We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data ...with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study ...of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in approximately 30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1l and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.
Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are ...associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.
Spinal meningiomas are the most common intradural, extramedullary tumor in adults, yet the least common entity when accounting for all meningiomas spanning the neuraxis. While traditionally ...considered a benign recapitulation of their intracranial counterpart, a paucity of knowledge exists regarding the differences between meningiomas arising from these two anatomic compartments in terms of histopathologic subtypes, molecular tumor biology, surgical principles, long-term functional outcomes, and recurrence rates. To date, advancements at the bench have largely been made for intracranial meningiomas, including the discovery of novel gene targets, DNA methylation profiles, integrated diagnoses, and alternative systemic therapies, with few exceptions reserved for spinal pathology. Likewise, evolving clinical research offers significant updates to our understanding of guiding surgical principles, intraoperative technology, and perioperative patient management for intracranial meningiomas. Nonetheless, spinal meningiomas are predominantly relegated to studies considering non-specific intradural extramedullary spinal tumors of all histopathologic types. The aim of this review is to comprehensively report updates in both basic science and clinical research regarding intraspinal meningiomas and to provide illustrative case examples thereof, thereby lending a better understanding of this heterogenous class of central nervous system tumors.
Neurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are ...associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12-26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3-7 Hz) and alpha (7-12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15-19 (B: 0.15-0.21, p < 10
). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.
Prior family and adoption studies have suggested a genetic relationship between schizophrenia and schizotypy. However, this has never been verified using linkage methods. We therefore attempted to ...test for a correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy. The Irish study of high-density schizophrenia families comprises 270 families with at least two members with schizophrenia or poor-outcome schizoaffective disorder (n=637). Non-psychotic relatives were assessed using the structured interview for schizotypy (n=746). A 10-cM multipoint, non-parametric, autosomal genome-wide scan of schizophrenia was performed in Merlin. A scan of a quantitative trait comprising ratings of DSM-III-R criteria for schizotypal personality disorder in non-psychotic relatives was also performed. Schizotypy logarithm of the odds (LOD) scores were regressed onto schizophrenia LOD scores at all loci, with adjustment for spatial autocorrelation. To assess empirical significance, this was also carried out using 1000 null scans of schizotypy. The number of jointly linked loci in the real data was compared to distribution of jointly linked loci in the null scans. No markers were suggestively linked to schizotypy based on strict Lander-Kruglyak criteria. Schizotypy LODs predicted schizophrenia LODs above chance expectation genome wide (empirical P=0.04). Two and four loci yielded nonparametric LOD (NPLs) >1.0 and >0.75, respectively, for both schizophrenia and schizotypy (genome-wide empirical P=0.04 and 0.02, respectively). These results suggest that at least a subset of schizophrenia susceptibility genes also affects schizotypy in non-psychotic relatives. Power may therefore be increased in molecular genetic studies of schizophrenia if they incorporate measures of schizotypy in non-psychotic relatives.
International consensus (ICON) on assessment of oropharyngeal dysphagia Espitalier, F.; Fanous, A.; Aviv, J. ...
European annals of otorhinolaryngology, head and neck diseases,
February 2018, 2018-Feb, 2018-02-00, 20180201, Letnik:
135, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
To present international recommendations regarding the proper evaluation of oropharyngeal dysphagia (OD), both objectively and subjectively (self-evaluation).
Following a thorough review of the ...literature, 5 experts in the field from 4 different continents answered separately a questionnaire regarding the work-up of OD. Individual answers were presented and discussed during the world ENT conference that was held in Paris in June 2017. This article will present the recommendations issued from that meeting.
For the initial objective assessment of OD, it is recommended to perform either a functional endoscopic evaluation of swallowing (FEES) or a videofluoroscopic swallowing study (VFSS). FEES is the more popular investigation given its increased ease of use and accessibility. When evaluating for the presence of aspiration during the objective evaluation of OD, it is recommended to perform either a FEES or a VFSS. In this case, FEES is the favored investigation given its likely increased sensitivity. In order to highlight the presence of oropharyngeal food residue following the deglutition process, it is recommended to perform either a FEES or a VFSS; FEES likely being the more sensitive investigation while VFSS allows a better quantification of the amount of pharyngeal residue. Is it also recommended to objectify the quality of the deglutition process by means of a score during the objective evaluation of OD. Finally, it is recommended to utilize a self-evaluation questionnaire during research studies exploring the deglutition process.
Abstract Mechanical thrombectomy, in conjunction with systemic thrombolysis, is currently the standard of care for the treatment of acute ischemic stroke. Mechanical thrombectomy extends the ...therapeutic window up to at least 8 hours from the time of symptom onset and is more efficient than systemic thrombolytic agents in removing clots resistant to enzymatic degradation. It is also a viable option for patients with various contraindications against the use of systemic thrombolysis. Treatment of patients with acute ischemic strokes using mechanical thrombectomy devices has yielded both higher rates of revascularization as well as superior clinical outcomes when compared with medical therapy with intravenous thrombolytics alone. The use of first-generation thrombectomy devices, most notably the Merci Retriever system (Stryker, Kalamazoo, MI, USA) and the Penumbra Aspiration device (Penumbra Inc., Alameda, CA, USA), achieved high rates of revascularization of occluded large cerebral vessels but did not necessarily result in high rates of favorable clinical outcomes. Second-generation devices, known as stent retrievers, were therefore created with the goal of achieving faster revascularization of occluded vessels and improved rates of favorable clinical outcomes. Stent retrievers, most notably the Solitaire (ev3/Covidien, Irvine, CA, USA) and the Trevo (Stryker), were shown to be superior to first-generation devices in terms of achieving higher rates of favorable clinical outcomes. Aspiration combined with stent retrievers or alone has also shown great promise. Moreover, several recent randomized control trials have demonstrated the superiority of medical therapy with mechanical thrombectomy using stent retrievers over medical therapy alone in achieving good clinical outcome in acute stroke patients. These clinical trials also demonstrated the relative safety of mechanical thrombectomy with stent retrievers compared to the safety of best medical therapy.
First branchial cleft anomalies are rare, accounting for only 10% of all branchial cleft anomalies. We report an even more rare and unique case of a branchial cleft cyst with features of both first ...and second arch derivatives.
A 6-year-old boy presented to us with a left conductive hearing loss associated with pre-tympanic keratin debris and an ipsilateral painful cervical mass. He had a past medical history of left ear surgery for presumed cholesteatoma 2 years prior and left neck abscess drainage 6 months prior. CT and MRI revealed a lesion originating in the external auditory canal and extending cervically through a bony canal located medial to the facial nerve and terminating as a parapharyngeal cyst. The complete removal was accomplished in one surgical stage consisting of three distinct steps: robotic assisted transoral resection of the pharyngeal cyst, an endaural approach and a parotidectomy approach.
We believe that our detailed description of this rare first branchial cleft cyst with pharyngeal extension, possibly a hybrid case between a first and second branchial cyst, can serve as a valuable tool to Otolaryngologists - Head and Neck Surgeons who come across a similar unusual presentations.
Introduction
In the following article, we are presenting a clinical observation of Baron Larrey. In 1804, Larrey was the inspector general of health, as well as the chief surgeon of the imperial ...Napoleonic Guard. He participated in all of Napoleon’s campaigns. A paleopathological study was performed on a skull from Dupuytren’s Museum (Paris) with a long metal stick in the head. We report here a clinical case as well as the autopsy description of this soldier’s skull following his death. We propose a different anatomical analysis of the skull, which allowed us to rectify what we believe to be an anatomical error and to propose varying hypotheses regarding the death of soldier Cros.
Materials and methods
The skull was examined, observed and described by standard paleopathology methods. Measurements of the lesion were performed with metric tools and expressed in centimeters. Historical research was made possible through the collaboration with the Museum of Medicine History-Paris Descartes University.
Results
Following the above detailed anatomical analysis of the path of the metal rod, we propose various possible lesions in soldier Cros due to the accident. At the inlet, the frontal sinuses could have been damaged. At the level of the second portion of the intracranial path, all of the anatomical elements present in the cavernous sinus could have been injured (cranial nerves III, IV, V1 and V2, VI, internal carotid artery and cavernous sinus). The exit orifice of the foreign body passes through the left condylar fossa of the occipital bone, points to a highly probable lesion of the left hypoglossal nerve (12th cranial nerve).
Conclusion
The paleopathological study of human remains, when combined with anatomical and clinical knowledge of the pathologies of the head and neck, can rectify diagnoses of the past.
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