Faculty Bibliography

Despite the importance of the discharge frequency in neuronal communication, little is known about the firing-rate patterns of cortical populations. Using large-scale recordings from multiple layers of the entorhinal-hippocampal loop, we found that the firing rates of principal neurons showed a lognormal-like distribution in all brain states. Mean and peak rates within place fields of hippocampal neurons were also strongly skewed. Importantly, firing rates of the same neurons showed reliable correlations in different brain states and testing situations, as well as across familiar and novel environments. The fraction of neurons that participated in population oscillations displayed a lognormal pattern. Such skewed firing rates of individual neurons may be due to a skewed distribution of synaptic weights, which is supported by our observation of a lognormal distribution of the efficacy of spike transfer from principal neurons to interneurons. The persistent skewed distribution of firing rates implies that a preconfigured, highly active minority dominates information transmission in cortical networks.

Anti-amyloid beta (Abeta) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Abeta1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Abeta1-42 or Abeta-derivative (K6Abeta1-30). We followed anti-Abeta40 immunoglobulin G and M responses and Abeta levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Abeta1-42 immunogen. This treatment induced immune response and increased Abeta levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Abeta-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials.

Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.

BACKGROUND AND PURPOSE: The spinal cord is a site of predilection for MS lesions. While diffusion tensor imaging is useful for the study of anisotropic systems such as WM tracts, it is of more limited utility in tissues with more isotropic microstructures (on the length scales studied with diffusion MR imaging) such as gray matter. In contrast, diffusional kurtosis imaging, which measures both Gaussian and non-Gaussian properties of water diffusion, provides more biomarkers of both anisotropic and isotropic structural changes. The aim of this study was to investigate the cervical spinal cord of patients with MS and to characterize lesional and normal-appearing gray matter and WM damage by using diffusional kurtosis imaging. MATERIALS AND METHODS: Nineteen patients (13 women, mean age = 41.1 +/- 10.7 years) and 16 controls (7 women, mean age = 35.6 +/- 11.2-years) underwent MR imaging of the cervical spinal cord on a 3T scanner (T2 TSE, T1 magnetization-prepared rapid acquisition of gradient echo, diffusional kurtosis imaging, T2 fast low-angle shot). Fractional anisotropy, mean diffusivity, and mean kurtosis were measured on the whole cord and in normal-appearing gray matter and WM. RESULTS: Spinal cord T2-hyperintense lesions were identified in 18 patients. Whole spinal cord fractional anisotropy and mean kurtosis (P = .0009, P = .003), WM fractional anisotropy (P = .01), and gray matter mean kurtosis (P = .006) were significantly decreased, and whole spinal cord mean diffusivity (P = .009) was increased in patients compared with controls. Mean spinal cord area was significantly lower in patients (P = .04). CONCLUSIONS: Diffusional kurtosis imaging of the spinal cord can provide a more comprehensive characterization of lesions and normal-appearing WM and gray matter damage in patients with MS. Diffusional kurtosis imaging can provide additional and complementary information to DTI on spinal cord pathology.

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of "acceptability" that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children.

OBJECTIVES: To evaluate changes in single-kidney glomerular filtration rate (SK-GFR) using low-dose dynamic contrast-enhanced magnetic resonance (MR) renography (MRR) in patients undergoing partial nephrectomy for renal masses. MATERIALS AND METHODS: In this Health Information Patient Protection Act-compliant prospective study, 18 patients with renal masses underwent preoperative MR imaging at 1.5 T for renal mass evaluation and low-dose gadolinium-enhanced MRR. Magnetic resonance renography was repeated approximately 48 to 72 hours and 6 months after partial nephrectomy. Single-kidney glomerular filtration rate was calculated from the MRR images, and the right and left kidney values were summed for total MR-GFR. Postoperative changes in SK-GFR and MR-GFR were compared with changes in estimated glomerular filtration rate calculated using modification of diet in renal disease formula, renal lesion characteristics, ischemia type (warm vs cold), and ischemia time. RESULTS: A decrease in the operated kidney SK-GFR was seen in 15 of the 18 patients, with a mean (SD) loss of 31% (23%), whereas estimated glomerular filtration rate decreased in 13 of the 18 patients with mean (SD) decrease of 19% (14%). Decrease in SK-GFR was greatest in the patients with warm ischemia time greater than 40 minutes and least in the patients with cold ischemia. In the immediate postoperative period, 6 of 7 patients (86%) with preoperative MR-GFR less than 60 mL/min per 1.73 m failed to demonstrate compensatory increase in SK-GFR in the nonoperated kidney, whereas 5 of 11 patients with baseline MR-GFR more than 60 mL/min per 1.73 m showed compensatory increase in nonoperated kidney SK-GFR. CONCLUSIONS: Magnetic resonance renography can demonstrate functional loss in the operated kidney and compensatory increase in the function of the contralateral kidney, thus enabling evaluation of various surgical techniques on kidney function.

BACKGROUND AND OBJECTIVES: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone >/=3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. RESULTS: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. CONCLUSIONS: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.

BACKGROUND: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. METHODS: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7 degrees +/- 1.0 degrees , and the range was very wide (2.8 degrees -18.1 degrees ); conversely, absolute error was only 2.7 degrees +/- 0.3 degrees (1.6 degrees -5.5 degrees ) in the controls and 3.0 degrees +/- 0.2 degrees (2.1 degrees -3.4 degrees ) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.