The importance of mindfulness in psychosocial distress and quality of life in dermatology patients.

BACKGROUND: Mindfulness, defined as purposively and nonjudgementally paying attention in the present moment, could be used within psychosocial interventions to reduce the distress associated with social anxiety and avoidance found in many skin conditions. However, little is known about the relationship between naturally occurring levels of mindfulness and distress in dermatology patients. OBJECTIVES: To examine the relationship between mindfulness and psychosocial distress in a dermatological population. It was hypothesized that higher levels of mindfulness would be associated with lower levels of social anxiety, anxiety, depression and skin shame, and with better quality of life. METHODS: Adult dermatology outpatients (n = 120) from one hospital completed items assessing subjective severity, skin shame, fear of negative evaluation, anxiety and depression, quality of life, and levels of mindfulness. RESULTS: Considering depression, 14% reported mild, 5% moderate and 2·5% severe symptoms. For anxiety, 22% reported mild, 23% moderate and 6% severe symptoms. In addition, 33·4% reported clinically significant social anxiety. After controlling for subjective severity, mindfulness explained an additional 19% of the variance in depression, 39% in anxiety, 41% in social anxiety, 13% in skin shame and 6% in dermatological quality of life. One specific facet of mindfulness (acting with awareness) was found to be the most consistent predictor of distress. CONCLUSIONS: The findings indicate that higher levels of mindfulness are associated with lower distress. This suggests that facilitating mindfulness may be helpful in reducing distress in dermatology patients, and the use of mindfulness techniques warrants further investigation.

Mutations in KERA, encoding keratocan, cause cornea plana.

Specialized collagens and small leucine-rich proteoglycans (SLRPs) interact to produce the transparent corneal structure. In cornea plana, the forward convex curvature is flattened, leading to a decrease in refraction. A more severe, recessively inherited form (CNA2; MIM 217300) and a milder, dominantly inherited form (CNA1; MIM 121400) exist. CNA2 is a rare disorder with a worldwide distribution, but a high prevalence in the Finnish population. The gene mutated in CNA2 was assigned by linkage analysis to 12q (refs 4, 5), where there is a cluster of several SLRP genes. We cloned two additional SLRP genes highly expressed in cornea: KERA (encoding keratocan) in 12q and OGN (encoding osteoglycin) in 9q. Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein. Our data establish that mutations in KERA cause CNA2. CNA1 patients had no mutations in these proteoglycan genes.

Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype.

BACKGROUND: Tumours contain hypoxic regions that select for an aggressive cell phenotype; tumour hypoxia induces metastasis-associated genes. Treatment refractory patients with metastatic cancer show increased numbers of circulating tumour cells (CTCs), which are also associated with disease progression. The aim of this study was to examine the as yet unknown relationship between hypoxia and CTCs. METHODS: We generated human MDA-MB-231 orthotopic xenografts and, using a new technology, isolated viable human CTCs from murine blood. The CTCs and parental MDA-MB-231 cells were incubated at 21 and 0.2% (hypoxia) oxygen, respectively. Colony formation was assayed and levels of hypoxia- and anoxia-inducible factors were measured. Xenografts generated from CTCs and parental cells were compared. RESULTS: MDA-MB-231 xenografts used to generate CTCs were hypoxic, expressing hypoxia factors: hypoxia-inducible factor1 alpha (HIF1alpha) and glucose transporter protein type 1 (GLUT1), and anoxia-induced factors: activating transcription factor 3 and 4 (ATF3 and ATF4). Parental MDA-MB-231 cells induced ATF3 in hypoxia, whereas CTCs expressed it constitutively. Asparagine synthetase (ASNS) expression was also higher in CTCs. Hypoxia induced ATF4 and the HIF1alpha target gene apelin in CTCs, but not in parental cells. Hypoxia induced lower levels of carbonic anhydrase IX (CAIX), GLUT1 and BCL2/adenovirus E1B 19-KD protein-interacting protein 3 (BNIP3) proteins in CTCs than in parental cells, supporting an altered hypoxia response. In chronic hypoxia, CTCs demonstrated greater colony formation than parental cells. Xenografts generated from CTCs were larger and heavier, and metastasised faster than MDA-MB-231 xenografts. CONCLUSION: CTCs show an altered hypoxia response and an enhanced aggressive phenotype in vitro and in vivo.

Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ.

Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.

Multifrequency forcing of a Hopf oscillator model of the inner ear.

In response to a sound stimulus, the inner ear emits sounds called otoacoustic emissions. While the exact mechanism for the production of otoacoustic emissions is not known, active motion of individual hair cells is thought to play a role. Two possible sources for otoacoustic emissions, both localized within individual hair cells, include somatic motility and hair bundle motility. Because physiological models of each of these systems are thought to be poised near a Hopf bifurcation, the dynamics of each can be described by the normal form for a system near a Hopf bifurcation. Here we demonstrate that experimental results from three-frequency suppression experiments can be predicted based on the response of an array of noninteracting Hopf oscillators tuned at different frequencies. This supports the idea that active motion of individual hair cells contributes to active processing of sounds in the ear. Interestingly, the model suggests an explanation for differing results recorded in mammals and nonmammals.

Evaluation of three automated nucleic acid amplification systems for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in first-void urine specimens.

A total of 500 first-void urine specimens were tested for the presence of Chlamydia trachomatis and Neisseria gonorrhoeae nucleic acids using ProbeTec ET reagents on a Viper platform (BD Diagnostics, Mississauga, Ontario, Canada), Aptima Combo 2 reagents on a Tigris platform (Gen-Probe, Inc., San Diego, CA), and Abbott RealTime CT/NG reagents on an m2000 platform (Abbott Molecular Diagnostics, Des Plaines, IL). The performance of the three assays for detection of N. gonorrhoeae was comparable, but detection of C. trachomatis by the three assays showed more variation. All three platforms were suitable for the detection of C. trachomatis and N. gonorrhoeae, but additional factors, such as maximum daily specimen throughput, are important in evaluating automated systems for C. trachomatis and N. gonorrhoeae detection in high-volume laboratories.

Informed consent and medical ordeal: a qualitative study.

BACKGROUND: Informed consent is a mainstay of clinical practice, with both moral and legal forces. Material disclosure about extreme treatments, however, is unlikely to convey the full impact of the experience of treatment. Informed consent may be flawed under such circumstances. The aims of this study were to compare expressed satisfaction with pretreatment information to satisfaction after experiencing autologous stem cell transplantation for recurrent lymphoma. METHODS: A qualitative, narrative-based cohort study was conducted in a bone-marrow transplant unit of a teaching hospital at Westmead Hospital, Sydney, Australia. The cohort consisted of 10 transplant recipients and 9 of their nominated lay carers. The outcome measure was satisfaction expressed in narrative interviews at the time of transplantation and 3 months later. We used discourse-analytic techniques to examine the narratives. RESULTS: Both patients and carers expressed high satisfaction with the information given by individual clinicians and by speakers at a formal Information Day held before transplantation. At the first interview, neither patients nor carers commented much on the forthcoming ordeal of chemotherapy and bone marrow ablation, although all patients had undergone previous chemotherapy. At the second interview, the ordeal dominated the narratives and retrospective dissatisfaction with information was common. CONCLUSION: This study suggests that information about treatment theories and protocols can be satisfactorily communicated, but personal experience of suffering defies communication. This finding has serious implications for the practices involved in obtaining informed consent and for the very notion of informed consent.

Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.

Cardiac myxomas are benign mesenchymal tumors that can present as components of the human autosomal dominant disorder Carney complex. Syndromic cardiac myxomas are associated with spotty pigmentation of the skin and endocrinopathy. Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24. We now demonstrate that the PRKAR1alpha gene encoding the R1alpha regulatory subunit of cAMP-dependent protein kinase A (PKA) maps to this chromosome 17q24 locus. Furthermore, we show that PRKAR1alpha frameshift mutations in three unrelated families result in haploinsufficiency of R1alpha and cause Carney complex. We did not detect any truncated R1alpha protein encoded by mutant PRKAR1alpha. Although cardiac tumorigenesis may require a second somatic mutation, DNA and protein analyses of an atrial myxoma resected from a Carney complex patient with a PRKAR1alpha deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1alpha alleles and that wild-type R1alpha protein is stably expressed. However, in this atrial myxoma, we did observe a reversal of the ratio of R1alpha to R2beta regulatory subunit protein, which may contribute to tumorigenesis. Further investigation will elucidate the cell-specific effects of PRKAR1alpha haploinsufficiency on PKA activity and the role of PKA in cardiac growth and differentiation.

Expression of the amplified domain in human neuroblastoma cells.

Screening of a partial cDNA library prepared from the human neuroblastoma cell line BE(2)-C with genomic DNA probes containing sequences representative of the amplified domain of that cell line allowed us to identify cloned transcripts from an active gene within the domain. The gene BE(2)-C-59 is amplified ca. 150-fold and encodes a 3.0- and a 1.5-kilobase RNA transcript, both of which are overproduced in BE(2)-C cells. A survey of a large variety of human tumor cell types indicated that this gene is amplified to varying degrees in all neuroblastoma cell lines and a retinoblastoma cell line that exhibit obvious cytological manifestations of DNA sequence amplification, i.e., homogeneously staining regions and double-minute chromosomes. The BE(2)-C-59 gene is not amplified, however, in other nonrelated tumor types, even those containing amplified DNA. Although the functional significance of this specific gene amplification in neuroblastoma cells remains unknown, an indication that it may relate to the malignant phenotype of these cells follows from the remainder of our data which show that the amplified BE(2)-C-59 gene shares partial homology with both the second and third exons, but not the first exon, of the human c-myc oncogene.

Negative and positive cis-acting elements control the expression of murine alpha 1-protease inhibitor genes.

The alpha 1-protease inhibitor (alpha 1-PI) proteins of mice are encoded by a group of genes whose members are expressed coordinately in a liver-abundant pattern and are regulated primarily at the transcriptional level. To better understand the developmental and tissue-specific regulation of this gene family, one member that is analogous to the human alpha 1-antitrypsin gene was chosen for study. Deletional analysis of the upstream regulatory region of this gene was performed, spanning from -10 kilobases to -80 base pairs relative to the transcriptional start site. Two functional positive cis-acting elements within the 522 bases immediately upstream of the start site for transcription were shown to modulate the level of expression from this promoter when introduced into human or mouse hepatoma cells, and a third region acted as a negative regulatory element in that its deletion resulted in a two- to sixfold increase of expression of a transfected minigene construct. Sequence comparison between the regulatory domains of two mouse alpha 1-PI genes and the human alpha 1-antitrypsin gene showed that the mouse gene contains a novel positive cis-acting element which is absent in human gene and that a specific eight-base-pair difference between species results in a strong positive cis-acting element in the human gene acting as a negative element in the mouse gene. An enhancer located approximately 3,000 base pairs upstream of the major start site for transcription was also identified. This element is position and orientation independent. Several different DNA-protein binding assays were used to demonstrate that each DNA segment with functional significance in transfection assays interacts specifically with proteins found in adult mouse liver nuclei. The major positive-acting element appeared to be specifically recognized by nuclear proteins found only in tissues that express alpha 1-PI, while the negative element binding proteins were ubiquitous. Thus, the distal regulatory domain including bases -3500 to -133 of this murine alpha 1-PI gene family member is more complex than was previously demonstrated. It is composed of a set of at least three additional functional cis-acting regulatory elements besides those which have been mapped by others and has a far upstream enhancer.

Amplification in the auditory periphery: the effect of coupling tuning mechanisms.

A mathematical model describing the coupling between two independent amplification mechanisms in auditory hair cells is proposed and analyzed. Hair cells are cells in the inner ear responsible for translating sound-induced mechanical stimuli into an electrical signal that can then be recorded by the auditory nerve. In nonmammals, two separate mechanisms have been postulated to contribute to the amplification and tuning properties of the hair cells. Models of each of these mechanisms have been shown to be poised near a Hopf bifurcation. Through a weakly nonlinear analysis that assumes weak periodic forcing, weak damping, and weak coupling, the physiologically based models of the two mechanisms are reduced to a system of two coupled amplitude equations describing the resonant response. The predictions that follow from an analysis of the reduced equations, as well as performance benefits due to the coupling of the two mechanisms, are discussed and compared with published experimental auditory nerve data.

'Right' way to 'do' illness? Thinking critically about positive thinking.

Exhortations to 'be positive' accompany many situations in life, either as a general injunction or in difficult situations where people are facing pressure or adversity. It is particularly evident in health care, where positive thinking has become an aspect of the way people are expected to 'do' illness in developed society. Positive thinking is framed both as a moral injunction and as a central belief system. It is thought to help patients cope emotionally with illness and to provide a biological benefit. Yet, the meanings, expectations and outcomes of positive thinking are infrequently questioned and the risks of positive thinking are rarely examined. We outline some of the latter and suggest that health professionals should exercise caution in both 'prescribing' positive thinking and in responding to patients and carers whose belief systems and feelings of obligation rest on it.

p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors.

The p27Kip1 gene codes for a cyclin-dependent kinase inhibitor implicated in G1 arrest by transforming growth factor beta, cell-cell contact, agents that elevate cyclic AMP, and the growth-inhibitory drug rapamycin. p27 binds to and inhibits complexes formed by cyclin E-cdk2, cyclin A-cdk2, and cyclin D-cdk4. The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene. Using a combination of somatic cell hybrid panels and fluorescence in situ hybridization p27Kip1 has been mapped to the short arm of chromosome 12 at the 12p12-12p13.1 boundary, reported to harbor deletions and rearrangements in leukemia and mesotheliomas. In order to assess potential p27Kip1 gene alterations, we have screened a total of 147 human primary solid tumors and found no detectable cancer-specific mutations. These results argue that the often observed loss of antimitogenic transforming growth factor beta responsiveness in human cancer cells is not due to structural defects in p27Kip1.

Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children's Oncology Group study.

Minimal residual disease (MRD) can be detected in the marrows of children undergoing chemotherapy either by flow cytometry or polymerase chain reaction. In this study, we used four-color flow cytometry to detect MRD in 1016 children undergoing therapy on Children's Oncology Group therapeutic protocols for precursor-B-cell ALL. Compliance was excellent, with follow-up samples received at the end of induction on nearly 95% of cases; sensitivity of detection at this time point was at least 1/10,000 in more than 90% of cases. Overall, 28.6% of patients had detectable MRD at the end of induction. Patients with M3 marrows at day 8 were much more likely to be MRD positive (MRD+) than those with M2 or M1 marrows. Different genetically defined groups of patients varied in their prevalence of MRD. Specifically, almost all patients with BCR-ABL had high levels of end-of-induction MRD. Only 8.4% of patients with TEL-AML1 were MRD+>0.01% compared with 20.3% of patients with trisomies of chromosomes 4 and 10. Our results show that MRD correlates with conventional measures of slow early response. However, the high frequency of MRD positivity in favorable trisomy patients suggests that the clinical significance of MRD positivity at the end of induction may not be the same in all patient groups.

The role of protein kinase C in the induction of VCAM-1 expression on human umbilical vein endothelial cells.

The role of protein kinase C (PKC) in interleukin-1 beta- (II-1 beta)-, tumor necrosis factor-alpha- (TNF-alpha)-, and lipopolysaccharide- (LPS)-induced vascular cell adhesion molecule-1 (VCAM-1) expression on human umbilical vein endothelial cells (HUVEC) was studied. PKC inhibition or downregulation diminished VCAM-1 mRNA accumulation and protein expression. Interleukin-1 beta, TNF-alpha, and LPS induce nuclear factor (NF)-kappa B-like binding activity, which precedes VCAM-1 transcription. PKC inhibition did not prevent NF-kappa B-like binding activity, indicating that this is PKC-independent, and NF-kappa B-like binding activity is insufficient for transcription of VCAM-1.

Comparison of the neuropsychological deficits associated with early and advanced Huntington's disease.

Patients with "recently" diagnosed Huntington's Disease (RHD) were compared on a neuropsychological test battery to patients who have had the disease three to 15 years (AHD) and to intact controls. While the patients with HD showed general nonfocal deficits on the Wechsler Adult Intelligence Scale, the Wechsler Memory Scale, and tests of short-term memory and verbal fluency, the patients with RHD had focal deficits that stressed their memory deficits. The patients with RHD had IQs within the normal range, but their memory quotients, their performance on short-term memory tests, and their ability to search and retrieve from long-term memory were severely imparied. These results suggest that the cognitive deficits of patients with HD do not develop uniformally; memory disorders are early focal signs that precede the patients' more widespread intellectual deterioration.

Effects of environmentally encountered epoxides on mouse liver epoxide-metabolizing enzymes.

Male mice were treated (i.p.) for 3 days with 15 different environmentally encountered epoxides, and the effects of these compounds on liver microsomal and cytosolic epoxide hydrolase (mEH and cEH), glutathione S-transferase (mGST and cGST) and carboxylesterase (mCE) activities were determined. The epoxides included the pesticides: heptachlor epoxide, dieldrin, tridiphane, and juvenoid R-20458; the natural products: disparlure, limonin, nomilin, and epoxymethyloleate; the endogenous steroids: lanosterol epoxide, cholesterol-alpha-epoxide, and progesterone epoxide; and the industrial or synthetic epoxides: epichlorohydrin, araldite, trans-stilbene oxide, and 4'-phenylchalcone oxide. The pesticide epoxides were the most effective inducers of liver weight, microsomal protein, and the enzyme activities measured, with mEH and cEH activities towards cis-stilbene oxide (mEHcso and cEHcso), cGST activities towards four of five substrates, and mCE towards clofibrate (mCEclof) and p-nitrophenylacetate (mCEpna) increased following treatment with most of the pesticides. The synthetic epoxides increased some of the same activities, while the natural products, except for increases in cGST activities, and endogenous steroid epoxides were generally not inductive. cEH activity towards trans-stilbene oxide (cEHtso) was increased only following treatment with the peroxisome proliferator, tridiphane, but decreased following treatment with several of the epoxides, while microsomal cholesterol epoxide hydrolase (mEHchol) was increased only moderately by disparlure. Microsomes could effectively conjugate glutathione to chlorodinitrobenzene (mGSTcdnb) and cis-stilbene oxide (mGSTcso). These two activities were differentially induced by a few of the epoxides, suggesting that they may be selective substrates for different isozymes of mGST. Correlation coefficients were determined for the relative response of liver weight, subfraction protein, and enzyme activities. A relatively high correlation was found between the response of liver weight and cytosolic hydrolysis of trans-stilbene oxide (r = 0.73) and cis-stilbene oxide (r = 0.62), and cytosolic glutathione conjugation of dichloronitrobenzene (r = 0.66) and trans-stilbene oxide (r = 0.75). In addition, relatively high correlations were found between the different cGST activities, in particular for dichloronitrobenzene with trans-stilbene oxide (r = 0.89). These studies show that there exists a wide variation in the response of xenobiotic-metabolizing enzymes to environmentally encountered epoxides and that a fairly strong correlation exists between the increases in liver size and increases in certain cytosolic enzyme activities; they also suggest further studies concerning the possibility of an additional isozyme of mGST.