Changes in urinary bladder function and somatic sensation may be mediated, in part, by inflammatory changes in the urinary bladder including the expression of chemokines. Male and female C57BL/6 mice were treated with cyclophosphamide (CYP; 75 mg/kg, 200 mg/kg, i.p.) to induce bladder inflammation (4 h, 48 h, chronic). We characterized the expression of CXC chemokines (CXCL9, CXCL10 and CXCL11) in the urinary bladder and determined the effects of blockade of their common receptor, CXCR3, at the level urinary bladder on bladder function and somatic (hindpaw and pelvic) sensation. qRT-PCR and Enzyme-Linked Immunoassays (ELISAs) were used to determine mRNA and protein expression of CXCL9, CXCL10 and CXCL11 in urothelium and detrusor. In urothelium of female mice treated with CYP, CXCL9 and CXCL10 mRNA significantly (p ≤ 0.01) increased with CYP treatment whereas CXC mRNA expression in the detrusor exhibited both increases and decreases in expression with CYP treatment. CXC mRNA expression urothelium and detrusor of male mice was more variable with both significant (p ≤ 0.01) increases and decreases in expression depending on the specific CXC chemokine and CYP treatment. CXCL9 and CXCL10 protein expression was significantly (p ≤ 0.01) increased in the urinary bladder with 4 h CYP treatment in female mice whereas CXC protein expression in the urinary bladder of male mice did not exhibit an overall change in expression. CXCR3 blockade with intravesical instillation of AMG487 (5 mg/kg) significantly (p ≤ 0.01) increased bladder capacity, reduced voiding frequency and reduced non-voiding contractions in female mice treated with CYP (4 h, 48 h). CXCR3 blockade also reduced (p ≤ 0.01) hindpaw and pelvic sensitivity in female mice treated with CYP (4 h, 48 h). CXC chemokines may be novel targets for treating urinary bladder dysfunction and somatic sensitization resulting from urinary bladder inflammation.

Background and Objectives:Focal cortical dysplasia is the most common cause of surgically-remediable epilepsy in children. Little is known about the risk factors for the timing and development of pharmacoresistance in this population. This study sought to evaluate the prevalence and risk factors for pharmacoresistance in pediatric FCD-related epilepsy.Methods:In this retrospective single-center cohort design, patients were identified from search of centralized radiology report database and a central epilepsy surgical database. Inclusion criteria consisted of: 3T MRI-confirmed FCD from January, 2011 to January, 2020; ages 0 days to 22 years at MRI; at least 18 months of documented follow-up after MRI, unless had single seizure or incidentally discovered FCD. Records were excluded if there was dual pathology (except for mesial temporal sclerosis), hemimegalencephaly, or tuberous sclerosis complex present in imaging or history.Results:One hundred forty-three patients with confirmed FCD met inclusion criteria. One hundred twenty-four children had epilepsy (87% of FCD patients) with median age of seizure onset 2.7 years (IQR 0.75-6 years, range 0 to 17 years). Twelve children (8.5%) had a single lifetime seizure (provoked or unprovoked) or recurrent provoked seizures. Seven children (4.9%) had incidental FCD. Ninety-two patients (74%) of those with epilepsy met criteria for pharmacoresistance. Of children with epilepsy of all types, 93 children (75%) were seizure-free at the last visit; Eighty-two patients underwent epilepsy surgery, of whom 59 (72%) achieved seizure freedom. 7% (9/124) achieved seizure freedom with a second ASM, and 5.6% (7/124) with a third or more ASMs. Failure of only one antiseizure medication is associated with enormous increased incidence and earlier development of pharmacoresistance (OR 346, 95% CI 19.6-6100). Cox regression showed FCD lobar location, pathologic subtype, and age of seizure onset are not.Conclusions:Failure of one antiseizure medication is associated with substantial risk of pharmacoresistance. These data support an operational re-definition of pharmacoresistance, for surgical planning, in FCD-related epilepsy to the failure of one antiseizure medication, and support early, potentially curative surgery to improve outcomes in this patient population.

Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. © 2018 International Parkinson and Movement Disorder Society.

Background: Phosphodiesterase 10A (PDE10A) is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. PDE10A regulates cAMP and cGMP, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of L-Dopa-induced dyskinesia (LID). The elevation of cAMP/cGMP levels by PDE10A inhibition may thus be targeted to reduce LID. Methods: Five 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID were used. MR1916, a selective PDE10A inhibitor, at doses 0.0015-0.05 mg/kg, s.c. or its vehicle (control test) was co-administered with L-Dopa methyl ester acutely (predetermined optimal and suboptimal s.c. doses) and oral L-Dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and LID by blinded examiners. Pharmacokinetics was also examined. Results: MR1916 consistently reduced LID in acute tests of L-Dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of L-Dopa at the optimal dose. The anti-LID effect of MR1916 (0.015 mg/kg, s.c.) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. Conclusions: Results show that regulation of striatal cyclic nucleotides by PDE10A inhibition could be a useful therapeutic approach for LID, and therefore, data support further studies of selective PDE10A inhibitors for PD therapy.

Aims While behavior‐based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson's disease (PD) patients, cognitive function may be a predictor of rehabilitation outcomes. Methods In a planned exploratory analysis, participants who had a Montreal Cognitive Assessment (MoCA) with a score ≥18 who were randomized in a clinical trial to behavioral treatment were classified by perceived improvement (Benefit vs. No Benefit) as reported on a validated Satisfaction and Benefit Questionnaire. General cognition (MoCA), motor procedural learning (Serial reaction time task), verbal memory (Buschke delayed recall), spatial memory (Nonverbal/Spatial selective reminding test), and working memory (Wisconsin card sorting task) were compared between the two groups using Wilcoxon rank‐sum test. Results Of the 26 participants randomized to behavioral treatment (70% male, mean age 71 ± 6.1 years), 22 participants (85%) reported Benefit and four reported No Benefit. General cognition, motor procedural learning, verbal memory, spatial memory, and working memory did not differ between these groups. While the difference between the time to complete the final practiced series and the random series of the Serial Reaction Time Task (SRTT) was statistically similar between the groups, the Benefit group performed the random sequence more quickly (567.0 ± 136.5 ms) compared to the No Benefit group (959.4 ± 443.0 ms; p = 0.03) and trended toward faster performance in the final practiced series. Conclusions Perceived benefit from behavioral treatment for overactive bladder was not associated with measures of baseline cognition other than faster completion of the SRTT. This is noteworthy because many behavior‐based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain‐specific cognitive function, particularly the assessment of implicit memory, could lead to individualized behavioral therapy recommendations.