Intravesical electromotive drug administration of mitomycin-C for non-muscle invasive bladder cancer

This article reviews intravesical application of electromotive drug administration (EMDA) for the treatment of bladder cancer and the evidence in support of intravesical passive diffusion chemotherapy in the management of non-muscle invasive bladder cancer. Two recently published randomised trials adopting protocols that use EMDA to enhance urothelial transport of intravesical mitomycin-C showed it provided a therapeutical advantage and suggested that intravesical passive diffusion administration of chemothera-peutic drugs may be suboptimal. Further studies are required to demonstrate feasibility and advantage of intravesical EMDA of mitomycin-C in the wider uro-oncological community

Oculomotor Assessment of Diurnal Arousal Variations

Saccadic and pupillary responses are reliable indices of arousal decrement (e.g. fatigue), that might be exploited to improve work schedule guidelines. In this study, we tested the sensitivity of a short 30-s oculomotor test to detect diurnal arousal variations. Twelve participants (5 females, 7 males, 37.7+-11.9 years) volunteered to be assessed every hour (66+-20 min) for three consecutive working days, during their regular office-hours. We used a fully automated testing system, the FIT 2000 Fitness Impairment Tester (Pulse Medical Instruments Inc., Rockville, MD, USA), to measure and record saccadic peak velocity, pupil diameter, and latency and amplitude of the pupillary light reflex. In addition, we collected subjective levels of arousal using the Stanford Sleepiness Scale, and body core temperature. We analyzed the data using a linear mixed model approach for longitudinal data. Both saccadic velocity and subjective alertness decreased over the course of a day, while body core temperature increased (all p-values.05). The data also weakly suggested an increase of the pupil diameter (p 07). The findings support the use of oculomotor indices in the assessment of arousal and fatigue in applied settings

Intravesical oxybutynin: mode of action assessed by passive diffusion and electromotive administration with pharmacokinetics of oxybutynin and N-desethyl oxybutynin.

PURPOSE: A proportion of patients with detrusor hyperreflexia who are unresponsive to oral oxybutynin often benefit from intravesical oxybutynin instillation. To our knowledge the precise mode of action of this method is obscure. MATERIALS AND METHODS: In 12 patients with detrusor hyperreflexia who were previously unresponsive to oral and intravesical passive diffusion of 5 mg. oxybutynin we administered 5 mg. oxybutynin orally as well as increased doses of 15 mg. oxybutynin intravesically with passive diffusion and with 15 mA. associated electric current. Each administration mode per patient was associated with an 8-hour urodynamic monitoring session during which oxybutynin and N-desethyl oxybutynin plasma levels, and intravesical oxybutynin uptake were measured. RESULTS: A dose of 5 mg. oxybutynin orally induced no urodynamic improvement with an area under the plasma concentration time curve of combined N-desethyl oxybutynin plus oxybutynin of 16,297 ng./8 hours and an area under the curve ratio of N-desethyl oxybutynin-to-oxybutynin of 11:1. Passive diffusion oxybutynin resulted in 12 mg. oxybutynin intravesical uptake and significant improvement in 3 of 8 urodynamic measurements, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was only 2,123 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was 1.1:1.0. Electromotive administration of oxybutynin resulted in almost complete intravesical uptake of the 15 mg. dose, significant improvement in all 8 urodynamic measurements and an increased oxybutynin level versus oral and passive diffusion, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was 4,574 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was inverted at 1.0:1.4. The oral dose of 5 mg. oxybutynin caused anticholinergic side effects in 8 of the 12 patients. Neither intravesical passive diffusion nor electromotive administration caused side effects with an uptake of 12 and 15 mg., respectively. CONCLUSIONS: A large proportion of intravesical oxybutynin is sequestered, probably in the urothelium. Intravesical oxybutynin administration confers therapeutic benefits via localized direct action within the bladder wall. Comment in Intravesical treatment of bladder dysfunction. [J Urol. 2001

Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity

Purpose: We investigated the effects of BTX-A on visceral afferent nerve transmission by measuring bladder tissue NGF levels in patients with neurogenic detrusor overactivity before and after intravesical treatment with BTX-A. We also compared the bladder tissue NGF content with clinical and urodynamic data. Materials and Methods: A total of 23 patients underwent clinical evaluation and urodynamics with detection of the UDC threshold, maximum pressure and maximum cystometric capacity before, and at the 1 and 3-month followups. Endoscopic bladder Wall biopsies were also obtained at the same time points. NGF levels were measured in tissue homogenate by enzyme-linked immunosorbent assay (Promega, Madison, Wisconsin). Results: At 1 and 3 months mean catheterization and incontinent episodes were significantly decreased (p < 0.05 and < 0.001, respectively). On urodynamics we detected a significant increase in the UDC threshold and maximum cystometric capacity, and a significant decrease in UDC maximum pressure at the 1 and 3-month followups compared to baseline (each p < 0.001). At the same time points we detected a significant decrease in NGF bladder tissue content (each p < 0.02). Conclusions: BTX-A intravesical treatment induces a state of NGF deprivation in bladder tissue that persists at least up to 4 months. As caused by BTX-A, the decrease in acetylcholine release at the presynaptic level may induce a decrease in detrusor contractility and in NGF production by the detrusor muscle. Alternatively BTX-A can decrease the bladder level of neurotransmitters that normally modulate NGF production and release

Celecoxib for the prevention of nonmuscle invasive bladder cancer: Results from a matched control study

New targets and approaches are under investigation for the treatment of nonmuscle invasive bladder cancer (NMIBC). Preclinical data suggest cyclooxygenase-2 (COX-2) as a promising target. Celecoxib, a COX-2 selective inhibitor, inhibits tumor development and enhances survival, both in vitro and in vivo models of bladder cancer. Therefore, we conducted a pilot study of celecoxib to prevent recurrence in patients with intermediate risk NMIBC

Intelligent speed adaptation for visibility technology affects drivers’ speed selection along curves with sight limitations

Sight obstructions along road curves can lead to a crash if the driver is not able to stop the vehicle in time. This is a particular issue along curves with limited available sight, where speed management is necessary to avoid unsafe situations (e.g., driving off the road or invading the other traffic lane). To solve this issue, we proposed a novel intelligent speed adaptation (ISA) system for visibility, called V-ISA (intelligent speed adaptation for visibility). It estimates the real-time safe speed limits based on the prevailing sight conditions. V-ISA comes with three variants with specific feedback modalities (1) visual and (2) auditory information, and (3) direct intervention to assume control over the vehicle speed. Here, we investigated the efficiency of each of the three V-ISA variants on driving speed choice and lateral behavioural response along road curves with limited and unsafe available sight distances, using a driving simulator. We also considered curve road geometry (curve direction: rightward vs. leftward). Sixty active drivers were recruited for the study. While half of them (experimental group) tested the three V-ISA variants (and a V-ISA off condition), the other half always drove with the V-ISA off (validation group). We used a linear mixed-effect model to evaluate the influence of V-ISA on driver behaviour. All V-ISA variants were efficient at reducing speeds at entrance points, with no discernible negative impact on driver lateral behaviour. On rightward curves, the V-ISA intervening variant appeared to be the most effective at adapting to sight limitations. Results of the current study implies that V-ISA might assist drivers to adjust their operating speed as per prevailing sight conditions and, consequently, establishes safer driving conditions. (c) 2024 Periodical Offices of Chang'an University. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY -NC - ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Sexual Health in Menopause

Sexual function worsens with advancing menopause status. The most frequently reported symptoms include low sexual desire (40–55%), poor lubrication (25–30%) and dyspareunia (12–45%), one of the complications of genitourinary syndrome of menopause (GSM). Declining levels of sex steroids (estrogens and androgens) play a major role in the impairment of sexual response; however, psychological and relational changes related with aging and an increase in metabolic and cardiovascular comorbidities should also be taken into account. Although first-line therapeutic strategies for menopause-related sexual dysfunction aim at addressing modifiable factors, many hormonal and non-hormonal, local and systemic treatment options are currently available. Treatment should be individualized, taking into account the severity of symptoms, potential adverse effects and personal preferences

Three-year tracking of fatty acid composition of plasma phospholipids in healthy children

Objectives: The fatty acid composition of plasma phospholipids reflects the dietary fatty acid intake as well as endogenous turnover. We aimed at investigating the potential tracking of plasma phospholipid fatty acid composition in children that participated in a prospective cohort study. Methods: 26 healthy children participated in a longitudinal study on health risks and had been enrolled after birth. All children were born at term with birth weights appropriate for gestational age. Follow-up took place at ages 24, 36 and 60 months. At each time point a 24-hour dietary recall was obtained, anthropometric parameters were measured and a blood sample for phospholipid fatty acid analysis was taken. Results: Dietary intake of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids at the three time points were not correlated. We found lower values for plasma MUFA and the MUFA/SFA ratio at 60 months compared to 24 months. In contrast, total PUFA, total n-6 and n-6 long-chain polyunsaturated fatty acids (LC-PUFA) were higher at 60 months. Significant averaged correlation coefficients (average of Pearson's R for 24 versus 36 months and 36 versus 60 months) were found for n-6 LC-PUFA (r = 0.67), n-6/n-3 LC-PUFA ratio (r = 0.59) and arachidonic acid/linoleic acid ratio (r = 0.64). Partial tracking was found for the docosahexaenoic acid/alpha-linolenic acid ratio (r = 0.33). Body mass index and sum of skinfolds Z-scores were similar in the three evaluations. Conclusions: A significant tracking of n-6 LC-PUFA, n-6 LC-PUFA/n-3 LC-PUFA ratio, arachidonic acid/ linoleic acid ratio and docosahexaenoic acid/alpha-linolenic acid ratio may reflect an influence of individual endogenous fatty acid metabolism on plasma concentrations of some, but not all, fatty acids. Copyright (c) 2007 S. Karger AG, Basel

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14&nbsp;weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48&nbsp;weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity