Sacral nerve stimulation for neuromodulation of the lower urinary tract.

Sacral neuromodulation (SNM) has become a standard treatment option for patients suffering from urinary urge incontinence, urgency-frequency, and/or nonobstructive urinary retention refractory to conservative and pharmacologic treatment. Since its initial development, the manufacturer of InterStim therapy (Medtronic, Inc., Minneapolis, MN, USA), has introduced technical modifications, while surgeons and researchers have adapted and published various innovations and alterations of the implantation technique. In this article, we feature our SNM technique including patient selection, comprehensive dialogue/evaluation, procedure details, and appropriate follow up. Although there is often great variability in patients with lower urinary tract dysfunction, we maintain that great success can be achieved with a systematic and methodical approach to SNM.

Bayley Scales of Infant Development Screening Test-Gross Motor Subtest: efficacy in determining need for services.

PURPOSE: To identify the efficacy of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Screening Test-Gross Motor Subtest (GMS) in identifying infants who are accepted for early intervention services. METHODS: This retrospective study included 93 infants with a neonatal intensive care experience who participated in a 6-month developmental assessment follow-up visit. All infants were examined using the BSID-III Screening Test-GMS and the Alberta Infant Motor Scale. A binary logical regression analysis was used to determine the best predictors of acceptance status in this sample. RESULTS: The BSID-III Screening Test-GMS accounted for a significant portion of the variance in acceptance status. CONCLUSION: The results suggest that the BSID-III Screening Test-GMS has great applicability for transdisciplinary/interdisciplinary teams as it effectively identified children who were eligible for early intervention.

Possible prevention and treatment of prostate cancer by exercise.

Exercise and physical activity have been linked to the prevention of certain types of cancer such as colon and breast. As prostate cancer is the most common malignancy diagnosed in the male population, there is obvious interest in determining a possible effect of exercise on disease prevention and improvement of disease-related outcomes. Thus far, data has been conflicting and there has been no clear determination of prostate cancer prevention through exercise. However, as prostate cancer treatment carries many side effects which may be bothersome and health-threatening, researchers have examined the effects of exercise training on reducing treatment-related complications and improving outcomes and quality of life (QOL). In this review, we discuss the impact of exercise on reducing side effects of prostate cancer treatment and improving cancer-specific and overall survival outcomes, as well as improving QOL in prostate cancer patients.

Corn-derived carbohydrate inositol hexaphosphate inhibits Barrett's adenocarcinoma growth by pro-apoptotic mechanisms.

Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is found in food sources high in fiber content. IP6 has been reported to have significant inhibitory effects against a variety of primary tumors. We hypothesized that IP6 would inhibit the cell growth rate of Barrett's adenocarcinoma in vitro. Two Barrett's-associated adenocarcinoma cell lines, SEG-1 and BIC-1, were treated with IP6 at 0.5, 1.0 and 5.0 mM concentrations. Cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V FITC assay. Reductions (P<0.001) in cellular proliferation were observed in both cell lines. IP6 decreased late apoptosis and necrosis in BIC cells, whereas in SEG-1 cells, early apoptosis, late apoptosis and necrosis were all increased by IP6. IP6 decreases cellular growth by pro-apoptotic mechanisms. Our findings suggest that IP6 has the potential to become an effective adjunct for Barrett's adenocarcinoma. Further studies are needed to evaluate safety and clinical utility of this agent in patients with Barrett's adenocarcinoma.

Sexual dysfunction in patients with painful bladder syndrome is age related and progressive.

INTRODUCTION/OBJECTIVE: The degree of sexual dysfunction in patients with painful bladder syndrome (PBS) across their lifespan has not been previously documented. MATERIAL AND METHODS: The Female Sexual Function Index (FSFI) is a research tool to measure the degree of clinical female sexual dysfunction (FSD). This 19-item questionnaire evaluates FSD in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. This study used the FSFI with the additional variables of age, geographical location, and current medications. The participants were not blinded to the fact that this study was examining the link between PBS and FSD. Each question in the survey was targeted to a specific variable of FSD and the answers were rated on a Lickert scale. RESULTS: When compared with controls, PBS patients self-report significant sexual dysfunction in all domains evaluated by the FSFI (p < 0.001). Age-specific results were observed in regards to the domains of arousal, lubrication, and pain (p < 0.01). CONCLUSIONS: PBS patients report significant FSD in all domains when compared to controls (p < 0.001). Significant differences in the domains of arousal, lubrication, and pain exist between respondents < 30 years old and in those > 50 years of age. The extent of sexual dysfunction is worse in the areas of pain in each age group evaluated. Pain is the most significant finding in patients with FSD and PBS.

Additive effects of Cox-1 and Cox-2 inhibition on breast cancer in vitro.

We hypothesized that combined treatment with Cox-1 and Cox-2 specific inhibitiors would exhibit synergistic effects against breast cancer in vitro. Two human breast cancer cell lines (HTB26, MCF-7) were treated with catechin (Cox-1 inhibitor) or NS398 (Cox-2 inhibitor) at 100 microM as both single and combined treatments. Reductions in cell growth were observed in both cell lines at 24 and 72 h in both single and combined treatments (p<0.001). Combined treatment produced a significantly greater inhibition as compared to single agents alone. Upon cell cycle evaluation, Cox-1 and -2 antagonism increased G1 and G2 phase fractions in MCF-7 cells (p<0.001 and p<0.05 respectively). No additive changes were observed when the two agents were combined. An increase in the G2 phase was observed in the HTB26 cells when treated with NS398 alone (p<0.001). However, a decrease in the S-phase was observed when these cells were treated with NS398, as a single agent (p<0.01) or when the two agents were combined (p<0.01). The significant and additive effects exhibited by the combination of Cox-1 and -2 inhibitors and their effects on cell cycle suggest that these agents could become an effective treatment modality for carcinoma of the breast.

Inhibition of melanoma growth by hemocyanin occurs via early apoptotic pathways.

BACKGROUND: We hypothesized that keyhole limpet hemocyanin (KLH) would reduce cellular proliferation and effect apoptosis of melanoma cell lines in vitro. METHODS: Two human melanoma cell lines (HTB68 and HTB72) were subjected to a dose-response treatment regimen of KLH (0.4 microg to 100 microg/well). Cell viability was tested by MTT assay (SIGMA, St Louis, MO) at 72 hours. Apoptosis and necrosis were measured by the Annexin V FITC assay (Biovision Inc, Mountain View, CA). RESULTS: Melanoma cell proliferation was significantly reduced in the HTB68 cell line treated with 6.3 microg or higher doses of KLH. A significant reduction in cell growth was also observed in the HTB72 cells at 50 and 100 microg of KLH. KLH increased early apoptotic activity, whereas both late apoptosis and necrosis were decreased by the addition of KLH. CONCLUSIONS: KLH significantly reduces cellular proliferation in vitro in melanoma, via early apoptotic pathways. The results warrant in vivo studies into the effects of KLH in melanoma.

In vitro effects of keyhole limpet hemocyanin in breast and pancreatic cancer in regards to cell growth, cytokine production, and apoptosis.

BACKGROUND: We have previously shown the inhibitory effects of keyhole limpet hemocyanin (KLH) against breast and pancreatic cancer in vitro. We hypothesize that its actions in breast and pancreas cancer cells are via apoptotic or cytokine pathways. METHODS: Two breast cancer cell lines, ZR75-1 and MCF-7, and one pancreas cancer cell line, PANC-1, were treated with KLH at 500 mug, 250 mug, and 250 ng/mL. Cell viability, cytokine production, and apoptosis were measured. RESULTS: Significant growth inhibition was observed in all cell lines at all KLH concentrations tested. Significant changes in cytokine production were observed in all cell lines. An increase in early and late apoptotic activity was observed in the MCF-7, whereas a reduction in late apoptotic activity was observed in the ZR75-1 cells. CONCLUSIONS: KLH directly inhibits the growth of human breast and pancreas cancer in vitro by apoptotic and nonapoptotic mechanisms.

Peptide YY inhibits the growth of Barrett's esophageal adenocarcinoma in vitro.

BACKGROUND: Peptide YY (PYY) is an endogenous gut hormone that inhibits the growth of certain cancers. Adenocarcinoma of the esophagus usually arises from Barrett's esophagus. We hypothesized that treatment of Barrett's adenocarcinoma with PYY would result in decreased proliferation. METHODS: Barrett's cancer cell lines (BIC and SEG-1) were treated with PYY (3-36) at 500 pmol/mL. Viability was measured by MTT at 24 and 72 hours. Apoptosis and necrosis was evaluated by flow cytometry. RESULTS: PYY reduced proliferation in SEG-1 cells at 24 hours (21.2% +/- 3.4%, P <0.001) and 72 hours (14.2% +/- 6.2%, P <0.001). In the BIC cells, growth was inhibited by 7.9% +/- 7.0%, P = 0.021 after 72 hours. PYY increased late apoptotic activity in SEG-1 cells by 31%, P = 0.014. CONCLUSIONS: This is the first report of antiproliferative effects of PYY against Barrett's carcinoma in vitro. Reductions in cell growth appear to be mediated by proapoptotic mechanisms. Further investigation of PYY in the treatment of Barrett's adenocarcinoma is warranted.

Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett's esophageal adenocarcinoma.

BACKGROUND: Keyhole limpet hemocyanin (KLH) is a recently described immune stimulant and hapten carrier derived from a circulating glycoprotein of the marine mollusk Megathura crenulata. We previously reported that KLH has significant antiproliferative effects in vitro against breast, pancreas, and prostate cancers. We hypothesized that KLH would be effective against Barrett's esophageal adenocarcinoma in an in vitro model. METHODS: Barrett's esophageal adenocarcinoma cell lines (SEG-1 and BIC-1) were cultured using standard techniques. Cells were plated at 1 x 10(5) and KLH was added at concentrations ranging from 400 ng to 100 microg/well. After 24 and 72 h incubation, cells were assayed for viability using the MTT technique. Statistical analysis was performed using ANOVA. Apoptosis was evaluated using a cell death detection kit after 16 hours of incubation with KLH. RESULTS: KLH treatment significantly (p < 0.001) reduced viability in a dose and time-dependent manner. Apoptosis was increased in treated SEG-1 cells, but no changes in apoptosis were seen in treated BIC-1 cells. CONCLUSIONS: KLH directly inhibits the growth of human Barrett's esophageal cancer in vitro by apoptotic and nonapoptotic mechanisms.

Synergistic effects of Cox-1 and -2 inhibition on bladder and prostate cancer in vitro.

BACKGROUND: We hypothesized that combined treatment with cyclooxygenase (Cox)-1 (catechin) and Cox-2 (NS398)-specific inhibitors would reduce cellular proliferation synergistically in genitourinary cancer. METHODS: Bladder (T24 and TCCSUP) and prostate (DU145, LnCaP, and PC3) cancer cell lines were treated with catechin and NS398 at a dose of 100 mumol/L as single and combined treatments. Viability was measured by MTT assay at 24 and 72 hours. RESULTS: Significant synergism of Cox-1 and Cox-2 inhibitors was observed in both bladder cancer lines at both 24 and 72 hours. Synergism of Cox-1 and -2 inhibitors also was noted in the DU145 cells at 72 hours, LnCap cells at 24 hours, and PC3 at both 24 and 72 hours. CONCLUSIONS: Significant synergistic effects exhibited by the combination of Cox-1 and Cox-2 inhibitors suggest that these could become a highly effective treatment modality for carcinoma of both the bladder and prostate.

In vitro effects of pentosan polysulfate against malignant breast cells.

BACKGROUND: Pentosan polysulfate (Elmiron); (Alza Pharmaceuticals, Mountain View, CA) is the only Food and Drug Administration-approved oral therapy for interstitial cystitis (IC). Women with IC and breast cancer are often in the same age range; therefore, we hypothesize that pentosan polysulfate may also have a therapeutic effect on breast cancer cells in vitro. METHODS: Breast cancer lines MCF-7, ZR75-1, and HTB26 were treated with pentosan polysulfate at various concentrations. Cell viability was measured at 24 hours by MTT. Annexin V assay was used to determine the effect of pentosan polysulfate on apoptotic and necrotic activity. RESULTS: Pentosan polysulfate significantly inhibited the growth of the ZR75-1 cells; however, significant cellular proliferation was observed in the MCF-7 cells. A significant change in late apoptotic activity was observed with pentosan polysulfate treatment in vitro. CONCLUSIONS: Caution should be used in prescribing pentosan polysulfate for the treatment of IC in patients who are both in high-risk groups for breast cancer and premenopausal females.

COX-2 inhibition and cancer: experimental findings and clinical correlates.

To test our hypothesis that Cyclooyxgenase-2 (COX-2) inhibitors would stop the growth of breast and prostate cancer cells in vitro, two breast (MCF-7, ZR75-1) and two prostate cancer cell lines (PC-3, DU145) were treated with rofecoxib (Vioxx) or NS398. Cell growth was measured by MTT at 24 and 72 hours. Statistical analysis was performed by ANOVA. Significant growth inhibition (p < 0.05) was observed in all cell lines in a dose-dependent manner after treatment with COX-2 inhibitors. Rofecoxib inhibited cellular proliferation by inducing (p < 0.001) apoptosis in breast cancer cells. Our study indicates that COX-2 inhibition reduces the growth of human breast and prostate cancer in vitro. Human studies are needed to evaluate the clinical utility of rofecoxib treatment in breast or prostate cancers.

Long-term neurodevelopmental outcomes in children born with gastroschisis: the tiebreaker.

PURPOSE: We evaluated 2-year neurodevelopmental outcomes in children with gastroschisis. METHODS: We reviewed the records of children with gastroschisis treated between August 2001 and July 2008. Children discharged from the neonatal intensive care unit were referred to the state-sponsored Developmental Tracking Infant Progress Statewide (TIPS) program. We reviewed TIPS assessments performed before age 2 years. School districts evaluated children referred by TIPS and determined their eligibility for early intervention services. Poor outcomes were defined as scores of "failure" or "moderate/high risk" on the screening assessment or enrollment in early intervention services by 2 years. Children with gastroschisis were compared with case-matched nonsurgical, nonsyndromic children of similar gestational age and birth weight. RESULTS: One hundred five children were born with gastroschisis, and 46 were followed up with TIPS. There was no statistically significant difference in performance on screening assessments or in the rate of enrollment in early intervention services between the gastroschisis children and controls. CONCLUSIONS: Children born with gastroschisis have similar 2-year neurodevelopmental outcomes as nonsurgical, nonsyndromic neonatal intensive care unit children of similar gestational age and birth weight. Both groups of children have a higher rate of enrollment in early intervention than their healthy peers. These data suggest that neurodevelopmental outcomes in gastroschisis children are delayed secondary to prematurity rather than the presence of the surgical disease.

Dietary influence on pancreatic cancer growth by catechin and inositol hexaphosphate.

INTRODUCTION: Pancreatic cancer is an extremely virulent form of cancer with few effective treatments. Catechin and inositol hexaphosphate (IP6), two naturally occurring molecules found in green tea and high-fiber foods, respectively, are compounds that have been shown to demonstrate anti-proliferative effects when administered as single therapeutic agents against a number of cancers. We hypothesized that, alone and in combination, IP6 and catechin would be effective against pancreatic cancer. MATERIALS AND METHODS: Pancreatic (PANC-1 and MIAPACA) cancer cell lines were cultured and treated with IP6 (0.8 mM/well), catechin (100 microM/well), and the combination of the two. Cell viability was measured by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) at 24, 48, and 72 h. Vascular endothelial growth factor (VEGF) was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC). RESULTS: The combination of catechin and IP6 significantly inhibited proliferation in the PANC-1 cell line at 24, 48, and 72 h compared to single agents (P < 0.001). Growth of the MIAPACA cell line was inhibited (P < 0.01) by each agent alone, but additive inhibitory effects were not seen. An increase in early apoptosis was attributed to catechin therapy in both cell lines (P < 0.01). The combination of these agents also increased early apoptotic activity when compared to the control (P < 0.001). IP6 reduced VEGF in both cell lines (P < 0.01). In combination, catechin and IP6 amplified VEGF reduction compared to each agent in MIAPACA and control (P < 0.002). CONCLUSIONS: These results, combined with the prevalence of these compounds in safe, naturally occurring foods, make catechin and IP6 attractive therapies for treatment, and possibly in preventative trials, of pancreatic cancer.

Keyhole limpet hemocyanin potentiates standard immunotherapy for melanoma.

INTRODUCTION: Our hypothesis was that keyhole limpet hemocyanin (KLH) would augment the effects of standard immunotherapies for melanoma including interferon-alpha (AIFN) and interleukin (IL)-2. METHODS: The HTB68 melanoma cell line was treated with KLH, AIFN, and IL-2 as single and combined agents. Cell viability, apoptotic activity, and vascular endothelial growth factor levels were all evaluated. RESULTS: Cell growth was reduced with KLH (28%), AIFN (54%), and IL-2 (29%) (all P < .001). KLH and IL-2 combined exhibited a 47% inhibition of cell growth, whereas KLH and AIFN combined yielded a 67% reduction in cell growth (both P < .001). KLH and AIFN combined significantly increased both early (10%) and late (14%) apoptotic activity compared with controls (5% and 7%, P < .001). CONCLUSIONS: The additive effects exhibited by the combination of KLH with AIFN or IL-2 are encouraging and support combination therapy as an effective treatment for this aggressive disease.

Keyhole limpet hemocyanin: an effective adjunct against melanoma in vivo.

BACKGROUND: We have previously demonstrated the potent in vitro antiproliferative effects of keyhole limpet hemocyanin (KLH) against melanoma. Our prior studies directed us to hypothesize that KLH would be effective in vivo against melanoma, alone and in combination with conventional immunotherapy. METHODS: Mice were inoculated with 2 x 10(7) HTB68 cells and randomized to 6 groups. Treatment groups consisted of control, KLH 200 microg, alpha interferon (AIFN) 1000 IU, interleukin-2 (IL-2) 5000 IU, KLH + AIFN, and KLH + IL-2. RESULTS: KLH + IL-2 exhibited the greatest reduction in tumor volume (30%) as compared to control (P = .014), followed by KLH + AIFN (28%, P = .031). Singly treated animals had less tumor inhibition: IL-2 (30%, P = .022), KLH (18%, not significant), and AIFN (16%, not significant). CONCLUSIONS: KLH augments the effects of AIFN, one of the standard immunotherapeutic agents against melanoma in vivo. Further in vivo and early clinical studies into the effects of KLH as both a single and combined agent are warranted.

Inositol hexaphosphate (IP6) inhibits cellular proliferation in melanoma.

BACKGROUND: Inositol Hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate found in food sources high in fiber content. We have previously reported IP6 to have significant inhibitory effects against pancreatic cancer in vitro. We hypothesized that the IP6 would significantly inhibit cell growth of cutaneous melanoma in vitro. MATERIALS AND METHODS: The melanoma line HTB68 was cultured using standard techniques and treated with IP6 at doses ranging from 0.2 to 1.0 mM/well. Cell viability was measured by MTT at 72 h. VEGF production was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-FITC and results calculated using FACS analysis. Statistical analysis was performed by ANOVA. RESULTS: Significant reductions (P < 0.001) in cellular proliferation were observed with IP6. Overall, IP6 exhibited a mean inhibition of cell growth of 52.1 +/- 11.5% (range, 1.6-83.0%) at 72 h of incubation. VEGF production was significantly reduced (P < 0.001) by the addition of IP6 (7.5 pg/ml) compared to control (40.9 pg/ml). IP6 significantly increased (P = 0.029) late apoptosis from 5.3 to 7.0% gated events. No changes in necrosis or early apoptosis were observed. CONCLUSIONS: Adjuvant treatment of melanoma continues to challenge clinicians and patients. Our findings that IP6 significantly decreased cellular growth, VEGF production and increased late apoptosis in melanoma suggest its potential therapeutic value. Further in vivo studies are planned to evaluate safety and clinical utility of this agent.

Peptide YY reverses TNF-alpha induced transcription factor binding of interferon regulatory factor-1 and p53 in pancreatic acinar cells.

BACKGROUND: Cytokine activation in the pancreatitis induces local and systemic cellular damage. Transcription factors interferon regulatory factor-1 (IRF-1) and the tumor suppressor gene p53 collaborate to enhance p21 related cell cycle regulation during pathological disease progression. However, little is known about their role in the pancreas after cytokine challenge. Our laboratory has previously shown that TNF-alpha induces the binding of many transcription factors, including NF-kappa B, and treatment with the gut hormone, Peptide YY (PYY), ameliorates the effects. We hypothesized that TNF-alpha would induce IRF-1 and p53 protein binding in pancreatic acinar cells and that PYY would attenuate the effect. MATERIALS AND METHODS: Rat pancreatic acinar AR42J cells were treated with rat recombinant TNF-alpha (200 ng/ml). To verify that our model was inducing pancreatitis, alpha-amylase activity was measured in the cell culture supernatant by fluorescence spectroscopy. PYY [3-36] was added at 500 pM 30 min post-TNF treatment; cells were harvested at 2 h for extraction of nuclear protein. Transcription factor binding of IRF-1 and p53 were determined by protein/DNA array analysis using chemiluminescence detection, and relative spot densities were measured by densitometry. A two-fold increase or decrease in density was considered significant. RESULTS: Amylase enzyme activity was significantly (P < 0.05) elevated in the TNF-alpha-treated cells by 2 h. Protein/DNA array analysis revealed significant up-regulation of both IRF-1 and p53 protein in nuclear extracts. Induction by TNF-alpha increased IRF-1 protein binding 3.5-fold, while binding levels of p53 protein increased six-fold. The addition of PYY to TNF-treated cells reduced IRF-1 and p53 binding to control levels. CONCLUSIONS: We have shown for the first time that short-term exposure to TNF-alpha induces the binding activity of transcription factors IRF-1 and p53 in rat pancreatic acinar cells, and that addition of PYY reduces it. Regulation of transcription factor activity by PYY may have therapeutic potential in altering the progression of pancreatitis.

MAPK and PI3K inhibition reduces proliferation of Barrett's adenocarcinoma in vitro.

BACKGROUND: Esophageal adenocarcinoma often arises from Barrett's esophagus. Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) play critical roles in cell survival. We hypothesized that inhibition of these pathways in Barrett's adenocarcinoma would decrease cell proliferation and alter apoptosis in vitro. MATERIALS AND METHODS: Two Barrett's-associated adenocarcinoma cell lines, SEG-1 (wild-type p53) and BIC-1 (mutant p53), were treated with MAPK (U0126) and PI3K (LY294002) inhibitors at 20 microm concentrations. After 24 and 72 h, cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V-FITC assay. Statistical analysis was performed by ANOVA. RESULTS: LY294002 and U0126 treatment produced significant reductions (range 15.7 to 62.0%, P < 0.05) in cellular proliferation at both 24 and 72 h in the SEG-1 cells. BIC-1 cell viability was reduced (39.3 to 56.4%, P < 0.05) at 72 h. Both early and late apoptotic activity were significantly increased (P < 0.05) in the SEG-1 cells using both inhibitors. Necrosis was significantly reduced (P < 0.05) using both inhibitors. No changes in either early or late apoptosis or necrosis were observed in the BIC-1 cells. CONCLUSIONS: Herein, we report significant antiproliferative effects against Barrett's adenocarcinoma by MAPK and PI3K inhibition in vitro. Pro-apoptotic mechanisms prevail in the wild-type p53 cells. Further investigation is warranted to advance the clinical treatment of this devastating disease.