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Biomedical subjects

J Williams

Publications and source records attributed to J Williams.

At least 19 recordsLinked to original sources
PubMed1995

Evidence for positional differentiation of prestalk cells and for a morphogenetic gradient in Dictyostelium.

We present evidence that Dictyostelium slug tip cells, the pstA cells, may arise by positional differentiation, but at a site remote from that which they will eventually occupy. When first detectable, the pstA cells form a peripheral ring surrounding the other prestalk cell subtype, the pstO cells, but subsequently move above the pstO cells to form the tip. Because pstA cell differentiation requires a 10-fold higher concentration of differentiation-inducing factor, the stalk cell inducer, the initial patterning seems likely to reflect the existence of a morphogenetic gradient. The subsequent redistribution of the two cell types is explicable by their different rates of chemotaxis to cyclic AMP. These results help reconcile the two apparently opposing views of pattern formation in Dictyostelium, that there is positional differentiation and that pattern formation occurs by cell sorting.

Animals↗
PubMed1995

Peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl alpha-ketobenzoxazoles.

A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in vitro potency (Ki = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vivo activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.

Amino Acid Sequence↗
PubMed1995

Metacarpal fracture associated with lymphosarcoma-induced osteolysis in a horse.

A 19-year-old Appaloosa gelding was reluctant to move. Radiography revealed diffuse, permeative lysis of the cortex and subchondral bone of the phalanges, third metacarpal bones, proximal sesamoid bones, radius, carpal bones, tibia, mandible, and nasal bones of the skull. A comminuted fracture of the distal aspect of the left third metacarpal bone was identified on a lateral to medial radiographic view of the left metacarpophalangeal joint. Histologic examination of the first phalanx, third metacarpal bone, and sternum revealed multifocal infiltrates of nodular lymphosarcoma in cortical and subchondral bone. Osteoclastic cavities were apparent in bone trabeculae contiguous with nodular foci of lymphosarcoma. Osteoclastic osteolysis was not evident at bone surfaces that were not directly adjacent to neoplastic cells. Although lymphosarcoma is the most frequent malignant neoplasia encountered in horses, diffuse neoplastic infiltration of cortical and subchondral bone of the appendicular and axial skeleton represents an unusual presentation of lymphosarcoma.

Animals↗
PubMed1995

GPs in principle but not in practice: a study of vocationally trained doctors not currently working as principals.

OBJECTIVES: To identify doctors who are vocationally trained but not currently practising as principals in general practice; their reasons for not practising as principals; and whether the prospect of a re-entry course would appear to this group. DESIGN: Postal questionnaire survey based on semistructured interviews. SUBJECTS: Doctors who had been vocationally trained but were not currently practising as principals: 351 possible subjects identified by a process of "networking." SETTING: Trent Regional Health Authority. RESULTS: 166 of the doctors who replied fitted the criteria (100 women; 66 men). The out of hours commitment was ranked as the most important factor for not practising as a principal--95 women and 50 men rated it important--followed by difficulty in combining work with family commitments--84 women, 31 men. 82 respondents (49%) said they would be interested in a re-entry course if one were available. CONCLUSIONS: There is a pool of vocationally trained doctors in Trent region who are not practising as principals in general practice. More flexible working patterns and the availability of a re-entry course could make the post of principal in general practice a more attractive proposition to these doctors.

Adult↗
PubMed1995

Tay-Sachs disease in persons of French-Canadian heritage in northern New England.

This study sought to determine whether persons of French-Canadian heritage in northern New England are at high risk for the lethal infantile form of Tay-Sachs disease. In order to accomplish this, death records and laboratory diagnostic records were surveyed to ascertain Tay-Sachs deaths in a cohort of 372,000 live births between 1977-1986. The proportion of the total population with French-Canadian or Jewish heritage was determined from census and birth records, and the ethnic background of Tay-Sachs cases was determined from the corresponding birth records. In 1,860 births, both parents were of Ashkenazi Jewish heritage. One of those children was diagnosed with Tay-Sachs disease. In 41,000 births, both parents were of French-Canadian heritage, and in an additional 93,000 births, one parent was of French-Canadian heritage. No cases of Tay-Sachs disease were identified in the offspring of those individuals. Approximately 14 cases (95% confidence interval 8-20) would be expected, if the gene frequency approximated that reported for individuals of Ashkenazi Jewish heritage. Based on the results of this study, routine testing for Tay-Sachs disease heterozygosity is not indicated for persons of French-Canadian heritage in northern New England. This conclusion may not necessarily be valid for persons of French-Canadian heritage residing in other states. Further studies of Tay-Sachs disease mutations and prevalence among persons of French-Canadian heritage will be important to determine possible regional variations in gene frequencies.

Child↗
PubMed1995

Cloning, sequencing and bacterial expression of human glycine tRNA synthetase.

The human glycine tRNA synthetase gene (GlyRS) has been cloned and sequenced. The 2462 bp cDNA for this gene contains a large open reading frame (ORF) encoding 685 amino acids with predicted M(r) = 77,507 Da. The protein sequence has approximately 60% identity with B. mori GlyRS and 45% identity with S. cerevisiae GlyRS and contains motifs 2 and 3 characteristic of Class II tRNA synthetases. A second ORF encoding 47 amino acids is found upstream of the large ORF. Translation of this ORF may precede the expression of GlyRS as a possible regulatory mechanism. The enzyme was expressed in E. coli as a fusion protein with a 13 kDa biotinylated tag with an apparent M(r) = 90 kDa. The fusion protein was immunoprecipitated from crude bacterial extract with human EJ serum, which contains autoantibodies directed against GlyRS, and with rabbit polyclonal serum raised against a synthetic peptide derived from the predicted amino acid sequence of human GlyRS. Bacterial extract containing the fusion protein catalyses the aminoacylation of bovine tRNA with [14C]-gly at 10-fold increased level above normal bacterial extract and confirms that the cDNA encodes human GlyRS.

Acylation↗
PubMed1995

No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT).

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT.

Adolescent↗
PubMed1995

Non-peptidic inhibitors of human leukocyte elastase. 4. Design, synthesis, and in vitro and in vivo activity of a series of beta-carbolinone-containing trifluoromethyl ketones.

A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these trifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase.

Amino Acid Sequence↗
PubMed1995

Improved viability of hepatic allografts from fasted donors is associated with decreased peripheral TNF activity.

Despite improvements in preservation solutions, hepatic allografts continue to be lost from primary nonfunction. Previous work by this group and others has established that donor fasting improves the viability of hepatic allografts. We have also established an association between viability of stored organs and serum TNF levels. The purpose of this study was to determine whether improved viability of hepatic allografts from fasted donors is associated with lower peripheral serum TNF levels. TNF was measured using a bioassay employing a WEHI cell line. Transplanted livers from fasted donors displayed gross deglycogenation had less bile flow postrevascularization and increased postoperative AST, but had significant improvement in viability and were associated with significantly less TNF recovered from the peripheral circulation. The association of improved viability and diminished serum TNF and previous work that links changes in postrevascularization TNF levels with changes in Kupffer cell activity suggest a possible cause for improved survival of recipients of fasted allografts.

Animals↗
PubMed1995

Validation of an enzyme immunoassay for serodiagnosis of acute Q fever.

An enzyme immunoassay was validated for the serodiagnosis of acute Q fever. Minimum positive tests were determined for both serial dilutions and a single dilution of patient sera. To establish the specificity of the test, 152 serum samples were tested from individuals with no evidence of past Coxiella burnetii infection. Diagnostic titers were set at > or = 128 for the IgM and IgG responses to phase I, at > or = 512 for the IgM response to phase II and at > or = 1,024 for the IgG response to phase II Coxiella burnetii. These titers gave a false-positive rate of < or = 1%. Alternatively, testing a single dilution of sera (1:128) gave specificities ranging from 97.3 to 98.7%. Tests with the greatest sensitivities, using serially diluted early convalescent-phase sera, were the IgM (84%) and IgG (80%) responses to phase II Coxiella burnetii. At a single serum dilution, 92% of early convalescent sera had a positive IgG response to phase II Coxiella burnetii. With a high specificity and good sensitivity, the EIA can be used to diagnose acute Q fever with a single convalescent serum specimen. The duration of a positive response was greater than five years.

Coxiella burnetii↗
PubMed1995

Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in Dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats.

Dural plasma extravasation produced by electrical stimulation of the trigeminal ganglion was measured in rats and the concomitant expression of c-fos mRNA produced in the trigeminal nucleus caudalis (NtV) was measured using in situ hybridization techniques. The non-peptide NK1 receptor selective antagonist CP-99,994 (1-3000 micrograms kg-1) and the 5HT1D receptor agonist sumatriptan (1-1000 micrograms kg-1) reduced dural plasma extravasation dose-dependently with ID50S of 52 micrograms kg-1 and 30 micrograms kg-1 respectively. CP-99,994 (1000 micrograms kg-1). a compound known to have good brain penetration, decreased c-fos mRNA expression in the NtV by 37 +/- 7% without disruption of the blood brain barrier (BBB). Sumatriptan (1000 micrograms kg-1), known to be poorly brain penetrant, had no significant effect on c-fos mRNA expression in the NtV unless the BBB was disrupted by infusion of a hyperosmolar mannitol solution after which sumatriptan decreased c-fos mRNA expression by 65 +/- 11%. The results suggest that brain penetrant NK1 receptor antagonists may have anti-migraine effects peripherally through blockade of dural extravasation and centrally by inhibition of nociceptive pathways. Furthermore the data indicates that the anti-migraine action of sumatriptan must be predominantly peripherally mediated, be it via inhibition of plasma extravasation or direct vasoconstriction, since it had little effect on the activation of neurones in the NtV unless the BBB was disrupted.

Animals↗