Biomedical subjects
Publications and source records attributed to R L Jones.
Parapharyngeal abscess is not an uncommon condition and may be due to spread of infection from acute tonsillitis or dental disease or secondary to perforating injury of the pharynx. We present a case report of a patient with an external auditory meatus foreign body who developed a parapharyngeal abscess.
1. In the guinea-pig isolated vas deferens preparation bathed in Tyrode's solution, the prostacyclin analogues, cicaprost, TEI-9063, iloprost, taprostene and benzodioxane-prostacyclin, enhanced twitch responses to submaximal electrical field stimulation (20%-EFS). The high potency of cicaprost (EC150 = 1.3 nM) and the relative potencies of the analogues (equi-effective molar ratios = 1.0, 0.85, 1.6, 17 and 82, respectively) suggest the involvement of a prostacyclin (IP-) receptor. 2. Maximum enhancement induced by cicaprost in 2.5 mM K+ Krebs-Henseleit solution was similar to that in Tyrode solution (2.7 mM K+), but was progressively reduced as the K+ concentration was increased to 3.9, 5.9 and 11.9 mM. There was also a greater tendency for the other prostacyclin analogues to inhibit EFS responses in 5.9 mM standard K+ Krebs-Henseleit solution; this may be attributed to their agonist actions on presynaptic EP3-receptors resulting in inhibition of transmitter release. 3. The EFS enhancing action of cicaprost was not affected by the alpha1-adrenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 200 nM) did not affect contractile responses of the vas deferens to either ATP (5 microM) or alpha,beta-methylene ATP (1 microM) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 microM) in the absence of TTX, as shown previously by others, was not seen. Prostaglandin E2 (PGE2, 10 nM) and another prostacyclin analogue TEI-3356 (20 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 microM) partially inhibited contractions elicited by 10-1000 microM ATP; contractions elicited by 1-3 microM ATP were unaffected. Further studies are required to establish whether a pre- or post-synaptic mechanism is involved. 4. In a separate series of experiments, cicaprost (5-250 nM), TEI-9063 (3-300 nM), 4-aminopyridine (10-100 microM) and tetraethylammonium (100-1000 microM) enhanced both 20%-EFS responses and the accompanying overflow of noradrenaline to a similar extent. In further experiments with the EP1-receptor antagonist AH 6809, TEI-3356 (1.0-100 nM) and the EP3-receptor agonist, sulprostone (0.1-1.0 nM) inhibited both maximal EFS responses and noradrenaline overflow, thus confirming previous reports of the high activity of TEI-3356 at the EP3-receptor. Cicaprost had no significant effect on noradrenaline overflow at 10 and 100 nM, but produced a modest inhibition at 640 nM. 5. In conclusion, our studies show that prostacyclin analogues (particularly TEI-3356) can inhibit EFS responses of the guinea-pig vas deferens by acting as agonists at presynaptic EP3-receptors. Prostacyclin analogues (particularly cicaprost and TEI-9063) can also enhance EFS responses through activation of IP-receptors. The mechanism of the enhancement has not been rigorously established but from our results we favour a presynaptic action to increase transmitter release.
The endometrium contains a resident population of leukocytes, the number and subtype of which vary throughout the menstrual cycle and in early pregnancy. Factors controlling these fluctuations are unknown, but a combination of proliferation in situ and migration from the vasculature has been proposed. Locally acting inflammatory mediators, including specific chemokines and prostaglandins, have been implicated in these processes. Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are potent chemoattractants and activators for neutrophils and monocytes respectively. Locally acting prostaglandins modulate vascular permeability, and a synergistic action of prostaglandin E (PGE) with IL-8 has been described. In the present study IL-8, MCP-1 and cyclooxygenase-2 (COX-2), the inducible isoform of prostaglandin synthase, were all localized in the endometrium by immunohistochemistry throughout the menstrual cycle and in early pregnancy. All three inflammatory mediators were localized to the perivascular cells of blood vessels in endometrium and decidua, and additional immunoreactivity for COX-2 was identified in the glandular epithelium. The intensity of immunostaining was reduced in the periovulatory, early and mid-secretory phases and significantly increased premenstrually. These results further support the hypothesis that there is a premenstrual migration of leukocytes into the endometrium mediated by chemokines.
The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.
1. Four types of prostanoid receptor are present on pulmonary arterial vessels of man. Thromboxane (TP) receptors mediate constriction and are blocked by antagonists such as BAY u-3405, GR 32,191 and EP 169. Prostaglandin (PG) EP3 receptors also mediate constriction, the agonist potency ranking being SC 46,275 > sulprostone > misoprostol > or = PGE2; this action needs to be borne in mind when PGE analogues are used therapeutically. 2. Prostaglandin E2 causes relaxation in a few pulmonary artery preparations: an EP2 receptor may be involved. Prostacyclin, acting through i.p. receptors, consistently produces relaxation and studies are in progress to determine the contribution made by K(+)-channel opening. Agonist potencies of stable prostacyclin analogues and non-prostanoid prostacyclin mimetics, such as BMY 45,778 and the novel diphenylindole CU 23, on human pulmonary artery and platelets are well correlated. Interestingly, the non-prostanoid mimetics show persistent relaxant effects in vitro, which may be related to their high lipophilicities. 3. Prostacyclin and iloprost are being used to treat severe pulmonary hypertension; further study of the pharmacodynamic and pharmacokinetic properties of other i.p. receptor agonists could produce improved therapy.
BACKGROUND: Barrett's oesophagus is acquired by severe gastro-oesophageal reflux and is a premalignant condition. Acid suppression or anti-reflux surgery alone do not cause significant regression of the metaplastic mucosa nor reduce the malignant potential. Recent reports have suggested that the combination of mucosal ablation with acid suppression may result in squamous regeneration. AIMS: To destroy Barrett's mucosa by thermal ablation (in the setting of acid suppression) and so induce squamous regeneration. PATIENTS: Sixteen patients with non-dysplastic Barrett's oesophagus were recruited from a surveillance programme. All had been on a proton pump inhibitor. METHODS: At intervals, non-circumferential areas of columnar mucosa were ablated using the KTP laser. Acid suppression was obtained with 40 mg omeprazole daily. Multiple biopsy specimens were obtained for histological examination from ablated areas. RESULTS: Ablation of all areas of glandular mucosa resulted in squamous regeneration. The number of treatments required depended on the length of the Barrett's segment. In 11 patients there was evidence of squamous regeneration over remaining Barrett's glands (in some of the post-treatment biopsy specimens) whilst in nine patients squamous metaplasia was seen within Barrett's glands. CONCLUSION: Mucosal ablation of Barrett's oesophagus by laser, in the setting of acid suppression, results in squamous regeneration (though some burying of Barrett's glands did occur).
This study investigated the effects of approach mode (ascending, descending, random) on the normal loudness function using the Loudness Contour Test suggested by the Independent Hearing Aid Fitting Forum. We also assessed how increasing the number of trials from one to five affects the short-term reliability of the Loudness Contour Test. Additionally, we examined the relationship between loudness judgments (very soft to uncomfortably loud) for warble tones and loudness judgments for speech. Thirty-one normal-hearing subjects were tested using 500-Hz and 3000-Hz tones and speech (CID W-22 words preceded by a carrier phrase). The results revealed that 5- to 12-dB higher SPLs were found with the descending approach than with the ascending approach. The reliability results suggest that it is not beneficial to present more than one or two trials when administering the Loudness Contour Test. The true sound pressure level (SPL) for a given loudness category will fall within +/-10 to 12 dB of the obtained SPL approximately 95 percent of the time. This 20- to 24-dB range is fairly large and it is questionable whether reliability is sufficient to justify obtaining individual loudness measurements. When the relationship between warble tones and speech was investigated, the results revealed an overall standard error of estimate of approximately 8 dB. These data suggest that warble tones are not accurate predictors of the corresponding loudness categories for speech. If the clinician wants to ascertain SPLs that correspond to the various loudness categories for speech, then direct measurement with a speech stimulus appears necessary.
A retrospective study was performed to assess the incidence of sinus disease in patients with MS. The MRI scans of 108 patients referred to a regional Neurosciences Unit with a diagnosis of multiple sclerosis were examined. There were 71 females and 37 males with an age range of 22 to 67 years (mean: 39.7 years). The sagittal and axial images were reviewed and the degree of sinus disease noted. This was graded as absent, minimal, polypoid and pansinus. Fifty-seven patients (53%) had disease, the most common sinus involved was the maxillary followed by the ethmoid, frontal and sphenoid. Thirty-six patients had bilateral disease affecting the ethmoid sinuses most commonly. Three patients had fluid levels and four patients had retention cysts. The incidence of sinus disease is higher than in some other studies of normal populations.
The plant cell vacuole has multiple functions, including storage of proteins and maintenance of an acidic pH where proteases will have maximal activity. It has been assumed that these diverse functions occur in the same compartment. Here, we demonstrate that antibodies to two different tonoplast intrinsic proteins, alpha-TIP and TIP-Ma27, label vacuole membranes of two different compartments within the same cell. These compartments are functionally distinct, because barley lectin, a protein stored in root tips, is exclusively contained within the alpha-TIP compartment, while aleurain, a protease that serves as a marker for an acidified vacuolar environment, is exclusively contained within the TIP-Ma27 compartment. As cells develop large vacuoles, the two compartments merge; this may represent a process by which storage products in the alpha-TIP compartment are exposed to the acidic lytic TIP-Ma27 compartment for degradation.
The effect of salbutamol (S) on cycling performance was examined in 15 highly trained non-asthmatic male cyclists. A double-blind, randomized cross-over design was used with S or placebo (P) administered using a metered-dose inhaler and a spacer device 20 min before each testing session. The S dose was 400 micrograms (four puffs), which is twice the normal therapeutic level. Subjects were habituated to all the laboratory procedures in the week prior to actual data collection. The subjects performed four tests under S and P conditions on separate days over 2 weeks. These included measurement of maximal O2 uptake (VO2max) (cycle ergometry) with assessment of pulmonary function before and after, a submaximal (90% of ventilatory threshold) square-wave work transition from a base of unloaded cycling, a 60-s modified Wingate test, and a simulated 20 km time trial. No significant differences were observed in any of the dependent variables related to aerobic endurance or cycling performance between the S and P conditions. These results support other findings that an acute dose (400 micrograms) of S has no performance-enhancing properties.
Prostacyclin (PGI2) has been traditionally regarded as an important regulator of haemostasis, mediating its effects through prostacyclin (IP) receptors coupled to adenylate cyclase. Recent evidence suggests, however, that IP receptor agonists can activate multiple signalling pathways via the same IP receptor. Moreover, IP receptor agonists have interesting actions outside of the cardiovascular system, even extending to the release of non-adrenergic non-cholinergic (NANC) transmitters from enteric neurones. Here, Helen Wise and Robert Jones highlight some of this new information on PGI2 and its receptors, describe the properties of some chemically novel PGI2 mimetics, and report on current therapeutic uses of PGI2.
We determined if decreases in relative free intracellular calcium concentration ([Ca2+]i) caused by salbutamol, a selective beta2-adrenoreceptor agonist, were paralleled by calcium egression from the cytosol in bovine trachealis muscle strips. [Ca2+]i, or tissue-surface extracellular calcium changes (Ts[Ca2+]ext), were monitored using Fluo-3 acetoxymethylester or Fluo-3 pentaammonium salt simultaneously with isometric tension. Salbutamol (1 microM) decreased histamine-induced isometric tension from an average peak tension of 128.5 +/- 18.4 to -4.9 +/- 0.3 mN/mm2, and reduced the associated sustained increases in [Ca2+]i from 100% at peak to 20.4 +/- 7.6%. Both histamine-induced elevation in [Ca2+]i and isometric tension were reversed completely by forskolin (1 microM). In muscle strip at active resting tension, salbutamol caused a decrease (49.6 +/- 12.1%) in [Ca2+]i. Following precontraction with histamine, salbutamol caused an immediate and sustained increase in Ts[Ca2+]ext which was not seen in a Na(+)-free solution. Finally, propranolol (10 microM) blocked both increases in Ts[Ca2+]ext and muscle relaxation caused by salbutamol. These findings indicate that in bovine trachealis muscle, the effect of salbutamol to decrease [Ca2+]i and isometric tension is via a beta2-adrenoceptor, and the changes in [Ca2+]i are by an increase in calcium egression via the Na(+)/Ca2+ exchanger, and reuptake by myoplasmic stores.
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OBJECTIVE: While the effects of age on the growth hormone/insulin-like growth factor (IGF) axis are well documented, the influence of ethnic background is unknown. The differences in IGF and IGF binding proteins (IGFBPs) were investigated in two ethnic groups. DESIGN: A cross-sectional study of an age-selected cohort of healthy, normoglycaemic, non-obese Caucasian (C) and Asian (A) subjects. PATIENTS: Fifty-three (27 C, 26 A) subjects with a mean age (+/- SD) of 20.6 +/- 0.8 years were studied. MEASUREMENTS: Fasting measurements of glucose, insulin, IGF-I, IGF-II, IGFBP-1 and IGFBP-3. Western ligand blotting and immunoblotting with IGFBP-2 and IGFBP-3 of serum samples. RESULTS: There were no significant differences in IGF-I levels between Caucasian and Asian subjects (C 218 +/- 55 vs A 229 +/- 40 micrograms/l; P = 0.44). IGF-II (C 707 +/- 110 vs A 583 +/- 75 micrograms/l; P < 0.0001) and IGFBP-3 (C 5.9 +/- 1.2 vs A 5.12 +/- 1.17 mg/l; P = 0.01) levels were significantly higher in Caucasian subjects. Immunoblotting of ligand blots revealed no protease activity on either IGFBP-3 or IGFBP-2 to account for these ethnic differences. CONCLUSIONS: Ethnic differences in IGFBP-3 and associated IGF-II levels may affect the inter-relationships of IGFs and their binding proteins and need to be considered when interpreting IGF data on growth and metabolism.
Endometrial leukocyte subpopulations vary over the reproductive cycle, but no data exist on the mechanism regulating their recruitment into uterine tissue. This study has evaluated the role of progesterone in the recruitment of selected leukocyte populations in early pregnancy decidua. Decidua was collected from women in early pregnancy at the time of vacuum aspiration of the uterus 6, 12, 24 and 36 h after taking 200 mg mifepristone (RU486). Standard immunohistochemical techniques were employed to demonstrate the selected leukocyte populations in decidual tissue and these were analysed using imaged analysis. Fresh decidua was incubated in medium for 24 h and supernatants assayed for interleukin (IL-8) (neutrophil chemotactic factor) and MCP-1 (monocyte chemoattractant protein-1) content. Analysis of variance demonstrated a significant increase in tissue monocyte number in decidua 12-36 h after mifepristone administration. No significant changes in other leukocyte subpopulations were observed. Decidua IL-8 concentrations were significantly increased (P = 0.019) 6 h after mifepristone and decidual MCP-1 concentration rose (non-significant) and fell significantly (P = 0.029) between 6 and 12 h after mifepristone. Progesterone withdrawal may initiate a local cascade of events involving inflammatory mediators which in turn are responsible for the influx of monocytes. This influx may be essential in the process of shedding of endometrium or decidua since monocytes and neutrophils are important sources of proteases and collagenases. Furthermore, these cells are potential local sources of immunomodulatory cytokines.
Family physicians provide the greatest proportion of care in rural communities. Yet, the number of physicians choosing family practice and rural practice has continued to decline. Undesirable aspects of rural practice, such as professional isolation and a lack of or inadequate resources, are assumed to be associated with this decline. This article reports on the practice support and continuing medical education needs of rural family physicians. A mail survey was conducted in 1993 on a purposive sample of family physicians in 39 of 67 rural-designated or urban Pennsylvania counties with low population densities. The physicians identified needs that included patient education materials and programs, community health promotion, federal regulation updates, technical assistance with computers and business management, database software and a videotape lending library, a drug hotline, and mini-fellowships on clinical skill development. A majority of respondents were willing to participate in clinical educational experiences for students and residents. Some physicians indicated a lack of interest in access to information through telecommunications, e.g., video conference referrals and consultations. Overall, findings revealed that family physicians need and are receptive to a variety of practice support and continuing education programs. A practice support program coupled with policy coordination among public and private organizations is likely to lessen complaints by rural primary care physicians.
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OBJECTIVE: NIDDM is associated with stiffer arteries and an increased incidence of macrovascular disease. NIDDM has strong familial inheritance. We studied the associations of a family history of NIDDM with blood pressure-corrected aortic distensibility (Cp). RESEARCH DESIGN AND METHODS: Because age is a strong determinant of arterial distensibility, we studied an age-select cohort of 67 healthy normotensive normoglycemic young adults along with fasting measurements of glucose and insulin concentrations. Cp was calculated from noninvasive Doppler ultrasound measurements of pulse wave velocity along the descending thoracoabdominal aorta. RESULTS: The mean age of the subjects was 20.6 +/- 0.7 (mean +/- SD) years. A total of 22 subjects gave a positive family history of NIDDM in a parent or grandparent. Subjects with a positive family history of NIDDM had significantly less distensible (i.e., stiffer) aortas than their age- and sex-matched counterparts who gave no family history of NIDDM (Cp [dimensionless]: 0.22 +/- 0.04 vs. 0.25 +/- 0.04, P = 0.02). Subjects with a positive family history of NIDDM also had significantly higher fasting glucose (5.1 +/- 0.4 vs. 4.9 +/- 0.4 mmol/l, P = 0.009) and insulin (7.5 +/- 5.5 vs. 4.2 +/- 2.0 mU/l, P = 0.02) levels and BMIs (23.2 +/- 2.3 vs 21.1 +/- 2.5 kg/m2, P = 0.002). On multivariate regression analysis, family history of NIDDM (P = 0.03) was the only significant independent predictor of Cp. CONCLUSIONS: A positive family history of NIDDM is associated with decreased aortic distensibility in early adult life. The relevance of these observations to future cardiovascular events merits further investigation.