PubMed Health⌕ Search

Biomedical subjects

D M Williams

Publications and source records attributed to D M Williams.

At least 19 recordsLinked to original sources
PubMed1996

An approach to random mutagenesis of DNA using mixtures of triphosphate derivatives of nucleoside analogues.

We describe a new method for random mutagenesis of DNA based on the use of a mixture of triphosphates of nucleoside analogues. The method relies on DNA amplification in vitro with Taq polymerase and in the presence of the 5'-triphosphates of 6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido-[4,5-C] [1,2]oxazin-7-one(dP) and of 8-oxo-2' deoxyguanosine (8-oxodG). The newly synthesised triphosphate derivative of dP (dPTP) is an excellent substrate for Taq polymerase (Km = 22 microM versus Km = 9.5 microM for TTP); it is incorporated in place of TTP and, with a approximately fourfold lower efficiency, in place of dCTP. After 30 cycles of DNA amplification, equimolar mixtures of the four normal dNTPs and dPTP yield the following frequencies of the four transition mutations: A-->G (4.4 x 10(-2), T-->C (4.3 x 10(-2), G-->A (1.1 x 10(-2) and C-->T (1.0 x 10(-2). The triphosphate derivative of 8-oxodG (8-oxodGTP) is incorporated opposite template adenine and yields two transition mutations (A-->C and T-->G) at frequencies of 0.8 x 10(-2) and 1.2 x 10(-2) respectively. Reaction mixtures containing dPTP and 8-oxodGTP results in both dP and 8-oxodG-induced mutations and an extensive array of codon changes in the absence of insertions and deletions. The method described differs from previous mutagenesis procedures in three respects: (1) it enables very high frequencies of base substitutions (up to 1.9 x 10(-1) (2) it allows control of the mutational load via the number of DNA amplification cycles and (3) it yields both transition and transversion mutations. The procedure may find application in the generation of libraries of DNA and protein mutants from which species with improved or novel activities may be selected.

Amino Acid Sequence↗
PubMed1995

Increased prevalence of dysplastic and malignant lip lesions in renal-transplant recipients.

BACKGROUND: Renal-transplant recipients are known to have increased rates of skin cancer associated with exposure to the sun. Little is known, however, about the prevalence and histologic features of lesions of the lips in these patients, or about risk factors for such lesions. METHODS: We examined the lips of 160 renal-transplant recipients (105 men and 55 women; mean [+/- SD] age, 48 +/- 13 years) and 160 normal subjects matched with the transplant recipients for age, sex, and skin type. The mean length of time between transplantation and the examination was 69 +/- 52 months; 58 percent of the recipients had received their grafts more than 60 months earlier. RESULTS: Among the 160 renal-transplant recipients, 21 (13 percent) had leukoplakia; in 2 (1.2 percent) the leukoplakia contained squamous-cell carcinoma. In contrast, only one normal subject (0.6 percent) had leukoplakia. Histologically, 13 of the 21 leukoplakias (62 percent) in the renal-transplant recipients who underwent biopsy were dysplastic, and 2 (10 percent) contained squamous-cell carcinoma. Actinic change was evident in 91 percent of the dysplastic lesions but not in the nondysplastic lesions (P < 0.001). Exposure to the sun and smoking were risk factors for dysplastic and malignant lip lesions in the renal-transplant recipients (P < 0.001 and P = 0.003, respectively). Among these recipients, only men had dysplastic or malignant lip lesions (P = 0.006); lipstick was used frequently by 73 percent of the women. The clinical appearance of lip lesions did not predict the presence of dysplasia or cancer. CONCLUSIONS: Renal-transplant recipients have an increased prevalence of leukoplakia, dysplasia, and cancer of the lip.

Adolescent↗
PubMed1995

Species-dependent induction of peroxisome proliferation by haloxyfop, an aryloxyphenoxy herbicide.

The potential of haloxyfop [2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid; HAL] to induce the proliferation of hepatocellular peroxisomes (PP) was examined in rats, mice, dogs, and monkeys. Chemically induced PP is associated with the development of liver tumors in rodents via an apparent species-dependent, nongenotoxic mechanism of action. HAL is nongenotoxic yet has been shown to cause liver tumors in female B6C3F1 mice. Ingestion of HAL by rats and/or mice (0.1-14 mg/kg/day for 2 to 4 weeks) resulted in significant dose-related PP as evidenced by hepatocellular hypertrophy, increased peroxisome volume density (VD), and induction of peroxisomal enzymes and CYP4A1. Only a relatively weak induction of PP was noted at a carcinogenic dosage in female mice. In contrast to rodent species, ingestion of up to 20 mg/kg/day HAL by male and female Beagle dogs for 13 weeks failed to increase peroxisomal VD while causing only a slight increase in peroxisomal enzyme activity at the highest dosages. Oral administration of up to 30 mg/kg/day HAL by male and female Cynomolgus monkeys for 13 weeks failed to induce PP. While a direct relationship of PP with tumor formation, at least in mice, was not demonstrated, these data still support the concept that PP represents a potential marker of nongenotoxic tumorigenic activity, at some dosage, in rodents.

Animals↗
PubMed1995

Malignant ameloblastoma revisited.

A case of a malignant ameloblastoma in a 49-year old Sri Lankan woman with widespread pulmonary metastases is presented, the diagnosis confirmed by needle biopsy. The current histological classification of odontogenic carcinomas and the management of metastatic pulmonary deposits are discussed.

Ameloblastoma↗
PubMed1995

Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity.

Hypothermic circulatory arrest has become an accepted technique for a variety of cardiac and complex aortic operations. However, prolonged periods (> 45 min) of hypothermic circulatory arrest in older patients is associated with marginal cerebral protection and an increased incidence of adverse neurologic events. In an effort to minimize such morbidity, we used a technique of retrograde cerebral perfusion with continuous monitoring of cerebral hemoglobin oxygen saturation during hypothermic circulatory arrest in 35 patients who underwent thoracic aortic operations or resection of intracardiac tumor. There were 27 men and 8 women (mean age 60 years, range 21 to 83 years). Sixteen patients had acute dissection, 6 had contained rupture of a thoracic aortic aneurysm, 10 had either a chronic dissection or aneurysm, and 3 had hypernephromas extending into the heart. Six patients underwent root replacement by means of an open technique for their distal anastomosis, 7 underwent root and partial arch replacement, 12 had root and total arch replacement, 7 had total arch replacement, and 3 had resection of tumor in the heart and retrohepatic vena cava. Seven patients had simultaneous coronary artery bypass grafting, 3 had replacement of one of the arch vessels, and 2 patients had a cesarean section. Sixteen cases were emergency, 6 urgent, and 13 elective. Nine (26%) were reoperations. Thirty-four patients underwent the procedure via a median sternotomy and one patient through a posterolateral thoracotomy. The mean retrograde cerebral perfusion time was 63 minutes (range 35 to 128 minutes), with 30 (86%) patients having more than 45 minutes, 12 (34%) having more than 65 minutes, and 4 (11%) having more than 90 minutes. There was 1 operative death caused by a preoperative myocardial infarction from an aortic dissection, and there were 2 late deaths (multiple organ failure and ruptured total aortic aneurysm). One patient had a stroke with a residual right hemiplegia and a pronounced aphasia. There were no other significant neurologic events or reoperations for bleeding. The average length of stay for patients having elective operations was 11 days and for those having emergency operations, 27 days. At a mean follow-up of 6 months all surviving patients (91%) are well. Hypothermic circulatory arrest is a relatively simple technique that provides a bloodless field and good visualization without the need for aortic crossclamps. Moreover, retrograde cerebral perfusion with continuous monitoring of cerebral oxygen saturation extends the "safe" time for hypothermic circulatory arrest, allowing ample opportunity to perform complicated cardiac and aortic operations with reduced risk of adverse neurologic events.

Aortic Dissection↗
PubMed1995

Gadolinium-enhanced magnetic resonance angiography of abdominal aortic aneurysms.

PURPOSE: The objective of this study was to assess the usefulness of gadolinum-enhanced magnetic resonance angiography (MRA) for defining anatomic features relevant to performing aortic surgery for aneurysmal disease. METHODS: Anatomic data defined by MRA, including abdominal aortic aneurysm (AAA) size and character, as well as the status of the celiac, mesenteric, renal, and iliac arteries, were correlated with angiography, ultrasonography, computed tomography, or operative data in 43 patients. Five MRA sequences were obtained in an hour-long examination optimized for aortoiliac, splanchnic, and renal artery imaging at 1.5 T in a body coil. Four of the sequences were performed during or after infusion of gadolinium to improve image quality. RESULTS: MRA correctly defined the maximum aneurysm diameter, as well as its proximal and distal extent in all patients. MRA detected 33 of 35 significant stenoses among 153 splanchnic, renal, or iliac branches examined (sensitivity = 94% and specificity = 98%). MRA did not resolve the degree of aortic branch stenotic disease sufficiently to precisely grade its severity. MRA did not reliably define the status of the inferior mesenteric artery, lumbar arteries or internal iliac arteries. One ruptured AAA and one inflammatory AAA were correctly diagnosed by MRA. No patient had a contrast reaction or contrast-induced renal toxicity related to administration of gadolinium. CONCLUSION: Gadolinium-enhanced MRA of AAA provides appropriate, essential anatomic information for aortic reconstructive surgery in a 1-hour examination devoid of contrast-related renal toxicity or catheterization-related complications attending conventional arteriography.

Adult↗
PubMed1995

Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor.

Recombinant human granulocyte colony-stimulating factor (G-CSF) has substantially improved life expectancy for children with severe congenital neutropenia (SCN). Severe osteoporosis, reported in this population, may relate to the disease process, or be a therapeutic side-effect. This report details bone loss, quantitated absorptiometrically and histomorphometrically, in a child with SCN and vertebral collapse, and the positive response to anabolic steroid and bisphosphonate therapy.

Anabolic Agents↗
PubMed1995

Effects of Porphyromonas gingivalis culture products on the morphology of peripheral blood polymorphonuclear leucocytes from periodontitis patients and healthy subjects.

The effects of Porphyromonas gingivalis culture supernatant from strain W50, its avirulent variant (W50/BE1) and sterile BM culture medium on the morphological changes in polymorphonuclear leucocytes (PMN) from 10 patients with periodontitis (3 juvenile periodontitis, 7 rapidly progressive periodontitis) were compared with those from 10 healthy controls. Large non-polar cells ( > 160 microns2) were increased in patients to 182.8% (p = 0.0076) and 245.5% (p = 0.0002) of control values with W50 and W50/BE1 supernatant respectively. In contrast, numbers of small non-polar cells ( < 80 microns2) and polarised cells were decreased in the patient group. Patient/control ratios for small non-polar cells were 30.3% (p = 0.0007) and 33.6% (p = 0.0005) with W50 and W50/BE1, respectively, and 38.2% (p = 0.0147) for polarised cells exposed to W50 supernatant. The data indicate that PMN from patients with periodontitis differ significantly from those of healthy controls in the shape changes which occur after exposure to P. gingivalis culture supernatant.

Adolescent↗
PubMed1995

Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme.

Erythema multiforme may be recurrent and the oral cavity is often affected. A series of 82 patients with unequivocal recurrent cutaneous erythema multiforme were examined to determine the incidence and nature of oral lesions. Seventy per cent of patients had oral lesions, comprising multiple, large, shallow, extremely painful and debilitating ulcers, which affected the entire oral mucosa in over 20%. The buccal mucosa and tongue were the most frequently affected sites in the remainder and the lips were affected in 13% of patients. Lesions generally lasted for 1-3 weeks. In over 60% of cases these attacks followed an episode of herpes simplex virus infection during the preceding fortnight. Recurrent attacks showed a different site distribution from the initial attacks, with a greater proportion having genital as well as skin and oral mucosal involvement. Detailed case histories of five patients are presented to illustrate the role of azathioprine in treating oral lesions and to document a familial case of recurrent erythema multiforme, with severe mucosal involvement.

Adolescent↗
PubMed1995

Contralateral and ipsilateral suppression of the 2f1-f2 distortion product in human subjects.

The amplitude of the 2f1-f2 distortion product was measured under four conditions in human subjects: during simple two-tone stimulation, during stimulation with a third, pure tone in the ipsilateral ear, during contralateral stimulation with broadband noise, and with combined ipsilateral third tone and contralateral noise. The amount of ipsilateral suppression produced varied with suppressor frequency but was maximum close to the f2 primary frequency as previously demonstrated using similar stimulus parameters [A. M. Brown and D. T. Kemp, Hear. Res. 13, 29-37 (1984); F. P. Harris, R. Probst, and L. Xu, ibid. 64, 133-141 (1992)]. Contralateral stimulation also suppressed the level of distortion. During ipsilateral suppression combined with contralateral stimulation, the amount of ipsilateral suppression of the distortion product was reduced. This interaction may indicate a common mechanism for ipsilateral and contralateral suppression. The decrease in ipsilateral suppression under contralateral stimulation was most pronounced at the peak of the ipsilateral suppression tuning curves and this produced some broadening of the function. In the majority of ipsilateral suppression curves, the peak ipsilateral suppression frequency was observed to shift upwards during contralateral stimulation. These results suggest that contralateral stimulation alters the frequency-selective properties of the cochlear response.

Adult↗
PubMed1995

Role of CD8 T cells in primary Chlamydia infection.

The role of CD4 and CD8 T cells in primary Chlamydia trachomatis pneumonia was investigated by using in vivo depletion techniques to eliminate T-cell populations. Reduction of either CD4 T cells or CD8 T cells caused a significant increase in organism burden in the lungs, as measured by both quantitative culture and detection of chlamydial antigen on day 14 postinfection. Chlamydia-specific antibody levels in plasma or antigen-induced gamma interferon (IFN-gamma) production by spleen cells was dramatically reduced by depletion of CD4 cells. The reduction in IFN-gamma achieved by depletion of CD8 cells did not reach statistical significance. In the survival studies, depletion of CD4 cells led to a significant increase in mortality. Although there was a trend toward higher mortality, depletion of CD8 cells did not significantly increase mortality. The role of CD8 T cells in host defense was clarified in studies using beta 2-microglobulin-deficient (major histocompatibility class I antigen-deficient, C1D) mice which are defective in CD8 T-cell function. In this model, a significant increase in organism burden was seen during infection in C1D mice compared with that C57BL/6 controls and a significant increase in mortality was observed as well. However, surviving C1D mice were able to clear the infection by day 34. C1D mice had increased numbers of CD4 T cells in both the spleen and the lungs during infection compared with those of C57BL/6 controls. IFN-gamma in C57BL/6 mice was produced by both CD4 and CD8 cells. Thus, there is a protective role for both CD4 and CD8 cells in host defense against Chlamydia infection, but the former appear to be dominant.

Animals↗
PubMed1995

Breath-hold gadolinium-enhanced MR angiography of the abdominal aorta and its major branches.

PURPOSE: To develop and evaluate a sequence for breath-hold three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography of the abdominal aorta. MATERIALS AND METHODS: In 63 patients, the abdominal aorta and its branches were imaged for 29, 43, or 58 seconds with breath holding. A fast spoiled gradient-echo sequence was used at 1.5 T during infusion of 42 mL of a gadolinium chelate. Correlation with conventional angiography was performed in 19 patients. MR image quality (signal-to-"total" noise ratio [S/N*]) with breath holding was compared with that with free breathing (104 patients). RESULTS: With breath-hold gadolinium-enhanced MR angiography, renal, celiac, and superior mesenteric artery occlusive disease was graded appropriately in 15 of 19 patients, and 10 of 11 accessory renal arteries were depicted correctly. Renal artery branches were visualized in 86 of 95 kidneys on breath-hold images compared with only 84 of 236 kidneys with free breathing (P < .001). Distal renal artery S/N* was 3.1 with breath holding and 2.1 with free breathing (P < .001). CONCLUSION: Breath holding statistically significantly improves three-dimensional gadolinium-enhanced MR angiography of the renal, celiac, and superior mesenteric arteries.

Adult↗
PubMed1995

Visceral leishmaniasis in the BALB/c mouse: a comparison of the in vivo activity of five non-ionic surfactant vesicle preparations of sodium stibogluconate.

Five non-ionic surfactants (Surfactants V-IX) were screened for their ability to produce vesicles for the delivery of sodium stibogluconate. Mean vesicle diameter and antimony content were determined prior to in vivo assessment of antiparasitic activity in a mouse model of acute visceral leishmaniasis. V/D suspensions (i.e. stibogluconate loaded vesicles kept in the hydrating drug solution) were more effective against spleen, liver and bone marrow parasites than drug loaded vesicle suspensions that had unentrapped drug removed. A Surfactant IX V/D suspension was the most active antileishmanial preparation causing 74 +/- 10%, 99 +/- 1% and 38 +/- 8% suppression of liver, spleen and bone marrow parasite burdens respectively. Contrary to previous findings, a reduction in splenic and bone marrow parasite burdens was achieved using large vesicles (mean diameter > 800nm). The significance of these results is discussed.

Animals↗
PubMed1994

Biodiversity at the molecular level: the domains, kingdoms and phyla of life.

The results of comparative sequence analysis, mainly of small subunit (SSU) ribosomal (r)RNA sequences, have suggested that all of cellular life can be placed in one of three domains: the Archaea, Bacteria or Eucarya. There is some evidence that the Archaea may not be a monophyletic assemblage, but as yet this issue has not been resolved. Most of the lineages, and all of the deepest ones, in the tree based upon SSU rRNA sequences, are microbial. Traditional ideas of classification such as Whittaker's five kingdom scheme do not adequately describe life's diversity as revealed by sequence comparisons. There are many microbial groups that demonstrate much greater amounts of SSU rRNA sequence divergence than do members of the classical kingdoms, Animalia, Plantae and Fungi. The old microbial kingdoms Monera and Protista are clearly paraphyletic but as yet there is no consensus as to how they should be reorganized in taxonomic terms. New data from environmental analysis suggests that much of the microbial world is unknown. Every environment which has been analysed by molecular methods has revealed many previously unrecorded lineages. Some of these show great divergence from the sequences of cultured microorganisms suggesting that fundamentally new microbial groups remain to be isolated. The relationships of some of these new lineages may be expected to affect how the tree of life is organized into higher taxa, and to also influence which features will be recognized as synapomorphies. There is currently no objective measure whereby microbial diversity can be quantified and compared to the figures which are widely quoted for arthropods and other Metazoa.

Animals↗