Data to inform counseling on parathyroidectomy for secondary hyperparathyroidism of renal origin.

BACKGROUND: The risk of postoperative hungry bone syndrome after parathyroidectomy for secondary hyperparathyroidism of renal origin may alter the course of treatment, including the hospital length of stay and readmission rates. We sought to identify additional patient or hospital factors that might contribute to hungry bone syndrome after parathyroidectomy in patients with secondary hyperparathyroidism of renal origin. METHODS: Patients who underwent a parathyroidectomy for secondary hyperparathyroidism of renal origin were identified in a geographically diverse, 10-state, discharge data set. Covariates included demographic data, payer status, 31 comorbidities, and hospital characteristics. The primary outcome variable of interest was hospital length of stay. Secondary outcomes were complications and 30-day readmission. RESULTS: Of 796 patients studied, 164 patients (20.6%) were diagnosed with hungry bone syndrome. There were no differences in the rates of hungry bone syndrome by race or number of comorbidities. The average age of hungry bone syndrome patients (45.7 years ± 13.9) was younger than that of non-hungry bone syndrome patients (50.7 ± 14.8; P < .001). Hungry bone syndrome was more common among obese patients than nonobese patients (25.0% vs 15.8%; P < .001). Parathyroid autotransplant was performed at similar rates in hungry bone syndrome and non-hungry bone syndrome patients (23.8% vs 23.1%; P = .821). Median length of stay was significantly longer for hungry bone syndrome patients (6 days, interquartile range: [4, 8] versus 3 days, interquartile range: [2-6]; P < .001). Similar 30-day readmission rates were observed (hungry bone syndrome: 41 (25%) versus non-hungry bone syndrome: 147 (23%); P = .640). CONCLUSION: Hungry bone syndrome occurs in 1 of 5 patients after parathyroidectomy for secondary hyperparathyroidism of renal origin. Patients should be informed of the possibility of a relatively long (6 days) length of stay after surgery as well as the moderate possibility (>20%) of another hospitalization within the 30-day postdischarge period.

Effect of a behavioral intervention on anxiety and perceived performance of non-technical skills during surgical simulations.

BACKGROUND: Surgical trainees experience intrinsic stress and anxiety during high-acuity clinical situations which can negatively impact performance. Emerging data suggests that education in mindfulness-based coping techniques may improve performance. We evaluated the effects of a stress recovery intervention on novice trainees' perceived level of anxiety during an intentionally stressful simulation. METHODS: Participants were recruited from surgical intern classes over three consecutive years. All participants completed a simulation intentionally designed to evoke a stress response. Participants then completed a stress recovery intervention or received no additional training. All participants then completed a second novel simulation. RESULTS: Intervention participants had significantly higher self-reported ability to manage stress (intervention 2.4 to 3.6, p < 0.01; control 2.8 to 3.3, p = 0.06), and stop, think, and observe (intervention 2.5 to 3.7, p < 0.01; control 2.6 to 3.3, p = 0.08) during the second simulation. Both groups also had significantly lower levels of state anxiety during the second simulation as compared to the first (intervention 45.1 vs 59.3, p < 0.01; control 49.3 vs 57.4, p < 0.05). During the second simulation, trainees in both groups reported improvements in perceived abilities to: recognize stress (intervention 2.7 to 4.1, p < 0.01; control 2.9 to 3.6, p < 0.05), communicate with and lead their team (intervention 2.4 to 3.3, p < 0.05; control 2.3 to 3.3, p < 0.01), and to prioritize, plan, and prepare (intervention 2.1 to 3.1, p < 0.05; control 2.1 to 3.0, p < 0.01). CONCLUSION: Our research shows that a brief intervention was associated with a significant increase in trainee ability to both recognize internal stress and engage in proactive coping mechanisms. This research also shows that while repeated stress-inducing simulations may themselves decrease perceived anxiety levels in novice surgical trainees, training in coping strategies may potentiate this effect.

Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis.

Epigenetic modifications, including changes in DNA methylation, lead to altered gene expression and thus may underlie epileptogenesis via induction of permanent changes in neuronal excitability. Therapies that could inhibit or reverse these changes may be highly effective in halting disease progression. Here we identify an epigenetic function of the brain's endogenous anticonvulsant adenosine, showing that this compound induces hypomethylation of DNA via biochemical interference with the transmethylation pathway. We show that inhibition of DNA methylation inhibited epileptogenesis in multiple seizure models. Using a rat model of temporal lobe epilepsy, we identified an increase in hippocampal DNA methylation, which correlates with increased DNA methyltransferase activity, disruption of adenosine homeostasis, and spontaneous recurrent seizures. Finally, we used bioengineered silk implants to deliver a defined dose of adenosine over 10 days to the brains of epileptic rats. This transient therapeutic intervention reversed the DNA hypermethylation seen in the epileptic brain, inhibited sprouting of mossy fibers in the hippocampus, and prevented the progression of epilepsy for at least 3 months. These data demonstrate that pathological changes in DNA methylation homeostasis may underlie epileptogenesis and reversal of these epigenetic changes with adenosine augmentation therapy may halt disease progression.

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia.

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Changes in spontaneous activity assessed by accelerometry correlate with extent of cerebral ischemia-reperfusion injury in the nonhuman primate.

The use of accelerometry to monitor activity in human stroke patients has revealed strong correlations between objective activity measurements and subjective neurological findings. The goal of our study was to assess the applicability of accelerometry-based measurements in experimental animals undergoing surgically-induced cerebral ischemia. Using a nonhuman primate cortical stroke model, we demonstrate for the first time that monitoring locomotor activity prior to and following cerebrovascular ischemic injury using an accelerometer is feasible in adult male rhesus macaques and that the measured activity outcomes significantly correlate with severity of brain injury. The use of accelerometry as an unobtrusive, objective preclinical efficacy determinant could complement standard practices involving subjective neurological scoring and magnetic resonance imaging in nonhuman primates. Similar activity monitoring devices to those employed in this study are currently in use in human clinical studies, underscoring the feasibility of this approach for assessing the clinical potential of novel treatments for cerebral ischemia.

Adenosine kinase determines the degree of brain injury after ischemic stroke in mice.

Adenosine kinase (ADK) is the major negative metabolic regulator of the endogenous neuroprotectant and homeostatic bioenergetic network regulator adenosine. We used three independent experimental approaches to determine the role of ADK as a molecular target for predicting the brain's susceptibility to ischemic stroke. First, when subjected to a middle cerebral artery occlusion model of focal cerebral ischemia, transgenic fb-Adk-def mice, which have increased ADK expression in striatum (164%) and reduced ADK expression in cortical forebrain (65%), demonstrate increased striatal infarct volume (126%) but almost complete protection of cortex (27%) compared with wild-type (WT) controls, indicating that cerebral injury levels directly correlate to levels of ADK in the CNS. Second, we demonstrate abrogation of lipopolysaccharide (LPS)-induced ischemic preconditioning in transgenic mice with brain-wide ADK overexpression (Adk-tg), indicating that ADK activity negatively regulates LPS-induced tolerance to stroke. Third, using adeno-associated virus-based vectors that carry Adk-sense or -antisense constructs to overexpress or knockdown ADK in vivo, we demonstrate increased (126%) or decreased (51%) infarct volume, respectively, 4 weeks after injection into the striatum of WT mice. Together, our data define ADK as a possible therapeutic target for modulating the degree of stroke-induced brain injury.

Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke.

Cerebral ischemic injury is a significant portion of the burden of disease in developed countries; rates of mortality are high and the costs associated with morbidity are enormous. Recent therapeutic approaches have aimed at mitigating the extent of damage and/or promoting repair once injury has occurred. Often, patients at high risk of ischemic injury can be identified in advance and targeted for antecedent neuroprotective therapy. Agents that stimulate the innate pattern recognition receptor, Toll-like receptor 9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke. Here, we demonstrate for the first time that pharmacological preconditioning against cerebrovascular ischemic injury is also possible in a nonhuman primate model of stroke in the rhesus macaque. The model of stroke used is a minimally invasive transient vascular occlusion, resulting in brain damage that is primarily localized to the cortex and as such, represents a model with substantial clinical relevance. Finally, K-type (also referred to as B-type) cytosine-guanine-rich DNA oligonucleotides, the class of agents employed in this study, are currently in use in human clinical trials, underscoring the feasibility of this treatment in patients at risk of cerebral ischemia.

Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant.

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.