Evidence that blood-CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen.

OBJECTIVE: Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls. BACKGROUND: Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology. METHODS: We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods. RESULTS: Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor ß, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein. CONCLUSIONS: The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS: We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS: Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION: CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING: Celladon Corporation.

Severe Headache or Migraine History is Inversely Correlated With Dietary Sodium Intake: NHANES 1999-2004.

OBJECTIVE: We investigated whether dietary sodium intake from respondents of a national cross-sectional nutritional study differed by history of migraine or severe headaches. BACKGROUND: Several lines of evidence support a disruption of sodium homeostasis in migraine. DESIGN: Our analysis population was 8819 adults in the 1999-2004 National Health and Nutrition Examination Survey (NHANES) with reliable data on diet and headache history. We classified respondents who reported a history of migraine or severe headaches as having probable history of migraine. To reduce the diagnostic conflict from medication overuse headache, we excluded respondents who reported taking analgesic medications. Dietary sodium intake was measured using validated estimates of self-reported total grams of daily sodium consumption and was analyzed as the residual value from the linear regression of total grams of sodium on total calories. Multivariable logistic regression that accounted for the stratified, multistage probability cluster sampling design of NHANES was used to analyze the relationship between migraine and dietary sodium. RESULTS: Odds of probable migraine history decreased with increasing dietary sodium intake (odds ratio = 0.93, 95% confidence interval = 0.87, 1.00, P = .0455). This relationship was maintained after adjusting for age, sex, and body mass index (BMI) with slightly reduced significance (P = .0505). In women, this inverse relationship was limited to those with lower BMI (P = .007), while in men the relationship did not differ by BMI. We likely excluded some migraineurs by omitting frequent analgesic users; however, a sensitivity analysis suggested little effect from this exclusion. CONCLUSIONS: This study is the first evidence of an inverse relationship between migraine and dietary sodium intake. These results are consistent with altered sodium homeostasis in migraine and our hypothesis that dietary sodium may affect brain extracellular fluid sodium concentrations and neuronal excitability.

An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients.

BACKGROUND AND OBJECTIVE: Long-acting injectable antipsychotics have shown benefits over oral medications with reduced hospitalization rates and improved health-related quality of life. RBP-7000 (PERSERIS®) is a monthly risperidone formulation (90 or 120 mg) for the treatment of schizophrenia administered by subcutaneous abdominal injection. The objective of this study was to assess a higher dose of 180 mg RBP-7000 and an alternate injection site. METHODS: Following stabilization on 6 mg/day (3 mg twice daily) oral risperidone, clinically stable schizophrenic participants received 3 monthly doses of 180 mg RBP-7000 in the abdomen followed by a fourth monthly dose of 180 mg RBP-7000 in the upper arm (each dose administered as two 90-mg injections). The primary endpoint was the steady-state average plasma concentration (Cavg(ss)) of risperidone and total active moiety after oral and RBP-7000 administration. Secondary endpoints included measures of clinical efficacy (Positive and Negative Syndrome Scale, Clinical Global Impression Scale for Severity of Illness), safety, and local injection-site tolerability to assess the switch from oral risperidone and compare injection sites. RESULTS: In all, 23 participants received at least one dose of RBP-7000, 16 received all four doses, and 15 completed the study. Monthly doses of 180 mg RBP-7000 provided similar Cavg(ss) of total active moiety compared with 6 mg/day oral risperidone. The pharmacokinetics of RBP-7000 were similar after injection in the abdomen versus upper arm. Clinical efficacy measures remained stable throughout the study. All RBP-7000 injections were well tolerated with no unexpected safety findings. CONCLUSIONS: The results support the use of 180 mg RBP-7000 in schizophrenic patients stable on 6 mg/day oral risperidone and a second injection site in the upper arm. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03978832.

Phospholipase C activity increases in cerebrospinal fluid from migraineurs in proportion to the number of comorbid conditions: a case-control study.

BACKGROUND: Migraineurs are more often afflicted by comorbid conditions than those without primary headache disorders, though the linking pathophysiological mechanism(s) is not known. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) activity in cerebrospinal fluid (CSF) increased during migraine compared to the same individual's well state. Here, we examined whether PC-PLC activity from a larger group of well-state migraineurs is related to the number of their migraine comorbidities. METHODS: In a case-control study, migraineurs were diagnosed using International Headache Society criteria, and controls had no primary headache disorder or family history of migraine. Medication use, migraine frequency, and physician-diagnosed comorbidities were recorded for all participants. Lumbar CSF was collected between the hours of 1 and 5 pm, examined immediately for cells and total protein, and stored at -80°C. PC-PLC activity in thawed CSF was measured using a fluorometric enzyme assay. Multivariable logistic regression was used to evaluate age, gender, medication use, migraine frequency, personality scores, and comorbidities as potential predictors of PC-PLC activity in CSF. RESULTS: A total of 18 migraineurs-without-aura and 17 controls participated. In a multivariable analysis, only the number of comorbidities was related to PC-PLC activity in CSF, and only in migraineurs [parameter estimate (standard error) = 1.77, p = 0.009]. CONCLUSION: PC-PLC activity in CSF increases with increasing number of comorbidities in migraine-without-aura. These data support involvement of a common lipid signaling pathway in migraine and in the comorbid conditions.

Treatment of high-grade anal intraepithelial neoplasia with infrared coagulation in a primary care population of HIV-infected men and women.

BACKGROUND: High-grade anal intraepithelial neoplasia, the putative anal carcinoma precursor, is more common in HIV-infected persons. The ideal treatment for these lesions has not been established. OBJECTIVE: The aim of this study was to evaluate the effectiveness of infrared coagulation treatment for high-grade anal intraepithelial neoplasia. DESIGN: This is a prospective cohort study. Patients with high-grade anal intraepithelial neoplasia either received infrared coagulation treatment or voluntarily did not receive treatment and were reevaluated at a subsequent time point. SETTING: This investigation was performed at a Ryan White-funded clinic located in the United States. PATIENTS: HIV-infected men and women with biopsy-confirmed high-grade anal intraepithelial neoplasia were included. MAIN OUTCOME MEASURES: The primary outcome measured was the histology collected by high-resolution anoscopy-directed biopsy. RESULTS: The study included 124 patients. Of 42 patients who either delayed treatment or were not treated, 37 (88%; 95% CI = 74%-96%) still had high-grade anal intraepithelial neoplasia on reevaluation and 2 (5%; 95%CI = 1%-16%) had squamous-cell carcinoma. Of 98 patients who received infrared coagulation treatment, 73 (74%; 95% CI = 65%-83%) patients had no evidence of high-grade anal intraepithelial neoplasia on their first posttreatment evaluation, and none had progressed to squamous-cell carcinoma (p < 0.0001 in comparison with untreated). Upon completing all initial and, if necessary, follow-up treatment, 85 (87%; 95% CI = 78%-93%) patients treated by infrared coagulation had no evidence of high-grade anal intraepithelial neoplasia and none had progressed to squamous-cell carcinoma. LIMITATIONS: The study population may not be representative of the general population, the study environment was uncontrolled, and patients were not randomly assigned to treatment. CONCLUSIONS: Infrared coagulation is an effective treatment for high-grade anal intraepithelial neoplasia.

Rapid Capsular Antigen Immunoassay for Diagnosis of Inhalational Anthrax: Preclinical Studies and Evaluation in a Nonhuman Primate Model.

Inhalational anthrax is a fatal infectious disease. Rapid and effective treatment is critically dependent on early and accurate diagnosis. Blood culture followed by identification and confirmation may take days to provide clinically relevant information. In contrast, immunoassay for a shed antigen, the capsular polypeptide gamma-d-polyglutamate (γDPGA), can provide rapid results at the point of care. In this study, a lateral flow immunoassay for γDPGA was evaluated in a robust nonhuman primate model of inhalational anthrax. The results showed that the time to a positive result with the rapid test using either serum or blood as a clinical specimen was similar to the time after infection when a blood culture became positive. In vitro testing showed that the test was equally sensitive with cultures of the three major clades of Bacillus anthracis. Cultures from other Bacillus spp. that are known to produce γDPGA also produced positive results. The test was negative with human sera from 200 normal subjects and 45 subjects with culture-confirmed nonanthrax bacterial or fungal sepsis. Taken together, the results showed that immunoassay for γDPGA is an effective surrogate for blood culture in a relevant cynomolgus monkey model of inhalational anthrax. The test would be a valuable aid in early diagnosis of anthrax, which is critical for rapid intervention and a positive outcome. Use of the test could facilitate triage of patients with signs and symptoms of anthrax in a mass-exposure incident and in low-resource settings where laboratory resources are not readily available. IMPORTANCE Patient outcome in anthrax is critically dependent on early diagnosis followed by effective treatment. We describe a rapid lateral flow immunoassay that detects capsular antigen of Bacillus anthracis that is shed into blood during infection. The test was evaluated in a robust cynomolgus monkey model of inhalational anthrax. Rapid detection of capsular antigen is an effective surrogate for the time-consuming and laboratory-intensive diagnosis by blood culture, direct fluorescent antibody staining, or other molecular testing. The test can be performed at the point of patient contact, is rapid and inexpensive, and can be used by individuals with minimal training.

Cerebrospinal fluid phospholipase C activity increases in migraine.

BACKGROUND: Adrenaline, serotonin, cannabinoid and estrogen receptors are involved in migraine pathophysiology. The signaling of these receptors change phosphatidylcholine-specific phospholipase C (PC-PLC) activity, but there have been no reported PC-PLC studies in migraine. METHODS: We identified PC-PLC activity in blood and cerebrospinal fluid (CSF), and quantified it in samples from ictal and interictal migraineurs without aura and healthy controls. RESULTS: Pre-incubation with a specific PC-PLC inhibitor, D609, inhibited enzyme activity (p < .0001) and confirms its presence in CSF. PC-PLC activity was higher in the CSF from ictal migraineurs compared to controls (mean relative fluorescence unit [RFU]/µg/min [standard deviation, SD] 13.1 [3.07] vs. 9.3 [1.97]; p = .002) and, in a paired analysis, in migraineurs during ictal compared to interictal states (11.7 [1.6] vs. 7.9 [1.5]; p = .02). CSF PC-PLC activity in the ictal state correlated negatively with migraine frequency (r = -0.82). Plasma PC-PLC activity was 250-300 times less than in CSF and did not increase in migraine, implicating the brain as the source of the CSF enzyme changes. CONCLUSION: This is the first report of PC-PLC activity in CSF and of its alteration in migraine. We propose that these PC-PLC changes in CSF reflect the overall receptor fluctuations in migraine.

Prevalence of anal intraepithelial neoplasia defined by anal cytology screening and high-resolution anoscopy in a primary care population of HIV-infected men and women.

BACKGROUND: Prevalence of high-grade anal intraepithelial neoplasia, the human papillomavirus-associated putative anal cancer precursor, is high in HIV-infected men who have sex with men, but less is known about its prevalence in other HIV-infected subgroups. Similarly, the prevalence of abnormal cytology, used as a screen, is not well-defined in these subgroups. OBJECTIVE: This study aimed to estimate the prevalence of abnormal cytology and anal intraepithelial neoplasia in a primary care HIV-infected population. DESIGN: This investigation was designed as a cross-sectional study. SETTING: This study took place at a Ryan White-funded clinic. PATIENTS: Included in the study were all (n = 779) HIV-infected patients receiving primary care services between March 2006 and March 2008. MAIN OUTCOME MEASURES: The main outcome measures were anal cytology and high-resolution anoscopy results. RESULTS: The prevalence of abnormal cytology was 43%: 62% in men who reported receptive anal intercourse, 39% in women who reported receptive anal intercourse, and 25% in all others (P trend <.0001). High-grade anal intraepithelial neoplasia prevalence was 27%: 44% in men who reported receptive anal intercourse, 26% in women who reported receptive anal intercourse, and 10% in all others (P trend <.0001). Two patients had squamous-cell cancer. Independent predictors of dysplasia were CD4 at screening, receptive anal intercourse, sexual orientation, and history of human papillomavirus disease. Anal cytology and histology findings were not well correlated. LIMITATIONS: The study population may not be representative of the general HIV-infected population, there were differences between screened and unscreened patients and between patients with abnormal cytology who had high-resolution anoscopy and those who did not, only patients with abnormal cytology had high-resolution anoscopy, and there were possible misclassification errors and uncontrolled possible confounders. CONCLUSIONS: High-grade anal intraepithelial neoplasia is relatively common in HIV-infected patients regardless of sexual practice. Although risk increases with receptive anal intercourse, patient-provided information on this sexual practice should not be used as a determining factor for screening. Strategies to prevent anal cancer are necessary for all HIV-infected patients.

Does directly observed therapy (DOT) reduce drug resistant tuberculosis?

BACKGROUND: Directly observed therapy (DOT) is a widely recommended and promoted strategy to manage tuberculosis (TB), however, there is still disagreement about the role of DOT in TB control and the impact it has on reducing the acquisition and transmission of drug resistant TB. This study compares the portion of drug resistant genotype clusters, representing recent transmission, within and between communities implementing programs differing only in their directly observed therapy (DOT) practices. METHODS: Genotype clusters were defined as 2 or more patient members with matching IS6110 restriction fragment length polymorphism (RFLP) and spoligotype patterns from all culture-positive tuberculosis cases diagnosed between January 1, 1995 and December 31, 2001. Logistic regression was used to compute maximum-likelihood estimates of odds ratios (ORs) and 95% confidence intervals (CIs) comparing cluster members with and without drug resistant isolates. In the universal DOT county, all patients received doses under direct observation of health department staff; whereas in selective DOT county, the majority of received patients doses under direct observation of health department staff, while some were able to self-administer doses. RESULTS: Isolates from 1,706 persons collected during 1,721 episodes of tuberculosis were genotyped. Cluster members from the selective DOT county were more than twice as likely than cluster members from the universal DOT county to have at least one isolate resistant to isoniazid, rifampin, and/or ethambutol (OR = 2.3, 95% CI: 1.7, 3.1). Selective DOT county isolates were nearly 5 times more likely than universal DOT county isolates to belong to clusters with at least 2 resistant isolates having identical resistance patterns (OR = 4.7, 95% CI: 2.9, 7.6). CONCLUSIONS: Universal DOT for tuberculosis is associated with a decrease in the acquisition and transmission of resistant tuberculosis.

Intranasal Surfactant for Acute Otitis Media: A Randomized Trial.

BACKGROUND: Acute otitis media (AOM) is the most frequent reason for children to be prescribed antimicrobial treatment. Surfactants are naturally occurring substances that may restore the eustachian tube's function and potentially enhance resolution of AOM. METHODS: This was a phase 2a, single-center, double-blind, randomized, placebo-controlled, parallel group clinical trial to assess safety, tolerability, and efficacy of 20 mg per day intranasal OP0201 as an adjunct therapy to oral antimicrobial agents for treating AOM in young children. We randomly assigned 103 children aged 6 to 24 months with AOM to receive either OP0201 or placebo twice daily for 10 days. All children received amoxicillin-clavulanate 90/6.4 mg/kg per day in 2 divided doses for 10 days. Participants were managed for up to 1 month. Postrandomization visits occurred between days 4 and 6 (visit 2), days 12 and 14 (visit 3), and days 26 and 30 (visit 4). Primary efficacy endpoints were resolution of a bulging tympanic membrane at visit 2 and resolution of middle-ear effusion at visit 3. RESULTS: No clinically meaningful differences between treatment groups were apparent for primary or secondary endpoints. There were no safety concerns identified. CONCLUSIONS: In young children with AOM, intranasally administered surfactant (OP0201) did not improve clinical outcomes. Further research may be warranted among children with persistent middle-ear effusion.

Cerebrospinal fluid sodium rhythms.

BACKGROUND: Cerebrospinal fluid (CSF) sodium levels have been reported to rise during episodic migraine. Since migraine frequently starts in early morning or late afternoon, we hypothesized that natural sodium chronobiology may predispose susceptible persons when extracellular CSF sodium increases. Since no mammalian brain sodium rhythms are known, we designed a study of healthy humans to test if cation rhythms exist in CSF. METHODS: Lumbar CSF was collected every ten minutes at 0.1 mL/min for 24 h from six healthy participants. CSF sodium and potassium concentrations were measured by ion chromatography, total protein by fluorescent spectrometry, and osmolarity by freezing point depression. We analyzed cation and protein distributions over the 24 h period and spectral and permutation tests to identify significant rhythms. We applied the False Discovery Rate method to adjust significance levels for multiple tests and Spearman correlations to compare sodium fluctuations with potassium, protein, and osmolarity. RESULTS: The distribution of sodium varied much more than potassium, and there were statistically significant rhythms at 12 and 1.65 h periods. Curve fitting to the average time course of the mean sodium of all six subjects revealed the lowest sodium levels at 03.20 h and highest at 08.00 h, a second nadir at 09.50 h and a second peak at 18.10 h. Sodium levels were not correlated with potassium or protein concentration, or with osmolarity. CONCLUSION: These CSF rhythms are the first reports of sodium chronobiology in the human nervous system. The results are consistent with our hypothesis that rising levels of extracellular sodium may contribute to the timing of migraine onset. The physiological importance of sodium in the nervous system suggests that these rhythms may have additional repercussions on ultradian functions.

OnabotulinumtoxinA treatment of mild glabellar lines in repose.

BACKGROUND: OnabotulinumtoxinA is an established treatment for glabellar frown lines, but its effects on lines at repose are less well documented. OBJECTIVE: To assess the effect of onabotulinumtoxinA on elimination of mild lines at repose. METHODS: Data from two randomized, double-blind, placebo-controlled studies were included. Elimination of mild lines at repose was defined as change from mild to none on the Facial Wrinkle Scale. RESULTS: Analysis included 183 participants who received 20 U of onabotulinumtoxinA and 64 participants who received placebo, all with mild lines at repose at baseline. Participants were evaluated 7, 30, 60, 90, and 120 days posttreatment. Compared to placebo, onabotulinumtoxinA-treated participants were significantly more likely to have their lines at repose eliminated at each study day; [odds ratios ranged from 42.7 (95% confidence interval (CI)=12.9-141.9) at day 30 to 4.9 (95% CI=2.2-10.8) at day 120 (p<.0001 at each day)]. The highest response rate was observed at day 30 (68%). CONCLUSION: OnabotulinumtoxinA has demonstrated the ability to eliminate mild glabellar lines at repose for a significant number of patients. This effect, albeit more subtle than the effect on dynamic or more severe glabellar lines, may be an important treatment goal for patients who seek a smoother appearance at repose.

Allogeneic cardiosphere-derived cells for the treatment of heart failure with reduced ejection fraction: the Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial.

AIMS: The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial. METHODS AND RESULTS: We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial. Intracoronary catheterisation delivered four escalating doses (totalling 37.5-75 million cells) by sequential non-occlusive technique to all three major coronary arteries. The primary safety endpoint was a composite of post-infusion TIMI flow, ventricular tachycardia/fibrillation, sudden death, major adverse cardiac events or acute myocarditis within 72 hours. Twelve patients were male and EF averaged 23.0% (±4.5%). No primary safety endpoints were observed. Two patients died of HFrEF progression nine and 12 months following infusion. Compared to baseline, there was an improvement in EF (26.8% vs 22.9%, p=0.023) and left ventricular end-systolic volume (139.5 vs 177.8 cm3, p=0.03) at six months. Quality of life (QoL) scores and NYHA class (p=0.006) improved at six months. At 12 months, the improvement in EF and QoL remained significant. CONCLUSIONS: Global intracoronary infusion of allogeneic CDCs is safe and feasible. The efficacy of allogeneic CDCs in HFrEF needs to be tested in larger randomised trials.

Correction: Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline.

[This corrects the article DOI: 10.1371/journal.pone.0232785.].

Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline.

BACKGROUND: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) µm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.

Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants.

BACKGROUND: OnabotulinumtoxinA for the treatment of facial lines is a widely used cosmetic medical procedure and, as such, the safety and tolerability profile is of interest to health care providers and patients. Based on data from individual studies that were conducted according to regulatory guidelines to provide adequate safety and efficacy data to support product licensure (registration studies), the overall benefit:risk profile of onabotulinumtoxinA for facial lines has been favorable. OBJECTIVE: Our objective was to increase statistical power through meta-analysis to detect treatment group differences in adverse event (AE) incidence that may not have been evident in individual registration studies. METHODS: Individual participant data (n = 1678) were from 6 randomized, double-blind, placebo-controlled and 3 open-label studies. Two double-blind, placebo-controlled studies were for lateral canthal lines (3-18 U/side) and all others were for glabellar lines (10 or 20 U). Doses used reflect global product labeling in countries where licensed. RESULTS: Participant population was non-Hispanic white (43%) or Asian (52%) and predominantly female (88%). In double-blind, placebo-controlled studies, overall AE incidence did not significantly differ by treatment group (onabotulinumtoxinA vs placebo). The only individual AEs with significantly greater incidence in the onabotulinumtoxinA group were eyelid sensory disorder (2.5% vs 0.3%, P = .004; verbatim phrases "tight," "pressured," "heavy," "drooping feeling," "feeling of droopiness") and eyelid ptosis (1.8% vs 0%, P = .02), both present only in glabellar studies. Overall treatment-related (per investigator) AE incidence was greater in the onabotulinumtoxinA group versus placebo (24% vs 16%, P = .005), and treatment-related eyelid edema was an additional AE with significantly higher incidence in the onabotulinumtoxinA group versus placebo (P = .04). Incidence of all 3 of these AEs significantly decreased as number of treatment cycles increased. Eyelid sensory disorder and eyelid edema were more common in Asian participants. Acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo-treated compared with onabotulinumtoxinA-treated participants. Serious AE incidence did not significantly differ by treatment (onabotulinumtoxinA vs placebo) and no serious AEs were treatment related. There were no symptoms of weakness remote to the injection site or related to the central nervous system. LIMITATIONS: Limitations included: (1) highly visible efficacy of onabotulinumtoxinA may have resulted in reporting bias; (2) reliance on participant intervisit recall; (3) a relatively short follow-up period (1 year); (4) conclusions are based solely on the doses analyzed (ie, those used in the respective trials); and (5) exclusion of patients with severe medical disease in registration studies. CONCLUSION: This meta-analysis confirms the safety and tolerability of onabotulinumtoxinA for glabellar and lateral canthal lines, at the doses studied, based on the most comprehensive controlled safety analysis of onabotulinumtoxinA performed to date. The AEs observed were generally mild to moderate; most treatment-related AEs were related either to physical injection of product or local pharmacologic effects. Even with the increased statistical power of a large sample size, no new onabotulinumtoxinA-associated AEs emerged.

Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial.

OBJECTIVE: To assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD). METHODS: The Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL). RESULTS: Twenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007). CONCLUSIONS: Intracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.