COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro.

PURPOSE: The purpose of this work was to determine the in vitro effect of Rofecoxib and specific COX 1 and COX 2 inhibitors in regards to cell growth and apoptotic and necrotic activity. INTRODUCTION AND OBJECTIVE: Rofecoxib (Vioxx) is a nonsteroidal anti-inflammatory agent (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). The inducible isoform of COX-2 is overexpressed in many gastrointestinal and genitourinary tract tumors. We hypothesized that in vitro treatment with both COX-1 and COX-2 inhibitors would significantly reduce cellular proliferation of bladder cancer cells by apoptotic pathways. MATERIALS AND METHODS: Two human bladder cancer cell lines were grown in culture using standard techniques and treated with Rofecoxib at doses ranging from 125 microg/well serially diluted down to 8.0 microg/well. Catechin (COX 1 inhibitor) and NS398 (COX 2 inhibitor) were used at doses of 50 and 100 microM. Cell viability was measured by MTT at 24 and 72 h. Apoptosis was evaluated by the Annexin V FITC Assay. Statistical analysis was performed by ANOVA. RESULTS: Rofecoxib, Catechin, and NS398 all exhibited significant inhibition of cell growth when compared to the nontreated controls. Significant changes in apoptotic activity were observed in all agents tested in both the T24 and the TCCSUP cells. CONCLUSIONS: Selective COX-2 inhibition, using the well-tolerated and commercially available Rofecoxib (VIOXX) and specific COX 1 and 2 inhibitors, reduced the growth of human bladder cancer in vitro by apoptotic mechanisms. Further in vivo and human studies are warranted to evaluate the safety and clinical utility of this agent in patients with bladder cancer.

Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies.

Of the many beneficial actions of garlic, inhibition of the growth of cancer is perhaps the most remarkable. Our previous animal studies demonstrated that aged garlic extract was highly effective, and unlike the approved immunotherapy for human bladder cancer, bacillus Calmette--Guérin (BCG), garlic was effective when added to the diet. To elucidate the mechanism of this antitumor effect, the literature describing antitumor and immune-enhancing effects of garlic is reviewed. Garlic can detoxify carcinogens by stimulation of cytochrome P(450) enzymes, antioxidant activity or sulfur compound binding. Studies demonstrate a direct toxic effect of garlic to sarcoma and gastric, colon, bladder and prostate cancer cells in tissue culture, but these effects cannot explain the inhibition of growth of transplanted cancer in animal models. The most likely explanation of this effect is immune stimulation. Comparison of the effects of garlic to BCG immunotherapy reveals many similarities. Both stimulate proliferation of lymphocytes and macrophage phagocytosis, induce the infiltration of macrophages and lymphocytes in transplanted tumors, induce splenic hypertrophy, stimulate release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma, enhance natural killer cell, killer cell and lymphokine-activated killer cell activity. These activities represent effective stimulation of the immune response. Studies suggest that garlic may be useful in preventing the suppression of immune response that is associated with increased risk of malignancy. Data suggest that maintenance of immune stimulation can significantly reduce the risk of cancer. Clinical trials should be initiated to test the hypothesis that the immune stimulation and other beneficial effects of garlic are able to reduce the incidence of cancer.

Risk for domestic violence: factors associated with perpetration and victimization.

The extent and potential dangerousness of the problem of domestic violence warrants systematic screening and assessment in all mental health settings. Few empirical studies have approached the question of domestic violence with the aim of identifying risk markers, making it impossible to identify a particular characteristic or set of characteristics that can be used to identify individuals at risk for perpetrating or becoming the victims of domestic violence. However, there are a number of factors that have been identified as correlates of domestic violence that may eventually prove useful for identifying individuals at risk, but the extant literature does not provide the empirical support at this time. Because many of these correlates may be brought to the attention of mental health and medical professionals (e.g., depression, substance use/abuse, physical injuries) and given the absence of established risk factors for domestic violence, there is a need for clinicians to systematically assess for violence among all of their patients. By identifying factors that might help clinicians realize that many of their patients are at risk for domestic violence, we hope to encourage them to attend to this potentially dangerous problem. Ongoing assessment in the context of knowledge regarding correlates of domestic violence can provide important information for evaluating risk of a particular violent incident. In addition, we outline strategies for assessing violence and violence risk in both perpetrators and victims in order to assist clinicians in approaching this difficult topic in a clinical setting. A careful assessment of the potential for violence within clients' ongoing relationships is necessary for clinicians to provide appropriate clinical care.

Keyhole limpet hemocyanin immunotherapy of bladder cancer: laboratory and clinical studies.

BACKGROUND: Since the serendipitous observation by Olsson in 1974 that patients immunized with 5 mg of keyhole limpet hemocyanin (KLH) had a marked reduction in recurrence of superficial bladder cancer, multiple laboratory and clinical studies have confirmed the efficacy of KLH immunotherapy. RESULTS: In 1981, we reported that KLH immunotherapy reduced tumor growth and prolonged survival in the MBT-2 murine model of transitional cell carcinoma (TCC), and in 1988, Jurincic and co-workers demonstrated that KLH was superior to mitomycin C chemotherapy in preventing bladder tumor recurrence. Subsequent studies using Immucothel (Biosyn), crude KLH, and endotoxin-free KLH confirmed the efficacy of KLH immunotherapy in the MBT-2 murine bladder cancer model (p < 0.05), and resulted in up to 100% survival. CONCLUSIONS: To evaluate the efficacy of KLH immunotherapy in patients, a multicenter clinical trial was performed. Sixty-four patients with CIS or residual stage T(a), T(1) TCC, or both were enrolled in a phase I-II trial of escalating doses of weekly KLH given intravesically for 6 weeks. Patients were followed with cystoscopic examination, urine cytology, and bladder biopsy. Complete response was seen in 50% of patients with CIS, 20% of patients with residual T(a), T(1) TCC, and 33% of patients with both CIS and residual T(a), T(1) TCC. Responses occurred at all doses tested: 0.4, 2, 10 and 50 mg. No significant difference in response according to dose was noted, but optimal overall complete response was seen with a dose of only 2 mg. The toxicity of KLH is minimal. KLH appears to be a safe and highly effective immunotherapy for superficial bladder cancer.

Prevalence of personality disorders among combat veterans with posttraumatic stress disorder.

Many combat veterans with PTSD have co-occurring symptoms of other forms of psychopathology; however, there have been limited studies examining personality disorders among this population. The few extant studies typically have assessed only two or three personality disorders or examined a small sample, resulting in an incomplete picture and scope of comorbidity. This study assessed all DSM-III-R personality disorders in 107 veterans in a specialized, inpatient unit. Using the Structured Clinical Interview for DSM-III-R Personality Disorders, 79.4% of the participants were diagnosed with at least one personality disorder: 29.9% received only one diagnosis, 21.5% had two, 15.9% had three, and 12.1% had four or more. The most frequent single diagnoses were Avoidant (47.2%), Paranoid (46.2%), Obsessive-Compulsive (28.3%), and Antisocial (15.1%) personality disorders.

The potential application of Allium sativum (garlic) for the treatment of bladder cancer.

Additional studies are needed to identify the active ingredients in Allium Sativum (garlic) that are responsible for the observed antitumor activity and immune stimulation. Garlic seems to detoxify chemical carcinogens and prevent carcinogenesis and can also directly inhibit the growth of cancer cells. Current data suggest that low molecular weight sulfur compounds and protein F4 have immune-stimulation properties. Garlic is reported to stimulate immunity, including macrophage activity, natural killer and killer cells, and LAK cells, and to increase the production of IL-2, TNF, and interferon-gamma. These cytokines are associated with the beneficial Th1 antitumor response, which is characteristic of effective cancer immunotherapies. As is true of BCG, garlic stimulates the proliferation of macrophages and lymphocytes and protects against the suppression of immunity by chemotherapy and ultraviolet radiation. Garlic is clearly not a panacea for cancer, but its broad range of beneficial effects are worthy of serious consideration in clinical trials for the prevention and treatment of cancer.

Partners' ratings of combat veterans' PTSD symptomatology.

The current study examined the concordance of combat veterans' scores on the Mississippi Scale for Combat-Related PTSD, with scores on a parallel version of that instrument completed by partners to assess veterans' symptoms. Further, the study examined the impact of quality of the marital relationship on score concordance. Bivariate and multiple regression were used with a sample of 466 veteran-partner dyads obtained from the National Vietnam Veterans Readjustment Study. There was moderate agreement in symptom reporting between veterans and their partners and little evidence to suggest that the quality of the relationship impacted upon the association between partner and veteran scores.

Probing the environment of nascent RNA in Escherichia coli transcription elongation complexes utilizing a new fluorescent ribonucleotide analog.

We report the synthesis and characterization of 5-thioacetamidofluorescein-uridine 5'-triphosphate (5-SF-UTP), and its application to the characterization of the environment of the nascent RNA during trans-cription. This analog specifically replaced UTP as a transcription substrate for Escherichia coli and T7 RNA polymerases, and yeast RNA polymerase III. Escherichia coli transcription complexes containing analog incorporated at only position +21 of the RNA were prepared. The RNA was then elongated in the absence of analog, moving the fluorescent group further away from the enzyme active site, and the fluorescence polarization was measured. Analog positioned near the 3' end of the transcript exhibited significantly increased polarization relative to that of free probe, consistent with the constrained environment of the RNA in the DNA-RNA hybrid. Analog positioned 14 nucleotides from the 3' end exhibited significantly decreased polarization relative to that at the 3' end of the RNA, but only slightly above that of free RNA, suggesting that the probe was on the solvent-exposed surface of the polymerase. Molecular modeling of these analog-substituted RNAs produced structures consistent with the experimental data. The excellent substrate properties of this analog make it useful for the characterization of the environment of RNA not only during transcription and translation, but in any type of ribonucleoprotein complex.

Testing a mediational model of sexually aggressive behavior in nonincarcerated perpetrators.

This study examined a psychological model of male sexually aggressive behavior toward women. Forty-seven men who reported completing or attempting acts that legally represent rape in most states and 56 nonviolent men completed measures assessing early home environment, attitudes regarding women and relationships, impulsive behaviors, and peers' characteristics. As predicted, sexually aggressive behavior was associated with exposure to negative childhood experiences with fathers. These experiences included reports of emotionally distant, uncaring fathers and witnessing father-perpetrated domestic violence. The relationship between poorer fathering and sexually aggressive behavior was partially mediated by impulse control problems as a young adult. Although having delinquent peers and endorsements of hostile attitudes toward women and rigid sex-role beliefs, predicted perpetration, contrary to expectations, neither mediated the relationship between poorer fathering and perpetration.

Female partners' estimations of male veterans' combat-related PTSD severity.

This study investigated concordance between male Vietnam veterans' and their female partners' reports of veterans' posttraumatic stress disorder (PTSD) symptoms. Fifty male Vietnam combat veterans and their partners rated the severity of their own PTSD symptoms. Also, partners rated the severity of veterans' symptoms. Results indicated modest levels of agreement in reports of symptom presence/absence. Partner ratings of veterans' PTSD severity were positively correlated with veteran reports and partners' own self-reported PTSD symptoms. After controlling for veterans' self-reported symptoms, partners' symptoms significantly predicted their estimates of veterans' avoidance symptoms, but not veterans' reexperiencing or hyperarousal symptoms. Theoretical and practical implications of these findings are discussed.

Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis.

BACKGROUND: Osteoporosis occurs in patients with cystic fibrosis as they age, but its clinical implications are not well defined. OBJECTIVE: To determine the clinical effect of decreased bone mineral density in adults with cystic fibrosis and to assess possible clinical predictors of osteoporosis. DESIGN: Retrospective cohort study. SETTING: Academic cystic fibrosis center. PATIENTS: 70 adults with late-stage cystic fibrosis who were referred for lung transplantation. MEASUREMENTS: Bone mineral density was measured with dual-energy x-ray absorptiometry, patient-reported fracture events were confirmed by radiography, and kyphosis angles were measured by using the Cobb method. RESULTS: Mean bone mineral densities for the spine, femur, and total body were severely depressed in patients with cystic fibrosis, averaging 2 SDs below those of age-matched normal controls (P < 0.001). Patient interviews showed that 54 fractures had occurred over 1410 patient-years, and chest radiographs showed evidence of 14 additional rib and 62 additional vertebral compression fractures. The database (which covered 1410 patient-years) showed that fracture rates were approximately twofold greater in women with cystic fibrosis aged 16 to 34 years (P = 0.015) and men with cystic fibrosis aged 25 to 45 years (P = 0.04) than in the general population. Vertebral compression and rib fractures were 100- and 10-fold more common than expected, respectively (P < 0.001 for both comparisons). The mean kyphosis angle (+/- SD) for this group was markedly abnormal (44 +/- 14 degrees; 62% > or = 40 degrees) and probably contributed to diminished stature (mean height loss, 5.8 cm in men with cystic fibrosis and 5.9 cm in women with cystic fibrosis). Cumulative prednisone dose, body mass index, and age at puberty were the strongest predictors of bone mineral density. CONCLUSIONS: Osteoporosis is universal in adults with late-stage cystic fibrosis, and its complications include increased fracture rates and severe kyphosis.

The quality of the intimate relationships of male Vietnam veterans: problems associated with posttraumatic stress disorder.

This study examined the quality of the intimate relationships of male Vietnam veterans. Heterosexual couples in which the veteran had posttraumatic stress disorder (PTSD; n = 26) were compared to couples in which the veteran did not have PTSD (n = 24). Over 70% of the PTSD veterans and their partners reported clinically significant levels of relationship distress compared to only about 30% of the non-PTSD couples. Relationship difficulties appeared to encompass a wide range of areas, with PTSD veterans and their partners reporting that they had more problems in their relationships, more difficulties with intimacy, and had taken more steps toward separation and divorce than the non-PTSD veterans and their partners. The degree of relationship distress was correlated with the severity of veterans' PTSD symptoms, particularly symptoms of emotional numbing. Research and clinical implications of the results are discussed.

Allium sativum (garlic) treatment for murine transitional cell carcinoma.

BACKGROUND: Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model. METHODS: C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival. RESULTS: In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05). CONCLUSIONS: The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.

Thematic resolution, PTSD, and complex PTSD: the relationship between meaning and trauma-related diagnoses.

The role of modifying schemas in trauma-focused psychotherapy has received theoretical and clinical attention. However, the relationship of schematic processing to posttraumatic stress disorder (PTSD) diagnosis has not been examined empirically. The current study-compared measures of thematic disruption among individuals with PTSD alone, PTSD with concurrent complex PTSD, and no PTSD. Eighty two participants were interviewed to assess PTSD status, complex PTSD status, traumatic life events, and trauma-related thematic processing. Results indicated that variables quantifying thematic disruption and thematic resolution significantly distinguished those individuals with concurrent PTSD plus complex PTSD from the other two groups. Exploratory analyses indicated that PTSD symptom severity and the interpersonal nature of the trauma were related to thematic disruption.

The cycle of trauma; relationship aggression in male Vietnam veterans with symptoms of posttraumatic stress disorder.

This study examined the association between symptoms of Posttraumatic Stress Disorder (PTSD) in male Vietnam veterans and their use of aggressive behavior in relationships with intimate female partners. Fifty couples participated in the study. Veterans reported on their PTSD symptoms, and veterans and partners completed measures assessing the veterans' use of physical, verbal, and psychological aggression during the preceding year as well as measures of their own perceptions of problems in the relationship. Results indicated that PTSD symptomatology places veterans at increased risk for perpetrating relationship aggression against their partners. The association between veterans' PTSD symptoms and their use of aggression in relationships was mediated by relationship problems. Clinical implications of these findings and suggestions for future research are discussed.

Regulation of the RNA polymerase I and III transcription systems in response to growth conditions.

To better understand the mechanisms that regulate stable RNA synthesis, we have analyzed the RNA polymerase I and III transcriptional activities of extracts isolated from cells propagated under a variety of conditions. Under balanced growth conditions the levels of both RNA polymerase I- and III-specific transcription increased proportionally with growth rate. Upon nutritional starvation, RNA polymerase I transcription rapidly declined, followed by 5 S rDNA and eventually tDNA transcription. Transcriptional activities in extracts were restored when the nongrowing cultures were resuspended in fresh medium, although growth did not resume. The differential expression of 5 S rDNA and tDNA genes in extracts prepared from cells subjected to partial starvation was traced to a 5 S rDNA-specific inhibitor and not to a defect in any RNA polymerase III transcription factor. Characterization of this inhibitor indicated that it was not 5 S rRNA. It was sensitive to phenol extraction and resistant to RNase, and its target did not appear to be transcription factor IIIA. Not all treatments that slowed or stopped growth down-regulated the stable RNA transcription apparatus. Cells that have been subjected to either energy starvation or cycloheximide treatment still retain the ability to synthesize stable RNA in vitro, suggesting the presence of alternative regulatory mechanisms.

Coping strategies and posttraumatic stress disorder in female victims of sexual and nonsexual assault.

The coping behaviors and posttraumatic stress disorder (PTSD) symptoms of 215 female assault victims (103 rape victims and 112 nonsexual assault victims) were assessed within 2 weeks following the assault (Time 1), and 133 of them (62%) were followed up 3 months later (Time 2). Posttrauma symptom severity significantly decreased during the 3-month study period, but PTSD severity levels at Times 1 and 2 were highly correlated. Three coping scales were constructed on the basis of exploratory factor analyses: Mobilizing Support, Positive Distancing, and Wishful Thinking. Three months postassault, rape victims showed higher levels of wishful thinking and PTSD than nonsexual assault victims. Wishful thinking showed a positive association and positive distancing a negative association with PTSD severity, controlling for assault type, initial levels of PTSD severity, and other coping strategies. The clinical relevance of these findings is discussed.

Dissociative experiences and posttraumatic stress disorder among female victims of criminal assault and rape.

This study examines the relationship between posttraumatic stress disorder (PTSD) and dissociative experiences in a sample of 158 recent female assault victims (74 rape, 84 nonsexual assault) and 46 comparison subjects who had not been assaulted within the last year. Results indicated that victims had elevated scores on Dissociative Experiences Scale (DES) as compared to the comparison subjects, but that this elevation was not as high as for other traumatized samples. The level of dissociation reported by assault victims declined significantly over the three month course of the study. DES scores were related to PTSD diagnosis and symptom severity, but only among nonsexual assault victims. In rape victims, there was no correlation between dissociation and PTSD. Recent victims with a history of childhood sexual abuse were significantly more dissociative than those who did not report such a history. These results are discussed with regard to vulnerability factors for developing PTSD subsequent to a criminal assault.