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Biomedical subjects

A Bell

Publications and source records attributed to A Bell.

At least 37 records · Page 2Linked to original sources
PubMed2002

Development of a sensitive whole blood chemiluminescence method for assessing the bioactivity of calcium phosphate powders.

The development of simple, but highly sensitive and accurate in vitro methods for assessing the bioactivity of biomaterials is a key requirement for assuring their successful clinical application. Moreover, screening techniques that will allow various materials to be recommended, or otherwise, for further testing, have the potential to make appreciable savings in the time and expense associated with product development. This paper gives details of a novel whole blood chemiluminescence method, based on the photoprotein Pholasin, which emits light in the presence of the free radical superoxide. other reactive oxygen species and the enzyme myeloperoxidase. This whole blood assay may have the potential as a screening method for assessing calcium phosphate (Ca-P) bioceramic powders according to their relative bioactivity. The method employed involves exposure of samples of anti-coagulated (heparinised) blood to the various Ca-P materials and stimulating the contacted leukocytes in the blood with phorbol-12-myristate-13-acetate (PMA). PMA stimulates protein kinase C directly and sets in motion a cascade of events in the leukocytes leading to the activation of the superoxide generating NADPH oxidase system. PMA also promotes degranulation, which is the fusion of the granule membrane with the plasma membrane and the extracellular release of granule enzymes. Changes in the free radical and degranulation activity of the cells, as measured by the luminescent response of Pholasin to cells stimulated with PMA, after exposure to the Ca-P powders, are presented as percentage differences from the response to (control) blood samples not exposed to the powders. The resultant data clearly indicate significant differences in the light detected via Pholasin from the blood exposed to the bioceramic materials compared to that from the relevant controls. These differences correlate well with the ascribed bioactivity of the Ca-P powders. as assigned from the measured chemical and structural properties. Furthermore, the method can also be applied to samples of blood, which have been diluted in the ratio 1:100 in standard blood dilution buffer. The light output response in the diluted blood experiments is exactly the same as that observed with undiluted whole blood but occurs immediately as compared to the many minutes required to give response in the latter case. Thermally processed (800 degrees C) Ca-P materials have also been studied. A relationship between the heat-induced properties of the powders and the chemiluminescence responses recorded from blood cells stimulated with PMA has been established.

Biocompatible Materials↗
PubMed2002

A questionnaire assessment of nutrition knowledge--validity and reliability issues.

OBJECTIVE: This study describes an evaluation of validity and reliability measures in a questionnaire designed to assess knowledge of applied nutrition in children participating in an after-school care dietary intervention programme being undertaken in an area of high social disadvantage. DESIGN: Three domains were assessed: Knowledge of Applied Nutrition (KN), Knowledge of Food Preparation (KP) and Perceived Confidence in Cooking Skills (PC). Four pilot studies were undertaken to determine item reliability, test-retest reliability, discrimination and difficulty indices, and content, cognitive and face validity. SETTING: Primary schools in Dundee, Scotland and Newcastle upon Tyne, England. SUBJECTS: Ninety-eight children aged 11 years. RESULTS: The final instrument comprised 36 questions (18 KN items, 9 KP items and 9 PC items) presented on four sides of paper, which could be self-completed in less than 15 minutes. Question formatting included open and closed structures (KP) and multiple choice (KN and PC) items. All knowledge questions could be answered correctly by 5 to 95% of the target population, with discrimination scores ranging from 0.06 to 0.83. Retest reliability scores were significant (KN 0.458, KP 0.577, PC 0.381, ) and internal reliability (Cronbach's alpha) of each component was also significant. CONCLUSION: The test meets basic psychometric criteria for reliability and validity and forms a suitable instrument for measuring changes associated with intervention work aimed at improving food and dietary knowledge.

Child↗
PubMed2001

p73 is over-expressed in vulval cancer principally as the Delta 2 isoform.

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Delta 2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16(INK4a) in HPV-negative cases. There was a close correlation between expression of p73 and p14(ARF) in cancers with loss of p53 function. The frequent over-expression of p73 Delta 2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2001

The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum-infected erythrocytes.

Intra-erythrocytic Plasmodium parasites digest host cell haemoglobin and use the liberated amino acids for protein synthesis. Although several endoproteases (aspartic, cysteine, and metallo-) have been shown to be involved in the initial stages of haemoglobin degradation, little is known about the steps immediately before amino acid release. In our studies, fluorometric enzyme assays indicated that the stage of the P. falciparum erythrocytic cycle with highest aminopeptidase activity was the stage at which most haemoglobin degradation occurs, i.e. the trophozoite. Consistent with these results, metabolic growth assays indicated that the late ring/trophozoite stage was most susceptible to aminopeptidase inhibitors. To reconstitute the terminal stages of haemoglobin breakdown in vitro, we synthesised three peptides with amino acid sequences corresponding to known products of the endoproteolytic digestion of haemoglobin and employed them as substrates for aminopeptidases. Both trophozoite cytosolic extract, and partially-purified aminopeptidase, hydrolysed these peptide fragments to amino acids. Hydrolysis appeared to occur sequentially from the amino-termini of the peptides, and was inhibited in a concentration-dependent manner by the aminopeptidase-specific inhibitor nitrobestatin. The results suggest that P. falciparum aminopeptidases could be the enzymes responsible for the hydrolysis of haemoglobin-derived peptides to free amino acids. Lack of ultrastructural change in parasites treated with relevant concentrations of aminopeptidase-specific inhibitors, however, indicated that little feedback exists whereby the inhibition of cytosolic aminopeptidases results in obvious inhibition of initial haemoglobin degradation in the digestive vacuole.

Aminopeptidases↗
PubMed2001

Early toxicity from preoperative radiotherapy with continuous infusion 5-fluorouracil for resectable adenocarcinoma of the rectum: a Phase II trial for the Trans-Tasman Radiation Oncology Group.

PURPOSE: To assess the toxicity and the efficacy of preoperative radiotherapy with continuous infusion 5-fluorouracil (5-FU) for locally advanced adenocarcinoma of the rectum. METHODS AND MATERIALS: Eligible patients had newly diagnosed localized adenocarcinoma of the rectum within 12 cm of the anal verge, Stage T3-4, and were suitable for curative resection. Eighty-two patients were treated with radiotherapy-50.4 Gy in 28 fractions in 5.6 weeks, given concurrently with continuous infusion 5-FU, using either 96-h/week infusion at 300 mg/m(2)/day or 7-days/week infusion at 225 mg/m(2)/day. RESULTS: The median age was 59 years (range, 27-87), and 67% of patients were male. Pretreatment stages of the rectal cancer were T3, 89% and resectable T4, 11%, with endorectal ultrasound confirmation in 67% of patients. Grade 3 acute toxicity occurred in 5 of 82 patients (6%; 95% confidence interval [CI], 2-14%). Types of surgical resection were anterior resection, 61%; abdominoperineal resection, 35%; and other procedures, 4%. There was no operative mortality. Anastomotic leakage after low anterior resection occurred in 3 of 50 patients (6%; 95% CI, 1-17%). The pathologic complete response rate was 16% (95% CI, 9-26%). Pathologic Stages T2 or less occurred in 51%. CONCLUSION: Preoperative radiotherapy with continuous infusion 5-FU for locally advanced rectal cancer is a safe regimen, with a significant downstaging effect. It does not seem to lead to a significant increase in serious surgical complications.

Adenocarcinoma↗
PubMed2001

Lower respiratory tract infections in Inuit infants on Baffin Island.

BACKGROUND: It has long been suspected that Canadian Inuit children suffer from frequent severe lower respiratory tract infections (LRTIs), but the causes and risk factors have not been documented. This study assessed the infectious causes and other epidemiologic factors that may contribute to the severity of LRTI in young Inuit children on Baffin Island. METHODS: A prospective case study was carried out at the Baffin Regional Hospital in Iqaluit, Nunavut, of infants less than 6 months of age, who were admitted to hospital between October 1997 and June 1998 with a diagnosis of LRTI. Immunofluorescent antibody testing was used to identify respiratory viruses, and enzyme immunoassay (EIA) and polymerase chain reaction (PCR) were used to test for Chlamydia trachomatis. Demographic and risk factor data were obtained through a questionnaire. RESULTS: The annualized incidence rate of admission to hospital for bronchiolitis at Baffin Regional Hospital was 484 per 1000 infants who were less than 6 months of age; 12% of the infants were intubated. Probable pathogens were identified for 18 of the 27 cases considered in our study. A single agent was identified for 14 infants: 8 had respiratory syncytial virus, 2 adenovirus, 1 rhinovirus, 1 influenza A, 1 parainfluenza 3 and 1 had cytomegalovirus. For 4 infants, 2 infectious agents were identified: these were enterovirus and Bordetella pertussis, adenovirus and enterovirus, cytomegalovirus and respiratory syncytial virus, and respiratory syncytial virus and adenovirus. C. trachomatis was not identified by either EIA or PCR. All infants were exposed to maternal smoking in utero, second-hand smoke at home and generally lived in crowded conditions. INTERPRETATION: Inuit infants in the Baffin Region suffer from an extremely high rate of hospital admissions for LRTI. The high frequency and severity of these infections calls for serious public health attention.

Air Pollution, Indoor↗
PubMed2001

Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion.

This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors.

Acute Kidney Injury↗
PubMed2001

Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling.

The pathway of hemoglobin degradation by erythrocytic stages of the human malarial parasite Plasmodium falciparum involves initial cleavages of globin chains, catalyzed by several endoproteases, followed by liberation of amino acids from the resulting peptides, probably by aminopeptidases. This pathway is considered a promising chemotherapeutic target, especially in view of the antimalarial synergy observed between inhibitors of aspartyl and cysteine endoproteases. We have applied response-surface modelling to assess antimalarial interactions between endoprotease and aminopeptidase inhibitors using cultured P. falciparum parasites. The synergies observed were consistent with a combined role of endoproteases and aminopeptidases in hemoglobin catabolism in this organism. As synergies between antimicrobial agents are often inferred without proper statistical analysis, the model used may be widely applied in studies of antimicrobial drug interactions.

Algorithms↗
PubMed2001

An outbreak of hepatitis A among young men associated with having sex in public venues.

An increase in hepatitis A virus (HAV) infection was noted among young men in the former Thames regions during 1997. A retrospective case-control study, using a standardised questionnaire at interview, was conducted in the area most affected (London and East Sussex) to investigate the hypothesis that this increase was mainly among homosexual men and to establish the risk factors associated with transmission. Forty-eight cases and 161 controls completed questionnaires. Forty-one cases (85%) described their sexuality as homosexual (p < 0.0001). Cases were more likely than controls to have eaten shellfish (Odds Ratio (OR) 2.4; 95% Confidence Interval (CI) 1.16, 5.04) during the two months before onset of illness. Cases had more sexual partners (p = 0.015), and more casual sexual partners (p = 0.007) than controls. Cases were more likely to have had sex in a gay sauna (OR 3.5; 95% CI 1.53, 8.30), or in a gay club, pub or disco (OR 2.9; 95 CI 1.29, 6.63) than controls. After adjusting for confounding factors, cases were more likely to have eaten shellfish (adjusted [adj] OR 3.0; 95% CI 1.33, 6.59) and to have had sex in a gay sauna (adj OR 3.9; 95% CI 1.42, 10.59). Public health messages need to inform homosexual men about recognised risk factors such as eating shellfish and travel abroad to endemic areas, as well as sexual risks. Homosexual men can benefit from hepatitis A vaccine. We would suggest that in an outbreak situation men who have multiple anonymous partners and have sex in public venues should be targeted as a priority for health education and immunisation.

Adolescent↗
PubMed2000

Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blood. 2000;96:3982-3984)

Adult↗
PubMed2000

Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis.

Although activated Ras proteins are usually associated with driving growth and transformation, they may also induce senescence, apoptosis, and terminal differentiation. The subversion of these anti-neoplastic effects during Ras-dependent tumor development may be as important as the acquisition of the pro-neoplastic effects. None of the currently identified potential Ras effector proteins can satisfactorily explain the apoptotic action of Ras. Consequently, we have sought to identify novel Ras effectors that may be responsible for apoptosis induction. By examining the EST data base, we identified a potential Ras association domain in the tumor suppressor RASSF1. We now show that RASSF1 binds Ras in a GTP-dependent manner, both in vivo and directly in vitro. Moreover, activated Ras enhances and dominant negative Ras inhibits the cell death induced by transient transfection of RASSF1 into 293-T cells. This cell death appears to be apoptotic in nature, as RASSF1-transfected 293-T cells exhibit membrane blebbing and can be rescued by the addition of a caspase inhibitor. Thus, the RASSF1 tumor suppressor may serve as a novel Ras effector that mediates the apoptotic effects of oncogenic Ras.

3T3 Cells↗
PubMed2000

4-Hydroxycinnamoyl-CoA: an ionizable probe of the active site of the medium chain acyl-CoA dehydrogenase.

4-OH-Cinnamoyl-CoA has been synthesized as a probe of the active site in the medium chain acyl-CoA dehydrogenase. The protonated form of the free ligand (lambda(max) = 336 nm) yields the corresponding phenolate (lambda(max) = 388 nm) with a pK of 8.9. 4-OH-Cinnamoyl-CoA binds tightly (K(d) = 47 nM, pH 6) to the pig kidney dehydrogenase with a prominent new band at 388 nm, suggesting ionization of the bound ligand. However, this spectrum reflects polarization, not deprotonation, of the neutral form of the ligand. Thus, the 388 nm band is abolished as the pH is raised (not lowered), and analogous spectral and pH behavior is observed with the nonionizable analogue 4-methoxycinnamoyl-CoA. Studies with wild type, E99G, and E376Q mutants of the human medium chain acyl-CoA dehydrogenase showed that these two active site carboxylates strongly suppress ionization of the 4-OH ligand. Binding to the double mutant E99G/E376Q gives an intense new band as the pH is raised (pK = 7.8), with an absorbance maximum at 498 nm resembling the natural 4-OH-cinnamoyl-thioester chromophore of the photoactive yellow protein. Raman difference spectroscopy in water and D(2)O, using the free ligand and wild-type and double-mutant enzyme.ligand complexes, confirms that the 4-OH group of the thioester is ionized only when bound to the double mutant. These data demonstrate the strong electrostatic coupling between ligand and enzyme, and the critical role Glu376 plays in modulating thioester polarization in the medium chain acyl-CoA dehydrogenase.

Acyl Coenzyme A↗
PubMed2000

A logic for biological systems.

This paper proposes a specification language, hybrid projection temporal logic of modelling, analyzing and verifying biological systems which can be considered, in general, to be hybrid systems consisting of a non-trivial mixture of discrete and continuous components. The syntax and semantics of the logic are presented, and some examples of hybrid systems are modelled to illustrate the formalism.

Antigen-Antibody Reactions↗
PubMed2000

Pentamidine inhibits mitochondrial intron splicing and translation in Saccharomyces cerevisiae.

Pentamidine inhibits in vitro splicing of nuclear group I introns from rRNA genes of some pathogenic fungi and is known to inhibit mitochondrial function in yeast. Here we report that pentamidine inhibits the self-splicing of three group I and two group II introns of yeast mitochondria. Comparison of yeast strains with different configurations of mitochondrial introns (12, 5, 4, or 0 introns) revealed that strains with the most introns were the most sensitive to growth inhibition by pentamidine on glycerol medium. Analysis of blots of RNA from yeast strains grown in raffinose medium in the presence or absence of pentamidine revealed that the splicing of seven group I and two group II introns that have intron reading frames was inhibited by the drug to varying extents. Three introns without reading frames were unaffected by the drug in vivo, and two of these were inhibited in vitro, implying that the drug affects splicing by acting directly on RNA in vitro, but on another target in vivo. Because the most sensitive introns in vivo are the ones whose splicing depends on a maturase encoded by the intron reading frames, we tested pentamidine for effects on mitochondrial translation. We found that the drug inhibits mitochondrial but not cytoplasmic translation in cells at concentrations that inhibit mitochondrial intron splicing. Therefore, pentamidine is a potent and specific inhibitor of mitochondrial translation, and this effect explains most or all of its effects on respiratory growth and on in vivo splicing of mitochondrial introns.

Antifungal Agents↗
PubMed2000

Rapamycin inhibits human adipocyte differentiation in primary culture.

OBJECTIVE: The immunosuppressant drug rapamycin, has been reported to inhibit 3T3-L1 adipocyte differentiation by interfering with critical postconfluent mitoses that are required early on for successful differentiation of this cell line (clonal expansion phase). In contrast to the murine 3T3-L1 preadipocyte cell line, human preadipocytes in primary culture do not undergo clonal expansion during differentiation. We investigated whether rapamycin could inhibit human adipocyte differentiation. RESEARCH METHODS AND PROCEDURES: The effect of rapamycin on the induction of differentiation of human preadipocytes in primary culture into adipocytes was measured using Oil Red O staining and glycerol phosphate dehydrogenase activity. RESULTS: We have observed that rapamycin severely curtails human adipocyte differentiation of both omental and abdominal subcutaneous preadipocytes (to 14% and 19% of standard differentiation, respectively). The rapamycin-mediated inhibition of human adipocyte differentiation could be reversed in the presence of excess amounts of FK-506, which displaces rapamycin from its intracellular receptor, FKPB12. Measurement of cytosolic protein and [3H]thymidine incorporation into DNA confirmed the absence of proliferation during differentiation of human preadipocytes in primary culture. DISCUSSION: Our data indicate that rapamycin exerts important negative regulatory effects on adipogenesis in human preadipocytes, through a mechanism that does not depend on interruption of clonal expansion.

Adipocytes↗