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Biomedical subjects

J McMillan

Publications and source records attributed to J McMillan.

At least 19 recordsLinked to original sources
PubMed2006

Osteoinductivity of demineralized bone matrix in immunocompromised mice and rats is decreased by ovariectomy and restored by estrogen replacement.

The osteoinduction potential of human demineralized bone matrix (DBM) in females with low estrogen (E2) is unknown. Moreover, the osteoinductivity of commercial human DBM is tested in male athymic rats and mice, but DBM performance in these animals may not reflect performance in female animals or provide information on E2's role in the process. To gain insight, human DBM was implanted bilaterally in the gastrocnemius of twenty-four athymic female mice (10 mg/implant) and twenty-four athymic female rats (15 mg/implant). Eight animals in each group were sham-operated (SHAM), ovariectomized (OVX), or ovariectomized with E2-replacement (OVX+E2) via subcutaneous slow release capsules of 17beta-estradiol. OVX and OVX+E2 animals were pair-fed to SHAM animals. Four animals from each group were euthanized at 35 days and four at 56 days. Animal weight, uterine weight, and blood estrogen levels confirmed that pair feeding, ovariectomy, and E2 replacement were successful. Histological sections of implanted tissues were evaluated qualitatively for absence or presence of DBM, ossicle formation, and new bone or cartilage using a previously developed qualitative scoring system (QS) and by histomorphometry to obtain a quantitative assessment of osteoinduction. OVX mice had a small but significant QS decrease at 35 days compared to SHAM mice, confirmed by quantitative measurement of ossicle, marrow space, and new bone areas. The QS in rats was not affected by OVX but histomorphometry showed decreased new bone in OVX rats, which was restored by E2. The QS indicated that the number of new bone sites was not reduced by OVX in rats or mice at 56 days, but the relative amount of new bone v. marrow space was affected and differed with animal species. Residual DBM was less in OVX animals, indicating that DBM resorption was affected. Cartilage was present in rats but not in mice, suggesting that endochondral ossification was slower and indicating that bone graft studies in these species are not necessarily comparable. These results show the importance of E2 in human DBM-induced bone formation and suggest that E2 may be needed for clinical effectiveness in post-menopausal women.

Animals↗
PubMed2006

Sex-specific regulation of growth plate chondrocytes by estrogen is via multiple MAP kinase signaling pathways.

Both male and female rat growth plate cartilage cells possess estrogen receptors (ERs), but 17beta-estradiol (E(2)) activates protein kinase C (PKC) and PKC-dependent biological responses to E(2) only in cells from female animals. PKC signaling can elicit genomic responses via mitogen activated protein kinase (MAPK) and E(2) has been shown to activate ERK MAPK in many cells, suggesting that MAPK may play a role in growth plate chondrocytes as well. We tested if E(2) increases MAPK activity and if so, whether the response is limited to female cells, if it is PKC-dependent, and if the mechanism involves traditional ER pathways. We also determined the contribution of MAPK to the biological response of growth plate chondrocytes and assessed the relative contributions of ERK, p38 and JNK MAPKs. Female rat costochondral cartilage cells were treated with E(2) and MAPK-specific activity determined in cell layer lysates. The mechanism of MAPK activation was determined by treating the cells with E(2) conjugated to bovine serum albumin (E(2)-BSA) to assess if membrane receptors were involved; stereospecificity was determined using 17alpha-estradiol; PKC and phospholipase C (PLC) dependence was determined using specific inhibitors; and the ER agonist diethylstilbestrol, the ER antagonist ICI 182780, and tamoxifen were used to assess the role of traditional ER pathways. E(2) regulation of ERK1/2 MAPK was assessed and the relative roles of ERK1/2, p38 and JNK MAPKs determined using specific inhibitors. E(2) caused a rapid dose-dependent activation of MAPK that was greatest in cells treated for 9 min with 10(-9) M hormone; activity remained elevated for 3 h. E(2)'s effect on MAPK was stereospecific and comparable to that of E(2)-BSA. It was insensitive to DES and ICI 182780, dependent on PKC and PLC, blocked by tamoxifen and it did not require gene transcription or translation. E(2) had no effect on ERK1 or ERK2 mRNA or protein but it caused a rapid phosphorylation of ERK1/2 at 9 min. Inhibition of ERK1/2 and p38 MAPK reduced the stimulatory effects of E(2) on alkaline phosphatase activity and [(35)S]-sulfate incorporation. These results suggest that E(2) regulates MAPK through a sex-specific membrane-mediated mechanism that does not involve cytosolic ERs in a traditional sense and that ERK1/2 and p38 mediate the downstream biological effects of the hormone.

Animals↗
PubMed2006

Submissions from non-existent claimants: the non-identity problem and the law.

Some medical interventions (or indeed omissions) determine the identity of a person. Those interventions or omissions may themselves cause harm, for which a child subsequently sues. Even if they do not themselves cause harm they may result in the birth of a child who subsequently brings a claim for being allowed to exist in the state caused by the intervention. The obvious objection to a claim of either class is that in the absence of the medical intervention or omission of which the claimant complains, the claimant would never have existed at all. This objection arises from what philosophers have called the "non-identity problem". This article examines the attitude that the English courts would be likely to have to such a claim. It concludes that the English law has so far failed to appreciate the significance of the non-identity problem, but will have to grapple with it soon.

Humans↗
PubMed2004

What is a cure and how do we get there?

The absence of adequate treatment for most of the world's 400 000 individuals with haemophilia makes the development of a cure compelling. Advances in the basic molecular sciences over the past 20 years have resulted in the feasibility of curing haemophilia through the application of gene therapy. However, the reality of this therapeutic strategy is highly complex. In addition, challenges to achieving a cure exist beyond the basic scientific hurdles. Thoughtful attention must also be given to a number of interrelated issues, including ethical considerations in patient recruitment, informed consent and geographical variables of global clinical trials. The global inequalities in healthcare mean that the ethics of international medical research, especially when it includes countries where people usually do not receive quality care, become much more complicated. The majority of haemophiliacs lives in developing countries and is a valuable resource of human subjects who could be enrolled in clinical trials. When recruiting subjects globally, investigators must be ever mindful that the patient population is a precious resource, which must be treated with respect and care. This presents a major challenge for investigators engaged in trials of haemophilia gene therapy to ensure that the informed consent process is current and comprehensive, that therapeutic misconceptions are appropriately managed, and that the roles of the researcher and physician are clear. Global clinical gene-therapy trials are an important and appropriate component in the quest to achieve a cure for haemophilia. When trials follow identical internationally accepted standards, a successful outcome can be achieved for trials including developing countries, if country specific cultural and economic aspects are considered.

Clinical Trials as Topic↗
PubMed2004

Challenge studies of human volunteers: ethical issues.

There is a long history of medical research that involves intentionally infecting healthy people in order to study diseases and their treatments. Such research-what might be called "human challenge studies"-are an important strand of much current research-for example, in the development of vaccinations. The many international and national guidelines about the proper conduct of medical research do not specifically address human challenge studies. In this paper we review the guidelines on the risk of harm that healthy volunteers may be exposed to in the course of medical research. We examine the ethical arguments that are implicit or explicit in these guidelines. We then ask whether there is reason for limiting such studies on grounds independent of risk of harm. We conclude that the major ethical concern with challenge studies is that of risk of harm and that the fact that a study is a challenge study is not a wrong in itself.

Ethical Analysis↗
PubMed2002

Calpain 3 gene expression in skeletal muscle is associated with body fat content and measures of insulin resistance.

OBJECTIVE: To investigate whether skeletal muscle gene expression of calpain 3 is related to obesity and insulin resistance. DESIGN: Cross-sectional studies in 27 non-diabetic human subjects and in Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes. MEASUREMENTS: Expression of CAPN3 in skeletal muscle was measured using Taqman fluorogenic PCR. In the human subjects, body composition was assessed by DEXA and insulin sensitivity was measured by euglycemic-hyperinsulinemic clamp. In Psammomys obesus, body composition was determined by carcass analysis, and substrate oxidation rates, physical activity and energy expenditure were measured by whole-body indirect calorimetry. RESULTS: In human subjects, calpain 3 gene expression was negatively correlated with total (P = 0.022) and central abdominal fat mass (P = 0.034), and with blood glucose concentration in non-obese subjects (P = 0.017). In Psammomys obesus, calpain 3 gene expression was negatively correlated with circulating glucose (P = 0.013) and insulin (P = 0.034), and with body fat mass (P = 0.049). Indirect calorimetry revealed associations between calpain 3 gene expression and carbohydrate oxidation (P = 0.009) and energy expenditure (P = 0.013). CONCLUSION/INTERPRETATION: Lower levels of expression of calpain 3 in skeletal muscle were associated with reduced carbohydrate oxidation and elevated circulating glucose and insulin concentrations, and also with increased body fat and in particular abdominal fat. Therefore, reduced expression of calpain 3 in both humans and Psammomys obesus was associated with phenotypes related to obesity and insulin resistance.

Adipose Tissue↗
PubMed2002

Dementia in prison: ethical and legal implications.

As the number of elderly prisoners increases in the UK and other Western countries, there will be individuals who develop dementia whilst in custody. We present two case vignettes of men with dementia in English prisons, and explore some of the ethical implications that their continuing detention raises. We find little to support their detention in the various purposes of prison put forward by legal philosophers and penologists, and conclude by raising some of the possible implications of The Human Rights Act 1998.

Aged↗
PubMed2002

Extracorporeal membrane oxygenation for Legionnaires disease: a case report.

A case of Legionella pneumonia, severe adult respiratory distress syndrome (ARDS) and multiple organ failure is described in a patient who required extracorporeal membrane oxygenation (ECMO) prior to transfer to a hospital with ECMO facilities. She eventually made a good recovery, highlighting the potential benefits of ECMO in patients with severe and refractory ARDS.

Journal Article↗
PubMed2001

Allocating fertility services by medical need.

Infertility services often receive little or no public funding because they are perceived not to meet a medical need. This article argues that it is plausible to think of fertility treatment as a medical need. Medical needs deserve serious consideration in resource allocation. Such needs arise when there is a disruption of normal species function (disease), which results in a limitation of fair equality of opportunity. Fair equality of opportunity is important because it is required for a person's ability to live a good life. Infertility can result in a medical need because it can be a disruption of normal species function and can result in diminished opportunity, which it is highly relevant to the conception of a good life of many people. Infertility services deserve serious consideration in resource allocation.

Female↗
PubMed2001

What did we learn about national organizational collaboration at the advisory committee level?

This article provides an overview of the typical roles and tasks of advisory groups in general, followed by a discussion of the roles and tasks the Interdisciplinary Generalist Curriculum (IGC) Project Advisory Committee was asked to assume and how these were fulfilled. It analyzes the lessons learned about advisory committees as a result of the IGC Project experience. Key elements of success in fulfilling advisory committee obligations include well-defined expectations, periodic evaluations, and clear communication between project leadership and the members of the advisory committee. In the spirit of lessons learned from the IGC Project, this critique identifies several philosophical and logistic issues that might be considered in the design and implementation of future projects, such as the need to choose committed, high-energy advisory committee members who are willing to perform many complex, time-consuming tasks.

Curriculum↗
PubMed2001

Deciding for imperilled newborns: medical authority or parental autonomy?

The ethical issues around decision making on behalf of infants have been illuminated by two empirical research studies carried out in Scotland. In-depth interviews with 176 medical and nursing staff and with 108 parents of babies for whom there was discussion of treatment withholding/withdrawal, generated a wealth of data on both the decision making process and the management of cases. Both staff and parents believe that parents should be involved in treatment limitation decisions on behalf of their babies. However, whilst many doctors and nurses consider the ultimate responsibility too great for families to carry, the majority of parents wish to be the final arbiters. We offer explanations for the differences in perception found in the two groups. The results of these empirical studies provide both aids to ethical reflection and guidance for clinicians dealing with these vulnerable families. They demonstrate the value of empirical data in the philosophical debate.

Asphyxia Neonatorum↗
PubMed2000

A correlational test of the relationship between posttraumatic growth, religion, and cognitive processing.

The present study examined the degree to which event related rumination, a quest orientation to religion, and religious involvement is related to posttraumatic growth. Fifty-four young adults, selected based on prescreening for experience of a traumatic event, completed a measure of event related ruminations, the Quest Scale, an index of religious participation, and the Posttraumatic Growth Inventory. The three subscales of the Quest Scale, the two groups of rumination items (soon after event/within past two weeks), and the index of religious participation were entered in a standard multiple regression with the total score of the Posttraumatic Growth Inventory as the dependent variable. The degree of rumination soon after the event and the degree of openness to religious change were significantly related to Posttraumatic Growth. Congruent with theoretical predictions, more rumination soon after the event, and greater openness to religious change were related to more posttraumatic growth. Present findings offer some confirmation of theoretical predictions, and also offer clear direction for further research on the relationships of religion, rumination, and posttraumatic growth.

Adult↗