Faculty Bibliography
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93
Novel Common Genetic Susceptibility Loci for Colorectal Cancer
Background/UNASSIGNED:Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods/UNASSIGNED:We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results/UNASSIGNED:The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions/UNASSIGNED:This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
PMID: 29917119
ISSN: 1460-2105
CID: 3157862
Phase and amplitude of spontaneous retinal vein pulsations: An extended constant input - variable output model
The constant input - variable output (CIVO) theory correctly predicts that spontaneous pulsation of the retinal veins will be visible close to the point where the vein exits the eye at the lamina cribrosa but will decrease rapidly in amplitude and become too small to see only a short distance upstream. However, the phase of vein oscillation relative to the oscillation of the intraocular pressure (IOP) predicted by CIVO has been unclear and controversial. We show that the CIVO model is indeterminate in predicting such phase relations. We propose a simple extension of the CIVO model that retains its basic equations but applies them to a larger domain that includes not only the intraocular (pre-laminar) portion of the vein but also the retrobulbar (post-laminar) portion of the vein behind the eye. We show that this extended CIVO model makes definite predictions about the phase of vein oscillation relative to the oscillation of IOP. This phase relationship is determined by the relative amplitude and phase of pulsations of the IOP and of the cerebrospinal fluid pressure (CSFP). If IOP and CSFP oscillate in phase, then the pre-laminar vein oscillates in phase with IOP when the amplitude of CSFP exceeds the amplitude of IOP but oscillates in counter phase with IOP when the amplitude of IOP exceeds that of CSFP. These relationships are modified when there is a phase difference between the oscillations of IOP and CSFP. When CSFP leads IOP, the phase of vein oscillation is advanced if the amplitude of CSFP exceeds that of IOP and is delayed if the amplitude of IOP exceeds that of CSFP. The result in each case is that maximum vein size occurs during the rising phase of IOP (ocular systole). We conclude that the driving force of vein oscillation is the difference between the oscillations of IOP and CSFP. The phase of this difference determines the phase relationships above. We show that additional delays in the phase of venous pulsation relative to that of IOP are induced by constriction of the vein within the lamina cribrosa and by recording the vein pulsations upstream from the lamina cribrosa. The amplitude of vein oscillation is proportional to the amplitude of the driving force and to the venous capacitance. Loss of spontaneous retinal vein pulsation with increase in mean CSFP is determined primarily by reduced venous capacitance. Increased amplitude of pulsation may occur when IOP is increased. It is the result of increased venous capacitance and possibly increased driving force of the pulsation. However, in chronic glaucoma the increase in capacitance may be counteracted by venous outflow obstruction, and the increase in driving force may be counteracted by reduced ocular blood flow. As a result retinal vein oscillation may be reduced in amplitude.
PMID: 26997658
ISSN: 1095-9319
CID: 2051962
Babinski, J. (1914). Contribution to the Study of the Mental Disorders in Hemiplegia of Organic Cerebral Origin (Anosognosia). Translated by K.G. Langer & D.N. Levine: Translated from the original Contribution a l'Etude des Troubles Mentaux dans l'Hemiplegie Organique Cerebrale (Anosognosie)
PMID: 25481462
ISSN: 0010-9452
CID: 1395732
Hydrodynamic herniation: Pathophysiology of brain, spinal cord and nerve displacements associated with leakage or diversion of cerebrospinal fluid
Leakage or diversion of cerebrospinal fluid (CSF) is associated with a variety of displacements of nervous tissue that may affect the brain, spinal cord and nerve roots. The displacements may be classified by the site of the leak - spinal canal or cranial cavity - and by whether the displacements are global, affecting wide regions of the nervous system, or local, affecting only nervous tissue adjacent to the leak. We propose a common pathophysiology for these displacements. A leak or a shunt results in an abnormal spatial pattern of CSF flow governed by abnormally directed hydrodynamic forces that act upon the submerged nervous tissue to propel it towards the site of the leak or the orifices of the shunt. We argue that the hydrodynamic mechanism causing displacement is distinct from the physical mechanisms responsible for other frequent manifestations of CSF leak, such as orthostatic headache, low recumbent CSF pressure, and dilation of dural veins. The existence of distinct mechanisms allows understanding of how the effects of CSF loss may differ in patients with spinal CSF leak and patients with ventricular shunts. It clarifies many variant cases where some of the characteristic manifestations of CSF leak may be absent. We discuss the roles of abnormal hydrodynamic forces in the variety of presentations subsumed under the term "slit ventricle syndrome" and consider the therapeutic implications of the proposed pathophysiological mechanism.
ORIGINAL:0009691
ISSN: 0972-8252
CID: 1602122
Increased intracranial pressure
Philadelphia, PA : Elsevier/Saunders, 2014
pp. 410-417
ISBN: 1416024557
CID: 802562
Intracranial venous thrombosis after placement of a lumbar drain
BACKGROUND: Lumbar drains are frequently used in clinical neuroscience and are often managed in the neurointensive care unit. Complications are generally rare, and intracranial venous thrombosis (IVT) and infarction has not been reported. METHODS: We report the case of a 45-year-old woman who developed a cerebrospinal fluid (CSF) leak after spinal surgery. Fifteen hours after placement of a lumbar drain she developed pure alexia and color agnosia caused by left lateral sinus thrombosis with hemorrhagic infarction in the posterior inferior left temporal lobe. We review the literature on the association of IVT with injury to the spinal dura, and we propose a mechanism whereby the lumbar drain may facilitate its development. RESULTS: We found 29 cases in which spinal dural injury was followed by IVT. The association is not coincidental, because nearly all cases were associated with post-dural puncture headache, which occurs in only a minority of cases of dural puncture. Injury to the spinal dura alters the distribution of craniospinal elasticity causing profound intracranial CSF hypotension on assuming the erect posture. This causes acute dilation of cerebral veins resulting in both orthostatic headache and venous stasis. We propose that placement of the lumbar drain and elevation of the head of the bed aggravated intracranial CSF hypotension and facilitated IVT. CONCLUSIONS: When a lumbar drain is placed for treatment of a spinal CSF leak, the patient should remain flat in bed. Any patient with post-dural injury headache that intensifies after an initial plateau, persists for longer than a week, or loses its orthostatic character should be evaluated for intracranial sinus or venous thrombosis
PMID: 19834826
ISSN: 1541-6933
CID: 106519
Pathogenesis of rapidly reversible compressive neuropathy: revisiting the classic sphygmomanometer experiment
OBJECTIVE:Using the sequential inflation of 2 sphygmomanometers, Lewis et al. (Heart 16:1-32, 1931) concluded that compressive neuropathy was secondary to ischemia of the compressed nerve segment. Despite subsequent animal studies demonstrating that compressive lesions are more likely the result of mechanical nerve deformation, disagreement remains as to the etiology of rapidly reversible compressive neuropathy. Our hypothesis is that, during the classic sphygmomanometer experiments, the areas of nerve compression at the cuff margins overlapped, so that a region of transient nerve deformation persisted during the second cuff inflation. If true, the original results by Lewis et al. would be consistent with a mechanical pathogenesis. METHODS:In our study, 6 patients underwent sequential upper extremity dual-sphygmomanometer inflation with serial assessment by grip-dynamometer and 2-point discrimination. The order of cuff inflation, as well as the distance between cuffs, was varied. Mean grip force and 2-point discrimination values were statistically compared between conditions. RESULTS:Patients with overlapping cuffs maintained their neurological deficits, whereas those with separated cuffs experienced an improvement in both grip force (P = 0.02) and 2-point discrimination (P < 0.001) when cuff inflation was switched. CONCLUSION/CONCLUSIONS:Rapidly reversible compressive neuropathy seems to be secondary to mechanical nerve deformation at the margins of the compressive force rather than the result of ischemia of the compressed nerve segment. Overlap of the mechanically deformed nerve segments likely explains why neurological deficits persisted despite sequential cuff inflation in the classic experiments by Lewis et al.
PMID: 19927064
ISSN: 1524-4040
CID: 3589232
Intracranial pressure and ventricular expansion in hydrocephalus: have we been asking the wrong question?
The force that enlarges the cerebral ventricles and deforms the brain in hydrocephalus remains unclear. It is still widely thought to be elevated intraventricular pressure developing behind an obstruction to the flow of CSF. This view has led to the prediction that a large pressure difference should exist between the ventricles proximal to the obstruction and the subarachnoid space of the cerebral convexity distal to the obstruction. Yet measurements have shown consistently that such transmantle pressure differences are either small or absent. We propose a theory that reconciles the view that hydrocephalus is caused by obstruction to the flow of CSF with the observed absence of large pressure gradients across the cerebral mantle. Obstruction to CSF flow produces only a small pressure gradient -- usually less than 1 mm Hg -- that is sufficient to overcome the added resistance to flow and thereby to balance the absorption of CSF with its production. This mini-gradient is the effective force that initiates and sustains ventricular enlargement. It can coexist either with high or with normal intracranial pressure. The level of intracranial pressure is determined by the efficiency with which increments of ventricular pressure are transmitted through the parenchyma to the outer surface of the brain. In the presence of a rigid skull some transmission is required by basic laws of Newtonian mechanics. The efficiency of transmission depends primarily on the elastic properties of the brain. If the brain is relatively incompressible, transmission is efficient and high intracranial pressure is required to maintain the mini-gradient between the ventricles and the subarachnoid space, resulting in tension hydrocephalus. If the brain is more compressible, the parenchyma attenuates any increase of intraventricular pressure, reducing transmission to the outer surface. Intracranial pressure need not rise above normal levels to maintain the mini-gradient, leading to normal pressure hydrocephalus. The theory explains why tests measuring CSF resistance have limited diagnostic usefulness in hydrocephalus. It also predicts that very small stresses are sufficient to produce large deformations of the brain if these are allowed to occur slowly
PMID: 18234229
ISSN: 0022-510x
CID: 79423
Neuropsychiatric sequelae and life events: analysis and management [Meeting Abstract]
ORIGINAL:0006473
ISSN: 1747-4930
CID: 90723
The stuff that dreams are made on : the case of penduncular hallucinosis
A description of five cases, and a discussion of pathogenesis Covering: Benke T., J Neurol 2006 Dec; 253:1561-71
ORIGINAL:0006157
ISSN: 1524-0207
CID: 73599
