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Biomedical subjects

D M Jones

Publications and source records attributed to D M Jones.

At least 55 records · Page 3Linked to original sources
PubMed1997

New renin inhibitors containing novel analogues of statine.

Solid-phase methodology has been used to synthesize a series of peptides based on the N-terminal sequence of human angiotensinogen in which statine (Sta) or the novel analogues (3S,4S)-3,4-diamino- or (3R,4S)-3,4-diamino-6-methylheptanoic acid (Ads or R-Ads) and (3S,4S)-4-amino-3-aminomethyl- or (3R,4S)-4-amino-3-aminomethyl-6-methylheptanoic acid (Amd or R-Amd) replace either residue 10 or both residues 10-11 at the P1-P1' cleavage site. The synthesis of these novel analogues of statine together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereochemistry of the (3S,4S) Ads was determined by an X-ray crystallographic analysis of its N gamma-Boc, B beta-Z, R(+)-1-methyl benzamide derivative. Peptide Boc-His-Pro-Phe-His-Sta-Val-Ile-His-NH2 (VI) is the best inhibitor of human renin containing Sta at position 10. However, peptides containing Ads and Amd gave better rat renin inhibitors than the corresponding Sta-containing peptides. Peptides Boc-His-Pro-Phe-His-Ads-Val-Ile-His-NH2 (VII) having Ads at position 10 had an IC50 of 12 nM against rat renin. Although Sta has come to be accepted as an isosteric replacement for a dipeptide unit rather than for a single amino acid residue, in our series of inhibitors Sta is more effective when replacing only the amino acid at position 10 in the natural angiotensinogen sequence. None of the peptides gave any effect in vivo in a hypertensive rat model.

Amino Acid Sequence↗
PubMed1997

Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site.

Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-psi[CH2NH]Leu; Leu-psi[CH(OH)CH2]Val; Leu-psi[CH(OH)CH2]Leu and Leu-psi[CH(NH2)CH2]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human renin (IC50 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-psi[CH(OH)CH2] Leu-Val-Ile-His-NH2 (XX) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic renal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools.

Amino Acids↗
PubMed1997

Synthesis and biological activity of potent, low molecular weight renin inhibitors.

A series of renin inhibitors containing the dipeptide transition state mimics (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Ala) and (2R,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-psi[CH(OH)CH2]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R,S-Bpma-Ape-Cha-psi[CH(OH)CH2]Ala-NH2 (IC50 = 1.26 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related aspartic proteinase pepsin and angiotensin-1-converting enzyme. Examples are given of selected inhibitors showing encouraging evidence for intestinal absorption after intracolonic and oral administration in male Sprague-Dawley rats.

Administration, Oral↗
PubMed1997

Intra- and inter-modal repetition priming of familiar faces and voices.

Two experiments explored repetition priming for familiar voices and faces. Expt 1 revealed that, like faces, prior exposure to a voice in a gender judgment task speeds its subsequent classification as familiar or unfamiliar, some minutes later. Faces and voices do not prime one another, however; a result consistent with the notion that evidence is initially accumulated separately for voices and faces. In Expt 2, a prediction derived from the IAC model of Burton, Bruce & Johnston (1990) was explored. The results confirmed that inter-modal repetition priming occurs when the interval between exposures to different personal identification stimuli are separated by a short SOA. This result is consistent with similar ones reported by Calder (1993) and Young, Flude, Hellawell & Ellis (1994) for face-name combinations.

Auditory Perception↗
PubMed1996

Routine pulmonary function tests in young adolescents with asthma in general practice.

OBJECTIVE: To assess the value of performing routine pulmonary function tests by flow-loop spirometry in young adolescents with asthma. DESIGN: A prospective clinical study comparing clinical assessment and patients' self-reporting of asthma severity with the results of pulmonary function tests. SETTING: General practice in a small rural community of about 30,000 people. PATIENTS: Young adolescents with asthma, aged 10-15 years, were enrolled in the study over a two-year period from July 1993 to June 1995 when they presented for either elective, interval assessments or with an acute exacerbation of asthma. MAIN OUTCOME MEASURES: Discrepancy between (i) the doctor's and the patient's perception of asthma control (six scale measures) and the consequent management plans, and (ii) the results of pulmonary function tests that indicated less than adequate airway function (i.e., forced expiratory volume in one second as a percentage of predicted vital capacity for height and sex [FEV1%] less than 65% or average flow rate over the middle 50% of forced vital capacity as a percentage of predicted normal value [FEF25%-75%] less than 65%). RESULTS: Twenty-seven adolescents with asthma were assessed on a total of 37 occasions. The results of pulmonary function tests did not correlate with asthma symptoms and treatment in 11 of the 37 assessments (30%; 95% confidence interval [CI], 16%-47%). The 11 assessments were performed on eight patients. CONCLUSIONS: This small community-based study of adolescents with asthma supports the view that pulmonary function testing by flow-loop spirometry should be part of the routine assessment of acute and chronic asthmatics. Further study in a larger community is needed to clarify the frequency of over- and underestimation of asthma severity in this difficult age group.

Adolescent↗
PubMed1996

Mechanism of irritant-induced cough: studies with a kinin antagonist and a kallikrein inhibitor.

It has been suggested that bradykinin may play a role in stimulating cough in at least one pathological condition in humans. We have employed an animal model to investigate the possible role of this peptide in irritant-induced cough. The kinin antagonist Hoe 140 and codeine both produced dose-related inhibition of cough responses to inhalation of citric acid or bradykinin aerosols by conscious guinea pigs. The selective tissue kallikrein inhibitor CH694 inhibited cough caused by citric acid but not by bradykinin. Indomethacin pretreatment attenuated the responses to both stimuli as did phosphoramidon. It is concluded that cough produced by citric acid inhalation may be mediated, at least in part, by generation of kinins; secondary to this, a release of prostanoids also appears to participate in the response.

Administration, Inhalation↗
PubMed1996

Synthetic inhibitors of human tissue kallikrein.

We have developed a series of novel, potent low molecular weight (4-600 Da) inhibitors of TK which were stable to cleavage by the enzyme and showed a high degree of selectivity for TK over several other serine proteases. Compound 7 (CH-2856) was found to reduce eosinophilia in a model of allergic inflammation. The effects observed in vivo provide further evidence for the involvement of TK and kinins in the pathophysiology of allergic diseases such as asthma.

Amino Acids↗
PubMed1996

The application of genotyping techniques to the epidemiological analysis of Campylobacter jejuni.

Campylobacter jejuni serogroup reference strains and collections of sporadic and outbreak-associated isolates were examined for restriction fragment length polymorphisms (RFLPs), using C. jejuni random chromosomal and 16S rRNA gene probes. A collection of 48 Penner (HS) and 14 Lior (HL) serogroup reference strains, plus 10 clinical isolates, generated 35 RFLP and 26 ribotype patterns. In combination the two loci generated 48 distinct genotypes. Both probes were able to differentiate between certain random isolates of the same HS/HL serogroups but greater discrimination was obtained with RFLP than with ribotyping. Genotyping distinguished accurately between related and unrelated strains when applied to several outbreaks. Genotypic analysis of C. jejuni by restriction fragment length polymorphisms is a valuable technique for epidemiological typing. Chromosomal variation detected by the two unlinked probe loci provides some information about the genetic relationship between isolates.

Campylobacter Infections↗
PubMed1996

Conjugate meningococcal serogroup A and C vaccine: reactogenicity and immunogenicity in United Kingdom infants.

The reactogenicity and immunogenicity of a serogroup A and C meningococcal polysaccharide-CRM197 conjugate vaccine was evaluated in 58 infants who received three doses at 2, 3, and 4 months of age. The conjugate vaccine produced few systemic side effects, and local reactions were significantly less common than those produced by the routine vaccinations. The prevaccination geometric mean titers (GMTs) of A and C polysaccharide antibodies were, respectively, 2.8 and 0.6 microg/mL, rising to 21.5 and 38.5 microg/mL by 1 month after the third dose (age 5 months) and falling to 3.1 and 2.2 mircog/mL by 14 months of age. Prevaccination serum bactericidal titers against 2 serogroup C meningococci strains were <1/4 in 49 of 52 infants, rising to a GMT of 1/3082 at 1 month after the third dose and falling by age 14 months to a GMT of 1/10. Thus, this meningococcal conjugate vaccine proved to be safe and immunogenic, inducing high levels of anti-C polysaccharide antibodies that were bactericidal in young infants.

Antibodies, Bacterial↗
PubMed1996

A novel polymerase chain reaction assay for the detection and speciation of thermophilic Campylobacter spp.

A novel PCR amplification method is described which is specific for the thermophilic, enteropathogenic species Campylobacter jejuni, Camp. coli and Camp. upsaliensis. Rapid, accurate speciation of amplified strains is possible on the basis of restriction fragment length polymorphisms of PCR products digested with three restriction enzymes, AluI, DdeI and DraI. The sensitivity of detection is 25 cfu in water, and 2 x 10(3) cfu in full cream milk. An epidemiological application of the assay in detecting non-culturable campylobacters from a contaminated potable water supply is described.

Campylobacter↗
PubMed1996

Microbial ecology of Campylobacter jejuni in a United Kingdom chicken supply chain: intermittent common source, vertical transmission, and amplification by flock propagation.

A study of Campylobacter jejuni on a broiler chicken farm between 1989 and 1994 gave an estimated isolation rate of 27% (3,304 of 12,233) from a 0.9% sample of 1.44 million broiler chickens from six to eight sheds over 32 consecutive rearing flocks comprising 251 broiler shed flocks. During the study, C. jejuni was found in 35.5% of the 251 shed flocks but only 9.2% (23 of 251) had Campylobacter isolates in successive flocks, with 9 of those 23 sheds having the same serotype between consecutive flocks, indicating a low level of transmission between flocks. Analysis of a systematic sample of 484 of 3,304 (14.6%) C. jejuni isolates showed that 85% were of 10 serotype complexes but 58% were of 3 serotype complexes, indicating a high degree of strain similarity throughout the entire study. The three commonest types were detected in 8 of 32 flocks during the 5-year study period, suggesting an intermittent common external Campylobacter source. This hypothesis was tested by a retrospective cohort analysis of C. jejuni rates and types by reference to hatchery supplier of the 1-day-old chicks. Isolation rates of C. jejuni and frequency distribution of types were determined in 6-week-old broiler chickens identified by the hatchery supplying the original chicks. The isolation rate of C. jejuni in broilers, supplied by hatchery A, was 17.6%, compared to 42.9% (P < 0.0001) for broilers reared from chicks supplied by hatchery B. In two instances, when both hatcheries were used to stock the same farm flock, Campylobacter isolates were found only in those sheds with chicks supplied by hatchery B. Thus, the frequency distribution of Campylobacter types for chickens supplied by the two hatcheries over the 5-year period showed marked dissimilarity. These findings suggest that the isolation rate and type of Campylobacter isolates in broiler chickens was associated with the hatchery supplying chicks. The lack of diversity of types and the intermittent high positivity of sheds is evidence for a common source of C. jejuni introduced by vertical transmission rather than contamination at the hatchery or during transportation.

Animals↗
PubMed1996

Antigenic diversity of meningococcal outer membrane protein PorA has implications for epidemiological analysis and vaccine design.

The currently used serological subtyping scheme for the pathogen Neisseria meningitidis is not comprehensive, a proportion of isolates are reported as not subtypeable (NST), and few isolates are fully characterized with two subtypes for each strain. To establish the reasons for this and to assess the effectiveness of DNA-based subtyping schemes, dot blot hybridization and nucleotide sequence analyses were used to characterize the genes encoding antigenic variants of the meningococcal subtyping antigen, the PorA protein. A total of 233 strains, including 174 serologically NST and 59 partially or completely subtyped meningococcal strains, were surveyed. The NST isolates were chosen to be temporally and geographically representative of NST strains, isolated in England and Wales, and submitted to the Meningococcal Reference Unit in the period 1989 to 1991. The DNA-based analyses demonstrated that all of the strains examined possessed a porA gene. Some of these strains were serologically NST because of a lack of monoclonal antibodies against certain PorA epitopes; in other cases, strains expressed minor variants of known PorA epitopes that did not react with monoclonal antibodies in serological assays. Lack of expression remained a possible explanation for serological typing failure in some cases. These findings have important implications for epidemiological analysis and vaccine design and demonstrate the need for genetic characterization, rather than phenotypic characterization using monoclonal antibodies, for the identification of meningococcal strains.

Amino Acid Sequence↗
PubMed1996

Angiotensin II: a humoral mediator for the gastric sodium monitor.

Natriuresis in direct response to a gastric sodium stimulus (upper-gut sodium monitor) has paradoxically only been demonstrated in humans and animals on a low-sodium diet preceding each study. It is possible that the low-sodium diet itself induces or suppresses systems that mediate or oppose the ensuing natriuresis. In this study, we sought to determine whether a system activated by this diet, the renin-angiotensin system, mediates the natriuretic response. Specifically, we sought to show whether changes in the circulating concentration of angiotensin II (ANG II) may mediate the renal response to stimulation of the gastric sodium monitor. Male New Zealand White rabbits were randomly assigned to low- (0.008%) or normal (2.2%) sodium diets. After 1 wk on the experimental diet, they received a sodium load intragastrically or intravenously, and plasma ANG II was measured at 0, 5, 10, 30, 60, and 120 min. Urine was collected for 4 h after the sodium load, and plasma sodium was measured at 0, 2, and 4 h. Urinary sodium excretion was greater in the 4 h after gastric than after intravenous sodium administration (P < 0.025) in the rabbits on the low-sodium diet. No significant difference was noted in the rabbits on the normal sodium. In rabbits on the low-sodium diet, there was an immediate and significant decline in plasma ANG II after sodium was administered both intragastrically (P < 0.025) and intravenously (P < 0.05). This decrease was greater after intragastric than intravenous sodium (P < 0.0025), and the difference was still evident at 120 min (P < 0.05). No significant difference in plasma ANG II was found in the normal diet group. We conclude, therefore, that a prolonged decrease in ANG II concentration may play a role in mediating the natriuretic response to the gastric sodium monitor.

Angiotensin II↗
PubMed1996

From auditory image to auditory percept: facilitation through common processes?

Two experiments explored implicit memory for auditory stimuli as measured by a test of perceptual identification. The facilitative effect of perceived auditory primes was contrasted with that of imaged auditory primes. In Experiment 1, there was a significant priming effect from imaged spoken-word primes that did not differ significantly from the level of priming due to perceived spoken-word primes, measured by a test of auditory perceptual identification. There was no facilitation of spoken-word identification following creation of an image of a word's referent sound. In Experiment 2, identification of an environmental sound was facilitated by prior processing of an imaged sound from the same category, though there was significantly more transfer following processing of the actual sound.

Humans↗
PubMed1996

Video-assisted thoracic surgical procedures: the Mayo experience.

OBJECTIVE: To describe an initial 3-year experience with video-assisted thoracic surgical procedures (VATS) at Mayo Clinic Rochester. DESIGN: We review the cumulative data on 771 VATS performed between June 1, 1991, and May 31, 1994, and assess the applications for this technique. MATERIAL AND METHODS: The indications for VATS, our techniques used, and the associated mortality and morbidity are summarized. In addition, the frequency of conversion of VATS to open procedures and the reasons for choosing this strategy are discussed. RESULTS: The 771 study patients (401 male and 370 female patients) had a median age of 62 years (range, 7 to 96). For all VATS. we used one-lung general anesthesia, without carbon dioxide insufflation. Indications for performing VATS were a pulmonary nodule in 333 patients, pleural effusion in 208, pulmonary infiltrate in 117, pneumothorax in 51, mediastinal mass in 22, pleural mass in 17, air leak in 13, and other in 10. The procedure was a wedge excision in 352 patients, examination of the pleural cavity in 128, pleural biopsy in 86, talc pleurodesis in 85, wedge excision and mechanical pleurodesis in 46, decortication in 27, excision of a mediastinal mass in 12, sympathectomy in 4, and other in 16. The rate of conversion of VATS to thoracotomy was 33.1% and did not change throughout the period of the study. The most common reasons for conversion were to complete a resection of a malignant lesion or to remove a deep nodule. The overall operative mortality was 1.9%. Complications occurred in 43 patients (8.3%) who underwent VATS without conversion to an open procedure and included prolonged air leak in 14, respiratory failure in 8, pneumothorax in 6, and atrial fibrillation in 5. The median hospitalization was 5 days (range, 1 to 104). CONCLUSION: VATS is safe and useful for selected thoracic conditions. We favor conversion to thoracotomy when curative resection of a malignant lesion is intended.

Adolescent↗
PubMed1996

The prevalence and clinical characteristics of short segments of specialized intestinal metaplasia in the distal esophagus on routine endoscopy.

OBJECTIVE: To prospectively determine the prevalence and clinical characteristics of short segments of specialized intestinal metaplasia in the distal esophagus. Short segment is defined as extending less than 2 cm proximal to the esophagogastric junction. This has been referred to by some investigators as "short segment Barrett's esophagus." METHODS: One hundred and seventy two patients undergoing elective esophagogastroduodenoscopy were consecutively enrolled. Patients with known Barrett's esophagus were excluded. All study patients completed a symptom questionnaire. At endoscopy, the presence of esophagitis and locations of the diaphragmatic hiatus, esophagogastric junction, and the squamocolumnar junction were recorded. Biopsy specimens were obtained at the squamocolumnar junction to identify specialized intestinal metaplasia and 2 cm above the squamocolumnar junction to evaluate for histological esophagitis. RESULTS: Two patients (1.2%) had at least 2 cm of columnar-lined esophagus. Of the 170 patients without 2 cm of columnar-lined esophagus, 16 (9.4%) patients had short segments of specialized intestinal metaplasia. Twelve (7.0%) of these patients had specialized intestinal metaplasia limited to the esophagogastric junction. All patients with specialized intestinal metaplasia were Caucasian, and there was a slight male predominance. Patients without specialized intestinal metaplasia (n = 154, 90.6%) did not differ statistically with respect to age, gender, use of acid-suppressing drugs, alcohol, or smoking history. Pyrosis and regurgitation were significantly more common in patients with specialized intestinal metaplasia involving the distal 2 cm of the esophagus or the esophagogastric junction. Cough was more common in the group with specialized intestinal metaplasia limited to the esophagogastric junction. The groups were similar in frequency of dysphagia, globus sensation, nocturnal pyrosis, eructation, early satiety, nausea, and abdominal pain. CONCLUSIONS: Specialized intestinal metaplasia less than 2 cm proximal to the esophagogastric junction is common in Caucasian patients undergoing routine esophagogastroduodenoscopy. Pyrosis and regurgitation are significantly more common in patients with short segments of specialized intestinal metaplasia, whether involving the distal 2 cm of the esophagus or the esophagogastric junction alone. Alcohol and tobacco use are no more common in patients with specialized intestinal metaplasia than in those without metaplasia. The presence of specialized intestinal metaplasia did not correlate with either endoscopic or histological esophagitis.

Age Distribution↗
PubMed1996

Selective inhibitors of plasma kallikrein.

Based on a tetrapeptide fragment [Pro387-Ser390] of HK we have developed a series of potent low molecular weight (5-600 Da) inhibitors of PK which are stable to the enzyme. These inhibitors show good selectivity for PK versus tissue kallikrein, thrombin and plasmin. Such inhibitors will help define the role of PK and kinins in human physiology and pathophysiology. They may also find clinical use in the treatment of diseases where kinins are important mediators.

Amino Acid Sequence↗