Search PubMed⌕ Search

Biomedical subjects

S Weeks

Publications and source records attributed to S Weeks.

At least 19 recordsLinked to original sources
PubMed2026

Addressing the dual-use of antifungals and fungal antimicrobial resistance (fAMR) through a One Health approach.

Fungal antimicrobial resistance (fAMR) is accelerating, driven in part by the dual-use of antifungal modes of action in agriculture and medicine, threatening therapy. Addressing this challenge requires a unified One Health response that balances agricultural productivity, economic stability, and human and animal health. By focusing on the United Kingdom's policy approach, we argue that current efforts are constrained by fragmented governance, surveillance and regulation. To resolve this, we propose three policy recommendations: 1. a cross-government fAMR body, 2. mandatory environmental and clinical surveillance, and 3. for fungicide approvals to look beyond crop pathogens and integrate risk assessments for potential hotspots of resistance selection in human fungal pathogens. These measures will safeguard current and future antifungals while providing much-needed regulatory clarity and will be translatable to other national and regional contexts.

Journal Article↗
PubMed2002

Anti-V antigen antibody protects macrophages from Yersinia pestis -induced cell death and promotes phagocytosis.

The pathogenic Yersinia spp. harbor a common plasmid (pYV) essential for virulence. The plasmid encodes a type III secretion system that functions to translocate Yersinia outer proteins (Yops) into the host cytosol. Within the host cell, the Yops act to inhibit phagocytosis and induce apoptosis. One of the plasmid-encoded proteins, virulence antigen (V), is a major protective immunogen that is involved in Yop translocation. Yersinia pestis, like the enteric Yersinia spp., was both resistant to phagocytosis by and cytotoxic for J774.A1, a murine macrophage cell line. Both of these activities were dependent on culture of the bacteria at 37 degrees C for 1.5-2 h before infection. However, extending the preculture period at 37 degrees C to 24 h, which induced formation of a capsule, completely blocked cytotoxicity. Treating the bacteria with either rabbit polyclonal anti-V antibodies (R anti-V) or monoclonal antibody (MAb) 7.3, antibodies specific for V and protective against plague in vivo, protected J774.A1 cells from Y. pestis -induced cell death and also reversed the inhibition of phagocytosis. Whereas protection against cell cytotoxicity was afforded by the F(ab')(2) portion of R anti-V, the ability of anti-V to induce uptake of Y. pestis appeared to be dependent on the Fc portion of the Ab. The protective epitope(s) recognized by R anti-V was contained in the central region of Y. pestis V (aa 135-275) and were partially cross reactive with Y. pseudotuberculosis and Y. enterocolitica serotype 08 V antigens.

Animals↗
PubMed2002

In-vitro characterisation of the phagocytosis and fate of anthrax spores in macrophages and the effects of anti-PA antibody.

Antibodies (Abs) to the protective antigen (PA) component of the anthrax toxins have anti-spore as well as anti-toxin activities. Anti-PA antisera and purified anti-PA Abs enhance the phagocytosis by murine-derived macrophages (MQs) of spores of the Ames and Sterne strains and retard the germination of extracellular spores in vitro. The fate after phagocytosis of untreated and anti-PA-treated spores was further studied in culture medium that supported phagocytosis without stimulating spore germination (Dulbecco's minimal essential medium with horse serum 10%). The spores germinated within cells of primary peritoneal murine MQs (C3H/HeN) and MQs of the RAW264.7 MQ-like cell line; germination was associated with a rapid decline in spore viability. Exposure of MQs to inhibitors of phago-endosomal acidification (bafilomycin A and chloroquine) reduced the efficiency of MQ killing and allowed outgrowth and replication of the organisms. Treatment of spores with anti-PA Abs stimulated their phagocytosis and was associated with enhanced MQ killing of the spores. The enhanced killing of spores correlated with the greater extent of germination of anti-PA-treated spores after phagocytosis. A PA null mutant of the Ames strain exhibited none of the effects associated with anti-PA Ab treatment ofthe parental strain. Thus, the anti-PA Ab-specific immunity induced by vaccines has anti-spore activities and its role in impeding the early stages of infection with Bacillusanthracis needs to be assessed.

Animals↗
PubMed2001

A survey of threats and violent acts by patients against training physicians.

OBJECTIVES: The primary purpose was to determine the prevalence of various types of threats or assaults by patients against training physicians and to determine the psychological impact of the most distressing incidents. Differences between specialty of training and gender were examined. DESIGN: An anonymous mailed questionnaire. SETTING: The Medical School of the University of Auckland, New Zealand. SUBJECTS: All 160 postgraduate trainees in psychiatry, general medicine, surgery, and obstetrics and gynaecology. A response rate of 84% (n=135) was obtained. RESULTS: The majority of trainees had been verbally threatened (n=91, 67%) or physically intimidated (n=73, 54%) at some time during specialty training, while another 41% (n=55) had witnessed Health Board property being damaged in their presence and 39% (n=53) had been physically assaulted. Psychiatry trainees were significantly more likely to experience the various types of threat or violence. Females (n=20, 38%) were significantly more likely than men (n=8, 10%) to report having been sexually harassed (chi2=14, d.f.=1, P < 0.001). The overall mean on the Impact of Event Scale for those who described the most distressing incident was 8. On only one occasion was a training director directly informed about a trainee's most distressing incident and most trainees (n=95, 70%) had not had training on protecting against assault or on managing violence. CONCLUSION: These findings underscore a priority for developing programmes which effectively reduce threats and violence against trainees and which lessen the psychological sequelae of these incidents.

Adaptation, Psychological↗
PubMed2001

Characterization of the caspase inhibitor IDN-1965 in a model of apoptosis-associated liver injury.

Previous studies have shown that caspase inhibitors are effective at protecting against anti-Fas antibody (alpha-Fas)-mediated liver injury/lethality. The purpose of these experiments was to characterize more fully the efficacy of a broad-spectrum, irreversible caspase inhibitor, IDN-1965 (N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid), in this model and the role of caspase inhibition in long-term protection. The ED(50) for IDN-1965 by i.p. administration, based on alanine aminotransferase activities, was 0.14 mg/kg. The caspase inhibitor was also efficacious when administered intravenously and orally (ED(50) values of 0.04 and 1.2 mg/kg, respectively). Histologically, marked reduction in Fas-induced apoptosis with IDN-1965 (1 mg/kg, i.p.) was apparent at 6 h. Also, caspase 3-like activities were decreased in a dose-dependent manner, but the inhibition of caspase activity was transient. Immunohistochemical studies demonstrated that IDN-1965 greatly reduced the activation of caspase 3. In survival studies, a single i.p. treatment of 1 mg/kg IDN-1965 or continuous i.p. infusion via osmotic pumps completely blocked lethality measured up to 7 days after alpha-Fas administration. IDN-1965 was also effective in inhibiting liver injury when administered as long as 3 h after or 1 h before alpha-Fas administration. Lastly, Western blot analysis demonstrated that processing of caspases 3, 6, and 8, as well as Bid (a protein responsible for the release of mitochondrial cytochrome C and amplification of the apoptotic cascade) was inhibited by IDN-1965. In conclusion, the broad-spectrum caspase inhibitor IDN-1965 is markedly effective at inhibiting Fas-mediated apoptosis by multiple routes of administration. The therapeutic potential of caspase inhibitors appears promising for the treatment of apoptosis-mediated liver injury based on potency and postinsult efficacy.

Alanine Transaminase↗
PubMed2000

Qualitative assessment of the impact of health care reform on the availability of clinicians for preclinical medical instruction.

PURPOSE: Over the past 5 years, Calgary clinicians experienced the restructuring of health care delivery and a move to a presentation-based curriculum at the University of Calgary. Course coordinators have noted increased difficulty in recruiting clinical lecturers at the preclinical undergraduate level. This study was designed to evaluate the relative importance of factors that may influence the time clinicians spend teaching at this level. SUMMARY: This descriptive survey was conducted within the University of Calgary, Faculty of Medicine, a teaching institution affiliated with the Calgary Regional Health Authority, which is responsible for the delivery of health care within the City of Calgary. Basic scientists, residents, and adjunct medical professionals were excluded from a list of lecturers for the academic year 1996-97, leaving a target population of 386. Respondents were stratified according to university appointment, specialty, type of medical training, and hours taught in the 1996-97 academic year. Dependent variables included the financial constraints, time constraints, health care reform, changes in the undergraduate medical education curriculum, and lack of recognition on availability for teaching. Written comments were also categorized and analyzed according to the same variables. A response rate of 79% (n = 305) was achieved. Of the respondents, 52% agreed that recent reform has made it more difficult to teach; full-time faculty were less likely to agree compared to non-full-time faculty (60% vs. 44%; nonparametric median test, chi 2 = 6.18, p = .046). Twice as many family physicians reported that financial constraint was a factor (66%) when compared to other specialists, whereas relatively few full-time faculty noted it to be a concern (12%) when compared to major part-time (43%) and non-full-time/major part-time appointees (66%; chi 2 = 23.4, p < .0001). Clinicians reporting the most teaching hours (more than 30) were most likely to describe an increase in teaching hours (61%). Nonfaculty members were less aware of the recent curricular changes (73%); however, more family physicians felt that these changes had a positive impact on willingness to teach (10%) compared to surgical (8%) and nonsurgical specialists (9%; chi 2 = 6.07, p = .048). Forty-five percent of respondents agreed that they would be more willing to teach if offered some from of recognition. Two thirds of written comments suggested that recognition should be nonmonetary (e.g., faculty promotion, acknowledgment). CONCLUSIONS: The experience at the University of Calgary suggests that availability of teachers for preclinical undergraduate medical education has diminished as a result of health care reform. Family physicians have been affected the most, and the clinical environment will make it even more difficult to involve this important group of teachers in undergraduate medical education.

Alberta↗
PubMed2000

Middle-ear disease in remote Aboriginal Australia: a field assessment of surgical outcomes.

Chronic middle-ear disease is highly prevalent among Australian Aboriginal people, and many undergo surgical treatment. However, the outcomes of surgery in this group have not been fully evaluated. This is a descriptive study of operations for middle-ear disease (excluding grommets) on Aboriginal patients in Kimberley hospitals between 1 October 1986 and 31 December 1995. Logistic regression was used to model predictors of surgical outcome. Success was defined by an intact tympanic membrane and air-bone gap of < or = 25 dB at review at, or later than, six months post-operation. A success rate of 53 per cent was observed; increasing age was the only variable predictive of success. Successful outcomes were more likely in adults and children aged > 10 years, however, this does not take into account the necessity of hearing for language acquisition and learning. Dedicated resources must be allocated for post-operative follow-up of Aboriginal patients so that much-needed, rigorous evaluations of ENT surgery can be conducted.

Adolescent↗
PubMed1999

Spinal block levels and cardiovascular changes during post-Cesarean transport.

PURPOSE: Transport after surgery under spinal anesthesia is associated with cardiovascular changes. The extensively vasodilated patient may be unable to compensate for postural blood flow redistribution. This observational study investigated pre- and post-surgery sensory levels as well as hemodynamic changes during the postoperative transfer period. METHODS: One hundred ninety nine women, ASA 1 and 2, undergoing Cesarean section under spinal anesthesia were studied at the end of surgery. Hyperbaric bupivacaine 12-15 mg and morphine 0.25 mg were the agents used. Patients in group A (n = 111) were transferred to the Recovery Room on a stretcher with the upper body flexed 30 degrees head up: patients in group B (n = 88) remained supine during transport. RESULTS: At the end of Cesarean section 95% of patients had upper sensory levels of T4 and higher. In 17.5% the block ascended 2-7 dermatomes compared with the pre-operative level. The incidence of hypotension on arrival in Recovery Room was similar in both groups (group A 10% and group B 9%). CONCLUSION: These results draw attention to the persistence of extensive sympathetic block at the end of Cesarean section. Transport to the Recovery Room was associated with the development of considerable hypotension in 10% of patients and this was unaffected by position. We recommend recording the level of sensory block at the end of surgery and increased monitoring during transport to the Recovery Room.

Adult↗
PubMed1999

Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity.

We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.

Animals↗
PubMed1997

Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins.

Bad, an inducer of programmed cell death, was recently isolated from a mouse cDNA library by its ability to bind to the anti-apoptotic protein BCL-2. Sequence analysis suggested that Bad was a member of the BCL-2 gene family that encodes both inducers and inhibitors of programmed cell death. To further analyze the role of BAD in the network of homo- and heterodimers formed by the BCL-2 family, we have cloned the human homologue of BAD and assessed its biological activity and its interactions with wild type and mutant BCL-2 family proteins. Our results indicate that the human BAD protein, like its mouse homologue, is able to induce apoptosis when transfected into mammalian cells. Furthermore, in yeast two-hybrid assays as well as quantitative in vitro interaction assays, human Bad interacted with BCL-2 and BCL-XL. Sequence alignments of human BAD revealed the presence of a BH-3 homology domain as seen in other BCL-2 family proteins. Peptides derived from this domain were able to completely inhibit the dimerization of BAD with BCL-XL. Thus, as previously shown for BAX, BAK, BCL-2, and BCL-XL, the BH3 domain of BAD is required for its dimerization with other BCL-2 family proteins. BAD was further analyzed for its ability to bind to various mutants of BCL-2 and BCL-XL that have lost the ability to bind BAX and BAK, some of which retain biological activity and some of which do not. Surprisingly, all of the mutated BCL-2 and BCL-XL proteins analyzed strongly interacted with human BAD. Our data thus indicate that mutations in BCL-2 and BCL-XL can differentially affect the heterodimeric binding of different death-promoting proteins and have implications concerning the relationship between heterodimerization and biological activity.

Amino Acid Sequence↗
PubMed1997

Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group.

OBJECTIVES: To monitor incidence of insulin dependent diabetes in children in Oxford health region since 1985, and to look for any evidence of disproportionate increase in children aged under 5. DESIGN: Primary ascertainment of cases of childhood diabetes was by prospective registration of all patients with insulin dependent diabetes diagnosed before age 15 years between 1985 and 1996 and resident in Oxford region at time of diagnosis. This was supplemented by examination of centralised hospital discharge records and death certificates. Secondary case ascertainment was by postal surveys of general practitioners in 1987 and 1996. SETTING: Area formerly administered by Oxford Regional Health Authority. SUBJECTS: 1037 children presenting with insulin dependent diabetes under age of 15 years. MAIN OUTCOME MEASURES: Incidence of insulin dependent diabetes in children aged 0-4, 5-9, and 10-14 years during 1985-95. RESULTS: Overall incidence of diabetes in children aged 0-15 was 18.6 cases/100000/year and showed an annual increase of 4% from 1985 to 1996. This was mainly due to a rapid increase in children aged 0-4 years, in whom there was an annual increase of 11% (95% confidence interval 6% to 15%, P < 0.0001), while the annual increase in those aged 5-9 was 4% (0 to 7%, P = 0.05) and in those aged 10-14 was 1% (-2% to 4%, P = 0.55). CONCLUSIONS: Incidence of insulin dependent diabetes in children aged under 5 years has risen markedly in the Oxford region over the past decade. The cause of the increase is unknown, but environmental influences encountered before birth or in early postnatal life are likely to be responsible.

Adolescent↗
PubMed1997

Structural and functional complementation of an inactive Bcl-2 mutant by Bax truncation.

Interactions among proteins in the Bcl-2 family regulate the onset of programmed cell death. Previous work has shown that the death-inhibiting family members Bcl-2 and Bcl-xL form heterodimers with the death-promoting homologue Bax and that certain site-directed mutants of Bcl-2 and Bcl-xL lose both biological activity and the ability to bind Bax. To better understand the structural basis of heterodimer formation, we have used a yeast two-hybrid assay to screen for mutants of Bax that regain the ability to bind to these inactive Bcl-2(G145A) and Bcl-xL(G138A) mutants. This screen identified a series of C-terminally truncated Bax molecules that contain complete BH3 (Bcl-2 homology domain 3) domains but that have lost BH1 and BH2 sequences. These results indicate that while the Bcl-2 and Bcl-xL mutants fail to bind full-length Bax, they still retain a binding site for the critical BH3 domain. This suggests that conformational constraints in full-length Bax regulate its ability to bind to other Bcl-2 family members. Furthermore, we demonstrate that the normally inert Bcl-2(G145A) mutant effectively blocks apoptosis induced by a C-terminally truncated Bax molecule, but does not block apoptosis induced by wild-type Bax. This demonstrates that cell protection can be effected by directly binding pro-apoptotic members of the Bcl-2 family.

Amino Acid Sequence↗
PubMed1997

A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members.

Bcl-2 inhibits apoptosis induced by a wide variety of stimuli. In contrast, the Bcl-2 homologue, Bax, antagonizes Bcl-2's death protecting function. Bcl-2 forms protein-protein homodimers with itself and heterodimers with Bax, and previous experiments have shown that point mutations in Bcl-2 can abrogate Bax binding while leaving homodimerization intact. These mutagenesis results can be interpreted to suggest that Bcl-2 has separate binding sites that are responsible for homodimer and heterodimer formation. Results from yeast two-hybrid studies have also suggested that homodimerization and heterodimerization reflect distinct modes of interaction. However, using quantitative plate binding assays, we now show that Bax as well as peptides derived from the BH3 domains of Bax and Bak block both Bcl-2/Bax binding and Bcl-2/Bcl-2 binding. Similar assays demonstrate that Bcl-xL can form both homodimers and heterodimers and that these interactions are also inhibited by Bax and the BH3-derived peptides. These results demonstrate that the same binding motifs are responsible for both homodimerization and heterodimerization of Bcl-2 family members.

Amino Acid Sequence↗
PubMed1997

Double-blind comparison of epidural ropivacaine 0.25% and bupivacaine 0.25%, for the relief of childbirth pain.

PURPOSE: To evaluate the efficacy of ropivacaine 0.25% when administered epidurally for relief of labour pain and to compare it with bupivacaine 0.25%. METHODS: In a multicentre investigation, 60 ASA I and II labouring women were randomized in a double-blind fashion to receive either bupivacaine 0.25% or ropivacaine 0.25% administered epidurally by intermittent top-up for labour analgesia. Using a standardized technique, epidural analgesia was initiated after the woman received 10-15 ml-kg.1 crystalloid solution. Maternal blood pressure, heart rate, analgesia sensory level, degree of motor block and visual analogue pain scores were measured by the research nurse prior to, and at regular intervals, following the administration of analgesia. Total dose of local anaesthetic administered, duration of labour, mode of delivery, and maternal and fetal/neonatal side effects were noted. The fetus/neonate was assessed by the research nurse using the fetal heart rate tracing, Apgar scores at delivery and neonatal neurobehavioural assessments at 2 and 24 hr postnatally. Maternal and investigators' satisfaction with the analgesia achieved was assessed after delivery. RESULTS: No differences were found between the two agents in any of the variables studied. CONCLUSION: Ropivacaine 0.25%, when administered epidurally by intermittent top-ups for labour analgesia, was equally efficacious as bupivacaine 0.25%.

Adolescent↗
PubMed1997

Mutational analysis of the interacting cell death regulators CED-9 and CED-4.

The genes ced-3, ced-4 and ced-9 are central components in the cell death pathway of the nematode C. elegans. Ced-9, which functions to inhibit cell death, is homologous to the Bcl-2 family of mammalian anti-apoptotic genes. The ced-3 gene encodes a protein homologous to the caspases, a family of cysteine proteases involved in the execution of programmed cell death. It has recently been demonstrated that CED-4, an inducer of apoptosis for which no mammalian equivalent has been reported, can interact with CED-9 and Bcl-x(L). Here we confirm that CED-9 and CED-4 interact and using a series of deletion mutants, demonstrate that only short N-terminal deletions are tolerated in each molecule without loss-of-interaction. Two loss-of-function point mutations in different regions of CED-4 also lead to a significant loss of interaction suggesting further that the relevant interaction domains are not short linear sequences, but rather, are formed by more complex structural determinants in each molecule. Furthermore, we demonstrate that CED-4 not only interacts with Bcl-x(L) but also with its homologue, Bcl-2, and that the unstructured loop region present in Bcl-x(L) and Bcl-2 can regulate the CED-4 interaction. Lastly, we show that a BH3 peptide that can inhibit Bcl-2 family interactions also inhibits the interaction between Bcl-x(L) and CED-4.

Journal Article↗