier. Its cysteine proteases are recognized as major virulence factors, and in this study, we examined the interaction of the arginine-specific protease with epithelial cells in culture. Three cell lines (KB, HeLa, and SCC4) were incubated with strain W50 culture supernatant; stained with monoclonal antibody 1A1, which recognizes an epitope on the adhesin (beta) component of the cysteine protease-adhesin (alpha/beta) heterodimer; and viewed using immunofluorescence microscopy. Within 1 h, the protease traversed the plasma membrane and was localized around the nucleus before becoming concentrated in the cytoplasm after 24 to 48 h. In contrast, the purified arginine-specific heterodimeric protease (HRgpA) rapidly entered the nucleus within 15 to 30 min. This nuclear targeting (i) was seen with active and Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK)-inactivated HRgpA, indicating it was independent of the proteolytic activity; (ii) occurred at both 4 and 37 degrees C; and (iii) failed to occur with the monomeric protease (RgpA(cat)), indicating the importance of the adhesin chain of the HRgpA protease to this process. Rapid cell entry was also observed with recombinant catalytic (alpha) and adhesin (beta) chains, with the latter again targeting the nuclear area. After 48 h of incubation with HRgpA, significant dose-dependent stimulation of metabolic activity was observed (measured by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), and a doubling of mitotic activity combined with the presence of apoptotic cells indicated that HRgpA may interfere with cell cycle control mechanisms. These effects were seen with both active and TLCK-inactivated protease, confirming that they were not dependent on proteolytic activity, and thus provide new insights into the functioning of this P. gingivalis protease.

Bacterial Proteins↗
PubMed2002

Operative mortality rate for elective abdominal aortic aneurysm repair is not increased by the presence of a previous or concurrent thoracic or thoracoabdominal aortic dissection.

BACKGROUND: The objective of this study was to determine the likelihood of mortality after abdominal aortic aneurysm (AAA) repair in patients with thoracic or thoracoabdominal aortic dissection. METHODS: Fourteen patients (11 men, three women) with known thoracic or thoracoabdominal aortic dissections underwent elective AAA repair from 1986 to 2001, including three patients with acute dissections (less than 14 days) and 11 patients with chronic dissections (14 days or longer). All 14 patients had type III aortic dissections. Stent graft exclusion of the aortic dissection was performed in one patient before AAA repair. Preoperative patient characteristics, intraoperative events, perioperative complications, and 30-day and 1-year mortality rates were assessed. RESULTS: Elective AAA repair in the setting of thoracic or thoracoabdominal aortic dissection in this series was associated with no 30-day mortality and a 1-year mortality rate of 7.1%. Furthermore, preoperative patient characteristics, intraoperative events, and perioperative complications did not appear to be associated with late, 1-year, mortality. CONCLUSION: Elective AAA repair in the setting of acute or chronic aortic dissection is associated with mortality rates similar to those generally attributed to elective AAA repair without accompanying aortic dissection. Nevertheless, the conduct of the operation is usually complex, especially in the setting of an acute aortic dissection.

Acute Disease↗