Protodynamic therapy for bladder cancer: in vitro results of a novel treatment concept

OBJECTIVE

To present a novel treatment approach for urinary bladder cancer, protodynamic therapy, which comprises inhibition of cancer cell proliferation by intracellular acidification; cis‐urocanic acid (cis‐UCA) was investigated as a protodynamic drug in bladder cancer cell cultures and compared with conventional chemotherapeutic agents.

MATERIALS AND METHODS

The moderately differentiated cell line 5637 and the poorly differentiated T24 cell line were exposed to cis‐UCA for 0.25–2 h, and to epirubicin, doxorubicin, cisplatin and paclitaxel for 2 h, to simulate drug exposure on intravesical instillation. The combination of cis‐UCA and chemotherapeutic agents was also studied. Cell viability was measured with a colorimetric assay.

RESULTS

cis‐UCA inhibited proliferation and suppressed the survival of cells at an extracellular pH ≤ pK_a2 of 6.65 but to a lesser degree at pH > pK_a2, as suggested by the protodynamic theory. cis‐UCA caused dose‐dependent, irreversible termination of cell proliferation. The number of viable surviving BC cells decreased by >85% with 2%cis‐UCA (P < 0.001). Viable cells disappeared completely with 4% and 6%cis‐UCA after a 2‐h treatment, and by 90% with 6%cis‐UCA within a 15‐min exposure. These effects were associated with distinct morphological changes. The other drugs tested had a clearly lower effect on cell survival. Interestingly, when combined, cis‐UCA markedly enhanced the cytotoxic effect of epirubicin.

CONCLUSION

cis‐UCA is a potent antiproliferative agent in bladder cancer cell cultures. As our previous non‐clinical studies showed that cis‐UCA is locally and systemically well tolerated, protodynamic therapy with cis‐UCA is a promising intravesical treatment for bladder cancer.     

The reliability of determining “leg dominant pain”

Background contextPatients with back dominant pain generally have a worse prognosis after spine surgery when compared with patients with leg dominant pain. Despite the importance of determining whether patients with lumbar spine pain have back or leg dominant pain as a predictor for success after decompression surgery, there are limited data on the reliability of methods for doing so.PurposeTo assess the test-retest reliability of a patient's ability to describe whether their lumbar spine pain is leg or back dominant using standardized questions.Study design/settingProspective, blinded, test-retest cohort study performed in an academic spinal surgery clinic.Patient sampleConsecutive patients presenting for consultation to one of three spinal surgeons for lumbar spine pain were enrolled.Outcome measuresEight questions to ascertain a patient's dominant location of pain, either back dominant or leg dominant, were identified from the literature and local experts.MethodsThese eight questions were administered in a test-retest format over two weeks. The test-retest reliability of these questions were assessed in a self-administered questionnaire format for one group of patients and by a trained interviewer in a second group.ResultsThe test-retest reliability of each question ranged from substantial (eg, interviewer-administered percent question, weighted kappa=0.77) to slight (eg, self-administered pain diagram, weighted kappa=0.09). The Percent question was the most reliable in both groups (self-administered, interviewer). All questions in the interviewer-administered group were significantly (p<.001) more reliable than the self-administered group. Depending on the question, between 0% and 32% of patients provided a completely opposite response on test-retest. There was variability in prevalence of leg dominant pain, depending on which question was asked and there was no single question that identified all patients with leg dominant pain.ConclusionA patient's ability to identify whether his or her lumbar spine pain is leg or back dominant may be unreliable and depends on which questions are asked, and also how they are asked. The Percent question is the most reliable method to determine the dominant location of pain. However, given the variability of responses and the generally poorer reliability of many specific questions, it is recommended that multiple methods be used to assess a patient's dominant location of pain.     

The Longitudinal Examination of Arthritis Pain (LEAP) study: relationships between weekly fluctuations in patient-rated joint pain and other health outcomes

OBJECTIVE: To examine relationships between weekly fluctuations in self-rated joint pain and other health outcomes among adults with osteoarthritis (OA). METHODS: In this observational study, 287 adults (aged > or = 50 yrs) with hip or knee OA were recruited from 16 medical practices across the United States. Patients were telephoned weekly for 12 weeks to assess pain/stiffness, daily activities/function, productivity, emotional well-being, quality of life, and healthcare utilization. Associations between changes in joint pain levels and other health outcomes were evaluated using a generalized estimating equation model. RESULTS: The mean (SD) pain score at Week 1 was 4.2 (2.1) on the Western Ontario and McMaster Universities OA index (WOMAC) pain subscale (0 = no pain, 10 = extreme pain); during the study, 49% of patients reported a between-week fluctuation of > or = 2 points. A 2-point decrease in WOMAC pain subscale score was associated with a 22% decrease in number of days of limited activity/week (beta = -0.107; 95% confidence interval -0.163, -0.051); a 48% decrease in number of days of missed work/week (beta = -0.217; 95% CI -0.395, -0.039); a 14% decrease in number of nights with pain-related sleep interference/week (beta = -0.068; 95% CI -0.109, -0.027). Patients were 1.6 times more likely to contact a healthcare provider when their pain changed from "acceptable" to "unacceptable." CONCLUSION:Weekly fluctuations in pain levels and other health outcomes were identified among adults with OA. Decreases in patient-reported pain were associated with improvements in daily activities/functioning and decreases in work absenteeism, sleep interference, and healthcare resource use.     

Relationship between leptin and C-reactive protein in young Finnish adults

CONTEXT: Leptin and C-reactive protein (CRP) concentrations are increased in inflammation, and both have been linked to increased risk for cardiovascular diseases. OBJECTIVE: The objective of the study was to explore in a population-based sample whether the relation between leptin and CRP is independent of obesity level and whether genetic causes of CRP elevation contribute to leptin levels. DESIGN: This was a population-based study including 1862 young adults (971 women; 891 men) aged 24-39 yr. SETTING: The study was conducted at five centers in Finland. MAIN OUTCOME MEASURES: Associations between leptin and CRP adjusted for obesity indices, risk factors, genetic variables, and lifestyle variables were measured. RESULTS: Women had 3.0-fold higher median concentrations of leptin (12.5 vs. 4.1 ng/ml) and 1.3-fold higher median concentrations of CRP (0.75 vs. 0.56 mg/liter) than men (P < 0.0001 in both comparisons). In univariate analyses, CRP and leptin were significantly intercorrelated (r = 0.47, P < 0.0001 for women; r = 0.46, P < 0.0001 for men). In multiple regression analysis including age, body mass index, waist circumference, insulin, lipids, systolic and diastolic blood pressures, smoking status, and use of oral contraceptives in women, leptin was the main determinant of CRP in men (P < 0.0001) and the second most important determinant in women (P < 0.0001). A Mendelian randomization test based on genetic variants in the CRP gene (five single nucleotide polymorphisms) provided no support for CRP as a causal agent for leptin. CONCLUSIONS: Leptin, obesity, and oral contraceptive use in women were the main factors related to CRP. The relation between leptin and CRP was independent of obesity and cardiovascular risk factors.     

Loss of neurturin in frog--comparative genomics study of GDNF family ligand-receptor pairs

Four different GDNF family ligand (GFL)-receptor (GFRalpha) binding pairs exist in mammals, and they all signal via the RET receptor tyrosine kinase. However, the evolution of these molecules is poorly understood. We identified orthologs of all four GFRalpha receptors and GRAL (GDNF Receptor Alpha-Like) in all vertebrate classes, and a predicted GFR-like protein in several invertebrates. In addition, Gas1 (growth arrest-specific 1), a distant member of the GFR-superfamily, is present in both vertebrates and invertebrates. Analysis of exon structures suggests a common origin of GFR-superfamily proteins and early divergence of Gas1 from the common ancestor. Bony fishes have orthologs of all four mammalian GFLs, consistent with genome duplications in early vertebrates. Surprisingly, the clawed frog and chicken have only three GFLs: synteny analysis indicates loss of neurturin in frog and of persephin in chicken. Evolutionary trace analysis and protein structure homology modeling points at GDNF as the endogenous ligand of frog GFRalpha2.     

Correction of chronic lunotriquetral instability using extensor retinacular split: a retrospective study of 26 patients

Arthroscopy offers a welcome and reliable supplement to the current tool set for the diagnosis of lunotriquetral (LT) instability. This study reports the findings of LT-lesions during arthroscopy and the clinical results obtained after using dorsal stabilisation in its surgical management using extensor retinacular split. LT-instability of grade I-III was diagnosed in 26 patients. Imaging results were normal, Reagan's ballottement and Watson tests were positive in 47% and 79%, respectively. After arthroscopic diagnosis, the procedure was immediately continued with an open repair utilising an 8-10 mm wide and radial-based extensor retinacular split for dorsal capsular reinforcement. At 39 months (range: 14 to 84) follow-up, 64% had no or only occasional mild pain and 36% had pain with overuse or lifting. Overall scoring encompassing pain, patient satisfaction, range of motion and grip strength, was excellent in 24% and good in 64%. Only three patients had fair results, one after a further injury leading to distal radio-ulnar joint (DRUJ) instability, and two with concurrent DRUJ-stabilisation. One further patient required a secondary procedure. Arthroscopy seems to allow accurate diagnosis of LT-instability and can be continued in the same session using a straightforward reconstruction procedure providing satisfactory results.     

Factors associated with recurrent emergency department visits among people living with dementia: A retrospective cohort study

Background

Research on factors associated with recurrent emergency department (ED) visits and their implications for improving dementia care is lacking. The objective of this study was to examine associations between the individual characteristics of older adults living with dementia and recurrent ED visits.

Methods

We used health administrative databases to conduct a population-based retrospective cohort study among older adults with dementia in Ontario, Canada. We included community-dwelling adults 66 years and older who visited the ED between April 1, 2010, and March 31, 2019 and were discharged home. We recorded all ED visits within one year after the baseline visit. We used recurrent event Cox regression to examine associations between repeat ED visits and individual clinical, demographic, and health service use characteristics. We fit conditional inference trees to identify the most important factors and define subgroups of varying risk.

Results

Our cohort included 175,863 older adults with dementia. ED use in the year prior to baseline had the strongest association with recurrent visits (3+ vs.0 adjusted hazard ratio (aHR): 1.92 (1.89, 1.94), 2vs.0 aHR: 1.45 (1.43, 1.47), 1vs.0 aHR: 1.23 (1.21, 1.24)). The conditional inference tree utilized history of ED visits and comorbidity count to define 12 subgroups with ED revisit rates ranging from 0.79 to 7.27 per year. Older adults in higher risk groups were more likely to live in rural and low-income areas and had higher use of anticonvulsants, antipsychotics, and benzodiazepines.

Conclusions

History of ED visits may be a useful measure to identify older adults with dementia who would benefit from additional interventions and supports. A substantial proportion of older adults with dementia have a pattern of recurrent visits and may benefit from dementia-friendly and geriatric-focused EDs. Collaborative medication review in the ED and closer follow-up and engagement with community supports could improve patient care and experience.