Biomedical subjects

M A Stanley

Publications and source records attributed to M A Stanley.

At least 19 recordsLinked to original sources

PubMed2003

Overexpression of Skp2 in carcinoma of the cervix does not correlate inversely with p27 expression.

S-phase kinase associated protein 2 (Skp2) is a member of the F-box family of substrate recognition subunits of SCF-ubiquitin ligase complexes and controls progression from G(1)-S-phase by targeting cell cycle regulators such as p21 and p27. Its locus is at 5p13, a region of frequent amplification in several cancers including carcinoma of the cervix (CaCx). Overexpression of Skp2 has been observed in many cancers of an advanced stage. We examine the expression of Skp2 in 42 invasive CaCx and its correlation with tumour differentiation state and p27 expression. Using immunohistochemistry we found increased nuclear expression of Skp2 in 55% of invasive CaCx cases analysed. It is significant that poorly differentiated tumours invariably exhibit high Skp2 expression (>40% positive nuclei), whereas well-differentiated tumours express Skp2 at a lower level (<20% positive nuclei). Skp2 expression in normal cervical epithelia is <10% (positive nuclei). Increased Skp2 protein levels did not correlate inversely with p27 expression. Our data suggest that Skp2 may contribute to the progression of CaCx, however, unlike non-human papillomavirus (HPV) containing tumours, p27 is unlikely to be the major target protein contributing to malignant progression. The high prevalence of HPV types in CaCx may circumvent the need for Skp2 to eliminate p27.

Cell Cycle↗

PubMed2003

Altered expression of desmosomal components in high-grade squamous intraepithelial lesions of the cervix.

We have used immunohistochemistry to test the hypothesis that components of the desmosome are disrupted during neoplastic progression of squamous epithelial cells in the uterine cervix. Sections of normal cervix and squamous intraepithelial lesions (SILs) were immunostained for desmosomal proteins and glycoproteins, and results were assessed using a semi-quantitative grading system. No difference between normal cervix and low-grade SIL (LSIL) was found. A significant reduction in expression of desmogleins was seen between high-grade SIL (HSIL) and LSIL (P<0.01) and normal cervix (P<0.001). Desmocollin expression was not reduced significantly, although scores showed significantly greater variation in HSIL compared with LSIL (P<0.05) and normal cervix (P<0.05). There was no significant difference in desmoplakin expression among the three groups. The results suggest that there may be sequential disruption of desmosomal function during neoplastic progression of cervical squamous intraepithelial cells, with downregulation of desmogleins during the progression from LSIL to HSIL and loss of desmocollin expression occurring in some cases of established HSIL.

Biomarkers, Tumor↗

PubMed2003

Amplification of chromosome 5p correlates with increased expression of Skp2 in HPV-immortalized keratinocytes.

The oncogenic HPVs immortalize primary genital keratinocytes in vitro and there is evidence that such lines represent suitable models to examine HPV-induced carcinogenesis. Early in vivo studies and more recent CGH analyses have revealed amplification of chromosome 5p in advanced stage carcinoma of the uterine cervix (CaCx). In the present study, a panel of established CaCx-derived cell lines were analysed by M-FISH to identify recurrent karyotypic abnormalities. Amplification of 5p was observed in 11 of 13 CaCx cell lines harbouring HR (high-risk) HPV. The region of 5p undergoing amplification was confirmed using human band-specific paints. The F-box protein Skp2 is present at 5p13 and its protein is present at increased levels in many cancers of an advanced stage. The HPV16-harbouring cell line W12 shows progressive morphological abnormality with in vitro passage, culminating in an invasive phenotype. The expression of Skp2 at different stages of this progression was investigated utilizing Western blot and TaqMan quantitative PCR. At medium to late passage, gain of 5p as an isochromosome was observed. Increased expression of Skp2 and a reduction in the expression of its target p27 correlated with increasing passage in this line.

Cell Cycle Proteins↗

PubMed2002

Affective correlates of trichotillomania.

Affective correlates of hair pulling were investigated in a sample of 44 participants diagnosed with trichotillomania (TM). Participants completed the Hair Pulling Survey on which they rated the intensity of ten different affective states across three different phases of hair pulling (before, during and after). Repeated measures analysis of variance was used to examine the change of emotional experience across the hair pulling cycle. Results indicated significant decreases in boredom, anxiety and tension, and significant increases in guilt relief, sadness and anger across time (p<0.005). The role of co-existent anxiety and mood disorders also was examined using repeated measures analysis of variance. Results of these analyses indicated that patients with and without co-existent disorders differed only on patterns of anger across time, and therefore do not support affective subtypes of TM patients based on co-existent diagnosis. Implications of these findings for conceptualization and treatment of TM are discussed.

Adolescent↗

PubMed2002

Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential.

A central development of the past decade has been in our understanding of the interactions between, and interdependence of, the innate and adaptive immune responses. Innate immunity recognizes 'danger' signals and activates adaptive immunity in a targeted, appropriate and effective response. Dendritic cells and macrophages have a central role in this process, and pharmacological agents that modulate the functions of these cells could have therapeutic value. The imidazoquinolone compounds, of which imiquimod, formulated as Aldara trade mark, is the best characterized to date, are such molecules. Imiquimod and its homologues act by activating macrophages and other cells via binding to cell surface receptors, such as Toll receptor 7, thereby inducing secretion of pro-inflammatory cytokines, predominantly interferon (IFN)-alpha, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12. This locally generated cytokine milieu biases towards a Th1 cell mediated immune response with the generation of cytotoxic effectors, and this has been exploited clinically in the treatment of viral infections (human papillomavirus, herpes simplex virus, molluscum contagiosum) and nonmelanoma skin cancer. Imiquimod has been shown to be significantly more effective than placebo in clearing genital warts, and mechanism of action studies indicate that this is related to the ability to generate proinflammatory cytokines and a Th1 response. Intra-epithelial neoplasms of cutaneous and mucosal surfaces are associated with human papillomavirus infection and there is some evidence that immune response modifiers may have therapeutic value for these lesions. Topical immunotherapy with immunomodulators shows potential for effective and patient-friendly treatment of cutaneous viral infections. These compounds also have adjuvant properties that could significantly enhance conventional vaccine strategies.

Adjuvants, Immunologic↗

PubMed2002

Absence of canine oral papillomavirus DNA following prophylactic L1 particle-mediated immunotherapeutic delivery vaccination.

In the canine oral papillomavirus (COPV) model, following wart regression, COPV DNA was detected by PCR at the challenge site. However, following particle-mediated immunotherapeutic delivery (PMID) of COPV L1 and subsequent challenge, no COPV DNA could be detected. These data support PMID of COPV L1 as a protective vaccine and suggest that PMID of L1 may induce virus clearance.

Administration, Buccal↗

PubMed2001

Detection of viral DNA and E4 protein in basal keratinocytes of experimental canine oral papillomavirus lesions.

We studied experimental canine oral papillomavirus (COPV) infection by in situ hybridization and immunohistochemistry of weekly biopsies. After 4 weeks, viral DNA in rete ridges suggested a keratinocyte stem cell target. Abundant viral DNA was seen in E4-positive cells only. E4 was predominantly cytoplasmic but also nuclear, being concentrated in the nucleoli during wart formation. Infected cells spread laterally along the basal layer and into the parabasal layers, accompanied by E7 transcription and increased mitoses. Most of the lower epithelium was positive for viral DNA, but, in mature warts, higher levels of E4 expression and genome amplification occurred in only sporadic superficial cells. L1 expression was late and in only a subset of E4-positive cells. During regression, viral DNA was less abundant in deep epithelial layers, suggesting downregulation of replication prior to replacement of infected cells from beneath. Detection of viral DNA in post-regression tissue indicated latent infection.

Animals↗

PubMed2001

Regression of canine oral papillomas is associated with infiltration of CD4+ and CD8+ lymphocytes.

Canine oral papillomavirus (COPV) infection is used in vaccine development against mucosal papillomaviruses. The predictable, spontaneous regression of the papillomas makes this an attractive system for analysis of cellular immunity. Immunohistochemical analysis of the timing and phenotype of immune cell infiltration revealed a marked influx of leukocytes during wart regression, including abundant CD4+ and CD8+ cells, with CD4+ cells being most numerous. Comparison of these findings, and those of immunohistochemistry using TCRalphabeta-, TCRgammadelta-, CD1a-, CD1c-, CD11a-, CD11b-, CD11c-, CD18-, CD21-, and CD49d-specific monoclonal antibodies, with previously published work in the human, ox, and rabbit models revealed important differences between these systems. Unlike bovine papillomavirus lesions, those of COPV do not have a significant gamma/delta T-cell infiltrate. Furthermore, COPV lesions had numerous CD4+ cells, unlike cottontail rabbit papillomavirus lesions. The lymphocyte infiltrate in the dog resembled that in human papillomavirus lesions, indicating that COPV is an appropriate model for human papillomavirus immunity.

Animals↗

PubMed2001

Intra-epithelial vaccination with COPV L1 DNA by particle-mediated DNA delivery protects against mucosal challenge with infectious COPV in beagle dogs.

Protection against viral challenge with canine oral papillomavirus (COPV) was achieved by immunisation via particle-mediated DNA delivery (PMDD) of a plasmid encoding the COPV L1 gene to cutaneous and oral mucosal sites in beagle dogs. The initial dose of approximately 9 microg of DNA was followed by two booster doses at 6 week intervals. A similar approach was used to vaccinate a control group of animals with plasmid DNA encoding the Hepatitis B virus S gene. Following challenge at the oral mucosa with COPV all animals vaccinated with the COPV L1 gene were protected against disease. However five of six animals in the control group developed COPV induced papillomas at the oral mucosa. Both cell-mediated lymphoproliferative and humoral antibody responses to the DNA vaccine were observed. Our data indicate that PMDD of plasmid DNA can protect against mucosal challenge with papillomavirus.

Animals↗

PubMed2001

Assessing older adults with generalized anxiety: a replication and extension.

Anxiety is a major health problem for older adults. The cornerstone for further work in this area is research that establishes the psychometric utility of standardized measurement strategies to characterize anxiety in older adults. The goals of the current study were to replicate and extend prior research addressing the psychometric properties of five self-report measures of anxiety in a sample of 57 older adults with generalized anxiety disorder (GAD). Data addressed the descriptive characteristics, internal consistency, test-retest reliability, interrelation of subscales, and convergent and divergent validity of the Penn state worry questionnaire (PSWQ), worry scale (WS), Spielberger state-trait anxiety inventory - Form Y (STAI), and two versions of the fear questionnaire (FQ). Descriptive data generally replicated prior findings, with some increased state and trait anxiety in the current sample. Measures were internally consistent, with evidence that a revised version of the FQ that focuses on severity of fear irrespective of associated avoidance demonstrated greater internal consistency than the original version. Measures of content-specific fears and worries (WS, FQ) were stable over time and demonstrated convergent validity. Evidence of convergent validity also was evident for measures of worry and general anxiety (WS, PSWQ, STAI-Trait), but two of these measures (PSWQ, STAI) were not reliable over time. Only the PSWQ showed evidence of divergent validity with respect to self-report measures of depression.

Aged↗

PubMed2001

One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease.

BACKGROUND: We hypothesized that compared to an educational intervention, a single 2 h session of cognitive behavioural therapy (CBT), with 6-week follow-up, would reduce anxiety and depression, improve physical and mental functioning, and lead to a better quality of life and greater satisfaction with treatment in older patients with chronic obstructive pulmonary disease (COPD). METHODS: Fifty-six subjects were recruited from a large, urban, academically affiliated Veterans Affairs (VA) Hospital, a non-profit private hospital, and a local newspaper, for a single blind randomized controlled clinical trial. One 2 h session of group CBT was designed to reduce symptoms of anxiety, with specific components including relaxation training, cognitive interventions, and graduated practice, followed by homework and weekly calls for 6 weeks. This was compared to a group that received 2 h of COPD education, followed by weekly calls. Pre- and post-intervention subjects in both groups were administered SF-36, Geriatric Depression Scale, Beck Anxiety Inventory, 6 min walk test, and the FEV-1. Following the intervention, both groups completed the Client Satisfaction Questionnaire. RESULTS: When compared with a group that received education about COPD, 2 h CBT group showed decreased depression and anxiety. Contrary to our hypothesis, despite the decrease in depression and anxiety, there was no change in the physical functioning of the patients. CONCLUSIONS: Twenty to 40% of patients with COPD have high levels of anxiety and depression. Our study finds that as little as 2 h of CBT administered in a group setting is able to reduce these anxious and depressive symptoms.

Aged↗

PubMed2001

Psychometric comparability of English- and Spanish-language measures of anxiety and related affective symptoms.

An array of measures of anxiety and related disorders (viz., Albany Panic and Phobia Questionnaire; Anxiety Sensitivity Index; Beck Anxiety Inventory; Beck Depression Inventory-II; Body Sensation Questionnaire; Fear Questionnaire; Padua Inventory; Penn State Worry Questionnaire; Post-Traumatic Stress Disorder Diagnostic Scale; Social Interaction Anxiety Inventory; and Worry Scale) was edited or translated from English into Spanish. Following an extensive edit and translation process, bilingual participants (n = 98) were assessed with the English and Spanish versions of these measures. Coefficient alphas were excellent and comparable across language versions. Means and standard deviations were also comparable across language versions. Evidence of convergent and discriminant validity was found for both language versions. The two language versions of each measure correlated highly with each other. This psychometric comparability adds confidence in using the newly edited or translated Spanish language measures in clinical practice and research.

Adult↗

PubMed2001

Human papillomavirus and cervical carcinogenesis.

Epidemiological studies show that infection with a subset of genital human papillomavirus (HPV) infections is the major risk factor for the subsequent development of cervical cancer. Experimental studies show that that the E6 and E7 genes of these high risk HPVs are oncogenes that deregulate key cell cycle controls. In the normal infectious cycle high level expression of these genes is confined to non-dividing differentiated cells: HPV oncogenesis requires deregulation of viral and cellular genes permitting inappropriate expression of E6 and E7. These are rare events but viral persistence and chronic exposure to steroid hormones increase the probability of this deregulation.

Cell Cycle↗

PubMed2001

Worry content reported by older adults with and without generalized anxiety disorder.

This study investigated worry content in older adults with and without generalized anxiety disorder (GAD). This is an important topic of research, where findings may promote improved recognition and treatment of this disorder in late-life, as well as provide information about the nature of worry across the lifespan. Worry content was compared for 44 older adults diagnosed with GAD and 44 normal control (NC) volunteers matched for age, gender, and ethnicity. Results indicated that older adults with GAD reported a wider variety of worry topics than did NC participants. However, there were no differences in worry content patterns between older adults with and without GAD. These results suggest that pathological worry in later life is not uniquely defined by content, and implications of these findings for assessment and treatment of GAD in older adults are discussed. Worry content reported by older adults also was compared with previously published younger adult worry content data. Age differences in worry content were found in both the clinical and non-clinical groups in patterns that were generally consistent with common age-related developmental changes. Directions for future research of worry across the lifespan are proposed.

Activities of Daily Living↗

PubMed2001

Activation of mitogenic and antimitogenic pathways in cyclically stretched arterial smooth muscle.

Biophysical forces regulate vascular smooth muscle cell (VSMC) physiology and evoke vascular remodeling. Two VSMC autocrine molecules, insulin-like growth factor I (IGF-I) and nitric oxide (NO), are implicated in remodeling attributable to VSMC hyperplasia. We investigated the role of in vitro cyclic stretch on rat VSMC IGF-I, NO, and cellular growth. Cyclic stretch (1 Hz at 120% resting length for 48 h) stimulated VSMC proliferation 2.5-fold vs. unstretched cells and was accompanied by a 1.8-fold increase in VSMC IGF-I secretion. Despite activation of this proliferative pathway, cyclic stretch induced inducible (i) nitric oxide synthase (NOS) expression and a twofold increase in NO secretion, a molecule with documented antiproliferative effects. Cytokine treatment enhanced iNOS expression and NO secretion while inhibiting vascular growth by approximately 50% in static cells. Cytokine treatment of stretched VSMC enhanced NO secretion 2.5-fold while inhibiting growth by approximately 80%. Exogenous IGF-I increased NOS activity 1.5-fold and NO secretion 8.5-fold in static cells. In turn, iNOS inhibition increased IGF-I secretion 1.6-fold and enhanced VSMC growth 1.6-fold in stretched cells. An NO donor (sodium nitroprusside) similarly inhibited VSMC proliferation in static (24%) and stretched (50%) VSMC while also inhibiting IGF-I secretion from stretched cells by approximately 35%. Thus cyclic stretch stimulates mitogenic (IGF-I) and antimitogenic (NO) pathways in VSMC. These two molecules regulate each other's secretory rates, providing tight regulation of VSMC proliferation. These data may have profound implications in understanding vascular growth alterations in vascular injury and hypertension.

Animals↗

PubMed2000

The immunology of animal papillomaviruses.

Papillomaviruses are species- and tissue-specific double-stranded DNA viruses. These viruses cause epithelial tumours in many animals, including man. Typically, the benign warts undergo spontaneous, immune-mediated regression, most likely effected by T-cells (especially CD4, but also CD8 subsets), whereas humoral immunity can prevent new infections. Some papillomavirus infections fail to regress spontaneously and others progress to malignant epithelial tumours. Additionally, the impact of these lesions is greater in immunosuppressed individuals. Many therapies are ineffective, and there is much interest in the potential for immunological intervention in papillomavirus infections of man and animals. Vaccination can be achieved with 'live' virus, formalin-inactivated virus, synthetic virus-like particles, and DNA vaccination. There has been much recent progress in the development of such vaccines for papillomavirus infections in the rabbit, ox and dog. Success in these animal models suggests that similar approaches may prove useful for prophylactic or therapeutic vaccination against the important human papillomaviruses involved in the development of cutaneous and anogenital warts, laryngeal papillomatosis, and cervical cancer.

Animals↗

PubMed2000

Measures of depression in older adults with generalized anxiety disorder: a psychometric evaluation.

Generalized anxiety disorder (GAD) is the most common of the pervasive anxiety disorders among older adults, with lifetime prevalence estimates of 6%. Because of this high prevalence rate, it is important to establish the utility of assessment tools with this population. Preliminary data exist with regard to the use of anxiety measures with older anxious adults; however, no similar information is available for self-report measures of depression in this population. This study examined the psychometric properties of the Beck Depression Inventory (BDI) and the Geriatric Depression Scale (GDS) with a sample of 54 older adults diagnosed with GAD, 22 of whom were diagnosed with a coexistent depressive disorder. Internal consistency, convergent and divergent validity, construct validity, and discriminative validity of the BDI and the GDS were examined. Overall, the results support the reliability and validity of these self-report measures of depressive symptoms in a sample of older anxious adults.

Aged↗

PubMed2000

Generalized anxiety disorder in older adults: examining the relation between clinician severity ratings and patient self-report measures.

Generalized anxiety disorder (GAD) is the most prevalent of the chronic anxiety disorders for older adults. Although a variety of self-report measures are beginning to be utilized to assess anxiety and related symptoms in older adults, there is a paucity of data regarding the convergence of self-report measures with clinician ratings of symptom severity. This situation is problematic in that interpretability of assessment data is limited, as is our broader understanding of the construct of GAD in an older adult population. To address these issues, we examined convergence across assessment modalities among 64 older adults who met diagnostic criteria for GAD. In addition to two Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV) interviews conducted by independent raters, participants completed four self-report measures (Penn State Worry Questionnaire [PSWQ], Worry Scale [WS], State-Trait Anxiety Inventory [STAI], Beck Depression Inventory [BDI]) as part of a more extensive pretreatment assessment battery. Results revealed significant correlations between clinician-rated GAD severity and the BDI, STAI, and PSWQ. Regression analyses indicated that the BDI (r2 = .15) and the PSWQ (r2 = .07) were particularly useful predictors of clinician-rated GAD severity. A comorbid mood disorder, however, was identified as an important mediator of these relations. Specifically, presence of coexistent depression accounted for 17% of the variance in clinician severity ratings (CSR; P < .01), with individuals diagnosed with a comorbid mood disorder receiving higher clinician severity ratings. The only self-report measure that accounted for additional significant variance was the PSWQ (7%). The study highlights the need to address coexistent psychological conditions when examining convergence between assessment modalities, and expands upon the relatively neglected area of anxiety assessment in older individuals. Specifically, the BDI and the PSWQ are identified as particularly useful screening instruments that may be helpful in conceptualizing GAD severity within an older adult population.

Aged↗