bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights
Authors: Bell D. , Pediconi C. , Jacobs A. 
Published: February 2014

AbstractAimsThe application of α‐adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories.MethodsThis randomised, double‐blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence.ResultsTmax was at ~4.5 h post‐dose for all NRL001 doses. Median AUC0–tz, AUC0–∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0–tz, AUC0–∞ and Cmax (P > 0.05). For both suppository sizes, 20‐min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity.ConclusionsThe regression analysis concluded that the doses were dose proportional.
A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S‐methoxamine hydrochloride (NRL001) in healthy elderly subjects
Authors: Bell D. , Duffin A. , Gruss H. J. , Pediconi C. , Jacobs A. 
Published: February 2014

AbstractAimsThis study aimed to assess the effects of a single dose of 10 mg NRL001 (the 1R,2S stereoisomer of methoxamine hydrochloride) in a 2 g suppository on pharmacodynamic and pharmacokinetic (PK) variables, and safety, in a healthy elderly population.MethodsThis was a Phase I, single‐centre, randomised, double‐blind, placebo‐controlled crossover study during which subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. The main outcome measures were Holter‐, vital signs‐ and electrocardiogram‐derived cardiovascular variables; plasma PK analysis; and safety assessments.ResultsTwenty‐six subjects were dosed with study medication. Statistically significant reductions in Holter‐derived heart rate (HR), vital signs‐derived HR and diastolic blood pressure (BP) were observed comparing NRL001 with placebo treatment, and also with increasing NRL001 plasma concentration. No statistically significant relationships were observed between NRL001 concentration and systolic BP, mean arterial pressure or QTC interval (both Bazett's and Fridericia's correction). Thirty‐nine adverse events were reported in 20 (76.9%) subjects, mostly after dosing with NRL001.ConclusionAdministration of NRL001 suppositories led to decreases in HR when compared with placebo data. NRL001 was well tolerated with a good safety profile during the study. Healthy elderly subjects did not show significantly different biological responses to NRL001 suppositories compared with younger healthy volunteers in previous studies.
A double‐blind, placebo‐controlled, randomised, parallel‐group, dose‐escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days
Authors: Bell D. , Duffin A. , Jacobs A. , Pediconi C. , Gruss H. J. 
Published: February 2014

AbstractAimsThe 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1‐adrenoceptor agonist being developed for the local treatment of non‐structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg).MethodsHealthy volunteers aged 18–45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs.ResultsForty‐eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection.ConclusionsTreatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α‐adrenergic effect.
Meta‐analysis for cardiovascular effects of NRL001 after rectal application in healthy volunteers
Authors: Gruss H. J. , Pediconi C. , Jacobs A. 
Published: February 2014

AbstractAimsNRL001 is a highly specific α1–adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta‐analysis was to quantify the effect of NRL001 on cardiovascular parameters including heart rate, blood pressure and QT interval.MethodsData from the four Phase I healthy volunteer studies SUM (NCT00857467), SURD (NCT01099670), SUSD (NCT00850590) and SAGE (NCT01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of NRL001 on heart rate, blood pressure and QT intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate.ResultsSubjects given NRL001 experienced a dose related decrease in heart rate of up to 9.48 bpm compared with subjects in the placebo arms. No statistically significant evidence for a threshold effect was found. There was no clear evidence of dose effect of NRL001 on blood pressure. QT interval increased in all NRL001 subject as expected; QTCF also showed a statistically significant increase. However, QTCB was shortened with no significant treatment effect.ConclusionsNRL001 was found to have a dose‐dependent effect on heart rate; however clinically–relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically‐significant drug effect on blood pressure or mean arterial pressure was observed. QT intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent QT effect was observed, but a thorough QTC study will be required to confirm the effects of rectally applied NRL001.
Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant
Authors: Warsame Rahma , Bang Soo Mee , Kumar Shaji K. , Gertz Morie A. , Lacy Martha Q. , Buadi Francis , Dingli David , Hayman Suzanne R. , Kapoor Prashant , Kyle Robert A. , Leung Nelson , Lust John A. , Russell Stephen J. , Witzig Thomas E. , Zeldenrust Steven R. , Rajkumar S. Vincent , Dispenzieri Angela 
Published: February 2014

AbstractImmunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.
Emergency management of febrile status epilepticus: Results of the FEBSTAT study
Authors: Seinfeld Syndi , Shinnar Shlomo , Sun Shumei , Hesdorffer Dale C. , Deng Xiaoyan , Shinnar Ruth C. , O'Hara Kathryn , Nordli Douglas R. , Frank L. Matthew , Gallentine William , Moshé Solomon L. , Pellock John M. ,   FEBSTAT study team
Published: February 2014

SummaryObjectiveTreatment of seizures varies by region, with no standard emergency treatment protocol. Febrile status epilepticus (FSE) is often a child's first seizure; therefore, families are rarely educated about emergency treatment.MethodsFrom 2002 to 2010, 199 subjects, age 1 month to 6 years, were recruited as part of a prospective, multicenter study of consequences of FSE, which was defined as a febrile seizure or series of seizures lasting >30 min. The patients' charts were reviewed. No standardized treatment protocol was implemented for this observational study.ResultsOne hundred seventy‐nine children received at least one antiepileptic drug (AED) to terminate FSE, and more than one AED was required in 140 patients (70%). Median time from the seizure onset to first AED by emergency medical services (EMS) or emergency department (ED) was 30 min. Mean seizure duration was 81 min for subjects given medication prior to ED and 95 min for those who did not (p = 0.1). Median time from the first dose of AED to end of seizure was 38 min. Initial dose of lorazepam or diazepam was suboptimal in 32 (19%) of 166 patients. Ninety‐five subjects (48%) received respiratory support by EMS or ED. Median seizure duration for the respiratory support group was 83 min; for the nonrespiratory support group the duration was 58 min (p‐value < 0.001). Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration.SignificanceFSE rarely stops spontaneously, is fairly resistant to medications, and even with treatment persists for a significant period of time. The total seizure duration is composed of two separate factors, the time from seizure onset to AED initiation and the time from first AED to seizure termination. Earlier onset of treatment results in shorter total seizure duration. A standard prehospital treatment protocol should be used nationwide and education of EMS responders is necessary.
A survey of seizures and current treatments in 15q duplication syndrome
Authors: Conant Kerry D. , Finucane Brenda , Cleary Nicole , Martin Ashley , Muss Candace , Delany Mary , Murphy Erin K. , Rabe Olivia , Luchsinger Kadi , Spence Sarah J. , Schanen Carolyn , Devinsky Orrin , Cook Edwin H. , LaSalle Janine , Reiter Lawrence T. , Thibert Ronald L. 
Published: February 2014

SummaryObjectiveSeizures are common in individuals with duplications of chromosome 15q11.2‐q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population.MethodsA detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q.ResultsThere were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic–clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin.SignificanceThis is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire‐based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox‐Gastaut–type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other γ‐aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAβ3 receptor genes in the 15q11.2‐13 region.
Patterns of diagnosis and therapeutic care of epilepsy at a tertiary referral center in Nigeria
Authors: Igwe Stanley C. , Brigo Francesco , Beida Omeiza 
Published: February 2014

SummaryObjectiveEpilepsy care in developing countries is challenged by the paucity of trained specialists, diagnostic tools, and antiepileptic drugs (AEDs). We retrospectively evaluated how epilepsy was managed in a Nigerian tertiary referral center, with the goals of determining diagnostic accuracy by comparing clinical and electroencephalography (EEG) diagnoses, the appropriateness of prescribed therapy by clinician specialization, and the association between therapy and patient outcomes.MethodsWe examined the medical records of 372 patients diagnosed with epilepsy in the center over a 6‐month period from 2011 to 2012. Data were obtained on methods of diagnosis, clinician specialization, therapeutic care, and patient self‐ or caregiver‐reported outcome on follow‐up visits. Interrater agreement was assessed using Cohen's κ coefficient, and the diagnoses made by nonspecialist and specialist clinicians compared using the chi‐square test.ResultsOf 372 patients diagnosed with epilepsy, only one had a brain computerized tomography (CT) scan. Seventy‐six were differentially diagnosed for generalized or partial epilepsy by both clinical presentation and EEG. Low interrater agreement (κ = 0.05) was found between these methods of diagnosis. Of the 76 patients, 53 (69.7%) received therapies judged as appropriate, with no significant difference in prescription rates for appropriate therapy between nonspecialists and specialists (p = 0.536). Specific syndromic diagnoses were made only in 4% of patients, and only in patients who underwent EEG. Only three first‐generation AEDs were prescribed, with 97.6% of patients receiving carbamazepine.SignificanceThe discrepancy between diagnoses made on clinical features alone versus EEG diagnosis suggests that in many patients without concomitant EEG, the epileptic syndrome might have been erroneously classified, with increased risk of inappropriate treatment. Resources should be more properly directed toward increasing access to diagnostic facilities and newer generation AEDs.
Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility
Authors: Leventer Richard J. , Jansen Floor E. , Mandelstam Simone A. , Ho Alice , Mohamed Ismail , Sarnat Harvey B. , Kato Mitsuhiro , Fukasawa Tatsuya , Saitsu Hirotomo , Matsumoto Naomichi , Itoh Masayuki , Kalnins Renate M. , Chow Chung W. , Harvey A. Simon , Jackson Graeme D. , Crino Peter B. , Berkovic Samuel F. , Scheffer Ingrid E. 
Published: February 2014

SummaryFocal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co‐occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Circadian rhythms on skin function of hairless rats: light and thermic influences
Authors: Flo Ana , Díez‐Noguera Antoni , Calpena Ana C. , Cambras Trinitat 
Published: February 2014

AbstractCircadian rhythms are present in most functions of living beings. We have demonstrated the presence of circadian rhythms in skin variables (transepidermal water loss, TEWL; stratum corneum hydration, SCH; and skin temperature) in hairless rats under different environmental conditions of light and temperature. Circadian rhythms in TEWL and SCH showed mean amplitudes of about 20% and 14% around the mean, respectively, and appeared under light–dark cycles as well as under constant darkness. Environmental temperature was able to override TEWL, but not SCH rhythm, evidencing the dependency of TEWL on the temperature. Mean daily values of TEWL and SCH, and also the amplitude of TEWL rhythm, increased with the age of the animal. Under constant light, situation that induces arrhythmicity in rats, SCH and TEWL were inversely correlated. The results suggest the importance to take into account the functional skin rhythms in research in dermatological sciences.
Epidermal expression of Lgr6 is dependent on nerve endings and Schwann cells
Authors: Liao Xin‐Hua , Nguyen Hoang 
Published: February 2014

AbstractLgr5/6 proteins are stem cell markers in various tissues. However, what determines their restricted expression pattern in these tissues remains unknown. We found that in skin, Lgr6 is not only expressed in the central isthmus, directly above the hair follicle bulge cells as reported previously, but also in the interfollicular epidermis. Lgr6 expression in skin is highly correlated with the innervation sites of cutaneous nerves. In the hair follicle, Lgr6 closely localizes with the surrounding nerve endings and their corresponding Schwann cells throughout the entire hair cycle. Furthermore, ablation of cutaneous nerves leads to degeneration of Schwann cells and diminished expression of Lgr6. Our results demonstrate that the nerve endings/Schwann cells control Lgr6 expression in skin, implying that they play a role in regulation of skin epithelial cells.
Simulation of Water‐Table Aquifers Using Specified Saturated Thickness
Authors: Sheets Rodney A. , Hill Mary C. , Haitjema Henk M. , Provost Alden M. , Masterson John P. 
Published: February 2014

AbstractSimulating groundwater flow in a water‐table (unconfined) aquifer can be difficult because the saturated thickness available for flow depends on model‐calculated hydraulic heads. It is often possible to realize substantial time savings and still obtain accurate head and flow solutions by specifying an approximate saturated thickness a priori, thus linearizing this aspect of the model. This specified‐thickness approximation often relies on the use of the “confined” option in numerical models, which has led to confusion and criticism of the method. This article reviews the theoretical basis for the specified‐thickness approximation, derives an error analysis for relatively ideal problems, and illustrates the utility of the approximation with a complex test problem. In the transient version of our complex test problem, the specified‐thickness approximation produced maximum errors in computed drawdown of about 4% of initial aquifer saturated thickness even when maximum drawdowns were nearly 20% of initial saturated thickness. In the final steady‐state version, the approximation produced maximum errors in computed drawdown of about 20% of initial aquifer saturated thickness (mean errors of about 5%) when maximum drawdowns were about 35% of initial saturated thickness. In early phases of model development, such as during initial model calibration efforts, the specified‐thickness approximation can be a very effective tool to facilitate convergence. The reduced execution time and increased stability obtained through the approximation can be especially useful when many model runs are required, such as during inverse model calibration, sensitivity and uncertainty analyses, multimodel analysis, and development of optimal resource management scenarios.
An evaluation of the bihyperbolic function in the optimization of the backpropagation algorithm
Authors: Miguez Geraldo , Xavier Adilson Elias , Maculan Nelson 
Published: February 2014

AbstractThe backpropagation algorithm is one of the most used tools for training artificial neural networks. However, this tool may be very slow in some practical applications. Many techniques have been discussed to speed up the performance of this algorithm and allow its use in an even broader range of applications. Although the backpropagation algorithm has been used for decades, we present here a set of computational results that suggest that by replacing bihyperbolic functions the backpropagation algorithm performs better than the traditional sigmoid functions. To the best of our knowledge, this finding was never previously published in the open literature. The efficiency and discrimination capacity of the proposed methodology are shown through a set of computational experiments, and compared with the traditional problems of the literature.