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Biomedical subjects

W Williams

Publications and source records attributed to W Williams.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and biological evaluation of conformationally restricted 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenediam ines as sigma receptor ligands. 1. Pyrrolidine, piperidine, homopiperidine, and tetrahydroisoquinoline classes.

The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using [3H](+)-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.

Animals↗
PubMed1992

Ventricular tachycardia after surgical repair of tetralogy of Fallot: results of intraoperative mapping studies.

OBJECTIVES: Four patients with previous repair of tetralogy of Fallot and ventricular tachycardia underwent map-guided surgery to ablate the arrhythmias. BACKGROUND: Although patients with repaired tetralogy of Fallot are at increased risk of sudden death due to ventricular tachycardia, little is known of the origin and mechanism of this arrhythmia. METHODS: A customized right ventricular balloon with 112 electrodes was used to record endocardial activation and, where possible, simultaneous epicardial recordings were obtained with a sock electrode array. Three patients had an aneurysm of the right ventricular outflow tract and one had a septal aneurysm. All had moderate to severe pulmonary valve insufficiency. Preoperative electrophysiologic study demonstrated inducible rapid (cycle length 180 to 300 ms) hemodynamically unstable monoform ventricular tachycardias. RESULTS: Intraoperatively, five different tachycardias (two in one patient) were induced and mapped. The sites of earliest activation were located in the subendocardium of the right ventricular outflow tract in all, but they varied widely among the septum, free wall and parietal band and could not be identified by visible scar. All were due to a macroreentrant circuit initiated by a critical delay in activation beyond a functional arc of block. Two patients treated by cryoablation while the heart was beating and perfused at normal temperature had inducible ventricular tachycardia postoperatively. In the two subsequent patients, the application of cryoablation under anoxic cardiac arrest resulted in noninducibility of arrhythmia. CONCLUSIONS: Ventricular tachycardia in tetralogy of Fallot in these four patients was caused by macroreentry in the right ventricular outflow tract. Surgical success depends on detailed mapping and cryoablation under anoxic cardiac arrest. In patients at risk of sudden death, map-directed surgery may offer distinct advantages over either implantable devices or drug therapy.

Child↗
PubMed1992

Bilateral occipital lobe infarction in acute migraine: clinical, neurophysiological, and neuroradiological study.

A woman having common migraine attacks coincident with an asymmetrical bilateral occipital lobe infarction that spared the brainstem and cerebellum underwent these studies: serial electroencephalography, brainstem auditory, visual and somatosensory evoked potentials, magnetic resonance imaging of the brain and cerebral arteriography. The patient's vision improved greatly during a one-year follow-up. The absence of risk factors for stroke suggested that migraine caused the infarction in the posterior circulation network. The pathophysiological mechanisms of stroke in migraine remains speculative.

Acute Disease↗
PubMed1992

Antigen-binding diversity of human hybridoma autoantibodies derived from splenocytes of patients with SLE.

The antigen-binding specificity of human hybridoma-derived monoclonal autoantibodies (mAb) was analysed with mAbs derived from the spleens of two patients with active systemic lupus erythematosus (SLE). From one patient 72 mAbs (RSP clones) and from the other 173 mAbs (RT clones) were obtained. The binding specificity of these mAbs was analysed by solid- and fluid-phase ELISA against the autoantigens ssDNA, dsDNA, cardiolipin, SmRNP, histones, Sm-D and SS-B (La) synthetic peptides, and foreign antigens including bacterial polysaccharides. In addition, antinuclear antibody activity and anti-dsDNA binding were confirmed by fluorescence staining methods. Reflecting the patient's serological profile, none of the antibodies from the RSP clones reacted with ssDNA or dsDNA but 12 reacted with cardiolipin. In addition, three mAbs reacted with H4, five with U1 RNP, two with Sm-D peptides and 12 with SS-B peptides. In contrast, from the RT fusion, nine mAbs reacted with ssDNA, HI and SS-B peptides, seven with cardiolipin, four with dsDNA, two with Sm-D peptides and one each with H2A, H3 and H4. In many cases one mAb showed reactivity with more than one antigen: for example, mAb RT 72 binds to ssDNA, dsDNA, cardiolipin, H1, H4 and an Sm-D peptide; RT 6 binds to H1, SmRNP and ubiquitinated histone H2A. However, none of the antibodies showed 'across the board' polyreactivity; indeed, the selectivity of the reactions was notable and marked variation in antibody affinity was recorded. Eight of the mAbs bound to Salmonella typhimurium and two to the Klebsiella polysaccharide K-30.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Ubiquinone biosynthesis in Saccharomyces cerevisiae. Isolation and sequence of COQ3, the 3,4-dihydroxy-5-hexaprenylbenzoate methyltransferase gene.

Ubiquinone (or coenzyme Q) is a lipid component of the respiratory chain in the inner mitochondrial membrane, in which it functions in electron transport. Recent reports show that ubiquinone and ubiquinone biosynthetic enzymes are present in both mitochondrial and nonmitochondrial membranes of cells (Kalen, A., Appelkvist, E.-L., Chojnacki, T., and Dallner, G. (1990) J. Biol. Chem. 265, 1158-1164) although the functions that ubiquinone may play outside of the mitochondrion are not understood. To study coenzyme Q synthesis and function we cloned the 3,4-dihydroxy-5-hexaprenylbenzoate (DHHB) methyltransferase gene by functional complementation of a yeast coenzyme Q mutant strain, defective in the COQ3 gene (Tzagoloff, A., and Dieckmann, C. L. (1990) Microbiol. Rev. 54, 211-225). This gene restores both coenzyme Q synthesis in the mutant strain and the ability to grow on media containing glycerol, a nonfermentable substrate. A one-step in situ gene replacement with the cloned DHHB methyltransferase DNA directs integration to the yeast COQ3 locus on chromosome XV of Saccharomyces cerevisiae, establishing that the COQ3 locus encodes the DHHB methyltransferase structural gene. The predicted amino acid sequence of the yeast DHHB methyltransferase contains a methyltransferase consensus sequence and shows a 40% identity with an open reading frame of Escherichia coli, the gyrA5' hypothetical protein. This open reading frame is adjacent to the gyrA gene and close to the mapped location of the ubiG gene at 48 min on the E. coli chromosome. These results suggest that the E. coli gyrA5' open reading frame encodes a methyltransferase and may correspond to the ubiG gene, which is required for ubiquinone biosynthesis.

Amino Acid Sequence↗
PubMed1991

Detection of human and murine common idiotypes of DNA antibodies in tissues and sera of patients with autoimmune diseases.

The expression in tissue and serum of a panel of murine and human common DNA antibody idiotypes (Ids) (BEG 2, PR 4, F-423, I-402, II-28, IV-228, V-88) has been investigated. The murine V-88 Id was detected in eight out of 10 and the human BEG 2 Id in five out of 10 labial biopsies from patients with Sjögren's syndrome. The murine F-423, I-402 and IV-228 Ids were identified in one out of 10 biopsies. In each case the pattern of staining was similar with staining of the acinar basement membrane and a cell population. Using double-labelling immunohistochemistry this cell population were identified as plasma cells. No staining was seen in four normal labial biopsies. The V-88 Id was detected on the epithelial aspect of the thickened basement membrane in three out of nine renal biopsies from patients with systemic lupus erythematosus (SLE). None of the other Ids (BEG 2, PR4, IV-228, F-423 or I-402) could be detected in renal tissue. None of the Ids were found in skin biopsies from SLE patients. Id V-88 may, like the 16/6 Id to which it is phenotypically related, play a role in the pathogenesis of renal lesions in SLE. The BEG 2 Id could be detected in the serum of patients with rheumatoid arthritis (RA) and active untreated tuberculosis. Ids II-28, V-88 and I-402 were elevated in serum from patients with Sjögren's syndrome and II-28 Id in serum from patients with myositis and RA. None of the Ids were elevated in serum from patients with SLE. Apart from the BEG 2 Id, none of the Ids were elevated in serum from patients with tuberculosis or Gram-negative infections. The presence of murine Ids in human tissue and serum suggests that they are cross-species idiotypes and have been conserved through evolution.

Animals↗
PubMed1991

Steroid-eluting epicardial leads in pediatrics: improved epicardial thresholds in the first year.

From 1986 to 1991, we evaluated the clinical use of three new epicardial lead designs incorporating a steroid-eluting electrode. Medtronic models SP2114 (bipolar high profile), 10320 (bipolar low profile), 10295A/4965 (unipolar low profile) steroid epicardial (SE) leads were used on either atrium or ventricle for a total of 21 lead placements in 17 patients. Energy thresholds (T) were calculated and compared with our most recent 16 nonsteroid epicardial (NE) Medtronic model 4951 lead implants for which T was available. SE leads demonstrated no acute T rise and continued T improvements at 1 year of follow-up. We conclude that epicardial application of SE lead technology offers a major improvement in pacing lead function and potential pacemaker longevity over NE leads in pediatric patients in whom endocardial pacing is precluded by size or anatomy.

Animals↗
PubMed1991

Assessment of common idiotype PR4-Id in serial bleeds from lupus patients.

Marked fluctuations in the levels of a common DNA-antibody idiotype, PR4-Id have been found on IgM and IgA antibodies in particular and to a lesser extent on IgG in serial bleeds of 14 lupus patients. Few clear cut examples were found of the PR4-Id levels reflecting disease activity. However, the idiotype expression was not simply related to total immunoglobulin levels and the controlling mechanisms of idiotype expression on different isotypes remain a matter of conjecture.

Antibodies, Antinuclear↗
PubMed1991

Neutrophil chemotactic factors in the tears of giant papillary conjunctivitis patients.

This study was designed to determine the presence of neutrophil chemotactic factors in the tears of patients with giant papillary conjunctivitis (BPC) secondary to contact lenses. Chemotactic activity was measured using modified Boyden chambers and the chemoattractant formylmethionyl-leucyl-phenylalanine (f-MLP) for 100 percent response. Elevated levels of chemotactic activity were found in the tears of symptomatic patients (80.8 +/- 6.4, % f-MLP) compared with control tears of asymptomatic contact lens wearers (15.7 +/- 3.3%) and non-contact lens wearers (5.6 +/- 1.2%). Using radioimmunoassay, C5a (serum-derived chemoattractant), leukotriene-B4, and interleukin-1 (immune cell-derived chemoattractants) were not detected in the tears of symptomatic patients. The authors determined whether injured conjunctival cells participate in this process by releasing neutrophil chemotactic factors. Isolated rabbit bulbar conjunctiva incubated with culture medium for 4 and 6 hr released high levels of neutrophil chemotactic factors. The release of these factors from injured conjunctiva support the premise that physical trauma of conjunctival cells induced by contact lenses may be an important component of the pathophysiology of giant papillary conjunctivitis.

Adolescent↗
PubMed1991

Peritonitis in acute peritoneal dialysis at the University Hospital of the West Indies (a five-year review).

The records of patients receiving acute peritoneal dialysis during the years 1983-1987 were retrospectively evaluated. Of a total of 59 patients receiving dialysis, 10 developed peritonitis. Staphylococcus aureus was the single most frequently isolated organism. However, gram-negative bacilli as a group were more common. We recommend the use of cloxacillin orally and gentamicin intra-peritoneally as empiric antibiotic coverage until results of culture reports are available.

Adolescent↗
PubMed1991

Thyroid-gonad relationship in systemic lupus erythematosus.

Thirty women with systemic lupus erythematosus (SLE) were examined to assess the thyroid-gonad relationship. Significant decreases in mean serum tri-iodo-thyronine and testosterone levels and increases in mean serum estradiol and luteinizing hormone levels were observed in SLE patients as compared to control subjects. The serum levels of thyroxine, thyrotropin, tri-iodo-thyronine uptake, free thyroxine index and prolactin were, however, not significantly different in both groups. The interpretation of these findings is unclear but SLE could be regarded as one of the nonthyroidal systemic illness since low serum tri-iodo-thyronine with normal thyrotropin levels were observed in our patients. Furthermore, high levels of estradiol and low levels of testosterone in our female patients may indicate involvement of sex steroids in the pathogenesis of SLE.

Adolescent↗
PubMed1991

Colon cancer in blacks: a disease with a worsening prognosis.

Despite the fact that a significant national effort has been made over the past 10 years to improve the early detection and treatment of colorectal cancer, blacks have not had any change in their prognosis compared to whites, and their survival rate appears to be independent of stage at the time of diagnosis. The disease incidence is practically the same for both races, 49 per 100,000. We reviewed all patients with colorectal cancer in our Tumor Registry over a 10-year period to determine whether the experience at an all-black institution with a black patient base for much of its history would help clarify these crucial questions. There were 118 cases (73 women/45 men), and the mean age was 68 years (range: 29 to 93). The most common signs and symptoms were gross bleeding (34%) and abdominal pain (30%), with most patients presenting with a combination of symptoms. Remarkably, none were symptom-free. Of the 96 patients who were staged surgically and pathologically, 68 (71%) were beyond Duke's B staging at the time of diagnosis and surgery. The overall 5-year survival rate was 47%, significantly related to stage of disease at diagnosis (P less than .001). We concluded that blacks have not shared in the progress made in early diagnosis and treatment of colon cancer, and that special attention should be given to developing screening and surveillance methodology targeted specifically at blacks.

Adenocarcinoma↗
PubMed1991

Neutrophil chemotactic factors derived from conjunctival epithelial cells: preliminary biochemical characterization.

We have previously reported on the release of neutrophil chemotactic factors (NCF) from injured conjunctival tissue. The present study was designed to biochemically characterize these conjunctiva-derived chemotactic factors and determine their biological activities. Bulbar conjunctiva was surgically removed from a rabbit eye and incubated with 250 microL of minimal essential medium (MEM) for 6 hours at 37 degrees C in a 5% CO2 atmosphere. Chemotactic activity was assayed using modified Boyden chambers with rabbit peritoneal neutrophils as indicator cells. Following treatment with subtilisin protease for 90 minutes, chemotactic activity of the conjunctival factors was reduced by 74%. Similarly, activity was lost after heating at 56 degrees C for 60 minutes (41% inhibition). Using ultrafiltration techniques, we showed that the majority of the chemotactic activity remained above a 100 kilodalton filter, suggesting the existence of high molecular weight factors. We also showed that the conjunctival factors are not glycoproteins and bind to both anion and cation exchange resins. When 100 microL of conjunctival supernatant was injected in the superior tarsal conjunctiva of rabbits, significant recruitment of neutrophils was evident by 4 hours. Control rabbits injected with MEM did not show neutrophil recruitment. Results of these studies indicate that NCF from traumatized conjunctival tissue are proteins (and not glycoproteins) of high molecular weight, heat labile, exhibit anionic and cationic charges, and are active in vivo.

Animals↗
PubMed1991

Expression of a common idiotype PR4 in the sera of patients with leprosy.

The sera of 187 patients from across the leprosy spectrum were screened for the expression of the PR4 idiotype, which was first identified on a human hybridoma-derived monoclonal antibody from a patient with leprosy and found to react with the Mycobacterium leprae phenolic glycolipid and a variety of polynucleotides. Sixty per cent (51 out of 85) of patients with lepromatous leprosy (LL), 66% (33 out of 49) with borderline lepromatous (BL) disease, 47% (14 out of 30) with borderline tuberculoid (BT) leprosy, and 56% (13 out of 23) of tuberculoid (TT) patients were found to have significantly elevated titres of the PR4 idiotype in their sera compared with endemic controls, irrespective of the presence or absence of endemic malaria. Sera from 52 patients with tuberculosis were also screened as a control for mycobacterial infection. The PR4 idiotype was significantly elevated in 37% (19 out of 52) of these patients. No correlation between idiotype and serum immunoglobulins IgG and IgM was found, indicating that the concentrations of idiotype levels in sera were not merely a reflection of changes in serum immunoglobulin levels. It is hypothesized that the expression of the PR4 idiotype is due to certain germline genes preferentially expressed rather than being the result of polyclonal B cell activation.

Animals↗