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Biomedical subjects

H McDonald

Publications and source records attributed to H McDonald.

At least 19 recordsLinked to original sources
PubMed2006

TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists.

Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.

Administration, Oral↗
PubMed2005

Antibiotics for treating bacterial vaginosis in pregnancy.

BACKGROUND: Bacterial vaginosis is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lactobacillary flora. Bacterial vaginosis during pregnancy has been associated with poor perinatal outcome and, in particular, preterm birth. Identification and treatment may reduce the risk of preterm birth and its consequences. OBJECTIVES: To assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (May 2004). SELECTION CRITERIA: Randomized trials comparing antibiotic treatment with placebo or no treatment, or comparing two or more antibiotic regimens in pregnant women with bacterial vaginosis or intermediate vaginal flora. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials and extracted data independently. We contacted study authors for additional information. MAIN RESULTS: Thirteen trials involving 5300 women were included; all were of good quality. Antibiotic therapy was effective at eradicating bacterial vaginosis during pregnancy (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.19 to 0.24, nine trials of 3895 women). Treatment was not significant in reducing the risk of preterm birth before 37 weeks (OR 0.87, 95% CI 0.74 to 1.03, thirteen trials of 5300 women, and there was significant heterogeneity between trials, p-value 0.002), preterm birth before 34 weeks (OR 1.22, 95% CI 0.67 to 2.19, five trials of 851 women), preterm birth before 32 weeks (OR 1.14, 95% CI 0.76 to 1.70, four trials of 3565 women), or the risk of preterm prelabour rupture of membranes (OR 0.88, 95% CI 0.61 to 1.28, four trials of 2579 women). In women with a previous preterm birth, treatment did not affect the risk of subsequent preterm birth (OR 0.83, 95% CI 0.59 to 1.17, five trials of 622 women, with significant heterogeneity between these trials); however, it may decrease the risk of preterm prelabour rupture of membranes (OR 0.14, 95% CI 0.05 to 0.38, two trials of 114 women, and low birthweight (OR 0.31, 95% CI 0.13 to 0.75, two trials of 114 women). AUTHORS' CONCLUSIONS: Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. However, this review provides little evidence that screening and treating all pregnant women with asymptomatic bacterial vaginosis will prevent preterm birth and its consequences. For women with a previous preterm birth, there is some suggestion that treatment of bacterial vaginosis may reduce the risk of preterm prelabour rupture of membranes and low birthweight.

Anti-Bacterial Agents↗
PubMed2005

Development of a holistic admission assessment: an integrated care pathway for the hospice setting.

This article describes the development of a holistic admission assessment for all inpatients admitted to a 66-bedded hospice, structured in the form of an integrated care pathway (ICP). The need for an improved assessment process was identified by clinical staff, who recognized that the existing assessment was not truly holistic and was dependent on the skills of the assessors. The assessment also lacked appropriate goals and actions. The recently published National Institute for Clinical Excellence (NICE) guidance on Improving Supportive and Palliative Care for Adults with Cancer, has also highlighted key areas for the improvement of patient assessment in specialist palliative care (NICE, 2004). Implementation of the ICP has resulted in a systematic and timely holistic assessment process for patients. The ICP addresses effectively the NICE recommendations for the assessment of specialist palliative care patients.

Critical Pathways↗
PubMed2002

An international study of the interobserver variation between interpretations of vaginal smear criteria of bacterial vaginosis.

An international workshop on vaginal smear-based diagnosis of bacterial vaginosis was organized where 13 investigators scoring 258 slides with smears from vaginal fluid. Interobserver reproducibility of interpretations of Nugent scores, Hay/Ison scores and wet smear scores for the diagnosis of bacterial vaginosis was shown to be high. Detailed analysis of individual scoring results however indicated that basic standards of quality control to ensure robust individual readings of slides must be adhered to.

Bacteriological Techniques↗
PubMed2001

Phosphorylation of the integrin alpha 4 cytoplasmic domain regulates paxillin binding.

alpha4 integrins are essential for embryogenesis, hematopoiesis, inflammation, and immune response possibly because alpha4 integrins have distinct signaling properties from other integrins. Specifically, the alpha4 cytoplasmic domain binds tightly to paxillin, a signaling adaptor protein, leading to increased cell migration and an altered cytoskeletal organization that results in reduced cell spreading. The alpha4 tail contains potential phosphorylation sites clustered in its core paxillin binding region. We now report that the alpha4 tail is phosphorylated in vitro and in vivo. Furthermore, Ser(988) is a major phosphorylation site. Using antibodies specific for Ser(988)-phosphorylated alpha4, we found the stoichiometry of alpha4 phosphorylation varied in different cells. However, >60% of alpha4 was phosphorylated in Jurkat T cells. Phosphorylation at Ser(988) blocked paxillin binding to the alpha4 tail. A phosphorylation-mimicking mutant of alpha4 (alpha4S988D) blocked paxillin binding and reversed the inhibitory effect of alpha4 on cell spreading. Consequently, alpha4 phosphorylation is a biochemical mechanism to modulate paxillin binding to alpha4 integrins with consequent regulation of alpha4 integrin-dependent cellular functions.

Amino Acid Sequence↗
PubMed2001

Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk.

Selective degradation of single subunits of multimeric complexes by the ubiquitin pathway underlies multiple regulatory switches, including those involving cyclins and Cdk inhibitors. The machinery that segregates ubiquitinated proteins from unmodified partners prior to degradation remains undefined. We report that ubiquitinated Sic1 (Ub-Sic1) embedded within inactive S phase cyclin-Cdk (S-Cdk) complexes was rapidly degraded by purified 26S proteasomes, yielding active S-Cdk. Mutant proteasomes that failed to degrade Ub-Sic1 activated S-Cdk only partially in an ATP-dependent manner. Whereas Ub-Sic1 was degraded within approximately 2 min, spontaneous dissociation of Ub-Sic1 from S-Cdk was approximately 200-fold slower. We propose that the 26S proteasome has the intrinsic capability to extract, unfold, and degrade ubiquitinated proteins while releasing bound partners untouched. Activation of S-Cdk reported herein represents a complete reconstitution of the regulatory switch underlying the G1/S transition in budding yeast.

Adenosine Triphosphate↗
PubMed2001

After hospital: working with schools and families to support the long term needs of children with brain injuries.

Medical and rehabilitation systems care for children who sustain brain injuries. Their much needed services, however, are short in comparison with the long term needs of these children and their families. For the most part, it is schools and families who provide the long term supports to help children make the best outcomes and create a better quality of life. Professionals and families who develop collaborative models find that they can more effectively manage services for these children by carefully crafting Individual Education Plans (IEP's). Through the IEP process students' complex needs; the multiple transitions they experience; and their long term needs can be met.

Brain Injuries↗
PubMed2001

Changing practice: modified clean technique for intermittent catheterization.

The purpose of this article is to share an experience of putting research into practice. A review of the literature conducted in 1997 revealed considerable support for the use of clean technique for intermittent catheterization (IC). Based on this support, planning began for a change in practice. According to Lewin's Classical Change Theory (Scott & Rantz, 1994), the first stage in change is unfreezing, when plans were made to ready for the change. Preparing for change included establishing a core group of nurses and clarifying the rationale for changing practice. Once preparation was complete, a 3-month pilot project was initiated. During this stage, termed movement by Lewin, attention was focused on client and nurse education and collection of urinary tract infection data. According to Lewin, the final stage is refreezing. In this stage, the focus was on addressing concerns and issues as these arose. In our experience, changing practice was a complex activity that required careful coordination and planning in order to ensure a successful outcome.

Cross Infection↗
PubMed2000

Interventions for helping patients to follow prescriptions for medications.

BACKGROUND BACKGROUND: Efforts to assist patients with adherence to prescribed, self-administered medications might improve the benefits and efficiency of health care. OBJECTIVES OBJECTIVE: To update an ongoing review summarising the results of randomised controlled trials (RCTs) of interventions to help patients follow prescriptions for medications, focusing on trials that measured both adherence and clinical outcomes. SEARCH STRATEGY: Computerised searches to July 1998 in MEDLINE, CINAHL, The Cochrane Library, International Pharmaceutical Abstracts (IPA), PsychInfo, Sociofile, and HSTAR; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors. SELECTION CRITERIA: Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings. DATA COLLECTION AND ANALYSIS: Information on study design features, interventions and controls, and findings were extracted by one reviewer (PM) and a research assistant and confirmed by two of the other reviewers. The studies were too disparate to warrant meta-analysis. MAIN RESULTS: For short-term treatments, one study, of counselling and written information, showed an effect on adherence and clinical outcome. Ten of 19 interventions for long-term treatments reported in 17 RCTs were associated with improvements in adherence, but only nine interventions led to improvements in treatment outcomes. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, counselling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Two studies showed that telling patients about adverse effects of treatment did not affect their adherence. REVIEWER'S CONCLUSIONS: The full benefits of medications cannot be realised at currently achievable levels of adherence. Current methods of improving adherence for chronic health problems are mostly complex and not very effective. More studies of innovative approaches to assist patients to follow medication prescriptions are needed.

Drug Prescriptions↗
PubMed2000

Interventions for treating bacterial vaginosis in pregnancy.

BACKGROUND: Bacterial vaginosis has been associated with poor perinatal outcome. Since the infections are amenable to treatment, identification during pregnancy and treatment may reduce the risk of preterm birth and its consequences. OBJECTIVES: The objective of this review was to assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. SELECTION CRITERIA: Randomised trials comparing one antibiotic regimen with placebo or no treatment, or which compare two or more alternative antibiotic regimens in pregnant women with bacterial vaginosis. DATA COLLECTION AND ANALYSIS: Trial quality assessments and data extraction were done independently by three reviewers. Study authors were contacted for additional information. MAIN RESULTS: Five trials involving 1504 women were included. These trials were of good quality. Antibiotic therapy was highly effective at eradicating infection during pregnancy as judged by 'test-of-cure' following therapy (odds ratio 0.22, 95% confidence interval 0.17 to 0.27). The effect of treating bacterial vaginosis during pregnancy showed a trend to less births before 37 weeks gestation (odds ratio 0.78, 95% confidence interval 0.60 to 1.02). The prevention of preterm birth less than 37 weeks gestation was most marked in the subgroup of women with a previous preterm birth (odds ratio 0.37, 95% confidence interval 0.23 to 0. 60). REVIEWER'S CONCLUSIONS: The current evidence does not support screening and treating all pregnant women for bacterial vaginosis to prevent preterm birth and its consequences. For women with a history of a previous preterm birth there is some suggestion that detection and treatment of bacterial vaginosis early in pregnancy may prevent a proportion of these women having a further preterm birth. It is not known whether this is associated with an improvement in neonatal well-being.

Anti-Bacterial Agents↗
PubMed1998

Assessment of ocular trauma associated with head and neck injuries.

We reviewed the real and potential ocular problems in all head and neck injuries at a tertiary care and regional trauma center from April of 1994 to March of 1995. Through a retrospective study, 127 charts were reviewed, specifically looking at the mechanism of injury, types of injury, whether there was any ocular trauma noted in the chart, and whether there was a consultation to the ophthalmology department. Forty-one of these patients were seen by an ophthalmologist as the initial consultant for ocular and orbital injuries recognized by the emergency staff. In the 86 remaining patients, signs of potential ocular injury were recorded in the chart in 62 (72%) of these patients, yet an ophthalmology consultation was requested for only 23 of them (37%). This survey reveals the lack of awareness in a regional trauma center of certain ocular and periocular signs that may be indicative of more serious ocular injuries. It is the purpose of this article to highlight these concerns to the various health professionals involved with head and neck trauma patients in the hope that the patients will, in the end, benefit from a more thorough and complete assessment of the potential ocular and periocular injuries.

Adolescent↗
PubMed1995

Structural analysis of the 5' region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di- and trinucleotide polymorphisms.

We have previously cloned and characterized the murine homologue of the Huntington disease (HD) gene and shown that it maps to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16.3. Here we present a detailed comparison of the sequence of the putative promoter and the organization of the 5' genomic region of the murine (Hdh) and human HD genes encompassing the first five exons. We show that in this region these two genes share identical exon boundaries, but have different-size introns. Two dinucleotide (CT) and one trinucleotide intronic polymorphism in Hdh and an intronic CA polymorphism in the HD gene were identified. Comparison of 940-bp sequence 5' to the putative translation start site reveals a highly conserved region (78.8% nucleotide identity) between Hdh and the HD gene from nucleotide -56 to -206 (of Hdh). Neither Hdh nor the HD gene have typical TATA or CCAAT elements, but both show one putative AP2 binding site and numerous potential Sp1 binding sites. The high sequence identity between Hdh and the HD gene for approximately 200 bp 5' to the putative translation start site indicates that these sequences may play a role in regulating expression of the Huntington disease gene.

Animals↗
PubMed1995

Genomic organization of the human alpha-adducin gene and its alternately spliced isoforms.

The cDNA for the human alpha-adducin gene has been cloned, and different alternately spliced forms have been identified. We report the complete genomic organization of the human alpha-adducin gene and these alternately spliced forms. The human alpha-adducin gene, spanning approximately 85 kb, consists of 16 exons ranging in size from 34 to 1892 bp. One of the spliced forms of the human alpha-adducin gene results from alternate use of the 5' splice donor site for exon 10, while another results in a truncated protein following insertion of 34 bp comprising exon 15, followed by a premature stop codon. This alternate spliced form of alpha-adducin is predicted to result in an altered carboxyl terminus that would eliminate a protein kinase and calmodulin binding site. Seven nucleotide substitutions and 4 insertion/deletions were also identified. The 5' region of the human alpha-adducin gene contains one Sp1 site, two AP2 sites, and two CAAT boxes. No TATA box was apparent, consistent with features of a housekeeping gene. We have mapped another cDNA within the first intron of the human alpha-adducin gene, suggesting overlapping genes in this 4p16.3 genomic region.

Alternative Splicing↗
PubMed1994

Murine alpha-L-iduronidase: cDNA isolation and expression.

As an initial step toward the generation of a murine model for mucopolysaccharidosis type I, we have identified and characterized a full-length murine alpha-L-iduronidase cDNA. Expression of the murine cDNA in COS-1 cells results in the production of alpha-L-iduronidase enzyme activity at a level 20-fold higher than that of the endogenous gene. The murine cDNA shows strong homology with the coding region of both the human and the canine homologs with 78 and 75% nucleotide sequence identity, respectively. In contrast to the coding region, significant diversity of sequence exists for the 5' and 3' untranslated regions between the murine and both the human and the canine sequence. The 3' UTR of the murine transcript is 1193 bp in length, as compared to the human (100 bp) and canine (139 bp), and contains a CA dinucleotide repeat not seen in either the human or the canine genes. A portion of the murine iduronidase coding sequence overlaps with sequence reported for the 3' UTR of the murine SAT-1 cDNA. The sequence overlap involves the proposed exon II of murine iduronidase and covers 141 bp of sequence with the transcripts generated in opposite orientation. We report here the characterization of murine alpha-L-iduronidase cDNA and its relationship to SAT-1.

Animals↗
PubMed1994

Irradiated homologous aorta in eyelid reconstruction. Part 1: Technique and animal research.

Reconstruction of full thickness eyelid defects requires the correction of posterior lamella (tarsus, conjunctiva) and anterior lamella (skin, muscle). Various tarsal substitutes--conchal and nasal cartilage, banked sclera, hard palate, irradiated homologous tarsal plates, periosteum, temporalis fascia, and composite grafts from the opposite eyelid--have been used for posterior lamellar replacement over the years. Eyelid-sharing procedures and full thickness flaps have also been described. At times, because of extensive tissue loss, the eyelid reconstruction can be particularly challenging because of the shortage of tissue. We describe a new posterior lamellar technique using irradiated homologous aorta. The experimental surgical procedure in rabbits, the clinical response, and the histological fate of the donor aorta are described in Part 1 followed by our experience with four patients in Part 2.

Animals↗