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Biomedical subjects

M A Stanley

Publications and source records attributed to M A Stanley.

At least 37 records · Page 2Linked to original sources
PubMed2000

Anxiety disorders.

Research has only recently begun to address the nature and treatment of anxiety in later life. Prevalence rates suggest that anxiety disorders occur more than twice as frequently as depression among older adults, with the highest rates reported for generalized anxiety disorder and phobias. However, relatively little is known about the psychopathology and treatment of these and other anxiety disorders. In this review, recent clinical advances in this area are summarized. Particular attention is given to the prevalence and nature of late-life anxiety and its overlap with related conditions, psychometric properties of assessment tools for evaluating anxiety in older adults, and treatment outcome literature in both pharmacological and psychosocial domains. Directions for future research are provided throughout and summarized in a final section with the goal of stimulating additional empirical work in the area.

Aged↗
PubMed2000

Cytokine profile of draining lymph node lymphocytes in mice grafted with syngeneic keratinocytes expressing human papillomavirus type 16 E7 protein.

Studies on the immune response to human papillomaviruses are compromised by the extreme host and tissue specificity of these viruses. To circumvent this, a mouse model system has been used in which antigen is presented via a differentiated, syngeneic keratinocyte graft expressing human papillomavirus type 16 (HPV-16) E7 protein. Using this model, previous studies have shown that animals grafted with a high cell inoculum (1x10(7) NEK 16 cells) exhibit a delayed-type hypersensitivity response that is E7-specific and CD4(+)-mediated, but those receiving a low cell inoculum (5x10(5) NEK 16 cells) are rendered unresponsive to subsequent and repeated antigen challenge. To investigate the mechanisms underlying this phenomenon, we have analysed the early changes in the cytokine profile of the graft-draining lymph node (GDLN) after high- or low-dose grafts. At 4 days post-grafting, there was a peak secretion of IL-2 associated with a decreased secretion of IL-4 by gammadelta-TCR(+) cells in the group receiving 1x10(7) NEK 16 cells. At 5 days post-grafting, there was a peak secretion of IL-10 by CD8(+) cells in both the high- and low-dose graft groups compared with controls. In contrast, low dose-grafted animals showed an increase in IL-4 production by CD8(+) cells at this time-point. Low antigen challenge in this model system is associated with the appearance of a CD8(+) population in the GDLN that secretes both IL-4 and IL-10. This population may represent a Tc2 or Ts subset that could induce further unresponsiveness.

Animals↗
PubMed2000

Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts.

Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.

Aminoquinolines↗
PubMed1999

Naturally occurring, nonregressing canine oral papillomavirus infection: host immunity, virus characterization, and experimental infection.

Papillomaviruses occasionally cause severe, nonregressing or recurrent infections in their human and animal hosts. The mechanisms underlying these atypical infections are not known. Canine oral papillomavirus (COPV) typically regresses spontaneously and is an important model of mucosal human papillomavirus infections. A severe, naturally occurring, nonregressing COPV infection provided an opportunity to investigate some aspects of viral pathogenicity and host immunity. In this case, the papillomas proved refractory to surgical and medical treatments, including autogenous vaccination and vaccination with capsid (L1) virus-like particles. High levels of induced anti-L1 antibodies appeared to have no effect on the infection. The papillomas spread to oesophageal mucosa, perioral haired skin, and remote cutaneous sites. Isolation of COPV from the animal and sequencing of several regions of the viral genome showed no differences to the COPV prototype. Experimental infection of beagle dogs with this viral isolate resulted in the uncomplicated development and regression of oral warts within the usual period, indicating that the virus was not an unusual pathogenic variant. These findings support the hypothesis that the recurrent lesions seen in some human papillomavirus infections, such as recurrent laryngeal papillomatosis, are associated with specific defects in host immunity rather than variations in viral pathogenicity.

Animals↗
PubMed1999

Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%.

The mechanism of action of imiquimod 5% cream applied topically to patients with genital warts was evaluated in a double-blind, placebo-controlled study. Imiquimod (16 patients) or placebo (three patients) was applied three times per week for up to 16 weeks. All imiquimod-treated patients had a > or =75% reduction in total wart area while only one of three placebo-treated patients had a similar reduction. Wart biopsies were taken at prestudy, week 6, and end of treatment. Polymerase chain reaction (PCR) for human papillomavirus (HPV) DNA and reverse transcriptase (RT)-PCR for messenger (m)RNAs were used to identify cytokines, cellular markers, viral gene products, and cell cycle markers in these biopsies. Treatment with imiquimod, an immune response modifier, stimulated significant increases in mRNA for interferon (IFN)-alpha, IFN-gamma and 2',5' oligoadenylate synthetase (2',5'-AS) as well as a tendency towards increases in tumor necrosis factor (TNF)-alpha and interleukin-12 p40. Significant increases in mRNA for CD4 and a trend toward increases in CD8 were also observed in imiquimod-treated patients, suggesting activation of a cell mediated immune response. Imiquimod administration was also associated with a significant decrease in viral load as measured by HPV DNA and L1 mRNA. The effects on HPV markers were accompanied by an apparent decrease in mRNA expression for markers of cell proliferation and an increase in mRNA for markers of keratinocyte differentiation and tumor suppressors.

Adolescent↗
PubMed1998

A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod.

Imiquimod, an immune response modifier, has been demonstrated to be safe and effective in the treatment of external genital and perianal warts caused by human papillomavirus (HPV). To identify the molecular mechanism(s) by which condylomata acuminata clear during topical treatment with imiquimod, wart skin biopsies were taken from patients before treatment, at treatment week 6, and at the end of treatment. Tissues were analyzed for HPV DNA and for mRNA of several cytokines and HPV gene products. Wart clearance was associated with evidence of tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Regression of warts was strongly associated with a decrease in HPV DNA and in mRNA expression for both early and late viral proteins. Thus, topical imiquimod treatment of anogenital warts led to significant increases in local production of multiple interferon mRNAs and a significant reduction in virus load as measured by decreases in HPV DNA and mRNA for early HPV proteins.

Administration, Topical↗
PubMed1998

A C-terminal helicase domain of the human papillomavirus E1 protein binds E2 and the DNA polymerase alpha-primase p68 subunit.

The human papillomavirus (HPV) E1 and E2 proteins bind cooperatively to the viral origin of replication (ori), forming an E1-E2-ori complex that is essential for initiation of DNA replication. All other replication proteins, including DNA polymerase alpha-primase (polalpha-primase), are derived from the host cell. We have carried out a detailed analysis of the interactions of HPV type 16 (HPV-16) E1 with E2, ori, and the four polalpha-primase subunits. Deletion analysis showed that a C-terminal region of E1 (amino acids [aa] 432 to 583 or 617) is required for E2 binding. HPV-16 E1 was unable to bind the ori in the absence of E2, but the same C-terminal domain of E1 was sufficient to tether E1 to the ori via E2. Of the polalpha-primase subunits, only p68 bound E1, and binding was competitive with E2. The E1 region required (aa 397 to 583) was the same as that required for E2 binding but additionally contained 34 N-terminal residues. In confirmation of these differences, we found that a monoclonal antibody, mapping adjacent to the N-terminal junction of the p68-binding region, blocked E1-p68 but not E1-E2 binding. Sequence alignments and secondary-structure prediction for HPV-16 E1 and other superfamily 3 (SF3) viral helicases closely parallel the mapping data in suggesting that aa 439 to 623 constitute a discrete helicase domain. Assuming a common nucleoside triphosphate-binding fold, we have generated a structural model of this domain based on the X-ray structures of the hepatitis C virus and Bacillus stearothermophilus (SF2) helicases. The modelling closely matches the deletion analysis in suggesting that this region of E1 is indeed a structural domain, and our results suggest that it is multifunctional and critical to several stages of HPV DNA replication.

Antibodies, Monoclonal↗
PubMed1998

Presence of antibodies to human papillomavirus virus-like particles (VLPs) in 11-13-year-old schoolgirls.

To allow meaningful approaches to vaccine development, it is important to know the extent of exposure to human papillomavirus (HPV) within the general population, and particularly the age at which the at risk population is infected. The humoral response to human papillomavirus is directed largely to conformationally-dependent epitopes on the whole virion. Virus-like particles (VLPs) of HPV types 1, 2, and 16 were produced using a baculovirus expression system, and were used in the intact state as antigen in an indirect ELISA. Anonymised serum samples from a cohort of Edinburgh schoolgirls were tested for the presence of IgG antibodies directed against the VLPs. The reproducibility of the ELISA was assured by repeated testing of control samples, and by testing all samples in duplicate and, where possible, on several occasions. Of 1,192 tested with the HPV16 VLPs, 90 (7.6%) were classified as clearly positive, and a further 87 (7.3%) were positive but close to the cutoff calculated by comparison with a group of consistently negative sera. Antibodies to HPV2 were detected in 37.5% (407/1,139) and antibodies to HPV 1 in 51.9% (558/1,076) of the schoolgirls. Antibodies to both HPV1 and HPV2 were found frequently, being present in 29.7% (295/ 993) of samples tested; 40 samples had antibodies to all three types. The significance of these results is discussed.

Adolescent↗
PubMed1997

Alprazolam-reinforced medication use in outpatients with anxiety.

The reinforcing effects of alprazolam were investigated in 14 patients who had generalized anxiety or panic disorder, but were not current users/abusers of other psychoactive substances. Using a double-blind outpatient choice procedure, color-coded alprazolam (0.5 mg) and placebo capsules were provided to patients for use 'as needed' in the treatment of anxiety symptoms. Comparisons of alprazolam and placebo during a 2 week sampling period in which placebo and alprazolam were available sequentially revealed no significant differences on measures of medication usage or anxiety levels, although alprazolam did increase subjective ratings of drug effects side effects. During a 4 week choice period, alprazolam was strongly preferred over placebo in 11 out of 14 patients indicating that alprazolam functioned as a reinforcer. Medication usage ranged from zero to 4.0 mg alprazolam in a day. Variations in daily medication-use were positively correlated with anxiety level fluctuations for a majority of patients. For a majority of patients, the results indicate that alprazolam functioned as a reinforcer without accompanying signs of abuse or addiction.

Adult↗
PubMed1997

Integration of high-risk human papillomavirus DNA is linked to the down-regulation of class I human leukocyte antigens by steroid hormones in cervical tumor cells.

A crucial event in the malignant progression of cervical intraepithelial neoplasia appears to be the up-regulation of high-risk human papillomavirus (HPV) early gene expression. Steroid hormones have been linked to the progression from premalignant to neoplastic status in HPV positive lesions. This report demonstrates that at physiological levels, the glucocorticoid hormone hydrocortisone consistently down-regulates class I human leukocyte antigen (HLA) surface expression in HPV-positive cervical tumor cells but can up-regulate expression in HPV-negative epithelial tumor lines. Suppression of HLA expression was also seen with progesterone, another steroid hormone. The hydrocortisone-mediated modulation of HLA expression is dependent on integration and transcription of the HPV genome and can be blocked by Ru38486, an antagonist of both glucocorticoid and progesterone receptors, indicating the role of these receptors in mediating HLA suppression. The data suggest that HPV integration events in cervical epithelia correlate with hormone-dependent HLA suppression, possibly contributing to the avoidance of tumor recognition by cytotoxic T cells. These studies imply that clinical use of steroids may be contraindicated in HPV-positive individuals who have early premalignant cervical disease or neoplasia but provide evidence that the antiprogestin Ru38486 may be useful in the management of early stage cervical disease.

Carcinoma↗
PubMed1997

A cellular 65-kDa protein recognizes the negative regulatory element of human papillomavirus late mRNA.

Papillomavirus late gene expression is tightly linked to the differentiation state of the host cell. Levels of late mRNAs are only in part controlled by regulation of the late promoter, other posttranscriptional mechanisms exist that reduce the amount of late mRNA in undifferentiated cells. Previously we described a negative regulatory element (NRE) located upstream of the human papillomavirus type 16 late poly(A) site. We have delineated the NRE to a 79-nt region in which a G+U-rich region was the major determinant of NRE activity. UV-crosslinking assays identified a prominent nuclear protein of 65 kDa as the only factor in close contact with the NRE, and a complex of at least five proteins, including the 65-kDa protein, was enriched on NRE-RNA. Binding of the 65-kDa protein was depleted by preincubation with poly(U) Sepharose in high salt, a property characteristic of the U2 small nuclear ribonucleoprotein auxiliary factor U2AF65 and bacterially expressed U2AF65 exhibited NRE binding. The 65-kDa protein bound to the G+U-rich NRE 3' half which shows homology to the B2P2 sequence a known U2AF65 binding site in the alpha-tropomyosin gene, and the G+U-rich element can be replaced by B2P2 in the binding assay. Treatment of cells with phorbol 12-myristate 13-acetate reduced binding of the 65-kDa protein, induced NRE binding of a cytoplasmic protein, and relieved the NRE block on reporter gene expression.

Base Sequence↗
PubMed1997

Nonclinical panic and suicidality: prevalence and psychopathology.

Recent epidemiological studies have reported an increased risk of suicide in patients with panic disorder, raising the possibility that there may be a unique relationship between panic and suicide. However, other studies, such as large chart reviews, have not found a meaningful increase in suicidal behavior among panic patients, except in these patients with comorbid borderline personality diagnoses. The present study examined nonclinical panickers to explore the specificity of the relationship between panic and suicide. Six hundred and twenty-seven undergraduates were surveyed to assess experiences of panic, suicidal behavior in relation to panic and general levels of pathology. Forty-two percent of the sample had experienced at least one panic attack in the past year, and of those 18% had considered suicide and 2.65% had made a suicide attempt in relation to their panic attacks. In comparison to nonclinical panickers who did not consider suicide, ideating nonclinical panickers had more frequent attacks, considered their attacks to be more severe, and viewed themselves as more fearful and in less control of their attacks. They also endorsed significantly higher levels of pathology across every dimension assessed. Results are discussed in terms of the prevalence of suicidal ideation among nonclinical samples, associated psychopathology, and extrapolation of the findings to clinical samples allowing development of models to understand the relationship between panic and suicide.

Adolescent↗
PubMed1997

Fluvoxamine treatment of trichotillomania.

The present study examined the efficacy of fluvoxamine in the treatment of trichotillomania (TM) and coexistent clinical features. Twenty-one participants with a principal diagnosis of TM were given fluvoxamine in a 12-week open trial. For 13 patients who completed treatment, significant improvement was noted on only a few measures of hair pulling. End-state analyses for the entire group of participants, however, demonstrated significant improvement in measures of distress, duration, control, and resistance. Significant decreases over treatment were also found on measures of coexistent anxiety for both the completer and the entire participant groups; depressive symptoms improved for completers. Conclusions about the effectiveness of fluvoxamine for treatment of TM cannot be drawn, given the uncontrolled nature of the study; however, end-state analyses suggest the potential utility of fluvoxamine in a subset of patients with TM.

Adult↗
PubMed1996

Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: relationship of dysfunction to immortality and neoplasia.

We have previously suggested that a gene mapping to chromosome 9p21 could contribute to replicative senescence and suppress cullular immortality in squamous neoplasia. Two candidate genes, the cyclin D1/cyclindependent kinase inhibitors CDKN2A/p16INK4A (p16) and CDKN2B/p15INK4B (p15) have now been identified in this region and we show here that p16 is upregulated when normal human keratinocytes undergo replicative senescence but not when they undergo differentiation. Furthermore, all of 19 immortal neoplastic keratinocyte head and neck lines, including nine showing loss of heterozygosity (LOH) at 9p21, showed undetectable p16 expression, whereas five of six senscent neoplastic cultures showed normal levels of expression. The retinoblastoma protein (pRb) appeared functional in all the cell lines and cultures examined. The mechanism of p16 inactivation appeared to be transcriptional silencing in 10 of 18 lines and homozygous deletions in the rest. Treatment of two of the immortal cell lines which had transcriptionally silent wild type p16 genes with 5aza-2deoxycytidine resulted in the re-expression of p16, thus implicating DNA methylation as one mechanism of transcriptional silencing in the immortal SCC-HN lines. We observed no cases of p16 point mutation. In contrast, the p15 gene was rarely transcriptionally silent and was not deleted in any of the cell lines which showed p16 deletions. Our results show that p16 dysfunction correlates strongly with keratinocyte immortalisation but less strongly with the stage of tumour progression. P16 dysfunction was not related to the neoplastic state or the length of time spent in vitro. The results also suggest that p16 but not p15 is involved in the keratinocyte replicative senescence programme. However, two neoplastic cell cultures which lacked p16 expression were still mortal, suggesting that the loss of p16 is a necessary but insufficient condition for human keratinocyte immortality.

Animals↗
PubMed1996

Characteristics of generalized anxiety disorder in older adults: a descriptive study.

Despite the prevalence of Generalized Anxiety Disorder (GAD) in older adults, little is known about psychopathological features of excessive worry in the elderly. This investigation compared 44 GAD patients (mean age 67.6), diagnosed using structured interview, with a matched sample free of psychiatric disorders on self-report and clinician measures. Results indicated that GAD in the elderly is associated with elevated anxiety, worry, social fears, and depression. Using self-report measures alone, near-perfect classification of Ss into groups was achieved with four measures (PSWQ, WS-Soc, FQ-Soc, and BDI). Using clinician ratings, near-perfect classification was achieved with Hamilton anxiety ratings. Comparison of GAD patients whose symptoms began in childhood vs middle adulthood revealed few differences on these dimensions. Results are discussed in light of features of GAD in the elderly, highlighting implications for further study.

Aged↗
PubMed1996

Psychometric properties of four anxiety measures in older adults.

Despite relatively high prevalence rates of anxiety disorders in older adults, little attention has been paid to the establishment of psychometrically sound measures for this population. The current study addresses this issue by examining the psychometric properties of four self-report anxiety measures: the Spielberger State-Trait Anxiety Inventory (STAI), Worry Scale (WS), Fear Questionnaire (FQ), and Padua Inventory (PI). Two older adult community subsamples were assessed, one with Generalized Anxiety Disorder (GAD; n = 50) and the other with no anxiety complaints (Normal Controls: NC; n = 94). Descriptive data revealed that mean scores in the GAD sample were similar to those reported in studies of younger GAD patients. Mean scores in the NC sample, however, were lower than those reported in studies of younger control samples. Internal consistency for all measures generally was adequate in both the GAD and NC subsamples, although alpha coefficients for two of the FQ subscales were marginal. Test-retest reliability over a 2-4 week interval (assessed in a subgroup of NC subjects) was mixed, with some measures apparently assessing stable, trait-like dimensions of fear and anxiety, and others estimating more state-like clinical features. Intercorrelations among subscales for all four measures in both the GAD and NC groups generally were high and consistent with findings from prior research. Finally, some support for the convergent validity of the four anxiety measures was obtained, particularly in the NC sample. Results are discussed in terms of the utility of these instruments for future investigations of the psychopathology and treatment of anxiety disorders in the elderly.

Aged↗
PubMed1996

Patterns of change during cognitive behavioral treatment for panic disorder.

The present investigation examined patterns of change in basic features of panic and anxiety during cognitive behavioral treatment for panic disorder. Data were collected in the context of a study comparing the efficacy of cognitive therapy (CT) and relaxation training, both administered without exposure-based treatments of any kind. Thirty-six panic disorder patients completed 10 weeks of either CT or relaxation training. Weekly measures of panic frequency, state and trait anxiety, and associated fears were obtained. Data were examined using both multivariate techniques (which conceptualize change as incremental) and analysis of response slopes (wherein change is conceptualized as continuous). Results indicated that during the first half of treatment, relaxation training led to greater reductions in state and trait anxiety and agoraphobic fear, whereas CT demonstrated a slight advantage on change in panic frequency. During the second half of treatment, CT produced faster reductions in state anxiety and agoraphobic fears. Over the entire treatment course, CT conferred an advantage in rate of change in social fears. The data provide support for the utility of a more process-oriented approach to the examination of treatment effects.

Adult↗