Transcriptional profiling and pathway analysis of monosodium iodoacetate-induced experimental osteoarthritis in rats: relevance to human disease.

OBJECTIVE: The objective of this study was to characterize the rat monosodium iodoacetate (MIA)-induced model for osteoarthritis (OA) and determine the translatability of this model to human disease. This was accomplished through pathway, network and system level comparisons of transcriptional profiles generated from animal and human disease cartilage. METHODS: An OA phenotype was induced in rat femorotibial joints following a single injection of 200mug MIA per knee joint for a period of 2 or 4 weeks. Lesion formation in the rat joints was confirmed by histology. Gene expression changes were measured using the Agilent rat whole genome microarrays. Cartilage was harvested from human knees and gene expression changes were measured using the Agilent human arrays. RESULTS: One thousand nine hundred and forty-three oligos were differentially expressed in the MIA model, of these, approximately two-thirds were up-regulated. In contrast, of the 2130 differentially expressed oligos in human disease tissue, approximately two-thirds were down-regulated. This dramatic difference was observed throughout each level of the comparison. The total overlap of genes modulated in the same direction between rat and human was less than 4%. Matrix degradation and inflammatory genes were differentially regulated to a much greater extent in MIA than human disease tissue. CONCLUSION: This study demonstrated, through multiple levels of analysis, that little transcriptional similarity exists between rat MIA and human OA derived cartilage. As disease modulatory activities for potential therapeutic agents often do not translate from animal models to human disease, this and like studies may provide a basis for understanding the discrepancies.

A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history.

BACKGROUND: The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in approximately 10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms. METHODS: Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case-control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification. RESULTS: Ten coding sequence variants were identified, including the K1019X (3055A-->T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055A-->T mutation significantly increased risk for prostate cancer over twofold (Fisher's two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association. CONCLUSIONS: Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA.

Clinical characteristics of African-American men with hereditary prostate cancer: the AAHPC Study.

INTRODUCTION: The African-American Hereditary Prostate Cancer (AAHPC) Study was designed to recruit African-American families fulfilling very stringent criteria of four or more members diagnosed with prostate cancer at a combined age at diagnosis of 65 years or less. This report describes the clinical characteristics of a sample of affected AAHPC family members. METHODS: In all, 92 African-American families were recruited into the study between 1998 and 2002. Complete clinical data including age and PSA at diagnosis, number of affected per family, stage, grade, and primary treatment were available on 154 affected males. Nonparametric Wilcoxon two-sample tests and Fisher's exact test (two-tailed), were performed to compare families with 4-6 and >6 affected males with respect to clinical characteristics. RESULTS: The mean number of affected men per family was 5.5, with a mean age at diagnosis of 61.0 (+/-8.4) years. Age at diagnosis, PSA and Gleason score did not show significant differences between the two groups of families. Based on the Gleason score, 77.2% of affected males had favorable histology. Significantly, there were marked differences between the two groups in the frequency of node-positive disease (P=0.01) and distant metastases (P=0.0001). Radical prostatectomy was the preferred primary therapy for 66.2% of all affected men followed by 20.8% who chose radiation therapy. CONCLUSIONS: Our findings suggest that affected males who carry the highest load of genetic factors are at the highest risk for early dissemination of disease, thus efforts at early diagnosis and aggressive therapeutic approaches may be warranted in these families. Since the primary therapy choices in our study favored definitive treatment (87.0%) when compared to the 1983 and 1995 SEER data in which 28 and 64% received definitive treatment, respectively, it appears that affected African-American men in multiplex families may be demonstrating the reported psycho-social impact of family history on screening practices and treatment decisions for prostate cancer.

Influence of exogenous GnRH on sexual behavior and frozen/thawed semen viability in stallions during the non-breeding season.

Twelve fertile stallions were divided into two groups, either receiving gonadotropin-releasing hormone (GnRH) (n = 6) or Placebo (n = 6). Based on the history of frozen/thawed semen characteristics three stallions within each group were assigned as being "good freezers" [GnRH (+); Placebo (+)] and three stallions were assigned as being "poor freezers" [GnRH (-); Placebo (-)]. The study was performed as a "blinded" investigation and stallions were treated twice daily by an intramuscular injection of 1 ml GnRH (Buserelin), 50 microg) or Placebo. The experiment was divided into three time periods. Period A (pre-treatment) was performed between 16 November and 20 December; Period B (treatment) was performed during 6 weeks between 21 December and 31 January; and Period C (post-treatment) was performed between 1 February and 12 February. Semen was collected every Monday, Wednesday, Friday, and analysed for motion characteristics by the use of a computerized semen analyser, and sperm morphology immediately after collection. The spermatozoa were cryopreserved, stored in liquid nitrogen, and evaluated for motility (computer assisted semen analysis), membrane integrity (carboxyfluoresceine diacetate (CFDA) combined with propidium-iodide (PI), CFDA/PI), viability and sperm morphology (Eosine-Nigrosine, EN), and osmotic reactivity (hypo-osmotic swelling test, HOS) following thawing in a water bath. The viability of spermatozoa was expressed as the difference between pre-freeze and post-thaw values. A libido score of 1-4, the number of mounts on the phantom before ejaculation, and ejaculation latency were used to evaluate the stallions sexual behavior. Effect of treatment was analysed by comparing time intervals within groups as well as comparing groups within time intervals using SAS statistics software. GnRH treatment decreased the number of mounts before ejaculation (GnRH (total): 2.5 +/- 1.14 versus 1.8 +/- 1.06, P < 0.05), and shortened ejaculation latency. Cessation of treatment increased ejaculation latency in the GnRH group (4.7 +/- 4.98 min versus 7.2+/-7.88min, P<0.05). With the exception of libido score all parameters of sexual behavior were superior in the GnRH (+) group compared to the Placebo (-) group during the treatment period (P < 0.05). GnRH administration increased progressive motility (GnRH (+): 30.7 +/- 10.74% versus 38.4 +/- 15.1%, P < 0.05; GnRH (total): 24.9 +/- 11.80% versus 31.9 +/- 14.68%, P < 0.05), membrane intact spermatozoa CFDA/PI (GnRH (-): 16.8 +/- 7.17% versus 26.2 +/- 7.02%, P < 0.05; GnRH (total): 23.1 +/- 12.33% versus 29.5 +/- 10.77%, P < 0.05) and HOS positive spermatozoa (GnRH (+): 33.2 +/- 11.29% versus 42.2 +/- 10.36%, P < 0.05; GnRH (total): 32.9 +/- 10.23% versus 40.1 +/- 10.30%, P < 0.05) of frozen/thawed spermatozoa. Following cessation of treatment, the viability of frozen/thawed spermatozoa decreased. GnRH treated stallions had lower losses of live stained spermatozoa (EN) compared to the Placebo group (GnRH (total): 17.6 +/- 4.77 versus Placebo (total): 27.2 +/- 5.44, P < 0.05). This was particularly observed in the "poor freezer" group (GnRH (-): 16.6 +/- 4.35 versus Placebo (-): 31.3 +/- 5.87; P < 0.05). In conclusion, exogenous GnRH was shown to improve sexual behavior and increase the quality of frozen/thawed spermatozoa in fertile stallions during the non-breeding season. Nevertheless, it seems that, although significance was achieved relative to improvement to post-thaw sperm quality, that the "real" change in sperm quality seems negligible in fertile stallions. The mechanism of GnRH effect was not determined but this study may support the possibility of a direct gonadal or epididymal effect of exogenous GnRH in the stallion.

Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for prostate cancer risk.

While studies have implicated alleles at the CAG and GGC trinucleotide repeats of the androgen receptor gene with high-grade, aggressive prostate cancer disease, little is known about the normal range of variation for these two loci, which are separated by about 1.1 kb. More importantly, few data exist on the extent of linkage disequilibrium (LD) between the two loci in different human populations. Here we present data on CAG and GGC allelic variation and LD in six diverse populations. Alleles at the CAG and GGC repeat loci of the androgen receptor were typed in over 1000 chromosomes from Africa, Asia, and North America. Levels of linkage disequilibrium between the two loci were compared between populations. Haplotype variation and diversity were estimated for each population. Our results reveal that populations of African descent possess significantly shorter alleles for the two loci than non-African populations (P<0.0001). Allelic diversity for both markers was higher among African Americans than any other population, including indigenous Africans from Sierra Leone and Nigeria. Analysis of molecular variance revealed that approx. 20% of CAG and GGC repeat variance could be attributed to differences between the populations. All non-African populations possessed the same common haplotype while the three populations of African descent possessed three divergent common haplotypes. Significant LD was observed in our sample of healthy African Americans. The LD observed in the African American population may be due to several reasons; recent migration of African Americans from diverse rural communities following urbanization, recurrent gene flow from diverse West African populations, and admixture with European Americans. This study represents the largest genotyping effort to be performed on the two androgen receptor trinucleotide repeat loci in diverse human populations.

Problem behaviour, caregiver reactions, and impact among caregivers of persons with Alzheimer's disease.

BACKGROUND: Problem behaviours that occur during Alzheimer's disease (AD) can have major impact on caregivers. How caregivers react to these behaviours may determine the total impact experienced from caregiving. PURPOSE: This study examined the relationships between problematic behaviours and caregiving impact in 30 primary caregivers of persons with AD. The first question explored the relationship between frequency of problem behaviour and impact; the second explored the relationship between caregiver reactions to problem behaviours and impact from caregiving. METHODS: The frequency of problem behaviour and the caregiver reaction was measured using The Revised Memory and Behaviour Problem Checklist (Teri et al. 1992). The impact from caregiving was operationalized using the Cost of Care Index developed by Kosberg and Cairl (1986). RESULTS: Significant associations were found for 11 of the 20 subscales that measured the association between the frequency of problem behaviour in the client and the impact from caregiving experienced by the caregiver. In comparison, the association between caregiver's reaction to problem behaviours and impact from caregiving was even more significant in value with 15 subscales of 20 being significant. Female caregivers experienced a greater reaction to disruptive and depressive behaviour when compared with male caregivers even though both genders reported similar frequencies of problem behaviours. In regard to findings about the impact from caregiving, four of the six indicators were higher for women than for men. CONCLUSIONS: Caregiver reaction to problem behaviours was more highly associated with impact from caregiving than the actual frequency of the behaviours. These findings have great implications for intervention programs. Caregivers, especially females, need to receive individualized, specific education/training on how to understand and manage disruptive and depressive behaviour in persons with AD.

Psychosocial stress and prostate cancer: a theoretical model.

African-American men are more likely to develop and die from prostate cancer than are European-American men; yet, factors responsible for the racial disparity in incidence and mortality have not been elucidated. Socioeconomic disadvantage is more prevalent among African-American than among European-American men. Socioeconomic disadvantage can lead to psychosocial stress and may be linked to negative lifestyle behaviors. Regardless of socioeconomic position, African-American men routinely experience racism-induced stress. We propose a theoretical framework for an association between psychosocial stress and prostate cancer. Within the context of history and culture, we further propose that psychosocial stress may partially explain the variable incidence of prostate cancer between these diverse groups. Psychosocial stress may negatively impact the immune system leaving the individual susceptible to malignancies. Behavioral responses to psychosocial stress are amenable to change. If psychosocial stress is found to negatively impact prostate cancer risk, interventions may be designed to modify reactions to environmental demands.

The debate about prostate cancer screening: what nurses need to know.

OBJECTIVES: Special challenges and unique opportunities for nurses in the 21st century related to prostate cancer screening are reviewed. DATA SOURCES: Current health care literature pertaining to prostate cancer screening issues. CONCLUSIONS: Decisions that weigh the immediate risks of incontinence and erectile dysfunction against the long-term potential risk of death from advanced cancer must be made with conflicting values and incomplete data. IMPLICATIONS FOR NURSING PRACTICE: With their expertise in patient education nurses are in a unique position to communicate the risks and benefits of prostate cancer screening in a manner in which patients can understand. A sample nursing care plan is presented for shared decision making.

Perceived health status in African American and Caucasian men 40 to 70 years old.

There is limited data on the relationship between perceived health status and the demographic variables of education and income in African American men. A sample of 2,001 men (72% African Americans and 28% Caucasians) who were participating in prostate cancer screening was studied to identify predictors of men's health status. Data on the concepts of self-rated health status, age, race, education, income, living arrangements, and marital status were collected. Findings indicated that men who were more likely to report excellent health status were older Caucasians, had more than a high school education, an annual income over 25,021 dollars, were living with others, and were married. Men more likely to report fair health status were older African Americans, unmarried, had less than a high school education, had an annual income less than 9,600 dollars, were living alone, and were unmarried. Implications for targeting at-risk men are presented.

African-American heredity prostate cancer study: a model for genetic research.

A genome-wide scan of high-risk prostate cancer families in North America has demonstrated linkage of a particular marker to Chromosome 1q (HPC1). An even greater proportion of African-American families have shown linkage to HPC1. Therefore, investigators at the National Human Genome Research Institute (NHGRI) in collaboration with Howard University and a predominantly African-American group of urologists established the African-American Hereditary Prostate Cancer (AAHPC) Study Network to confirm the suggested linkage of HPC in African Americans with a gene on Chromosome 1. Blood samples from recruited families were sent to Howard University for extraction of DNA. The DNA was sent to NHGRI at NIH where the genotyping and genetic sequence analysis was conducted. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage. From March 1, 1998, to June 1, 1999, a total of 40 African-American families have been recruited who met the study criteria. Preliminary results suggest that racial/ethnicity grouping may affect the incidence and extent of linkage of prostate cancer to specific loci. The importance of these findings lays in the future treatment of genetic-based diseases.

African-American heredity prostate cancer study: a model for genetic research.

A genome-wide scan of high-risk prostate cancer families in North America has demonstrated linkage of a particular marker to Chromosome Iq (HPC11. An even greater proportion of African-American families have shown linkage to HPC 1. Therefore, investigators at the National Human Genome Research Institute [NHGRI] in collaboration with Howard University and a predominantly African-American group of urologists established the African-American Hereditary Prostate Cancer (AAHPC) Study Network to confirm the suggested linkage of HPC in African Americans with a gene on Chromosome 1. Blood samples from recruited families were sent to Howard University for extraction of DNA. The DNA was sent to NHGRI at NIH where the genotyping and genetic sequence analysis was conducted. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage. From March 1, 1998, to June 1, 1999, a total of 40 African-American families have been recruited who met the study criteria. Preliminary results suggest that racial/ethnicity grouping may affect the incidence and extent of linkage of prostate cancer to specific loci. The importance of these findings lays in the future treatment of genetic-based diseases.

Obstacles to prostate cancer screening in African-American men.

The purpose of this correlational study was to measure structural obstacles to a free prostate cancer screening. The sample consisted of 549 men, 69% who were African-American. The men attended a prostate cancer educational program and were offered free prostate cancer screening at their physician of choice. Structural obstacles that were predictors in screening participation were "making an appointment" (p = 0.02), "planning for an appointment" (p = 0.05), and "reminders of prostate cancer screening" (p = 0.02). The demographic variables of race and marital status were also predictors of screening participation. Implications for health education are given.

Localization of telomerase hTERT protein and hTR in benign mucosa, dysplasia, and squamous cell carcinoma of the cervix.

Telomerase has been detected by telomerase repeat amplification protocol (TRAP) assay in cervical dysplasia and squamous cell carcinoma but not in most normal cervical tissues. In the present study, the cellular localization of the protein catalytic subunit of telomerase (hTERT) and the RNA component (hTR) were investigated by a sensitive immunohistochemical technique and by in situ hybridization, respectively. hTERT protein was detected in all diagnostic categories of cervical specimens. hTERT was localized predominantly to the lower suprabasal levels of normal squamous mucosa but was detected throughout virtually all levels of the lesional epithelium in low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and squamous cell carcinoma (SCC). Telomerase expression correlated with hTERT detection in SCC and HSIL but was not detected by TRAP assay in most samples of normal mucosa or LSIL. The distribution of hTR correlated with the localization of hTERT in HSIL and SCC but was restricted to the basal and suprabasal cell layers in normal mucosa and LSIL.

Immunohistochemical localization of telomerase hTERT protein and analysis of clonality in multifocal vulvar intraepithelial neoplasia.

Vulvar intraepithelial neoplasias (VINs) are potentially premalignant lesions of the squamous mucosa. The immunohistochemical distribution of the catalytic protein subunit of telomerase (hTERT) and the patterns of X chromosome inactivation were investigated as markers of neoplasia in samples from a patient with multifocal and diffuse VIN. hTERT nuclear staining in VIN correlated with squamous maturation and the degree of nuclear atypia. Normal mucosa revealed faint nuclear staining of parabasal cells and lower intermediate layer squamous cells. Monoclonal composition was demonstrated in 0 of 3 samples of VIN1, 2 of 3 samples of VIN2, and 13 of 13 samples of VIN3. The patterns of X chromosome inactivation indicated intramucosal extension and multifocal origin of individual lesions. Five samples of histologically normal vulvar squamous epithelium revealed a random pattern of X chromosome inactivation, consistent with polyclonal composition. All 19 samples from 9 lesions contained human papillomavirus (HPV)-16 sequences. Neither mutations in the p53 tumor suppressor gene or K-ras oncogenes nor loss of heterozygosity at 7 chromosomal loci were detected in any of the 19 samples of VIN. These results demonstrate that HPV-associated VIN may result from multifocal and diffuse 2-dimensional intraepithelial expansion of an immortalized monoclonal cell population.

Barriers to prostate cancer screening.

The revised prostate cancer screening guidelines of the American Cancer Society recommend that men be informed of the risks associated with prostate cancer screening. However, there are no published studies on men's fear of impotence and its impact on prostate cancer screening. In addition, little is known about barriers to prostate cancer screening when the two main barriers of cost and lack of knowledge are eliminated. This study reports the association between barriers and free prostate cancer screening after a prostate cancer education program. All men were called 1 month after a prostate cancer education program and asked: "What would (or did) make it hard for you to get your prostate checkup done?" A total postbarrier score was created to measure how many barriers each man indicated. The following barriers were significant in predicting participation in prostate cancer screening: "put it off," "doctor hours not convenient," "didn't know kind of doctor," "didn't know where to go," and "refuse to go." Fear of impotence was not a significant barrier. Suggestions for reducing barriers to prostate cancer screening are given.

The effects of foot reflexology on anxiety and pain in patients with breast and lung cancer.

PURPOSE/OBJECTIVES: To test the effects of foot reflexology on anxiety and pain in patients with breast and lung cancer. DESIGN: Quasi-experimental, pre/post, crossover. SETTING: A medical/oncology unit in a 314-bed hospital in the southeastern United States. SAMPLE: Twenty-three inpatients with breast or lung cancer. The majority of the sample were female, Caucasian, and 65 years or older; had 12 or fewer years of education and an annual income of $20,000 or more; and were receiving regularly scheduled opioids and adjuvant medications on the control and intervention day. METHODS: Procedures included an intervention condition (foot reflexology to both feet for 30 minutes total by a certified reflexologist) and a control condition for each patient (with at least a two-day break). No changes were made in patients' regular schedule or medications. MAIN RESEARCH VARIABLES: Anxiety and pain. FINDINGS: Following the foot reflexology intervention, patients with breast and lung cancer experienced a significant decrease in anxiety. One of three pain measures showed that patients with breast cancer experienced a significant decrease in pain. CONCLUSIONS: The significant decrease in anxiety observed in this sample of patients with breast and lung cancer following foot reflexology suggests that this may be a self-care approach to decrease anxiety in this patient population. IMPLICATIONS FOR NURSING PRACTICE: Professionals and lay people can be taught reflexology. Foot reflexology is an avenue for human touch, can be performed anywhere, requires no special equipment, is noninvasive, and does not interfere with patients' privacy.

Recruitment experience in the first phase of the African American Hereditary Prostate Cancer (AAHPC) study.

The African American Hereditary Prostate Cancer (AAHPC) Study is an ongoing multicenter genetic linkage study organized by Howard University and the National Human Genome Research Institute (NHGRI), with support from the Office for Research on Minority Health and the National Cancer Institute. The goals of the study are to: (i) look for evidence of involvement of chromosome 1q24-25 (HPC1) in African American men with hereditary prostate cancer (HPC) and (ii) conduct a genome-wide search for other loci associated with HPC in African American men. To accomplish these goals, a network has been established including Howard University, the NHGRI, and six Collaborative Recruitment Centers (CRCs). The CRCs are responsible for the identification and enrollment of 100 African American families. To date, 43 families have been enrolled. Recruitment strategies have included mass media campaigns, physician referrals, community health-fairs/prostate cancer screenings, support groups, tumor registries, as well as visits to churches, barber shops, and universities. By far, the most productive recruitment mechanisms have been physician referrals and tumor registries, yielding a total of 35 (81%) families. Approximately 41% (n = 3400) of probands initially contacted by phone or mail expressed interest in participating; the families of 2% of these met the eligibility criteria, and 75% of those families have been enrolled in the study, indicating a 0.5% recruitment yield (ratio of participants to contacts). As the first large-scale genetic linkage study of African Americans, on a common disease, the challenges and successes of the recruitment process for the AAHPC Study should serve to inform future efforts to involve this population in similar studies.

Effects of psychological distress on blood pressure in adolescents.

This cross-sectional survey measured relationships among blood pressure and measures of psychologic distress, family structure, and economic status in a sample of adolescents exposed to Hurricane Hugo. Spielberger's Anger Scale and Derogatis' Brief Symptom Inventory were used. Data analysis revealed 5% of the 1079 adolescents were hypertensive. Multiple regression analyses revealed the following predictors of higher diastolic blood pressure: African-American race, recipient of subsidized lunch, exposure to Hurricane Hugo, and higher anger-in scores in males. The effects of a catastrophic event such as a hurricane on blood pressure and the effects of introjected anger have implications for both health care consumers and providers.

Therapeutic massage in older persons: research issues.

Growing recognition of the importance of holistic nursing interventions is resulting in a revival in the use of therapeutic massage. Massage contributes to health and healing through enhancement of relaxation, and is a safe, caring, and inexpensive intervention. Therapeutic massage research using older populations is reviewed for identification of its theoretical framework, design, outcome variables, sample, procedures, instruments, analyses and results. To establish a scientific basis for therapeutic massage in the future, it is critical that nurses include the following key elements in their research studies: clear definitions: procedures for massage that include type(s) of massage performed, part of body massaged, and length of time of massage; and analyses that control for the pre-massage level of the variable of interest. Research variables need to focus on concepts that have major health consequences such as agitation, immune status, and pain.