Biomedical subjects
Publications and source records attributed to A Baxter.
The synthesis and pharmacological evaluation of a new series of potent P2X(7) receptor antagonists is disclosed. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. The distribution of the P2X(7) receptor in inflammatory cells, most notably the macrophage, mast cell and lymphocyte, suggests that P2X(7) antagonists have a significant role to play in the treatment of inflammatory disease.
BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC(50) values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis.
BACKGROUND: It is recommended that infants from the age of 6 months should be introduced to drinking from a cup and the use of a bottle should be actively discouraged after the age of 1 year. The number of young children using a feeder bottle after the age of 1 year is not known but it is recognized by health professionals as a 'growing' concern. AIMS: To obtain local information about the number of children using a bottle past the age of 1 year, what fluids were being offered and to assess parental awareness about when a cup can be introduced. METHODS: The study data was collected by questionnaire from 407 parents between June 1998 and January 1999. Socially disadvantaged groups were targeted for the sample group as well as care being taken to include a representative ethnic population. RESULTS: Ninety-nine per cent of the study infants were below the age of 2 years, with the age range being 12-28 months. Thirty per cent were using only a cup/beaker, 8% of infants still used a bottle only, and 62% used both a bottle and a cup. Drinks/food other than milk and water had been offered from the bottle by 47% of respondents. More than 60% of the parents thought that the age at which the use of a bottle should be discontinued was older than that recommended. Only 18% thought a cup/beaker could be introduced as early as 6 months. CONCLUSION: The results show that there is a need to actively encourage the use of a cup at an earlier age and to discourage the inappropriate and extended use of a feeder bottle. Barriers to change need to be addressed.
A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.
UNLABELLED: Hearing loss has long been associated with diabetes mellitus. Microangiopathy, associated with thickening of the basement membranes of small vessels, has been implicated as a major source of multiple system organ disease. OBJECTIVE: This study was designed to evaluate changes in basement membrane thickness in the inner ear of laboratory animals suffering from non-insulin-dependent diabetes mellitus (NIDDM) with, and without, exposure to moderate intensity noise exposure in an attempt to extrapolate the same disease process in humans. DESIGN: Spontaneously hypertensive-corpulent non-insulin-dependent rats (SHR/N-cp) were selected as a genetic model for the above study. Both lean and obese rats were used in this study. A genetically similar control group of animals (LA/N-cp) were used as controls. These animals express both the lean and obese phenotypes, but they lack the NIDDM gene. Forty-eight animals in each group were sacrificed at the end of the study. The cochleas were dissected and fixed. The basement membrane of the stria vascularis was examined using transmission electron microscopy. SETTING: This study was a laboratory-based, standard animal study. MAIN OUTCOME: This study was designed to show microangiography of the inner ear as related to NIDDM with, and without, obesity and noise exposure. RESULTS/CONCLUSIONS: NIDDM alone does not cause statistically significant basement membrane thickening; however, NIDDM in combination with obesity and/or noise exposure did show significant thickening and the combination of all three showed the greatest thickening. NIDDM appeared to be the greatest contributing factor.
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BACKGROUND: Carotid duplex ultrasonography (CDUS) is an established non-invasive tool for assessing patients with suspected carotid bifurcation disease. Current trends show an increased dependence on CDUS in recommending patients for stroke prevention surgery. The aim of the study was to evaluate routine practice in vascular laboratories across 26 countries participating in The Asymptomatic Carotid Surgery Trial (ACST), and to determine the areas which are in need of future standardisation if CDUS is to be the primary tool in recommending patients for CEA. METHODS: Retrospective. Information was gathered from questionnaires, and 22 on-site visits of vascular laboratories between August 1996 to September 1997. SETTING: Clinical vascular laboratory practice. PARTICIPANTS: Eligible participants were vascular laboratories of ACST collaborators. MEASURES: Laboratories were compared in 7 categories: ultrasound equipment, operators, experience, protocols, stenosis evaluation, interpretation criteria, and reporting. RESULTS: Information on 117 respondents showed that (i) experience: at least one operator in each laboratory had more than 3 years experience; (ii) equipment: 88% (103/117) had colour duplex capability; (iii) operators: 54% of laboratories had exams performed by technologists, 33% vascular surgeons, 28% radiologists, and 35% other. The most significant findings were in (iv) stenosis evaluation: only 29% (33/117) were using a standardised Doppler angle (this single factor may greatly alter exam results); and (v) interpretation criteria; with >41 different criteria reported. These specific laboratory variations can affect those patients considered appropriate for CEA. CONCLUSIONS: This study highlights the most significant areas for future standardisation to be Doppler angle and interpretation criteria, if CDUS is to be a primary tool in recommending patients for CEA, when indicated by clinical trial results.
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BACKGROUND: The ACST has randomised over 1670 patients to determine if carotid endarterectomy (CEA) prolongs stroke free survival versus best medical treatment alone. Some patients have had contralateral symptoms to the side under investigation, for which CEA may have been performed. This study aims to determine the prevalence of hemispheric cerebral infarcts in relation to prior contralateral symptoms. METHODS: Patients with preoperative CT or MR scans were divided into those with prior contralateral stroke, cortical TIA, amaurosis fugax or no symptoms. RESULTS: There were 1144 patients with preoperative CT and 170 patients with MR scans. Incidence of contralateral hemispheric CT and MR infarcts were 19% (222/1144) and 20% (34/170) respectively. Those with prior contralateral stroke (141) had the highest incidence of hemispheric CT infarcts (62%). Those with TIA (129) had a 30% incidence of CT infarct. Incidence of hemispheric CT infarcts were 17% with amaurosis fugax (46) and 10% with no prior symptoms (803). Mantel-Haenszel test for linear association was significant (p < 0.001) for increasing severity of symptoms. Considering MR scans, those with prior contralateral stroke (17) had the highest incidence of hemispheric MR infarcts (53%). Patients with TIA (23) or amaurosis fugax (6) had a 27% incidence of MR infarction. Those with no prior symptoms (121) had a 14% incidence of MR infarcts. Mantel-Haenszel test was significant (p < 0.001). CONCLUSIONS: In the ACST, currently asymptomatic patients have an incidence of contralateral hemispheric CT and MR infarcts proportional to the severity of prior contralateral symptoms.
BACKGROUND: The ACST has randomised over 1670 patients to determine if carotid endarterectomy (CEA) prolongs stroke free survival when compared with best medical treatment alone. This study aims to assess the prevalence of asymptomatic cerebral infarcts in patients grouped by sex, age, mean blood pressure (MBP), total cholesterol, diabetes and coronary artery disease (CAD). METHODS: The type of study was retrospective. Patients with preoperative CT scans were included. In those with previous stroke, only the contralateral cerebral hemisphere was studied for presence of infarcts. One thousand one hundred and forty-two patients were studied. RESULTS: The proportion of patients with CT infarcts was 19% (211/1142). Men (155/777) had a higher incidence of CT infarction (20% vs 15%, p = 0.01). Mean age was 68 years and mean MBP was 107 mmHg. The incidence of CT infarcts was not associated with age or MBP. Diabetics or those with definite CAD had no difference in the incidence of cerebral infarction. Diabetics with definite CAD (51/796) had a greater incidence of CT infarcts (33% vs 21%, p = 0.03) compared with those without evidence of CAD and diabetes together (745/796). CONCLUSIONS: In ACST, CT infarcts are more prevalent in men compared to women, and in diabetics with CAD. There was no difference in the incidence of CT infarction by age, mean BP, or by the presence of diabetes or CAD alone.
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Successful management of classical ballet dancers with overuse injuries requires an understanding of the art form, precise knowledge of anatomy and awareness of certain conditions. Turnout is the single most fundamental physical attribute in classical ballet and 'forcing turnout' frequently contributes to overuse injuries. Common presenting conditions arising from the foot and ankle include problems at the first metatarsophalangeal joint, second metatarsal stress fractures, flexor hallucis longus tendinitis and anterior and posterior ankle impingement syndromes. Persistent shin pain in dancers is often due to chronic compartment syndrome, stress fracture of the posteromedial or anterior tibia. Knee pain can arise from patellofemoral syndrome, patellar tendon insertional pathologies, or a combination of both. Hip and back problems are also prevalent in dancers. To speed injury recovery of dancers, it is important for the sports medicine team to cooperate fully. This permits the dancer to benefit from accurate diagnosis, technique correction where necessary, the full range of manual therapies to joint and soft tissue, appropriate strengthening programmes and maintenance of dance fitness during any time out of class with Pilates-based exercises and nutrition advice. Most overuse ballet conditions respond well to a combination of conservative therapies. Those dancers that do require surgical management still depend heavily on ballet-specific rehabilitation for a complete recovery.
Insulin-dependent diabetes mellitus is a multigenic autoimmune disease, for which one of the best animal models is the nonobese diabetic (NOD) mouse strain. In both humans and NOD mice, major histocompatibility complex genes are implicated as risk factors in the disease process. Other susceptibility genes are also involved, and a number have been mapped in the mouse to specific chromosomal locations. To identify further susceptibility genes, diabetic backcross mice, produced after crossing NOD/Lt to the nondiabetic strains SJL and C57BL/6 (B6), were examined for markers not previously associated with disease susceptibility. Linkage was found to loci on chromosomes 4 and 14. Of the candidate loci on chromosome 4, the gene encoding the Na+/H+ exchanger-1, Nhe-1, was the most likely, since the NOD allele was different from that of both nondiabetic strains. NOD lymphocytes were found to have a higher level of Na+/H+ exchange activity than lymphocytes from either B6 or SJL mice. Since the chromosome 4 susceptibility gene is recessive, the B6 allele should prevent diabetes. This prediction was tested in fourth-generation backcross mice, selected for retention of the B6 allele at Nhe-1. Mice homozygous for Nhe-1 developed diabetes after cyclophosphamide treatment, but heterozygotes were largely protected from disease. These results implicate the Na+/H+ exchanger (antiporter) in the development of type 1 diabetes and may provide a screening test for at-risk individuals as well as offering prospects for disease prevention.
Diabetes was dramatically accelerated in non-obese diabetic (NOD) transgenic mice that expressed interleukin-2 (IL-2) in their beta cells. A single cross to C57BL/6 completely prevented this effect and a further backcross to the NOD genetic background showed that at least two diabetes susceptibility loci (Idd1s and Idd3/10s) were required for the diabetes acceleration T cells activated to islet antigens were not circulating in the mice. The accelerating effect of IL-2 was present; but decreased, in NOD mice that lacked CD8+ T cells as well as in NOD SCID mice. The implications are that in the NOD genetic background, the production of cytokines, such as IL-2, by islet-specific CD4+ T cells can lead to beta cell damage and diabetes and that CD8+ T cells may have a role in accelerating diabetes onset.
Temporal bone dissection forms an important aspect in the training of an otolaryngologist. The more dissection one does the more confident one is in the operating room. The aim of this paper is to advise in the preparation of temporal bones for the purpose of display, exhibition or competition. The practical aspects of dissection are deliberately avoided concentrating on the selection of bones pre- and post-dissection, preparation of the bones, fixing and display of vessels and nerves and also mounting and lighting for exhibition purposes. The temporal bone laboratory should be well equipped with a microscope, a power drill with a range of cutting and polishing burrs, a range of fine instruments, a suction machine with different sizes of suction tips, water source, a place to store the bones etc., thus creating an ideal environment for temporal bone dissection.
A retrospective study was undertaken to identify recipients of blood from donors subsequently shown to be positive for hepatitis C virus using second-generation tests and polymerase chain reaction. The main aims were to determine the numbers of such recipients who were still alive and traceable, and to determine the risk of infection in this group. The feasibility and workload of this procedure, which is currently not practised in the U.K. or U.S.A., was also assessed. In the first six months of routine testing 42,697 donors were tested. Of 20 confirmed to be HCV-positive, 15 were regular donors. Eighty-three components were prepared from 63 anti-HCV positive previous donations from these donors. In all, nine recipients were found to be alive. All were positive for anti-HCV. We conclude that although this retrospective procedure is time-consuming and difficult, substantial numbers of infected recipients can be identified. The availability of treatment for chronic hepatitis C for such patients should encourage transfusion services to reassess current policies on the hepatitis C retrospective.