Newborn and rapid diagnosis of Niemann-Pick type C

Xuntian Jiang, Rohini Sidhu, Laurel Mydock-McGrane, Fong-Fu Hsu, Douglas F. Covey, David E. Scherrer, Brian Earley, Sarah E. Gale, Nicole Y. Farhat, Forbes D. Porter, Dennis J. Dietzen, Joseph J. Orsini, Elizabeth Berry-Kravis, Xiaokui Zhang, Janice Reunert, Thorsten Marquardt, Heiko Runz, Roberto Giugliani, Jean E. Schaffer,  Daniel S. Ory.  Development of a bile acid–based newborn screen for Niemann-Pick disease type C.  Science Translational Medicine  04 May 2016:Vol. 8, Issue 337, pp. 337ra63 DOI: 10.1126/scitranslmed.aaf2326

Expanding the newborn screen

Niemann-Pick disease type C (NPC) is a fatal neurologic disorder caused by the deficiency of an enzyme involved in cholesterol storage. Although this disease was untreatable in the past, new therapeutics are now in clinical trials, but they are most likely to be effective if treatment is started as early as possible, before neurodegeneration has occurred. Jiang et al. identified three bile acids that are greatly increased in the blood of patients with NPC compared to healthy controls. The authors also demonstrated that one of these bile acids can be reliably measured in dried blood spots using mass spectrometry, suggesting that this bile acid test should be evaluated for potential addition to neonatal screening programs.

Abstract

Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3β,5α,6β-trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β,5α,6β-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry–based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs.

http://stm.sciencemag.org/content/8/337/337ra63

Courtesy of a colleague

Reunert J, Fobker M, Kannenberg F, Du Chesne I, Plate M, Wellhausen J, Rust S, Marquardt T. Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening.  EBioMedicine. 2015 Dec 22;4:170-5.

Abstract

Niemann Pick type C (NP-C) is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol) as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2) and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay.

Chiropractic care and cervical artery dissection

Church E W, Sieg E P, Zalatimo O, et al. (February 16, 2016) Systematic Review and Meta-analysis of Chiropractic Care and Cervical Artery Dissection: No Evidence for Causation. Cureus 8(2): e498. doi:10.7759/cureus.498

http://www.cureus.com/articles/4155-systematic-review-and-meta-analysis-of-chiropractic-care-and-cervical-artery-dissection-no-evidence-for-causation?utm_medium=email&utm_source=transaction

Abstract

Background

Case reports and case control studies have suggested an association between chiropractic neck manipulation and cervical artery dissection (CAD), but a causal relationship has not been established. We evaluated the evidence related to this topic by performing a systematic review and meta-analysis of published data on chiropractic manipulation and CAD.

Methods

Search terms were entered into standard search engines in a systematic fashion. The articles were reviewed by study authors, graded independently for class of evidence, and combined in a meta-analysis. The total body of evidence was evaluated according to GRADE criteria.

Results

Our search yielded 253 articles. We identified two class II and four class III studies. There were no discrepancies among article ratings (i.e., kappa=1). The meta-analysis revealed a small association between chiropractic care and dissection (OR 1.74, 95% CI 1.26-2.41). The quality of the body of evidence according to GRADE criteria was “very low.”

Conclusions

The quality of the published literature on the relationship between chiropractic manipulation and CAD is very low. Our analysis shows a small association between chiropractic neck manipulation and cervical artery dissection. This relationship may be explained by the high risk of bias and confounding in the available studies, and in particular by the known association of neck pain with CAD and with chiropractic manipulation. There is no convincing evidence to support a causal link between chiropractic manipulation and CAD. Belief in a causal link may have significant negative consequences such as numerous episodes of litigation.

From the article:

Neck pain is a common complaint in physicians’ and chiropractors’ offices. Data from the Centers for Disease Control and from national surveys document 10.2 million ambulatory care visits for a neck problem in 2001 and 2002. By comparison, there were 11 million office-based visits for ischemic heart disease. Many patients with neck pain seek chiropractic care and undergo cervical manipulation. As many as 12% of North Americans receive chiropractic care every year, and a majority of these are treated with spinal manipulation.

In contrast to the frequency of neck pain and chiropractic treatments, spontaneous cervical artery dissection (CAD) is rare. The annual incidence of internal carotid artery dissection has been estimated at 2.5–3 per 100,000 patients and that of vertebral artery dissection at 1–1.5 per 100,000. Stroke occurs in a small proportion of those with CAD, and its true incidence is difficult to estimate. Overall, dissection accounts for two percent of all ischemic strokes.

Case reports and case series of cervical dissection following manipulation have been published. Despite their rarity, these cases are frequently publicized for several reasons. Patients are often young and otherwise in good health. Dissection accounts for 10–25% of ischemic strokes in young and middle aged patients.  If dissection is caused by cervical manipulation it is potentially a preventable condition. Recent reports, including case control studies, have suggested an association between chiropractic neck manipulation and cervical dissection. Notably, a recent study from the American Heart Association evaluated the available evidence and concluded such an association exists. This report did not include a meta-analysis, nor did it seek to classify studies and grade the body of evidence. We sought to examine the strength of evidence related to this question by performing a systematic review, meta-analysis, and evaluation of the body of evidence as a whole…

Cassidy et al. hypothesized that, although an association between chiropractor visits and vertebrobasilar artery stroke is present, it may be fully explained by neck pain and headache [5]. These authors reviewed 818 patients with vertebrobasilar artery strokes hospitalized in a population of 100 million person-years. They compared chiropractor and PCP visits in this population and reported no significant difference between these associations. For patients under 45 years of age, each chiropractor visit in the previous month increased the risk of stroke (OR 1.37, 95% CI 1.04-1.91), but each PCP visit in the previous month increased the risk in a nearly identical manner (<45 yrs OR 1.34, 95% CI .94-1.87; >45 yrs and OR 1.53, 95% CI 1.36-1.67). The authors conclude that, since patients with vertebrobasilar stroke were as likely to visit a PCP as they were to visit a chiropractor, these visits were likely due to pain from an existing dissection.

In spite of the very weak data supporting an association between chiropractic neck manipulation and CAD, and even more modest data supporting a causal association, such a relationship is assumed by many clinicians. In fact, this idea seems to enjoy the status of medical dogma. Excellent peer reviewed publications frequently contain statements asserting a causal relationship between cervical manipulation and CAD. We suggest that physicians should exercise caution in ascribing causation to associations in the absence of adequate and reliable data. Medical history offers many examples of relationships that were initially falsely assumed to be causal, and the relationship between CAD and chiropractic neck manipulation may need to be added to this list.

Conclusions

Our systematic review revealed that the quality of the published literature on the relationship between chiropractic manipulation and CAD is very low. A meta-analysis of available data shows a small association between chiropractic neck manipulation and CAD. We uncovered evidence for considerable risk of bias and confounding in the available studies. In particular, the known association of neck pain both with cervical artery dissection and with chiropractic manipulation may explain the relationship between manipulation and CAD. There is no convincing evidence to support a causal link, and unfounded belief in causation may have dire consequences.

Medical error

Medical error is the third leading cause of death in the United States, after heart disease and cancer, according to findings published today in BMJ.

As such, medical errors should be a top priority for research and resources, say authors Martin Makary, MD, MPH, professor of surgery, and research fellow Michael Daniel, from Johns Hopkins University School of Medicine in Baltimore, Maryland.

But accurate, transparent information about errors is not captured on death certificates, which are the documents the Centers for Disease Control and Prevention (CDC) uses for ranking causes of death and setting health priorities. Death certificates depend on International Classification of Diseases (ICD) codes for cause of death, so causes such as human and system errors are not recorded on them.

And it's not just the US. According to the World Health Organization, 117 countries code their mortality statistics using the ICD system as the primary health status indicator.

The authors call for better reporting to help capture the scale of the problem and create strategies for reducing it...

"Top-ranked causes of death as reported by the CDC inform our country's research funding and public health priorities," Dr Makary said in an university press release. "Right now, cancer and heart disease get a ton of attention, but since medical errors don't appear on the list, the problem doesn't get the funding and attention it deserves."

He adds: "Incidence rates for deaths directly attributable to medical care gone awry haven't been recognized in any standardized method for collecting national statistics. The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used."

The researchers examined four studies that analyzed medical death rate data from 2000 to 2008. Then, using hospital admission rates from 2013, they extrapolated that, based on 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error. 

That number of deaths translates to 9.5% of all deaths each year in the US — and puts medical error above the previous third-leading cause, respiratory disease.

In 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease, according to the CDC...

The authors suggest several changes, including making errors more visible so their effects can be understood. Often, discussions about prevention occur in limited and confidential forums, such as a department's morbidity and mortality conference.

Another is changing death certificates to include not just the cause of death, but an extra field asking whether a preventable complication stemming from the patient's care contributed to the death.

The authors also suggest that hospitals carry out a rapid and efficient independent investigation into deaths to determine whether error played a role. A root cause analysis approach would help while offering the protection of anonymity, they say.

Standardized data collection and reporting are also needed to build an accurate national picture of the problem.

Jim Rickert, MD, an orthopedist in Bedford, Indiana, and president of the Society for Patient Centered Orthopedics, told Medscape Medical News he was not surprised the errors came in at number 3 and that even those calculations don't tell the whole story.

"That doesn't even include doctors' offices and ambulatory care centers," he notes. "That's only inpatient hospitalization resulting in errors."

"I think most people underestimate the risk of error when they seek medical care," he said.

He agrees that adding a field to death certificates to indicate medical error is likely the way to get medical errors the attention they deserve.

"It's public pressure that brings about change. Hospitals have no incentive to publicize errors; neither do doctors or any other provider," he said.

However, such a major step as adding error information to death certificates is unlikely if not accompanied by tort reform, he said.

Still, this study helps emphasize the prevalence of errors, he said.

Human error is inevitable, the authors acknowledge, but "we can better measure the problem to design safer systems mitigating its frequency, visibility, and consequences."

They add that most errors aren't caused by bad doctors but by systemic failures and should 'not be addressed with punishment or legal action.

http://www.medscape.com/viewarticle/862832?nlid=104512_3901&src=wnl_newsalrt_160503_MSCPEDIT&uac=60196BR&impID=1084165&faf=1#vp_2

Martin A Makary, Michael Daniel.  Medical error—the third leading cause of death in the US.   BMJ 2016;353:i2139.

http://www.bmj.com/content/353/bmj.i2139

Brivaracetam

Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B. Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia. 2016 Apr;57(4):538-48.

Abstract

Despite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

Parental anxiety in childhood epilepsy

Jones C, Reilly C. Parental anxiety in childhood epilepsy: A systematic review. Epilepsia. 2016 Apr;57(4):529-37.

Abstract

The aim was to systematically review studies that have focused on symptoms of anxiety reported by parents of children (0-18 years) with epilepsy. PubMed was used to identify relevant studies. Selected studies were reviewed with respect to prevalence of above threshold scores and comparisons with controls on standardized measures of anxiety. Studies are also reported with respect to factors associated with parental anxiety, impact on child outcomes, and comparisons with studies that have included equivalent measures of symptoms of depression. Fifteen studies that met inclusion criteria were identified. None of the studies were population based. The percentage of parents scoring above cutoffs on standardized measures of anxiety was 9-58%. In comparison with parents of healthy controls, parents of children with epilepsy had higher mean scores in two of three studies where this was measured.  Possible correlates of parental anxiety in childhood epilepsy that were considered varied widely across studies. Factors such as seizure frequency and use of antiepileptic drugs (AEDs) have been associated with parental anxiety in some but not all studies. With respect to child outcome, increased parental anxiety has been associated with lower quality of life and lower scores on adaptive behavior domains. Symptoms of anxiety are common among parents of children with epilepsy. There is a need for more systematic, representative studies to identify the prevalence of clinically significant anxiety and track the course of symptoms. Such studies will help to identify more clearly factors associated with parental anxiety and impact of symptoms on child and parent outcomes. Intervention studies are needed to evaluate approaches that target a reduction in symptoms and the potential impact on parental and child functioning. Furthermore, there is a need to evaluate the impact of antiepileptic therapies and interventions that focus on child neurobehavioral comorbidities on parental anxiety.

Feed-forward cytokine signaling and glioblastoma

Arezu Jahani-Asl, Hang Yin, Vahab D Soleimani,  Takrima Haque, H Artee Luchman, Natasha C Chang, Marie-Claude Sincennes, Sidharth V Puram, Andrew M Scott,  Ian A J Lorimer, Theodore J Perkins, Keith L Ligon, Samuel Weiss, Michael A Rudnicki, Azad Bonni.  Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nature Neuroscience (2016) Published online 25 April 2016.

Abstract

EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis.

Courtesy of Doximity

High school football

Football results in more concussions than any other competitive sport; but a concussion diagnosis isn’t the sole measure of brain damage. It doesn’t take a 10-year career in the National Football League (NFL)to cause substantial changes in brain cells. In fact, researchers at the University of Texas Southwestern (UT Southwestern) Medical Center discovered that a single season at the high school level is enough to Football results in more concussions than any other competitive sport; but a concussion diagnosis isn’t the sole measure of brain damage. It doesn’t take a 10-year career in the National Football League (NFL)to cause substantial changes in brain cells. In fact, researchers at the University of Texas Southwestern (UT Southwestern) Medical Center discovered that a single season at the high school level is enough to do just that. “Studies like this are important to understand how and where long-term damage might be occurring, so that we can then take the necessary steps to prevent it,” first author Elizabeth Davenport, PhD, in the Department of Radiology and the Advanced Imaging Research Center, said in a news release.

A total of 38 football players wore sensory helmets which recorded head impact during practices and games. The researchers measured total impacts, summed acceleration, and Risk Weighted cumulative Exposure (RWE). None of the participants had been clinically diagnosed with a concussion. Pre- and post- season assessments included magnetic resonance imaging (MRI) and Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) revealed brain health outcomes.

The authors concluded that just one season of high school football is enough to cause brain cell changes noticeable in diffusional kurtosis imaging (DKI) – which measures water diffusion in biological cells. In addition, DKI revealed white matter abnormalities which were apparent in this population, as described in the Journal of Neurotrauma.

“Work of this type, combining biomechanics, imaging, and cognitive evaluation is critical to improving our understand of the effects of subconcussive impacts of the develop brain,” explained senior author Joseph Maldijan, MD, chief of the Neuroradiology Division and Director of the Advanced Neuroscience Imaging Research Lab at UT Southwestern.

http://www.hcplive.com/medical-news/just-one-season-of-high-school-football-is-enough-to-cause-serious-brain-damage?utm_source=Informz&utm_medium=HCPLive&utm_campaign=MDMagazine_Neurology_4-27-16

____________________________________________________________________________

Davenport EM, Apkarian K, Whitlow CT, Urban JE, Jensen JH, Szuch E, Espeland MA, Jung Y, Rosenbaum DA, Gioia G, Powers AK, Stitzel JD, Maldjian JA. Abnormalities in Diffusional Kurtosis Metrics Related to Head Impact Exposure in a Season of High School Varsity Football. J Neurotrauma. 2016 Apr 4. [Epub ahead of print]

Abstract

The purpose of this study is to determine if the effects of cumulative head impacts during a season of high school football produce changes in diffusional kurtosis imaging (DKI) metrics in the absence of clinically diagnosed concussion. Subjects were recruited from a high school football team and were outfitted with the Head Impact Telemetry System (HITs) during all practices and games. Biomechanical head impact exposure metrics were calculated including: total impacts, summed acceleration, and Risk Weighted cumulative Exposure (RWE). Twenty-four players completed pre- and post-season MRI, including DKI; players who experienced clinical concussion were excluded. Fourteen subjects completed pre- and post-season Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). DKI-derived metrics included mean kurtosis (MK), axial kurtosis (K axial), and radial kurtosis (K radial), and white matter modeling (WMM) parameters included axonal water fraction (AWF), tortuosity of the extra-axonal space, extra-axonal diffusivity (D_e axial and radial), and intra-axonal diffusivity. These metrics were used to determine the total number of abnormal voxels, defined as 2 standard deviations above or below the group mean. Linear regression analysis revealed a statistically significant relationship between RWE_CP and MK. Secondary analysis of other DKI-derived and WMM metrics demonstrated statistically significant linear relationships with RWE_CP after covariate adjustment. These results were compared with the results of DTI-derived metrics from the same imaging sessions in this exact same cohort. Several of the DKI-derived scalars (D_a, MK, K axial, and K radial) explained more variance when compared to RWE_CP, suggesting that DKI may be more sensitive to subconcussive head impacts. No significant relationships between DKI-derived metrics and ImPACT measures were found. It is important to note, the pathological implications of these metrics are not well understood. In summary, we demonstrate a single season of high school football can produce DKI measurable changes in the absence of clinically diagnosed concussion.