Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Traditionally, nephrolithiasis was considered a relative contraindication to kidney donation because of a risk of recurrent stones in donors and adverse stone-related outcomes in recipients. However, the scarcity of organs has driven the transplant community to re-examine and broaden selection criteria for living donors with stones. In this review, we summarize and contrast the guidelines published by various prominent national and international societies on this topic. RECENT FINDINGS/RESULTS:Although recent iterations of living donor guidelines are less stringent with respect to nephrolithiasis than those published in the 1990s, there is little consensus among national and international transplant society guidelines regarding selection criteria for potential kidney donors with nephrolithiasis. SUMMARY/CONCLUSIONS:The lack of evidence-based guidelines deters transplant centers from implementing selection criteria to accept donors with nephrolithiasis and discourages studies of outcomes in donors with nephrolithiasis and their recipients. In addition to drawing attention to the disparities in prevailing guidelines, we put forth several questions that must be answered before generalizable criteria for selection of donor with nephrolithiasis can be developed.

OBJECTIVES/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C- reactive protein, yearly frequency of hyper-adrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body Mass Index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower Inspiratory Capacity (IC) (42.7% predicted vs 62.8% predicted; p=0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

OBJECTIVE:Examine the relationship between duration of unilateral deafness and speech perception outcomes after cochlear implantation in adults with single-sided deafness. METHODS:A systematic review of PubMed articles containing individual speech perception and duration of deafness data from single-sided deaf adults. Studies were selected for detailed review and duration of deafness and speech perception outcomes were extracted, with speech scores reported as percent correct. A linear regression as a function of study and length of deafness was performed. RESULTS:A statistically significant negative effect of duration of unilateral deafness on speech perception was found, but there was substantial uncertainty regarding the strength of the effect. DISCUSSION/CONCLUSIONS:Existing data make it difficult to either support or reject a hard 5- or 10-year unilateral auditory deprivation limit on cochlear implant (CI) candidacy for patients with single-sided deafness. This is because the totality of available data are consistent with a very small effect, perhaps negligible in practical terms, and just as consistent with a very large effect. Regardless of effect size, the present results have important basic implications. They suggest that unilateral sound deprivation may have a deleterious effect on auditory processing even though more central parts of the auditory system have continued to receive input from a contralateral normal ear. CONCLUSIONS:Speech perception scores in SSD patients are negatively correlated with duration of deafness, but the limited amount of data from cochlear implant users with long-term single-sided deafness leads to substantial uncertainly, which in turn precludes any strong clinical recommendations. Further study of SSD CI users with long-term deafness will be necessary to generate evidence-based guidelines for implantation criteria in this population.

BACKGROUND:Measurement of the angular depth of insertion (aDOI) of cochlear implant electrode arrays has numerous clinical and research applications. Plain-film radiographs are easily obtained intraoperatively and have been described as a means to calculate aDOI. CT imaging with 3D reformatting can also be used for this measurement, but is less conveniently obtained and requires higher radiation doses, a particular concern in pediatrics. The extent to which plain-film and 3D CT image-based measurements are representative of the true position of the electrode within the cochlea is unknown. METHODS:Cochlear implantation was performed on 10 cadaveric temporal bones. Five bones were implanted with perimodiolar electrodes (Contour Advance TM, Cochlear, Sydney, Australia) and five were implanted with lateral wall electrodes (Slim Straight, Cochlear). The insertion depths of the electrodes were varied. Each bone was imaged with a radiograph and CT. aDOI was measured for each bone in each imaging modality by a neurotologist and a neuroradiologist. To obtain a 'gold standard' estimate of aDOI, the implanted temporal bones were embedded in an epoxy resin and methodically sectioned at 100 μm intervals; histologic images were captured at each interval. A 3D stack of the images was compounded, and a MATLAB script used to calculate aDOI of the most apical electrode. Measurements in the three modalities (radiograph, CT, and histology) were then compared. RESULTS:The average aDOI across all bones was similar for all modalities: 423° for radiographs, 425° for CT scans, and 427° for histology, indicating that neither imaging modality resulted in large systematic errors. Using the histology-measured angles as a reference, the average error for CT-based measures (regardless of whether the error was in the positive or negative direction) was 12°, and that for radiograph-based measures was 15°. This small difference (12 vs 15° error) was not statistically significant. CONCLUSION/CONCLUSIONS:Based on this cadaveric temporal bone model, both radiographs and CTs can provide reasonably accurate aDOI measurements. In this small sample, and as expected, the CT-based estimates were more accurate than the radiograph-based measurements. However, the difference was small and not statistically significant. Thus, the use of plain radiographs to calculate aDOI seems judicious whenever it is desired to prevent unnecessary radiation exposure and expense.

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls-an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction.

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD -) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD - cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD - cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD -, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD - cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD - cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.

Diet influences dopamine transmission in motor- and reward-related basal ganglia circuitry. In part, this reflects diet-dependent regulation of circulating and brain insulin levels. Activation of striatal insulin receptors amplifies axonal dopamine release in brain slices, and regulates food preference in vivo. The effect of insulin on dopamine release is indirect, and requires striatal cholinergic interneurons that express insulin receptors. However, insulin also increases dopamine uptake by promoting dopamine transporter (DAT) surface expression, which counteracts enhanced dopamine release. Here we determined the functional consequences of acute insulin exposure and chronic diet-induced changes in insulin on DAT activity after evoked dopamine release in striatal slices from adult ad-libitum fed (AL) rats and mice, and food-restricted (FR) or high-fat/high-sugar obesogenic (OB) diet rats. Uptake kinetics were assessed by fitting evoked dopamine transients to the Michaelis-Menten equation and extracting C_peak and V_max . Insulin (30 nM) increased both parameters in the caudate putamen and nucleus accumbens core of AL rats in an insulin receptor- and PI3-kinase-dependent manner. A pure effect of insulin on uptake was unmasked using mice lacking striatal acetylcholine, in which increased V_max caused a decrease in C_peak . Diet also influenced V_max , which was lower in FR versus AL. The effects of insulin on C_peak and V_max were amplified by FR but blunted by OB, consistent with opposite consequences of these diets on insulin levels and insulin receptor sensitivity. Overall, these data reveal acute and chronic effects of insulin and diet on dopamine release and uptake that will influence brain reward pathways.

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain and as cancer patients are living longer new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in pre-clinical models of post-surgical and soft tissue oral cancer pain by inducing an up-regulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2µg/g, i.p.) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant which reduced the number of responsive DRG neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Increased reaction time variability (RTV) is one of the most replicable behavioral correlates of attention-deficit/hyperactivity disorder (ADHD). However, this may not be specific to ADHD but a more general marker of psychopathology. Here we compare RT variability in individuals with ADHD and those with other childhood internalizing and externalizing conditions both in terms of standard (i.e., the standard deviation of reaction time) and alternative indices that capture low-frequency oscillatory patterns in RT variations over time thought to mark periodic lapses of attention in ADHD. A total of 667 participants (6-12 years old) were classified into non-overlapping diagnostic groups consisting of children with fear disorders (n = 91), distress disorders (n = 56), ADHD (n = 103), oppositional defiant or conduct disorder (ODD/CD; n = 40) and typically developing controls (TDC; n = 377). We used a simple two-choice reaction time task to measure reaction time. The strength of oscillations in RTs across the session was extracted using spectral analyses. Higher RTV was present in ADHD compared to all other disorder groups, effects that were equally strong across all frequency bands. Interestingly, we found that lower RTV to characterize ODD/CD relative to TDC, a finding that was more pronounced at lower frequencies. In general, our data support RTV as a specific marker of ADHD. RT variation across time in ADHD did not show periodicity in a specific frequency band, not supporting that ADHD RTV is the product of spontaneous periodic lapses of attention. Low-frequency oscillations may be particularly useful to differentiate ODD/CD from TDC.