The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (T(EM)) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3(+) T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7(-)), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7(+) central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7(-) T(EM), suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T(EM). These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.     

Randomized trial of safinamide add‐on to levodopa in Parkinson's disease with motor fluctuations

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add‐on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double‐blind, placebo‐controlled, parallel‐group study was to evaluate the efficacy and safety of safinamide, an α‐aminoamide with dopaminergic and nondopaminergic mechanisms, as add‐on to l ‐dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression‐Change (CGI‐C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI‐C were significantly greater in both safinamide groups versus placebo. There were no significant between‐group differences for incidences of treatment‐emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l ‐dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society     

Drugs and pregnancy--outcomes of women engaged with a specialist perinatal outreach addictions service

Substance misuse during pregnancy may result in harm to both mother and child. The aims of this study were to assess changes in outcomes of women seen by a specialist perinatal addictions outreach service (1989-1991 versus 2002-2005) and compare outcomes to the local hospital maternity population (2004-2005). A cross-sectional audit of health-care records was conducted comparing the outcomes of women in 2002-2005 with earlier data from 1989-1991 and the local maternity population (2004-2005). The service was attended by 126 women, of whom 83% of opioid-dependent women started/continued opioid maintenance treatment. Of 118 babies delivered, there were two stillbirths and one early neonatal death, 20% were premature, 28% were low birth weight, 21% required the Special Care Baby Unit and 21% of babies born to opioid-dependent mothers were treated for neonatal abstinence syndrome (NAS). Fewer babies required treatment for NAS in 2002-2005 compared to 1989-1991 (21% versus 44%). There were higher rates of miscarriage (3% versus <1%), low birth weight (28% versus 9%) and premature babies (20% versus 9%) compared to the local maternity population (2004-2005). Integrated perinatal addictions treatment may deliver benefits; however, engaging women into treatment earlier and reducing substance use before conception remains the objective.     

The existence of a local 5-hydroxytryptaminergic system in peripheral arteries

BACKGROUND AND PURPOSE: 5-HT is a vasoconstrictor exhibiting enhanced effects in systemic arteries from subjects with cardiovascular disease. The effect of endogenous 5-HT on arteries is controversial, because the concentration of free circulating 5-HT is low and a 5-hydroxytryptaminergic system has not been identified in peripheral arteries. We hypothesized that a local 5-hydroxytryptaminergic system (including 5-HT synthesis, metabolism, uptake and release) with physiological function exists in peripheral arteries. EXPERIMENTAL APPROACH: The presence of key components of a 5-hydroxytryptaminergic system in rat aorta and superior mesenteric artery was examined using western blot analyses, immunohistochemistry and immunocytochemistry. The function of the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), and 5-HT transporter was tested by measuring enzyme activity and 5-HT uptake, respectively. Isometric contraction of arterial strips was used to demonstrate the function of released endogenous 5-HT in arterial tissues. KEY RESULTS: mRNA for TPH-1 was present in arteries, with low levels of TPH protein and TPH activity. Expression and function of MAO A (5-HT metabolizing enzyme) was supported by immunohistochemistry, western analyses and the elevation of concentrations of 5-hydroxyindoleacetic acid (5-HT metabolite) after exposure to exogenous 5-HT. The 5-HT transporter was localized to the plasma membrane of freshly isolated aortic smooth muscle cells. Peripheral arteries actively took up 5-HT in a time-dependent and 5-HT transporter-dependent manner. The 5-HT transporter substrate, (+)-fenfluramine, released endogenous 5-HT from peripheral arteries, which potentiated noradrenaline-induced arterial contraction. CONCLUSIONS AND IMPLICATIONS: This study revealed the existence of a local 5-hydroxytryptaminergic system in peripheral arteries.     

Antiangiogenic Drug-Induced Proteinuria as a Prognostic Factor in Metastatic Colorectal Cancer

Treatment with bevacizumab is known to cause adverse events such as proteinuria and hypertension, amongst others. However, while bevacizumab-induced hypertension has been linked to increased overall survival (OS), data on proteinuria are controversial. We performed a retrospective analysis to observe the influence of adverse events developed during treatment with bevacizumab and chemotherapy on the OS in patients with metastatic colorectal cancer (mCRC). Kaplan–Meier and log-rank analyses were used to assess differences in OS, and hazard ratios (HR) were estimated using Cox models. Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Out of these, 50.7% experienced proteinuria and had reached a longer OS (40 versus 25 months, p = 0.015) and progression-free survival (15 versus 12 months, p = 0.039). The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.589; 95% CI 0.402–0.863; p = 0.007), one metastatic site (HR 0.533; 95% CI 0.363–0.783; p = 0.001), and non-metastatic stage at diagnosis (HR 0.459; 95% CI 0.293–0.720; p = 0.001). Patients with anemia and diabetes had an increased risk of death. Proteinuria emerges as a useful prognostic factor in mCRC patients undergoing bevacizumab-based systemic therapy, and it could be easily integrated into the decision-making process, thus allowing physicians to further individualize systemic treatments.     

Extrahepatic Portal Vein Thrombosis in Childhood: Risk Factors,Clinical Manifestations,and Management

ObjectiveExtrahepatic portal vein thrombosis (EHPVT) is a common cause of portal hypertension in children. The aim of the present study was to identify the clinical manifestations and the risk factors for development of EHPVT in pediatric patients.Subjects and MethodsThis was a single-center retrospective cohort study. A total of 12 children (6 boys and 6 girls) took part in the study. We noted the clinical presentations and the predisposing risk factors for development of EHPVT in all patients. In addition, as all of them had undergone an esophagogastroduodenoscopy for detection and grading of esophageal varices as part of the treatment algorithm, we analyzed the endoscopic findings and the therapeutic approach.ResultsThe median age of subjects at diagnosis was 3.5 years (range: 1–17 years). The most frequent initial clinical manifestation was upper gastrointestinal bleeding (6 cases, 50.0%) followed by splenomegaly (3 cases, 25.0%). The most frequent systemic risk factor for EHPVT was presence of inherited prothrombotic disorder (10 cases, 83.3%), and the most common local risk factor for EHPVT was umbilical vein catheterization (5 cases, 41.7%). Esophageal varices were revealed in all the study participants, and in the most cases, they were grade ≥2. Propranolol was used as primary or secondary prophylaxis in 7 children (58.3%), and in 5 children (41.7%), a shunt was performed (Meso-Rex bypass in 3 children and splenorenal shunt in 2 children).ConclusionPatients with known systemic or local risk factors for EHPVT are indicated for proactive ultrasound screening for early diagnosis and timely management.