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Biomedical subjects

M McKenzie

Publications and source records attributed to M McKenzie.

At least 19 recordsLinked to original sources
PubMed2004

Development and initial characterization of xenomitochondrial mice.

Xenomitochondrial mice harboring trans-species mitochondria on a Mus musculus domesticus (MD) nuclear background were produced. We created xenomitochondrial ES cell cybrids by fusing Mus spretus (MS), Mus caroli (MC), Mus dunni (Mdu), or Mus pahari (MP) mitochondrial donor cytoplasts and rhodamine 6-G treated CC9.3.1 or PC4 ES cells. The selected donor backgrounds reflected increasing evolutionary divergence from MD mice and the resultant mitochondrial-nuclear mismatch targeted a graded respiratory chain defect. Homoplasmic (MS, MC, Mdu, and MP) and heteroplasmic (MC) cell lines were injected into MD ova, and liveborn chimeric mice were obtained (MS/MD 18 of 87, MC/MD 6 of 46, Mdu/MD 31 of 140, and MP/MD l of 9 founder chimeras, respectively). Seven MS/MD, 1 MC/MD, and 11 Mdu/MD chimeric founder females were mated with wild-type MD males, and 18 of 19 (95%) were fertile. Of fertile females, only one chimeric MS/MD (1% coat color chimerism) and four chimeric Mdu/MD females (80-90% coat color chimerism) produced homoplasmic offspring with low efficiency (7 of 135; 5%). Four male and three female offspring were homoplasmic for the introduced mitochondrial backgrounds. Three male and one female offspring proved viable. Generation of mouse lines using additional female ES cell lineages is underway. We hypothesize that these mice, when crossbred with neurodegenerative-disease mouse models, will show accelerated age-related neuronal loss, because of their suboptimal capacity for oxidative phosphorylation and putatively increased oxidative stress.

Animals↗
PubMed2003

Radiation induced mucositis: co-ordinating a research agenda.

AIMS: A one-day workshop was hosted by the Symptom Control Committee of the National Cancer Institute of Canada, Clinical Trials Group (NCIC-CTG), in conjunction with the October 2002 annual meeting of the Canadian Association of Radiation Oncologists in Toronto, Ontario. The primary intention of the workshop was to direct the future research agenda of the Symptom Control Committee. Large group presentations were held initially to review the contemporary research issues of four selected areas of interest: fatigue, brain metastasis, bone metastasis and radiation-induced mucositis. Panel members were then charged with the identification of specific research proposals that could be considered for further development. Research questions were to be clinically relevant and currently appropriate. Any additional information needed before the launch of any potential trial was also requested. In this paper, we will review and summarise the outcomes from the radiation-induced mucositis sessions. MATERIALS AND METHODS: Thirty-four participants participated in the large group sessions and contributed to one of four panel discussions on selected supportive care issues relevant to radiation oncologists. RESULTS: Three potential and non-overlapping research questions were identified; two involving mucositis management in patients receiving radical radiation for head and neck cancer, and a third for patients with advanced lung cancer undergoing combined radiation and chemotherapy and at risk for the development of symptomatic oesophagitis. CONCLUSION: The workshop successfully identified three potential research questions. The large group and the smaller panel discussions successfully established consensus on important aspects of future study designs. The current 'standard of care', appropriate experimental treatments, primary outcomes of interest and study population parameters were each important issues that were discussed. The importance of developing meaningful biological assays was reviewed, as was the need to ensure the appropriate storage of biological samples from patients for future study.

Head and Neck Neoplasms↗
PubMed2003

Aftercare attendance and post-treatment functioning of severely substance dependent residential treatment clients.

The present study evaluated the impact of a structured aftercare programme following residential treatment for severe alcohol and/or heroin dependent clients. Over 17 months, 77 participants were recruited to the study and allocated randomly to either a structured aftercare (SA) programme or to unstructured aftercare (UA) of crisis counselling on request. Independent clinicians interviewed participants and collaterals, at 4-month (median) intervals, for 12 months following residential treatment. SA compared to UA was associated with a fourfold increase in aftercare attendance and one-third the rate of uncontrolled principal substance use at follow-up. Participants who attended either type of aftercare relapsed a median of 134 days later than those who attended no aftercare. Overall, 23% of monitored participants remained abstinent throughout, 21% maintained controlled substance use and 56% relapsed, within a median of 36 days following residential treatment. The only significant predictor of days to relapse, controlling for age, was pretreatment use of additional substances. Participants with pretreatment additional substance use relapsed a median of 192 days earlier than those who had used no other substances. The degree of agreement between participant self-reports and collateral reports was fair-to-moderate and moderate among collaterals. Intention-to-treat analyses revealed significant and clinically meaningful reductions in substance use in this sample of severely dependent residential treatment clients. The generalizability of these results is limited because of significant differences in age and presenting substance between the study sample and other clients admitted to the service during the study. This latter group of younger, male, heroin-dependent clients with polydrug use who refuse opioid pharmacotherapy, are more likely to drop out of treatment or relapse early following treatment and continue to present a challenge to treatment services.

Adult↗
PubMed2003

The use of resolvases T4 endonuclease VII and T7 endonuclease I in mutation detection.

Mutation and polymorphism detection is of increasing importance in the field of molecular genetics. This is reflected by the plethora of chemical, enzymatic, and physically based methods of mutation detection. The ideal method would detect mutations in large fragments of DNA and position them to single base-pair (bp) accuracy. Few methods are able to quickly screen kilobase lengths of DNA and position the mutation at the same time. The Enzyme Mismatch Cleavage (EMC) method of mutation detection is able to reliably detect nearly 100% of mutations in DNA fragments as large as 2 kb and position them to within 6 bp. This method exploits the activity of a resolvase enzyme from T4, T4 endonuclease VII, and, more recently, a second bacteriophage resolvase, T7 endonuclease I. The technique uses these enzymes to digest heteroduplex DNA formed by annealing wild-type and mutant DNA. Digestion fragments indicate the presence, and the position, of any mutations. The method is robust and reliable and much faster and cheaper than sequencing. These attributes have resulted in its increasing use in the field of mutation detection.

Algorithms↗
PubMed2002

Whole blood impedance aggregometry for the assessment of platelet function in patients with congestive heart failure (EPCOT Trial).

OBJECTIVE: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of the whole blood aggregometry (WBA) in a random outpatient CHF population. METHODS: Blood samples were obtained for measurement of whole blood aggregation, shear-induced closure time, platelet contractile force, expression of GP IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. RESULTS: Substantial inter-individual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Surprisingly, aspirin use did not affect instrument readings as well. Whole blood aggregometry correlates well with the closure time (r(2)=0.587), and with GP IIb/IIIa expression (r(2)=0.435). Significant but less strong correlation has been observed for the WBA with platelet P-selectin expression (r(2)=0.295), and no correlation was present for the platelet contractile force measures (r(2)=0.030). CONCLUSIONS: Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes, in their platelet characteristics, whole blood impedance aggregometry is indeed capable to serve as a valuable diagnostic tool, and may be successfully used as an established screening device in this population. Ability of the whole blood aggregometry to predict clinical outcomes, or for the monitoring of anti-platelet agents in CHF patients, will be evaluated in the ongoing clinical trials.

Aged↗
PubMed2001

Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy.

PURPOSE: To evaluate efficacy, safety, and quality of life (QOL) changes with epoetin alfa therapy for anemia in patients with nonmyeloid malignancies. PATIENTS AND METHODS: Anemic cancer patients were enrolled onto this prospective, open-label study from 34 centers across Canada. The trial had two cohorts: patients who were and were not receiving chemotherapy during the 16-week study. All patients initially received epoetin alfa 150 IU/kg subcutaneously three times per week. The dose was doubled after 4 weeks for patients who did not experience sufficient response. RESULTS: Of the 183 patients enrolled in the nonchemotherapy cohort, statistically significant and clinically relevant improvements in QOL were observed with epoetin alfa therapy using both the FACT-An questionnaire and linear analog scale assessment. Hemoglobin levels increased significantly (P <.001; mean increase 2.5 g/dL from baseline to end of study) and these increases were positively correlated with improved QOL and change in Eastern Cooperative Oncology Group (ECOG) scores. There was a significant reduction in the percentage of patients who required blood transfusions. The 218 patients in the chemotherapy cohort also experienced significant improvements in QOL, decreased transfusion use, and increased hemoglobin levels that correlated with QOL improvements and change in ECOG scores. Epoetin alfa was well-tolerated in both cohorts. CONCLUSION: Epoetin alfa administered to patients with cancer-related anemia for up to 16 weeks resulted in significantly improved QOL, increased hemoglobin levels, and decreased transfusion use. These benefits were observed in cancer patients who were not receiving chemotherapy as well as those who were.

Aged↗
PubMed2001

AlphaIIb's cytoplasmic domain is not required for ligand-induced clustering of integrin alphaIIbbeta3.

The platelet integrin alphaIIbbeta3 exhibits bidirectional signaling, in that intracellular messengers enable adhesive macromolecules to bind to its ectodomain, while ligation promotes the association of cytoskeletal proteins with its cytoplasmic domains. In order to understand the linkage between these distant regions, we investigated the effects of receptor occupancy on the solution structure of both full-length recombinant alphaIIbbeta3 and alphaIIbDelta991beta3, an integrin truncation mutant which lacks one cytoplasmic domain. Lysates of (35)S-labeled human A549 cells expressing either full-length alphaIIbbeta3 or alphaIIbDelta991beta3 were examined by sucrose density gradient sedimentation followed by immunoprecipitation to determine the distributions of integrin protomers and oligomers. Recombinant alphaIIbbeta3 exhibited a weight-average sedimentation coefficient, S(w)=11.3+/-1.4 S with 73% sedimenting as protomers/dimers (9.1+/-1.0 S) and 27% as oligomers (15.4+/-0.4 S). Truncation mutant alphaIIbDelta991beta3 exhibited a similar pattern with 65% sedimenting as protomers/dimers. Upon ligation with eptifibatide, both full-length alphaIIbbeta3 and alphaIIbDelta991beta3 sedimented mainly at >14 S, indicating 2-3-fold increased oligomerization. Thus we have demonstrated that alphaIIb's cytoplasmic region is not required for integrin clustering, a key event in outside-in signaling.

Cell Line↗
PubMed2001

Differences in length of stay for Hospital in the Home patients: comparing simple clinical coding with medical record review.

AIM: To determine whether the apparently longer length of stay (LOS) reported for patients with cellulitis managed in Hospital in the Home (HITH) compared with those managed as inpatients was correct. METHODS: Data, including LOS, from the Victorian In-patient Minimum Database (VIMD) of all patients with cellulitis managed between July 1998 and June 1999 at a large metropolitan teaching hospital were analysed and compared with a retrospective medical record review of the same patients. RESULTS: In the VIMD data, there were 266 episodes of cellulitis during the study period. However, the medical record review found that six episodes were not separate, but rather a continuation of treatment for the same episode of cellulitis, and that 18 were not episodes of cellulitis, but were pilonidal sinus infections. In the VIMD data set, the mean LOS for patients treated in HITH was generally longer than that for inpatients (7.2 days vs 5.1 days, respectively, P = 0.002). However, in the retrospective medical record review, the LOS for patients treated in HITH was similar to inpatients (7.3 days versus 7.0 days, respectively, P = 0.68). CONCLUSIONS: In contrast to the VIMD data, the medical record review demonstrated that, overall, patients with cellulitis had a similar LOS irrespective of whether they were managed at home or in hospital. This study confirms that caution is required in interpreting the VIMD data, highlights the importance of carefully monitoring the introduction of new treatment modalities and indicates areas for further research.

Analysis of Variance↗
PubMed2001

Prescribing syringes to prevent HIV: a survey of infectious disease and addiction medicine physicians in Rhode Island.

This article describes the assessment of physicians' attitudes and practices regarding prescribing syringes to injection drug users (IDUs). A brief, anonymous, self-administered questionnaire was sent to all Infectious Disease and Addiction Medicine specialists in Rhode Island. Of 49 eligible physicians, 39 responded (response rate 80%). Most (95%) indicated that there is a legitimate medical reason for IDUs to obtain sterile syringes. Many (71%) agreed that they would prescribe syringes to prevent disease in IDUs if it were clearly legal to do so. We can conclude that physician syringe prescription to IDUs may be an acceptable supplement to existing HIV prevention strategies.

Adult↗
PubMed2001

Syringe prescription to prevent HIV infection in Rhode Island: a case study.

Injection drug users (IDUs) are a population at high risk for many diseases, including AIDS, and are clearly in need of medical and substance abuse treatment. Access to sterile syringes is critical for lowering the risk of transmission of HIV and other blood-borne pathogens among IDUs. Previously tried strategies include needle exchange programs and changing laws to allow the legal purchase and possession of syringes. An alternative strategy is to have physicians prescribe syringes to IDUs. To the best of our knowledge, this has previously been tried by only a few physicians in rare situations and never on a programmatic basis. This report describes the genesis of physician's syringe prescription in Rhode Island and some of the lessons learned to date. Because of the illicit nature of drug use, a tremendous amount of mistrust and fear on the part of IDUs often leads to poor interaction with the medical establishment. Prescription of syringes by a physician can serve as a tool for reaching out to a high-risk and often out-of-treatment population of drug users. It is a way for the health care community to tap into drug-using networks and bring those populations into a medical care system.

Adult↗
PubMed2001

Enhancing adherence to HAART: a pilot program of modified directly observed therapy.

Based on the model of directly observed therapy (DOT) for tuberculosis, we implemented an uncontrolled pilot program of modified DOT to increase adherence to HAART. Participants met every weekday with an outreach worker who observed them taking the morning dose of HAART. Thirty-seven patients with a history of poor adherence were enrolled and followed for a mean duration of 10 months. The program was feasible and well accepted by the participants. Self-reported adherence to nonobserved doses improved, and those who remained in the program for a year (n = 18) demonstrated a mean 1.53-log decrease from baseline in plasma HIV RNA level.

Adult↗
PubMed2000

Expression of Rattus norvegicus mtDNA in Mus musculus cells results in multiple respiratory chain defects.

The production of in vitro and in vivo models of mitochondrial DNA (mtDNA) defects is currently limited by a lack of characterized mouse cell mtDNA mutants that may be expected to model human mitochondrial diseases. Here we describe the creation of transmitochondrial mouse (Mus musculus) cells repopulated with mtDNA from different murid species (xenomitochondrial cybrids). The closely related Mus spretus mtDNA is readily maintained when introduced into M. musculus mtDNA-less (rho(0)) cells, and the resulting cybrids have normal oxidative phosphorylation (OXPHOS). When the more distantly related Rattus norvegicus mtDNA is transferred to the mouse nuclear background the mtDNA is replicated, transcribed, and translated efficiently. However, function of several OXPHOS complexes that depend on the coordinated assembly of nuclear and mtDNA-encoded proteins is impaired. Complex I activity in the Rattus xenocybrid was 46% of the control mean; complex III was 37%, and complex IV was 78%. These defects combined to restrict maximal respiration to 12-31% of the control and M. spretus xenocybrids, as measured polarographically using isolated cybrid mitochondria. These defects are distinct to those previously reported for human/primate xenocybrids. It should be possible to produce other mouse xenocybrid constructs with less severe OXPHOS phenotypes, to model human mtDNA diseases.

Animals↗
PubMed2000

Lack of germline CDK6 mutations in familial melanoma.

Germline mutations in genes encoding several components of the retinoblastoma pathway have been linked with inherited predisposition to melanoma. Most commonly, such mutations involve CDKN2A, a cyclin-dependent kinase inhibitor of two kinases, CDK4 and CDK6, which phosphorylate the retinoblastoma protein (pRB) and thereby promote passage through the G1/S cell-cycle restriction point. Less frequently, germline mutations in the CDK4 gene have also been linked with an increased risk of melanoma. Despite the sequence and functional homology between CDK4 and CDK6, the role of germline mutations in CDK6 in melanoma predisposition is unknown. We detected no CDK6 mutations within the p16 (CDKN2A) binding domain in index cases from 60 melanoma-prone kindreds that lacked germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. We conclude that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition.

Amino Acid Sequence↗
PubMed2000

High street prices of syringes correlate with strict syringe possession laws.

The current epidemic of injection drug use in the United States and abroad has precipitated an increase in transmission of infectious diseases, including human immunodeficiency virus (HIV), hepatitis B, hepatitis C, and human T-lymphotrophic virus II (HTLV-II) in injection drug users (IDUs) who share syringes and other injection equipment. Sharing is often due to a lack of available sterile syringes, which is, in part, a result of laws and regulations controlling the purchase and possession of syringes. These laws, in turn, raise the price of questionably sterile black market syringes, inadvertently encouraging the reuse and sharing of syringes. To date, very little information has been gathered on the street price of syringes in different communities. We surveyed 42 needle exchange programs (NEPs) in the United States in July and August 1998 to determine the street prices of syringes. The relationship among local laws regulating syringe possession, the enforcement of those laws, and street syringe prices was examined. There was a strong correlation between the presence of syringe possession laws and higher street syringe price ($2.87 vs. $1.14, p< .01). In areas with syringe possession laws, cost was significantly higher when laws were perceived to be enforced strictly ($3.66 vs. $2.08, p<.01). Street prices for syringes are an easily quantifiable indirect measure of availability of sterile syringes and may reflect syringe sharing and reuse.

Communicable Disease Control↗
PubMed2000

Treating cancer patients. Practical monitoring and management of therapy-related complications.

OBJECTIVE: To review investigation and management of some common long-term complications associated with cancer chemotherapy and radiation therapy. QUALITY OF EVIDENCE: Databases searched using MeSH key words "cancer chemotherapy," "cancer chemotherapy complications," "radiation therapy," and "radiation therapy complications" included Ovid and CANCERLIT. Overall the literature in this area is not strong; treatment guidelines and consensus conferences generally are lacking. Recommendations in this paper are mainly based on the results of individual studies and case reports, as few randomized controlled trials have been performed. Where appropriate, recommendations incorporate results of published treatment guidelines and consensus conferences. MAIN MESSAGE: For most solid tumours, patients should be most frequently monitored during the first 3 years after completing initial treatment for cure. Follow-up monitoring usually incorporates physical examination as well as radiologic and laboratory investigations. Patients should not be lost to follow up once treatment is completed, but monitored regularly, especially while they are at highest risk for disease recurrence. Long-term complications associated with cancer therapy include postsplenectomy sepsis syndrome; central and peripheral nervous system toxicities; ocular complications; thyroid, pituitary, testicular, or ovarian dysfunction; pulmonary toxicity; vascular or lymphatic, gastrointestinal, or osseous complications; genitourinary problems; and possible secondary malignancy. CONCLUSION: Primary care physicians are key to facilitating appropriate follow up of treated cancer patients. To do this, they must be aware of practical aspects of monitoring and management of therapy-related complications.

Antineoplastic Agents↗