Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · May 2015
A conceptual approach to managing severe traumatic brain injury in a time of uncertainty.
Current controversies in the literature suggest that a reassessment of the current management of severe traumatic brain injury (sTBI) is necessary. This article presents a conceptual framework toward individualizing sTBI treatment with respect to targeting thresholds and strategies on the basis of known physiologic processes and available monitors. Intracranial pressure (ICP) is modeled as an epiphenomenon of cerebral compliance and herniation tendency, as well as cerebral ischemia. ⋯ Similarly, by collecting and trending clinical, imaging, and monitoring data on the status of cerebral blood flow, the balance of oxygen consumption and delivery, and the status of cerebral static pressure autoregulation, and analyzing them with respect to measured parameters, such as blood pressure, ICP, and cerebral perfusion pressure, one can attempt to fine-tune these variables as well. Such individualization of management optimizes the possibility of successfully treating demonstrated pathophysiological processes while avoiding unnecessary interventions and treatment toxicity. Monitor values must not be seen as targets but rather as indicators of targetable pathology.
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Ann. N. Y. Acad. Sci. · May 2015
ReviewKetamine as a promising prototype for a new generation of rapid-acting antidepressants.
The discovery of ketamine's rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. ⋯ This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders.
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Ann. N. Y. Acad. Sci. · May 2015
What is wrong with the tenets underpinning current management of severe traumatic brain injury?
The results of a recent randomized controlled trial comparing intracranial pressure (ICP) monitor-based treatment of severe traumatic brain injury (sTBI) to management without ICP monitoring prompt this skeptical reconsideration of the scientific foundation underlying current sTBI management. Much of current practice arises from research performed under conditions that are no longer relevant today. The definition of an episode of intracranial hypertension is incomplete, and the application of a fixed, universal ICP treatment threshold is poorly founded. ⋯ Similar concerns also apply to manipulation of cerebral perfusion with respect to maintaining universal thresholds for contrived variables rather than tailoring treatment to monitored processes. As such, there is a failure to either optimize management approaches or minimize associated treatment risks for individual sTBI patients. The clinical and research TBI communities need to reassess many of the sTBI management concepts that are currently considered well established.
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Benign paroxysmal positional vertigo (BPPV) presentations are unique opportunities to simultaneously improve the effectiveness and efficiency of care. The test and treatment for BPPV--the Dix-Hallpike test (DHT) and the canalith repositioning maneuver (CRM), respectively--are supported by two evidence-based guidelines (American Academy of Otolaryngology--Head and Neck Surgery and American Academy of Neurology). ⋯ Despite this large effect size, less than 10% of affected patients receive the treatment, which shows that the management of BPPV in routine care is suboptimal. Future research is necessary to disseminate and implement the DHT and the CRM into routine practice.
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Ann. N. Y. Acad. Sci. · Apr 2015
Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions.
Humans carry two copies of the survival motor neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS-N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide-mediated splicing correction in SMA. ⋯ Located in the middle of intron 7, the 3' strand of ISTL1 falls within an inhibitory region that we term ISS-N2. We demonstrate that an antisense oligonucleotide-mediated sequestration of ISS-N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high-order RNA structure of a human intron.