Showing papers by "Atlantic Health System published in 2018"

Melatonin treatment enhances Aβ lymphatic clearance in a transgenic mouse model of amyloidosis

Abstract: Background It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. Objective To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. Methods For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues. Results Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain. Conclusion The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.

Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections.

Abstract: Introduction: Sleep and migraine share a common pathophysiological substrate, although the underlying mechanisms are unknown. The serotonergic and orexinergic systems are both involved in the regulation of sleep/wake cycle and numerous studies show that both are involved in the migraine etiopathogenesis. These two systems are anatomically and functionally interconnected. Our hypothesis is that in migraine a dysfunction of orexinergic projections on the median raphe nuclei, interfering with serotonergic regulation, may cause NREM parasomnias, such as somnambulism. Hypothesis/Theory: Acting on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would conduct to a higher release of serotonin. The activation of serotonergic receptors located on the walls of large cerebral vessels would lead to abnormal vasodilatation and consequently increasing of transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. By consequence, there is activation of sensory nerve endings at the level of hard vessels in the meninges, with release of pro-inflammatory peptides (e.g. substance P and CGRP). Within this hypothetical frame, the released serotonin could also interact with trigemino-vascular afferents to activate and/or facilitate the release of the neuropeptide at the level of the trigeminal ganglion. The dysregulation of the physiological negative feedback of serotonin on the orexinergic neurons, in turn, would contribute to an alteration of the whole system, altering the sleep-wake cycle. Conclusion: Serotonergic neurons of the median raphe nuclei receive an excitatory input from hypothalamic orexin/hypocretin neurons and reciprocally inhibit orexin/hypocretin neurons through the serotonin 1A receptor (or 5-HT1A receptor). Considering this complex system, if there is an alteration it may facilitate the pathophysiologic mechanisms involved in the migraine, while it may produce at the same time an alteration of the sleep-wake rhythm, causing sleep disorders such as sleepwalking. Understanding the complex mechanisms underlying migraine and sleep disorders and how these mechanisms can interact with each other it would be crucial to pave the way for new therapeutic strategies.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Abstract: Background Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. Methods Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. Results The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. Conclusions The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

Abstract: The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS) Collectively, the mutant alleles encompass a 5′-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity While the bi-allelic combination of the SJV with a pArg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs

Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma.

Abstract: Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

Neuroimmunomodulators in Neuroborreliosis and Lyme Encephalopathy.

Abstract: Background Lyme encephalopathy, characterized by nonspecific neurobehavioral symptoms including mild cognitive difficulties, may occur in patients with systemic Lyme disease and is often mistakenly attributed to central nervous system (CNS) infection. Identical symptoms occur in many inflammatory states, possibly reflecting the effect of systemic immune mediators on the CNS. Methods Multiplex immunoassays were used to measure serum and cerebrospinal fluid (CSF) cytokines in patients with or without Lyme disease to determine if there are specific markers of active CNS infection (neuroborreliosis), or systemic inflammatory mediators associated with neurobehavioral syndromes. Results CSF CXCL13 levels were elevated dramatically in confirmed neuroborreliosis (n = 8), less so in possible neuroborreliosis (n = 11) and other neuroinflammatory conditions (n = 44). Patients with Lyme (n = 63) or non-Lyme (n = 8) encephalopathy had normal CSF findings, but had elevated serum levels of interleukins 7, 17A, and 17F, thymic stromal lymphopoietin and macrophage inflammatory protein-α. Conclusions CSF CXCL13 is a sensitive and specific marker of neuroborreliosis in individuals with Borrelia-specific intrathecal antibody production. However, it does not distinguish individuals strongly suspected of having neuroborreliosis, but lacking confirmatory intrathecal antibodies, from those with other neuroinflammatory conditions. Patients with mild cognitive symptoms occurring during acute Lyme disease, and/or after appropriate treatment, have normal CSF but elevated serum levels of T-helper 17 markers and T-cell growth factors, which are also elevated in patients without Lyme disease but with similar symptoms. In the absence of CSF abnormalities, neurobehavioral symptoms appear to be associated with systemic inflammation, not CNS infection or inflammation, and are not specific to Lyme disease.

Veganism as a cause of iodine deficient hypothyroidism.

Abstract: Background Iodine deficiency is the most common cause of acquired hypothyroidism worldwide. Although uncommon in the Western world, the incidence of iodine deficiency may be rising due to the increased use of restrictive diets. Case presentation We present a 23-month-old boy diagnosed with iodine deficiency hypothyroidism, induced by a vegan diet. Conclusions This case highlights the risk for iodine deficiency in children on a vegan diet after discontinuation of breast/formula feeding that could lead to acquired hypothyroidism.

Cognitive Deficits Are Attenuated in Neuroglobin Overexpressing Mice Exposed to a Model of Obstructive Sleep Apnea.

Abstract: Background: Obstructive sleep apnea (OSA) is a highly prevalent disease manifesting as intermittent hypoxia during sleep (IH) and is increasingly recognized as being independently associated with neurobehavioral deficits. These deficits may be due to increased apoptosis in the hippocampus and cerebral cortex, as well as increased oxidative stress and inflammation. It has been reported that neuroglobin (Ngb) is upregulated in response to hypoxia-ischemia insults and exhibits a protective role in ischemia-reperfusion brain injury. We hypothesized that transgenic overexpression of Ngb would attenuate spatial learning deficits in a murine model of OSA. Methods:Wild-type mice and Ngb overexpressing male mice (Ngb-TG) were randomly assigned to either IH or room air (RA) exposures. The effects of IH during the light period on performance in a water maze spatial task were assessed, as well as anxiety and depressive-like behaviors using elevated plus maze (EPM) and forced swim tests. Cortical tissues from all the mice were extracted for biochemical studies for lipid peroxidation. Results:Ngb TG mice exhibited increased Ngb immunoreactivity in brain tissues and IH did not elicit significant changes in Ngb expression in either Ngb-TG mice or WT mice. On a standard place training task in the water maze, Ngb-TG mice displayed preserved spatial learning, and were protected from the reduced spatial learning performances observed in WT mice exposed to IH. Furthermore, anxiety and depression levels were enhanced in WT mice exposed to IH as compared to RA controls, while alterations emerged in Ngb-TG mice exposed to IH. Furthermore, WT mice, but not Ngb-TG mice had significantly elevated levels of malondialdehyde in cortical lysates following IH exposures. Conclusions:In a murine model of OSA, oxidative stress responses and neurocognitive and behavioral impairments induced by IH during sleep are attenuated by the neuroprotective effects of Ngb.

Executive functioning and central coherence in anorexia nervosa: Pilot investigation of a neurocognitive endophenotype

Abstract: A neurocognitive profile characterized by problems in set shifting, executive functioning, and central coherence may pre-date and maintain anorexia nervosa (AN). To test this pattern as a possible endophenotype for AN, 10 youth with current AN, 14 healthy youth, and their biological parents, participated in a neuropsychological battery. Youth with AN demonstrated significantly weaker central coherence, related to enhanced detail-focused processing. Youth with AN and their parents demonstrated significantly greater psychopathology relative to controls, and youth-parent scores were significantly correlated. The study, limited by a small sample size, found little evidence supporting a neuropsychological endophenotype for AN. Identifying a neurocognitive profile for children and adolescents with AN has important implications for the treatment of young patients.

The female continence mechanism measured by high resolution manometry: Urethral bulking versus midurethral sling.

Abstract: Author(s): Wasenda, Erika J; Kirby, Anna C; Lukacz, Emily S; Nager, Charles W | Abstract: AIMS:Traditional technology to characterize urethral pressure changes during dynamic conditions is limited by slow response times or artifact-inducing withdrawal maneuvers. The 8F high-resolution manometry (HRM) catheter (ManoScan™ ESO, Covidien) has advantages of fast response times and the ability to measure urethral pressures along the urethral length without withdrawal. Our objective was to determine static and dynamic maximum urethral closure pressures (MUCPs) and resting functional urethral length (FUL) in women using HRM before and after transurethral bulking and compare results to other women who underwent midurethral sling (MUS). METHODS:We recorded rest, cough, and strain MUCPs and FUL in 24 women before and after transurethral bulking with polydimethylsiloxane (Macroplastique®) using the HRM catheter and compared these changes to HRM values from 26 women who had the same measures before and after MUS. RESULTS:At rest, MUCPs increased minimally after both urethral bulking and MUS (3 vs 0.4 cm H2 O respectively, P = 0.4). Under dynamic conditions there were statistically insignificant small increases in MUCP and these increases were markedly less than after MUS (cough: 1.5 vs 63.8 cm H2 O, P l 0.001 and strain: 11.5 vs 57.7 cm H2 O, P l 0.001). FUL increased by 0.5 cm after transurethral bulking (P = 0.003), and decreased by 0.25 cm after MUS placement (P = 0.012). CONCLUSIONS:The mechanism of continence after urethral bulking differs from MUS. While MUS increases dynamic MUCP, bulking may rely on increasing the length of the continence zone.

Pelvic Tuberculosis Diagnosed during Operative Laparoscopy for Suspected Ovarian Cancer.

Abstract: Background. While the combination of a pelvic mass, very high serum level of CA-125, chest adenopathy, and ascites is concerning for advanced-stage ovarian cancer, the etiology of such a presentation can be due to disseminated pelvic tuberculosis. Case. A 67-year-old para 2 African-American woman presented with abdominal pain and shortness of breath. Subsequent CT and MR imaging demonstrated chest adenopathy, a pelvic mass, omental caking, and ascites. The patient underwent diagnostic laparoscopy with biopsy revealing noncaseating granulomas and subsequent tissue culture revealed Mycobacterium tuberculosis. The patient was diagnosed with disseminated pelvic tuberculosis and multidrug therapy was initiated. Conclusion. Pelvic tuberculosis can mimic advanced-stage ovarian cancer; thus obtaining a tissue sample may be beneficial to more appropriately direct treatment and planning for neoadjuvant therapies given the ineffectiveness of extensive surgical procedures in treating pelvic tuberculosis commonly employed in the treatment of advanced-stage ovarian cancer.

Daily Spirometry in an Acute Exacerbation of Adult Cystic Fibrosis Patients

Abstract: To help answer the question of length of intravenous antibiotics during an acute exacerbation of cystic fibrosis (CF), we had subjects to follow daily home spirometry while on intravenous antibiotics. CF patients, 18 and older, with an acute exacerbation requiring intravenous antibiotics had a daily FEV1. The average time to a 10% increase over their initial sick FEV1 was calculated, as well as the time to a new baseline. A total of 25 subjects completed the study. Ten of the 25 subjects did not have a sustainable 10% increase in FEV1. Of the 15 subjects with a sustainable 10% increase in FEV1, it took 5.2 days (±4.5) after day 1, while a new baseline was achieved on average at 6.6 days (±4.8) after day 1. Given the wide range of time to a 10% improvement and new baseline, it is recommended there should be flexibility in length of intravenous antibiotics in CF, not by a preset number.

Hemiplegic Migraine as the Initial Presentation of Biopsy Positive Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Abstract: The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in adults can be challenging. Initially, this disease can mimic embolic cerebral infarction, multiple sclerosis, and other neurological diseases on imaging studies. CADASIL is the most common hereditary cerebral angiopathy which is inherited in an autosomal dominant fashion. There is a wide variety of clinical presentations including a migraine headache, mood disturbances, cognitive dysfunction, and recurrent subcortical cerebral infarctions. This case details the hospital course and diagnosis of a 41-year-old male who initially presented with symptoms consistent with his previous diagnosis of a hemiplegic migraine who was later found to have biopsy-positive CADASIL after the symptoms failed to remit.

Epileptic Encephalopathies: Clinical Aspects, Molecular Features and Pathogenesis, Therapeutic Targets and Translational Opportunities, and Future Research Directions:

Abstract: Epileptic encephalopathies encompass a heterogeneous group of epilepsy syndromes that manifest with cognitive, behavioral, and neurologic deficits, seizures that are often intractable and multiform, aggressive electroencephalographic paroxysmal activity, and sometimes early death. As more is learned about the etiologies and manifestations of epileptic encephalopathies, progress has been made toward better treatment options. However, there is still a great need for further randomized controlled trials and research to help create clinically effective therapies. The 2015 Neurobiology of Disease in Children symposium, held in conjunction with the 44th annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of epileptic encephalopathy, (3) discuss clinical management and therapies for epileptic encephalopathy, and (4) define future directions of research. This article summarizes the presentations and includes an edited transcript of question-and-answer sessions.

A phase 2, multicenter study to assess the efficacy and safety of autologous tumor-infiltrating lymphocytes (LN-144) for the treatment of patients with metastatic melanoma.

Abstract: TPS9595Background: Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma and other solid tumors elliciting durable and ...

The Answer is Vitamin D! From Pediatrics to Geriatrics in Orthopaedics.

Abstract: Vitamin D is necessary for the regulation of calcium and phosphate in the human body. Decreased vitamin D levels can alter the bone mineralization process. The prevalence of vitamin D deficiency in the general population is high, and low vitamin D levels are associated with disorders such as rickets and osteoporosis. As knowledge about vitamin D metabolism increases, physicians of all specialties are becoming more attentive to the vitamin D status of their patients. Similarly, orthopaedic surgeons, through various initiatives such as "Own the Bone," are making greater efforts to medically manage skeletal disorders. Unfortunately, universal guidelines for the optimization of vitamin D levels have not been adopted by orthopaedic surgeons, and, despite substantial efforts, vitamin D is not an integral part of most orthopaedic residency training programs. Although this may be partially attributed to attitudes among orthopaedic surgeons, the large number of vitamin D recommendations in the literature may be confusing and require substantial effort to synthesize into a viable approach for a given patient. Despite this confusion, orthopaedic surgeons should understand how to diagnose and manage disorders related to vitamin D and calcium deficiency.

Case Report: Expanded Access Treatment of an Infantile Neuroaxonal Dystrophy Patient with a Novel Stabilized Polyunsaturated Fatty Acid Drug (P3.327)

Abstract: Objective: The objective was to determine if D-PFUAs could provide clinical benefit to INAD patients. Background: Stabilized polyunsaturated fatty acid drugs (D-PUFAs) have been demonstrated in many neurodegenerative disease preclinical models to mitigate both cell death and disease symptoms. The gene defect underlying >90% of INAD disease, PLA2G6, causes increased cell death due from accelerated lipid peroxidation. These effects were reversed over controls in INAD stem cell and fibroblast studies with D-PUFA dosing, and climbing performance in a drosophila model improved. Since D-PUFAs are well distributed, were safe in preclinical toxicity studies and a clinical phase 1/2 study in Friedreich’s ataxia, and showed benefit in multiple INAD models, the risk/benefit profile for a trial in INAD was favorable. Design/Methods: The patient, a ~2.5-year-old female, had developed normally until about 15 months of age, and received a confirmed genetic diagnosis of PLA2G6-deficient INAD at around 28 months. At baseline, she had lost many previous development milestones, was mostly unresponsive, non-verbal and exhibiting classical INAD symptoms including, hypotonia, nystagmus, strabismus, and psychomotor regression, with little spontaneous motor activity. At the trial start, she discontinued 3.5–7 grams of omega 3/6 supplement, and began dosing of 1.8 g, BID of RT001 softgels. Results: Within the first week, chronic constipation resolved. After 2 months on drug, she regained sufficient bulbar function to terminate syringe feeding of liquids and returned to drinking from a child’s sippy cup. After 6 months, she improved in qualitative measures captured in videotaped therapy sessions or exams, including eye tracking, responsiveness to verbal commands, head control, lifting, and reaching and grasping for her spoon (a lost skill). Conclusions: INAD is a strictly progressive disease, only worsening with time. Stabilization of regressions and recovery of lost milestones appears to indicate effectiveness of the test treatment in a single, severely affected INAD child. Disclosure: Dr. Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BioMarin, Inc. Dr. Adams has received research support from BioMarin, Inc. Dr. Dastgir has nothing to disclose. Dr. Molinari has nothing to disclose. Dr. Heerinckx has nothing to disclose.

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Abstract: An apparatus includes a structure having a plurality of first sides and a second side detachably joined to the plurality of first sides The plurality of first sides define a volume, wherein the second side has a closed position in which the second side is joined to the plurality of first sides and an open position in which the side is detached from the plurality of sides, the plurality of first sides comprising a first material having electromagnetic interference (EMI) shielding properties, the second side comprising a second material having EMI shielding properties The apparatus also includes a movable chassis adapted to move between a first chassis position in which the chassis is entirely within the volume and a second chassis position in which at least a portion of the chassis is outside the volume, the chassis being adapted to hold an electronic device