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Biomedical subjects

L McCarthy

Publications and source records attributed to L McCarthy.

At least 19 recordsLinked to original sources
PubMed2006

Psychological therapies for people with borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a relatively common personality disorder with a major impact on health services as those affected often present in crisis, often self-harming. OBJECTIVES: To evaluate the effects of psychological interventions for people with borderline personality disorder. SEARCH STRATEGY: We conducted a systematic search of 26 specialist and general bibliographic databases (December 2002) and searched relevant reference lists for further trials. SELECTION CRITERIA: All relevant clinical randomised controlled trials involving psychological treatments for people with BPD. The definition of psychological treatments included behavioural, cognitive-behavioural, psychodynamic and psychoanalytic. DATA COLLECTION AND ANALYSIS: We independently selected, quality assessed and data extracted studies. For binary outcomes we calculated a standard estimation of the risk ratio (RR), its 95% confidence interval (CI), and where possible the number need to help/harm (NNT/H). For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were summated using a weighted mean difference (WMD). MAIN RESULTS: We identified seven studies involving 262 people, and five separate comparisons. Comparing dialectical behaviour therapy (DBT) with treatment as usual studies found no difference for the outcome of still meeting SCID-II criteria for the diagnosis of BPD by six months (n=28, 1 RCT, RR 0.69 CI 0.35 to 1.38) or admission to hospital in previous three months (n=28, 1 RCT, RR 0.77 CI 0.28 to 2.14). Self harm or parasuicide may decrease at 6 to 12 months (n=63, 1 RCT, RR 0.81 CI 0.66 to 0.98, NNT 12 CI 7 to 108). One study detected statistical difference in favour of people receiving DBT compared with those allocated to treatment as usual for average scores of suicidal ideation at 6 months (n=20, MD -15.30 CI -25.46 to -5.14). There was no difference for the outcome of leaving the study early (n=155, 3 RCTs, RR 0.74 CI 0.52 to 1.04). For the outcome of interviewer-assessed alcohol free days, skewed data are reported and tend to favour DBT. When a substance abuse focused DBT was compared with comprehensive validation therapy plus 12-step substance misuse programme no clear differences were found for service outcomes (n=23, 1 RCT, RR imprisoned 1.09 CI 0.64 to 1.87) or leaving the study early (n=23, 1 RCT, RR 7.58 CI 0.44 to 132.08). When dialectical behaviour therapy-oriented treatment is compared with client centred therapy no differences were found for service outcomes (n=24, 1 RCT, RR admitted 0.33 CI 0.08 to 1.33). However, fewer people in the DBT group displayed indicators of parasuicidal behaviour (n=24, RR 0.13 CI 0.02 to 0.85, NNT 2 CI 2 to 11). There were no differences for outcomes of anxiety and depression (n=24, 1 RCT, RR anxiety BAI >/=10 0.60 CI 0.32 to 1.12; RR depression HDRS >/=10 0.43 CI 0.14 to 1.28) but people who received DBT had less general psychiatric severity than those in the control (MD BPRS at 6 months -7.41 CI -13.72 to -1.10). Finally this one relevant study reports skewed data for suicidal ideation with considerably lower scores for people allocated to DBT. When psychoanalytically oriented partial hospitalization was compared with general psychiatric care the former tended to come off best. People who received treatment in a psychoanalytic orientated day hospital were less likely to be admitted into inpatient care when measured at different time points (e.g. n=44, RR admitted to inpatient 24 hour care >18 to 24 months 0.05 CI 0.00 to 0.77, NNT 3 CI 3 to 10) Fewer people in psychoanalytically oriented partial hospitalization needed day hospital intervention in the 18 months after discharge (n=44, 1 RCT, RR 0.04 CI 0.00 to 0.59, NNT 2 CI 2 to 8). More people in the control group took psychotropic medication by the 30 to 36 month follow-up, than those receiving psychoanalytic treatment (n=44, 1 RCT, RR 0.44 CI 0.25 to 0.80, NNT 3 CI 2 to 7). Anxiety and depression scores were generally lower in the psychoanalytically oriented partial hospitalization group (n=44, 1 RCT, RR >/=14 on BDI 0.52 CI 0.34 to 0.80, NNT 3 CI 3 to 6), as are global severity scores. People receiving psychoanalytic care in a day hospital had better social improvement in social adjustment using the SAS-SR at 6 to 12 months compared with people in general psychiatric care (MD -0.70 CI -1.08 to -0.32). Rates of attrition were the same (n=44, 1 RCT, RR leaving the study early 1.00 CI 0.23 to 4.42). AUTHORS' CONCLUSIONS: This review suggests that some of the problems frequently encountered by people with borderline personality disorder may be amenable to talking/behavioural treatments but all therapies remain experimental and the studies are too few and small to inspire full confidence in their results. These findings require replication in larger 'real-world' studies.

Behavior Therapy↗
PubMed2006

Pharmacological interventions for people with borderline personality disorder.

BACKGROUND: Borderline Personality Disorder (BPD) is prevalent (2% in the general population, 20% among psychiatry in-patients) and has a major impact on health facilities as those affected often present in crisis but then make poor use of further attempts to help them. OBJECTIVES: To evaluate the effects of pharmacological interventions for people with borderline personality disorder. SEARCH STRATEGY: We conducted a systematic search of 26 specialist and general bibliographic databases (October 2002) and searched relevant reference lists for further trials. SELECTION CRITERIA: We included all randomised clinical trials comparing any psychoactive drugs with any other treatment for people with borderline personality disorder. DATA COLLECTION AND ANALYSIS: We independently selected, quality assessed and data extracted studies. For binary outcomes we calculated a standard estimation of the risk ratio (RR), its 95% confidence interval (CI), and where possible the number need to help/harm (NNT/H). For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were synthesised using a weighted mean difference (WMD). MAIN RESULTS: We found ten small (total n=554), short, randomised studies involving eight comparisons from which we could extract usable data. Studies comparing antidepressants with placebo were small (total n=79, 2 RCTs) but for ratings of anger fluoxetine may offer some improvement for those on antidepressant therapy over placebo (n=22, 1 RCT, RR anger not improved 0.30 CI 0.10 to 0.85, NNT 2 CI 2 to 9). The one small study investigating the important outcome of attempted suicide found no difference between mianserin and placebo (n=38, 1 RCT, RR 0.82 CI 0.44 to 1.54). Haloperidol may be better than antidepressants for symptoms of hostility and psychotism. There were few differences between MAOIs and placebo except that people given MAOIs were less hostile (n=62, 1 RCT, MD -9.19 CI -16.12 to -2.26). Although some ratings were statistically significant the comparison of MAOIs with antipsychotics did not show convincing differences. Antipsychotics may effect some mental state symptoms more effectively than placebo but results are difficult to interpret clinically and there is little evidence of advantage of one antipsychotic over another. Finally mood stabilisers such as divalporex may help mental state (n=16, 1 RCT, RR no improvement in mental state 0.58 CI 0.36 to 0.94, NNT 3 CI 2 to 17) but data are far from conclusive. AUTHORS' CONCLUSIONS: Pharmacological treatment of people with BPD is not based on good evidence from trials and it is arguable that future use of medication should be from within randomised trials. Current trials suggest that the positive effect of antidepressants, in particular, could be considerable. Well designed, conducted and reported clinically meaningful trials are possible and needed with, perhaps, the question of antidepressant versus placebo being addressed first.

Antidepressive Agents↗
PubMed2005

Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein.

Mice overexpressing mutant alpha-synuclein develop a progressive loss of motor function associated with the accumulation of aggregated alpha-synuclein in neurons of the brainstem. Recent reports suggest that tau pathology might also be associated with Parkinson disease (PD) and aggregation of alpha-synuclein. We now report that mice overexpressing A30P alpha-synuclein develop abnormally phosphorylated tau in parallel with the accumulation of aggregated alpha-synuclein. Enhanced phosphorylation of tau occurs only in symptomatic mice that also harbor abundant aggregated alpha-synuclein. The increased phosphorylation of tau occurs at S396/404 and S202 as shown by immunoblotting and immunocytochemical studies with the antibodies PHF-1 and AT8. Neurons that accumulated alpha-synuclein occurred in the dorsal brainstem and did not show strong colocalization with neurons that showed abnormal tau phosphorylation, which largely occurred in the ventral brainstem. Aggregation of alpha-synuclein and phosphorylation of tau are associated with increased levels of phosphorylated c-jun kinase (JNK), which is a stress kinase known to phosphorylate tau protein. These results suggest that alpha-synuclein pathology can stimulate early pathological changes in tau.

Age Factors↗
PubMed2003

MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion.

The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway has been implicated in the regulation of cellular proliferation. MEK5 expression has been detected in prostate cancer cells, although the significance of the MEK5/ERK5 pathway in human prostate cancer has not been tested. We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters. We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue. Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival. Furthermore, among the patients with high Gleason score of 8-10, MEK5 overexpression has an additional prognostic value in survival. MEK5 transfection experiments confirm its ability to induce proliferation (P < 0.0001), motility (P = 0.0001) and invasion in prostate cancer cells (P = 0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the -670/MMP-9 promoter is upregulated by MEK5 and electromobility shift assay further suggests the involvement of activator protein-I (AP-1), but not the NF-kappa B, binding site in the MMP-9 promoter. Using an AP-1 luciferase construct, activation of MEK5 was confirmed to enhance AP-1 activities up to twofold. Taken together, our results establish MEK5 as a key signalling molecule associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly specific, it represents a potential target of therapy.

Adenocarcinoma↗
PubMed2001

Opioids, opioid receptors, and the immune response.

It is now clear that opioid receptors participate in the function of the cells of the immune system, and evidence suggests that opioids modulate both innate and acquired immune responses. We review literature here which establishes that mu-, kappa-, and delta-opioid compounds alter resistance to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). The nature of the immunomodulatory activity of the opioids has been the subject of a great deal of research over the last ten years. There is increasing evidence that effects of opioids on the immune response are mediated at several levels. Modulation of the inflammatory response appears to be a target of these compounds, including effects on phagocytic activity, as well as the response of cells to various chemoattractant molecules. Moreover, findings from several laboratories have demonstrated the impact of opioid treatment on antibody responses, and the molecular basis for this effect is likely due, at least in part, to the modulation of both cytokine and cytokine receptor expression. Future research should provide a clearer understanding of the cellular and molecular targets of opioid action within the immune system.

Antibodies, Viral↗
PubMed2001

Expression of functional mu-opioid receptors during T cell development.

We have examined the chemotactic responsiveness of thymocytes to selective mu-, kappa-, and delta-opioid agonists. Our results show that developing T cells migrate in response to mu-, but not kappa- or delta-opioids. The mu-opioid response appears to be dependent on the classical mu-opioid receptor (MOR-1) since the chemotactic response is blocked by a selective mu-opioid antagonist, and is absent in thymocytes from MOR-1-deficient mice. Flow cytometric analysis of the mu-opioid responsive cells shows that these cells consist predominantly of highly immature CD4- CD8- T cells. These results represent the first demonstration of the functional expression of mu-opioid receptors by developing T cells.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

Organ donation in children: role of the pediatric intensive care unit.

OBJECTIVES: Children waiting for organ transplants continue to die because of the shortage of available organs. Studies of organ donation in children are scarce. The evaluation of the organ donation experience in a pediatric tertiary care hospital may identify factors that influence actual organ donation rates and lead to strategies to improve pediatric organ donation. DESIGN: Retrospective study. SETTING: Pediatric intensive care unit in a Canadian pediatric referral center. PATIENTS: All children with brain death over an 8-yr period (1990-1997). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 199 children who fulfilled the criteria for brain death, 153 were medically suitable for organ donation. Families were approached for consent to organ donation in 128 (84%) of the 153 suitable cases. Consent was obtained in 63% (81/128) of those asked. Brain death caused by acute neurosurgical lesions was highly correlated to medical suitability and consent. Families identified as ethnic minorities were significantly more likely to refuse. After consent was granted, organs were procured from 63 (78%) of 81 donors, for an average of 3.6 organs transplanted per donor. There was a failure to procure organs in 22% (18/81) of cases after consent had been granted, primarily as a result of cardiocirculatory instability while in the intensive care unit. CONCLUSIONS: Despite an encouraging 63% consent rate for organ donation when families are approached, only 41% of potential donors proceeded to actual donation. Strategies for a prospective pediatric study should focus on mandatory request, multicultural issues, and aggressive postconsent medical management and procurement. The pivotal role of the pediatric intensive care unit practitioner should be emphasized.

Journal Article↗
PubMed2000

Poppies in a wheat field: exploring the lives of rural lesbians.

Many believe that lesbian identity is predicated upon the availability of opportunities in urban life to find information, support, and like others (Bell and Valentine 1995a). Indeed, exploring one's lesbian sense of self often involves identifying with a visible reference group, seeking out social arenas where there are other gays and lesbians, connecting with a local community, and taking part in gay and lesbian oriented activities. For rural residents, these opportunities are mostly unavailable, and the lack of access to information, to a public meeting space, and to connections with other lesbians further hinders the development of social group identity. Given that gay and lesbian identity has as its basis a social reference group, how might rural lesbians develop and sustain their sense of personal and group lesbian identity? With few exceptions (D'Augelli 1989; D'Augelli et al. 1987; Kramer 1995; Krieger 1982) the empirical research conducted on the lives of gays and lesbians has utilized urban and suburban samples. Likewise, research on rural life has omitted the experiences of gay and lesbian residents. Either way, information about rural lesbian life remains mostly uncovered. This pilot study attempts to provide new information about the experiences of rural lesbians. Utilizing focus group interviews, the challenges of sustaining lesbian identity in a rural setting are explored. The data show that for this sample, although rural lesbians initially felt isolated and unsure of how to develop a sense of group identity, the opportunity to connect with a small informal network of friends and acquaintances helped alleviate these problems. Further, because these women have little access to information, public gathering space, or to local gay culture, this network was said to be crucial. Without it, the women feel invisible and isolated, that is, their identity remains unseen.

Adolescent↗
PubMed1999

The adjuvant combination monophosphoryl lipid A and QS21 switches T cell responses induced with a soluble recombinant HIV protein from Th2 to Th1.

The induction of protective immunity with recombinant vaccines is dependent on the identification of adjuvant or delivery systems that can augment immune responses, especially cellular immune responses, to soluble protein antigen. In this study we demonstrate that an adjuvant formulation comprising QS21, a purified form of saponin and 3D-monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS), enhances cellular and humoral immune responses to a recombinant HIV protein. Analysis of cytokine secretion by antigen-specific T-cells from the spleen demonstrated that QS21 augmented Th1 and Th2 responses, whereas addition of 3D-MPL resulted in preferential induction of type 1 T-cells. Furthermore, analysis of the subclass of the IgG antibody in the serum in mice immunized with gp120 with the combined adjuvant formulation confirmed the selective activation of Th1 cells in vivo. 3D-MPL was found to enhance B7-1 expression and IL-12 production by macrophages, which are known to be involved in the LPS-induced enhancement of Th1 responses. Thus 3D-MPL appears to act as an adjuvant, without the toxicity associated with LPS, by controlled and selective potentiating effects on antigen presentation and T-cell activation.

AIDS Vaccines↗
PubMed1998

Characterization of whole genome radiation hybrid mapping resources for non-mammalian vertebrates.

Radiation hybrid panels are already available for genome mapping in human and mouse. In this study we have used two model organisms (chicken and zebrafish) to show that hybrid panels that contain a full complement of the donor genome can be generated by fusion to hamster cells. The quality of the resulting hybrids has been assessed using PCR and FISH. We confirmed the utility of our panels by establishing the percentage of donor DNA present in the hybrids. Our hybrid resources will allow inexpensive gene mapping and we expect that this technology can be transferred to many other species. Such successes are providing the basis for a new era of mapping tools, in the form of whole genome radiation hybrid panels, and are opening new possibilities for systematic genome analysis in the animal genetics community.

Animals↗
PubMed1998

Pertussis toxin potentiates Th1 and Th2 responses to co-injected antigen: adjuvant action is associated with enhanced regulatory cytokine production and expression of the co-stimulatory molecules B7-1, B7-2 and CD28.

Pertussis toxin (PT) is a major virulence factor of Bordetella pertussis which exerts a range of effects on the immune system, including the enhancement of IgE, IgA and IgG production, delayed-type hypersensitivity reactions, and the induction of experimental autoimmune diseases. However, the mechanism by which PT mediates adjuvanticity remains to be defined. In this investigation we have shown that PT can potentiate antigen-specific T cell proliferation and the secretion of IFN-gamma, IL-2, IL-4 and IL-5 when injected with foreign antigens. A chemically detoxified PT and a genetic mutant with substitutions/deletions in the S-1 and B oligomer components that abrogate enzymatic and binding activity displayed no adjuvant properties. In contrast, a non-toxic S-1 mutant devoid of enzymatic activity but still capable of receptor binding retained its adjuvanticity, augmenting the activation of both Th1 and Th2 subpopulations of T cells. In an attempt to address the mechanism of T cell activation, we found that PT stimulated the production of IFN-gamma and IL-2 by naive T cells and IL-1 by macrophages. Therefore potentiation of distinct T cell subpopulations may have resulted in part from the positive influence of IFN-gamma on the development of Th1 cells and the co-stimulatory role of IL-1 for Th2 cells. Furthermore, PT augmented expression of the co-stimulatory molecules B7-1 and B7-2 on macrophages and B cells, and CD28 on T cells, suggesting that the adjuvant effect may also be associated with facilitation of the second signal required for maximal T cell activation. This study demonstrates that the immunopotentiating properties of PT are largely independent of ADP-ribosyltransferase activity, but are dependent on receptor binding activity and appear to involve enhanced activation of T cells.

Adjuvants, Immunologic↗
PubMed1997

A retrospective review of a large cohort of patients undergoing the process of withholding or withdrawal of life support.

OBJECTIVES: To determine the proportion of patients who died as a result of the withdrawal or withholding of life support (WD/WHLS) in the intensive care units (ICUs) of three teaching hospitals and to describe the process involved by determining: a) why the decision was made to withdraw support (WDLS); b) when WDLS took place; and c) how the WDLS process was conducted. DESIGN: Retrospective cohort study. SETTING: Three university-affiliated ICUs. PATIENTS: Four hundred nineteen patients who died in one of three academic, tertiary care ICUs over a 1-yr period. INTERVENTIONS: Retrospective chart review. Data collected included age, gender, admitting diagnoses, comorbid disease, Acute Physiology and Chronic Health Evaluation II score, and mode of death (brain death, death due to withholding of life support, death due to WDLS, or death despite ongoing therapy). For those patients dying due to WDLS, the reason for WDLS, person initiating discussion, timing of WDLS, degree of organ dysfunction, order of withdrawal of life support modalities, and the use of sedatives and analgesics were recorded. MEASUREMENTS AND MAIN RESULTS: Seventy percent of patients died by WD/WHLS and 8.4% were brain dead. Patients undergoing WD/WHLS were older and had a longer length of stay than patients dying from other causes. Poor prognosis was the most common reason given for WDLS, reflected by significant organ dysfunction at the time of WDLS. Future quality of life was a less frequently cited reason. Most patients undergoing WDLS did so early in their ICU stay, although time to WDLS appeared to reflect diagnostic group. Few meetings occurred before WDLS and death occurred soon after initiating WDLS. There was a preference of withdrawing mechanical ventilation last and large amounts of morphine (mean 21 +/- 33 [SD] mg/hr) and benzodiazepines (mean 8.6 +/- 11 mg/hr) were used. Little variability in practice was apparent among the studied ICUs. CONCLUSIONS: Similar to other studies, WD/WHLS was the most common cause of death in academic ICUs and poor patient prognosis was considered the most important factor in deciding on WDLS. However, in contrast to other studies, future quality of life was not as frequently cited a reason for WDLS and larger amounts of morphine were used during WDLS. These discrepancies suggest areas for potential future research.

APACHE↗
PubMed1995

Efficient high-resolution genetic mapping of mouse interspersed repetitive sequence PCR products, toward integrated genetic and physical mapping of the mouse genome.

The ability to carry out high-resolution genetic mapping at high throughput in the mouse is a critical rate-limiting step in the generation of genetically anchored contigs in physical mapping projects and the mapping of genetic loci for complex traits. To address this need, we have developed an efficient, high-resolution, large-scale genome mapping system. This system is based on the identification of polymorphic DNA sites between mouse strains by using interspersed repetitive sequence (IRS) PCR. Individual cloned IRS PCR products are hybridized to a DNA array of IRS PCR products derived from the DNA of individual mice segregating DNA sequences from the two parent strains. Since gel electrophoresis is not required, large numbers of samples can be genotyped in parallel. By using this approach, we have mapped > 450 polymorphic probes with filters containing the DNA of up to 517 backcross mice, potentially allowing resolution of 0.14 centimorgan. This approach also carries the potential for a high degree of efficiency in the integration of physical and genetic maps, since pooled DNAs representing libraries of yeast artificial chromosomes or other physical representations of the mouse genome can be addressed by hybridization of filter representations of the IRS PCR products of such libraries.

Animals↗
PubMed1994

Administration of GM-/G-CSF prior to bone marrow harvest increases collection of CD34+ cells.

This study compares differences in the cellularity and levels of CD34 positive cells in bone marrows from patients treated with G-/GM-CSF prior to harvest and marrows from untreated patients. The average volume of marrow aspirated was 1302mL in the untreated group containing an average of 2.6 x 10(10) nucleated cells, while an average volume of 1147mL of marrow was aspirated from patients treated with GM-/G-CSF prior to harvest which contained an average of 5.6 x 10(10) nucleated cells. Analysis of these marrows by flow cytometry revealed a higher percentage of CD34 positive cells within the lymphoid gate of marrow specimens from patients receiving GM-/G-CSF as compared with their untreated counterparts (21.4% vs. 9.1%). All patients receiving GM-/G-CSF prior to harvest were also given G-CSF subcutaneously (5 micrograms/kg/day) following the infusion of autologous marrow after high dose myelosuppressive chemotherapy and the duration of neutropenia (AGC < 500/mm3) in this group was shortened, an average of 12 days as compared to 24 days in untreated patients. This decreased duration of neutropenia is similar to that reported in patients receiving GM-/G-CSF only after transplantation (Lieschke & Burgess, 1992). Further studies are needed to determine whether the administration of GM-/G-CSF prior to bone marrow harvest is clinically beneficial.

Adult↗
PubMed1993

High resolution cosmid and P1 maps spanning the 14 Mb genome of the fission yeast S. pombe.

Gridded on high density filters, a P1 genomic library of 17-fold coverage and a cosmid library of 8 genome equivalents, both made from S. pombe strain 972h-, were ordered by hybridizing genetic markers and individual clones from the two libraries. Yeast artificial chromosome (YAC) clones covering the entire genome were used to subdivide the libraries, and hybridization of short oligonucleotides and DNA pools made from randomly selected cosmids provided further mapping information. Restriction digests were generated as an independent confirmation of the clone order. The high resolution clone map was aligned to the genetic map and the physical Notl and YAC maps. The usefulness of the various mapping techniques and cloning procedures could be assessed upon the different data sets.

Bacteriophage P1↗