Biomedical subjects

D K Williams

Publications and source records attributed to D K Williams.

At least 19 recordsLinked to original sources

PubMed2006

Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants.

OBJECTIVE: To examine whether hypercapnia in very low birth weight (VLBW) infants during the first 3 days of life is associated with severe intraventricular hemorrhage (IVH). STUDY DESIGN: Retrospective cohort study of inborn VLBW infants between January 1999 and May 2004 with arterial access during the first 3 days of life. A multiple logistic regression analysis was used where IVH was dichotomized ((grades 0/1/2) = non-severe; (grades 3/4) = severe). Measures of hypercapnia were entered into the model to ascertain their association with severe IVH. RESULTS: In total, 574 VLBW infants met entry criteria. Worst IVH grade was 0 in 400; 1: 54; 2: 42; 3: 47; and 4: 31 infants. The logistic regression model consisted of the following predictors of severe IVH: gestational age, gender, 1 min Apgar score (dichotomized into two groups: >3 vs < or =3), multifetal gestation, vasopressor use, and maximum PaCO(2). CONCLUSION: In addition to traditional risk factors, it appears maximum PaCO(2) is a dose-dependent predictor of severe IVH during the permissive hypercapnia era.

Cerebral Hemorrhage↗

PubMed2005

Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16.

We report three related and one unrelated child with an apparently novel neurodevelopmental disorder. The clinical course was very similar in all the four patients: congenital microcephaly with severe failure of post-natal brain growth, neonatal onset of intractable seizures associated with lack of developmental progression and death within the first 3 years of life. The appearance on cerebral neuroimaging was almost identical, with simplified gyration associated with a non-thickened cortex, severe hypoplasia of the corpus callosum, a small flattened brain stem, and specific cystic lesions in the white matter around the temporal and occipital horns. To our knowledge these patients represent a previously unreported, autosomal recessive syndrome. Homozygosity mapping in the consanguineous family has identified a candidate region on the chromosome 2p16.

Abnormalities, Multiple↗

PubMed2005

Effectiveness of payment for reduced carbon monoxide levels and noncontingent payments on smoking behaviors in cocaine-abusing outpatients wearing nicotine or placebo patches.

In a 2-week intervention to reduce cigarette smoking among outpatients in treatment for cocaine addiction, 20 subjects were randomly assigned to a contingent group, receiving monetary vouchers for breath samples with carbon monoxide (CO) levels of 8 ppm or less, or to a noncontingent group, receiving vouchers regardless of CO level. Subjects wore either nicotine or placebo patches in a randomized crossover design. Contingent subjects had significantly lower CO levels and met the 8 ppm target significantly more often than did noncontingent subjects; however, number of cigarettes reported smoked did not differ between groups. Use of nicotine patches resulted in CO levels significantly lower than did use of placebo patches, but levels still exceeded 8 ppm regardless of type of patch. Because contingent reward helped cocaine-dependent smokers achieve nonsmoking CO targets, behavioral antismoking interventions merit continued study in similar populations.

Administration, Cutaneous↗

PubMed2004

The P50 midlatency auditory evoked potential in patients with chronic low back pain (CLBP).

OBJECTIVE: Patients with Chronic Low Back Pain (CLBP) show arousal, attentional and cognitive disturbances. The sleep state-dependent P50 midlatency auditory evoked potential was used to determine if patients with CLBP [with and without co-morbid depression (DEP)] show quantitative disturbances in the manifestation of the P50 potential. METHODS: P50 potential latency, amplitude and habituation to repetitive stimuli at 250, 500 and 1000ms interstimulus intervals (ISIs) was recorded, along with the McGill Pain Questionnaire-Short Form (MPQ-SF). CLBP subjects (n=42) were compared with Controls (n=43), and with subjects with DEP only (n=6). Of the CLBP subjects, 20/42 had clinical depression (CLBP+DEP); 8/20 were taking anti-depressant medication (CLBP+DEP+med), the others were not (CLBP+DEP-med). RESULTS: There were no differences (ANOVA) in age, sex or P50 potential latency, although there was a trend towards increased latencies in CLBP groups. P50 potential amplitude was lower in CLBP groups, but not in sub-groups, again indicating a trend. P50 potential habituation was decreased in the DEP only subjects at the 250m ISI, and decreased in CLBP+DEP-med subjects at the 500ms ISI. This difference was not present in CLBP+DEP+med subjects. The MPQ-SF revealed that patients with CLBP and CLBP+DEP-med showed lower pain scores than CLBP+DEP+med patients. CONCLUSIONS: There is decreased habituation of the P50 potential habituation in unmedicated patients with CLBP+DEP compared to Controls. SIGNIFICANCE: Patients with CLBP+DEP-med may be less able to disregard incoming sensory information, including painful sensations, but anti-depressant medications help correct this deficit. However, their perception of pain may be increased by medication.

Acoustic Stimulation↗

PubMed2001

Increasing levels of dietary homocystine with carotid endarterectomy produced proportionate increases in plasma homocysteine and intimal hyperplasia.

PURPOSE: The role that homocysteine may play in post-carotid endarterectomy (CEA) restenosis due to intimal hyperplasia is not well understood. This study was designed to investigate the effects of different levels of dietary homocystine on: (1) plasma homocysteine; (2) post-CEA intimal hyperplasia; and (3) levels of the methyl donor S-adenosylmethionine (SAM) and its counterpart S-adenosylhomocysteine (SAH) in the homocysteine pathway. METHODS: Male rats were fed specialized diets for 2 weeks pre- and post-CEA. Groups included control (0 homocystine added, n=9), 1.5 (1.5 g/kg homocystine added, n=10), 3.0 (3.0 g/kg homocystine added, n=9), and 4.5 (4.5 g/kg homocystine added, n=11). The rats underwent a surgical carotid endarterectomy. Endpoints included; plasma homocysteine, intimal hyperplasia, replicative index using with alpha-SM actin and BrdU, hepatic SAM levels, SAH levels, and the hepatic activities of methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS). RESULTS: Increasing dietary homocystine produced a proportionate increase in plasma homocysteine and an increase in intimal hyperplasia. Regression analysis of plasma homocysteine levels and intimal hyperplasia showed a significant correlation (r=0.71,P=0.003). Plasma homocysteine levels above 15 microM were associated with significant increases in intimal hyperplasia above 6.5% (P=0.04). Elevation of plasma homocysteine levels to moderate levels (5-25 microM) resulted in significant post-CEA intimal hyperplasia. Cellular analysis of the area of intimal hyperplasia in all diet groups showed comparable amounts of cells positive for alpha-SM actin. However, with increasing levels of dietary homocystine and plasma homocysteine there was an increase in replicative index (P<0.001) as determined by BrdU staining. Increasing dietary homocystine increased plasma homocysteine and was followed by increases in the replicative index thus producing increased intimal hyperplasia and lumenal stenosis. In hepatic measurements the 1.5 and 3.0 g/kg homocystine diets caused: increased liver activity of MTHFR (P=0.03) and decreased hepatic levels of SAM, SAH and SAM/SAH ratios compared to controls. Homocystine treatment did not cause significant alterations in CBS levels (P=0.992). These studies also showed no correlation of the MTHFR and CBS enzymes with plasma homocysteine levels or intimal hyperplasia. However, hepatic levels of SAM showed significant negative correlations with plasma homocysteine (r=-0.58; P=0.006) and with BrdU percentages of cellular proliferation (r=-0.69; P=0.06). CONCLUSION: The degree of post-CEA intimal hyperplasia in a rat model is directly related to the plasma level of homocysteine. The hyperplastic effects of homocysteine may be mediated in part by a physiological insufficiency of methyl donors as shown by decreases in SAM. Thus, increasing levels of plasma homocysteine enhanced and accelerated the smooth muscle cell response after CEA which led to increased intimal hyperplasia and lumenal stenosis.

Animals↗

PubMed2001

Health-related quality-of-life measure enhances acute treatment response prediction in depressed inpatients.

BACKGROUND: Many nonbiological variables are reported to predict treatment response for major depression; however, there is little agreement about which variables are most predictive. METHOD: Inpatient subjects (N = 59) diagnosed with current DSM-IV major depressive disorder completed weekly depressive symptom ratings with the Hamilton Rating Scale for Depression (HAM-D-17) and Beck Depression Inventory (BDI), and weekly health-related quality-of-life (HRQL) ratings with the Quality of Well-Being Scale (QWB). Acute responders were identified by a 50% decrease in HAM-D-17 score from baseline within 4 weeks of medication treatment. Predictor variables were initially chosen from a literature review and then tested for their association with acute treatment response. RESULTS: An initial predictive model including age at first depression, admission BDI score, and melancholia predicted acute treatment response with 69% accuracy and was designated as the benchmark model. Adding the admission QWB index score to the benchmark model did not improve the prediction rate; however, adding the admission QWB subscales for physical and social activity to the benchmark model significantly improved acute treatment response prediction to 86% accuracy (p = .001). CONCLUSION: In addition to being designed for use in cost-effectiveness analyses, the QWB subscales appear to be useful HRQL variables for predicting acute inpatient depression treatment response.

Adult↗

PubMed2000

The design, synthesis and physical chemical properties of novel human vasopressin V2-receptor antagonists optimized for parenteral delivery.

Ionizable groups were introduced onto the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine scaffold of the vasopressin V2-antagonist WAY-VPA-985 in the search for molecules optimized for parenteral formulation. The synthesis and structure activity relationships (SAR) are presented together with solubility data in a model parenteral system. The amine, WAY-140288 (4f), was chosen for further development. p6

Antidiuretic Hormone Receptor Antagonists↗

PubMed2000

One-year results of laser vision correction for low to moderate hyperopia.

OBJECTIVE: To assess the efficacy and safety of hyperopic laser vision correction using a refined ablation architecture and the VISX STAR Excimer Laser. DESIGN: Prospective noncomparative case series. PARTICIPANTS: Fifty-two eyes with hyperopia from +1 to +6 diopters (D) spherical equivalent (SE) with or without cylinder < or =1.5 D based on cycloplegic refraction. Hyperopia was primary or caused by prior overcorrection of myopia. INTERVENTION: Hyperopic laser vision correction using a 9 mm/5 mm ablation profile and a pulse rate of 10 Hz. We prescribed ciprofloxacin and fluorometholone four times a day for 1 week. MAIN OUTCOME MEASURES: SE; uncorrected visual acuity (UCVA); predictability within +/- 0.5 D, +/- 1.0 D, and +/- 2.0 D of target refraction (emmetropia); loss of best-corrected visual acuity (BCVA); haze, and all complications at 1, 3, 6, and 12 months. RESULTS: We treated 52 eyes (mean preoperative SE; +3.03 D). Forty-one eyes (78.8%) had primary hyperopia. At 3, 6, and 12 months, 66%, 67%, and 79% of all eyes had refraction within +/-0.5 D of emmetropia. At these same intervals, 83%, 88%, and 79% were within +/-1.0 D of emmetropia. At 12 months, all eyes were within +/-2.0 D. At 3 months, 85.4% of eyes had UCVA of 20/40 or better, with 95.3% achieving 20/40 or better at 6 months. At 1 year, all eyes (n = 19) had gained from 1 to 8 Snellen lines of UCVA, with most (n = 16) gaining between 3 and 7 lines. At 12 months, all eyes maintained preoperative BCVA or gained 1 to 4 lines. There was some early, transient haze < or = grade 1.5. There were no corneal infiltrates, decentered ablations, or infections. CONCLUSIONS: These data suggest that the 9 mm/5 mm hyperopic ablation profile of the VISX STAR can produce accurate corrections without significant, progressive regression. Refractive stability was achieved 3 months after surgery. We did not observe any differences in outcomes between eyes treated for primary hyperopia and eyes treated for prior myopic overcorrections. We believe the quicker ablation time (10 Hz pulse rate) helped patients maintain fixation and reduced the risk of decentration. There was a high degree of satisfaction among all patients, especially those with presbyopia.

Adult↗

PubMed1999

Acromelic frontonasal dysostosis.

We report on 3 male and 2 female infants with acromelic frontonasal dysostosis. All 5 had a frontonasal malformation of the face and nasal clefting associated with striking symmetrical preaxial polysyndactyly of the feet and variable tibial hypoplasia. In contrast, the upper limbs were normal. This rare variant of frontonasal dysplasia may represent a distinct autosomal-recessive disorder. We suggest that the molecular basis of this condition may be a perturbation of the Sonic Hedgehog (SHH) signalling pathway, which plays an important part in the development of the midline central nervous system/craniofacial region and the limbs.

Abnormalities, Multiple↗

PubMed1999

Reduced sensory gating of the P1 potential in rape victims and combat veterans with posttraumatic stress disorder.

The P1 midlatency auditory evoked potential was studied in female rape victims with Posttraumatic Stress Disorder (PTSD) and compared to an age-matched female control group; and in male combat veterans with PTSD and compared to three groups of age-matched male control subjects. Sensory gating of the P1 potential was determined using a paired click stimulus paradigm in which the stimuli were presented at 250, 500 and 1000 msec interstimulus intervals (ISI). Results showed that sensory gating of the P1 potential was significantly decreased at the 250 msec ISI, and that there was a numerical, but not a statistically significant, decrease in sensory gating at the other intervals tested in both male and female PTSD subjects compared to all control groups. Since the P1 potential may be generated, at least in part, by the reticular activating system, dysregulation of sensory processing by elements of this system may be present in PTSD.

Acoustic Stimulation↗

PubMed1999

Purkinje cell vulnerability to developmental ethanol exposure in the rat cerebellum.

BACKGROUND: Ethanol exposure is a consistent and reliable producer of neuronal toxicity, especially during periods of enhanced neuronal vulnerability. For rat cerebellar Purkinje cells, the postnatal period during the time of the brain growth spurt exhibits the greatest vulnerability to ethanol. Analyses of studies completed over more than 20 years provides sufficient detail to allow for the determination of the specific vulnerable window for ethanol-induced loss of Purkinje cells. METHODS: Data reporting Purkinje cell counts after ethanol exposure were compiled from 18 studies published since 1975. We conducted linear regression analysis between peak blood ethanol concentration (BEC) and percent reduction in Purkinje cells for the following individual postnatal (PN) days: PN4, PN5. PN6, PN7, and PN8 or beyond (+). The slope of the regression and the coefficients of determination (r2) were the primary factors of interest. Analysis of variance of the regressions was conducted to identify whether the slopes were significantly different from zero, or from each other. RESULTS: Exposures involving the PN4-6 period demonstrated the greatest significance in the relationship between BEC and reduction of Purkinje cell number. No significant differences were identified between different ethanol exposure techniques or for different Purkinje cell counting techniques. In addition, the initial day of exposure and the duration of exposure were not identified as critical variables. CONCLUSIONS: The literature database, developed over the past 20 years is clear in its direction that studies designed to identify the ethanol-specific mechanisms of Purkinje cell death are best designed to involve ethanol exposure during the vulnerable window of postnatal days 4-6.

Animals↗

PubMed1998

Triplication of 15q11-q13 with inv dup(15) in a female with developmental delay.

A 4 year old female referred with developmental delay was found to have two de novo abnormal derivatives of chromosome 15, a supernumerary inverted duplicated marker chromosome (inv dup(15)) and an interstitial triplication of proximal 15q11-q13 or 14 in one of the two 15 homologues (trip(15)). Fluorescence in situ hybridisation (FISH) using probes within and flanking the Prader-Willi/Angelman syndrome critical region (PWASCR) confirmed the triplication in the abnormal 15 homologue. The inv dup(15) was dicentric, positive for IR39d which maps proximal to the PWASCR, but was negative for all the PWASCR FISH probes used. Results using polymorphic microsatellite repeats confirmed that the additional material in the trip(15) was maternal in origin and included several PWASCR loci. The presence of two de novo abnormalities involving the proximal region of 15q suggests a linked mechanism of origin.

Child, Preschool↗

PubMed1997

Multizone photorefractive keratectomy for high and very high myopia: long-term results.

PURPOSE: To compare 2 year results of multizone excimer laser photorefractive keratectomy (PRK) in eyes with myopia (spherical equivalent [SE]) from 6.00 to 10.00 diopters (D) with those in eyes with myopia from 10.25 to 25.75 D. SETTING: Wellington Hospital and Laser Vision Harley Street, London, England. METHODS: Of the 281 PRK cases with an SE of at least -6.00 D, 59 eyes had a minimum follow-up of 2 years. Twenty-six of these had an SE from -6.00 to -10.00 D and 33, from -10.25 to -25.75 D. The single-pass, multizone technique was used to create ablation zones at 5.0, 5.5, and 6.0 mm. Postoperatively, patients received a minimum of 4 weeks of fluorometholone 0.1%; those exhibiting regression after corticosteroids were discontinued were restarted on a tapering regimen. RESULTS: The refraction stabilized 3 months postoperatively in the -6.00 to -10.00 D group, and the final mean SE refraction was a small undercorrection. Two years postoperatively, 88.5% of eyes had a visual acuity of 20/40 or better, and 77.0% were within +/- 1.00 D of the intended correction. In eyes with myopia greater than 10.00 D, regression continued during the 2 years and refraction did not stabilize. Forty-two percent had an uncorrected acuity of 20/40 or better, and 48.0% were within +/- 1.00 D of the intended correction. The incidence and severity of haze were higher in the group with myopia greater than 10.00 D. The overall incidence of complications was low. CONCLUSION: Two years after multizone PRK, refractive and visual acuity results in eyes with myopia from 6.00 to 10.00 D were good. Results in eyes with myopia of more than 10.00 D were not satisfactory, and refraction had not stabilized.

Adult↗

PubMed1997

Marshall-Smith syndrome: the expanding phenotype.

We report a child of 3 years 9 months with the Marshall-Smith syndrome (MSS), characterised by the typical facial features, developmental delay, and advanced bone age. After the diagnosis was made at 5 months of age, careful observation for respiratory complications and failure to thrive was initiated. By 3 1/2 years of age, although our patient had no life threatening respiratory complications, investigation showed significant upper airway obstruction, which has been successfully treated. Aggressive treatment for failure to thrive has also allowed her to maintain a weight on the 50th centile. The purpose of this report is to suggest that early diagnosis and aggressive management may improve the ultimate prognosis with respect to the respiratory and feeding difficulties seen in this rare syndrome.

Abnormalities, Multiple↗

PubMed1997

Pterygia associated with otomandibular anomalies: a new autosomal recessive condition?

We report a male baby with an unusual pattern of malformations comprising severe micrognathia, ear abnormalities and popliteal and elbow webbing. Absence of a single phalanx in the fifth finger of each hand was also noted. Although there is no clear diagnosis there is a history of parental consanguinity and we suggest this may represent a new autosomal recessive disorder.

Abnormalities, Multiple↗

PubMed1996

NMR and molecular modeling study of the conformations of taxol 2'-acetate in chloroform and aqueous dimethyl sulfoxide solutions.

Taxol 2'-acetate, an analog of the antitumor drug taxol, displays no significant in vitro microtubule polymerization activity, thus underscoring the importance of a free 2'-OH group to the biological activity of taxol. Previous work had suggested that the inactivity of taxol 2'-acetate is not due to steric interference by the acetyl group. The present study examined the conformations of taxol 2'-acetate in deuteriochloroform and (2)H2O-deuteriodimethyl sulfoxide solutions and found them to be essentially the same as the respective conformations adopted by taxol itself. Thus, neither destabilization of an active taxol conformation by the acetyl group nor the formation of an important taxol conformation determining role for the 2'-OH group appears likely. The implication of these findings is that the taxol 2'-OH group interacts directly with a protein residue in the taxol-microtubule complex, perhaps as a hydrogen bond donor.

Acetates↗

PubMed1996

Polysialylated neural cell adhesion molecule and plasticity of ipsilateral connections in Xenopus tectum.

The optic tectum of Xenopus offers a readily manipulated system for testing the hypothesis that polysialylation of the neural cell adhesion molecule is associated with axonal plasticity. Axons relaying input to the tectum from the ipsilateral eye employ visual input to establish a topographic map in register with the contralateral map, despite naturally-occurring or surgically-induced repositioning of the eyes. This capacity for activity-dependent refinement or re-organization of the ipsilateral map is normally confined to a period between about one and four months postmetamorphosis but can be restored in adults by local application of N-methyl-D aspartate to the tectum. In addition, dark-rearing prolongs plasticity indefinitely. We have used immunohistochemical staining with antibodies to polysialic acid to determine whether conditions of high plasticity are correlated with high levels of polysialylated neural cell adhesion molecule in the tectum. We find that the staining level is high in tecta from one to three month postmetamorphic frogs but is low both before and after this period. Thus, in normal Xenopus frogs, anti-polysialic acid staining is heavier in the period of high plasticity than in the preceding or following postmetamorphic periods. As a further test of this relationship, we examined brains of adults with experimentally-induced plasticity. Tecta of N-methyl-D-aspartate-treated adults and of dark-reared adults showed higher levels of staining than did the tecta of normally-reared adults. These results also support the hypothesis that the presence of high levels of polysialic acid on neural cell adhesion molecules is causally related to activity-related changes in axonal growth patterns.

Animals↗

PubMed1996

Excimer laser photorefractive keratectomy for extreme myopia.

PURPOSE: To determine the efficacy, predictability, and safety of excimer laser photorefractive keratectomy (PRK) in treating very high myopia. SETTING: Laser Vision Harley Street, London, England. METHODS: Eighty-eight patients whose spherical errors ranged from -6.00 to -20.00 diopters (D) had PRK with the VISX 20/20B excimer laser and a multizone ablation technique. The patients were divided into two groups of 44: those with errors up to -10.00 D and those with errors above -10.25 D. Visual acuity, manifest refraction, corneal haze, and topography were examined 1 week and 1, 2, 3, 6, and 12 months postoperatively. RESULTS: Minimum follow-up was 1 year. Predictability of results was greater in Group 1 than in Group 2 patients: 90.0% were within 1.00 D of intended correction and 70.0% were within 2.00 D, respectively. The average for both groups was 85.0% within 2.00 D and 63.6% within 1.00 D of intended correction. No serious complications or overcorrections were seen in either group. Preoperative astigmatism ranged from 1.50 to 5.50 D. Postoperatively, 82.0% of patients had no residual astigmatism; in the other 18.0%, it ranged from 0.50 to 2.50 D (83.0% had 1.00 D or less). Results with the multizone technique were more successful than those reported with the single- or dual-zone ablation techniques. CONCLUSIONS: High myopia was treated with reasonable success using the VISX 20/20B excimer laser system and a multizone technique. Comparable studies using single- and dual-zone approaches appear to have less successful outcomes.

Adult↗