Comparison of Patiromer to Sodium Polystyrene Sulfonate in Acute Hyperkalemia.

Background: Patiromer and sodium polystyrene sulfonate (SPS) are cation-exchangers approved for the treatment of chronic hyperkalemia. Data regarding their efficacy acutely is lacking. Despite this, both drugs are frequently used in the emergent setting. Objective: The purpose of this study was to compare the potassium reduction of patiromer to SPS within 6 to 24 hours following a single dose. Methods: This retrospective quality improvement project included hyperkalemic patients receiving 1 dose of patiromer or SPS and had a second potassium level drawn in 6 to 24 hours. Doses of 8.4 g of patiromer and 15 g of SPS were considered "low dose" while 16.8 g of patiromer and 30 g of SPS were considered "high dose." The presence of a dose-response relationship was assessed through a linear regression analysis. Results: Mean (SD) potassium reduction was higher in SPS than patiromer [0.76 (0.63) mEq/L vs 0.32 (0.65) mEq/L, (P = .001)]. A dose response relationship was not demonstrated in low versus high dose groups [-0.21 (0.14), P = .13] and CKD, ESRD, and renal transplant patients when compared to patients with normal renal function [0.11 (0.17), P = .51, -0.07 (0.19), P = -0.07 (0.19), P = .73, and -0.10 (0.22), P = .65]. Conclusions: This study suggests a clinically significant reduction in potassium with SPS compared to patiromer. Although SPS was successful in demonstrating this outcome, due to well-documented adverse reactions in the literature and a time to onset of 6 hours, it cannot be recommended for use in acute hyperkalemia either.

Impact of antimicrobial selection for prophylaxis of left ventricular assist device surgical infections.

BACKGROUND: Surgical site infections (SSIs) after left ventricular assist device (LVAD) implantation are associated with high mortality, while surgical prophylaxis is variable. METHODS: This retrospective study included adult patients who underwent LVAD implantation at a single center. We compared outcomes in patients who received narrow antimicrobial prophylaxis (cefazolin, vancomycin, or both) to those who received broad antimicrobial prophylaxis (any antimicrobial combination targeting gram-positive and gram-negative organisms not included in the narrow group) at 30-day and 1-year postimplantation. Cox-proportional hazards models and log-rank tests were used for survival analysis. RESULTS: Among the 39 and 65 patients comprising narrow and broad groups respectively, there was no difference in rate of SSI at 30 days (6.2% vs. 12.8%, p = .290) and 1 year (16.9% vs. 25.6%, p = .435). Comparing narrow to broad prophylaxis, the risk of mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.15-1.35, logrank p = .14), and composite of mortality and infection was reduced (HR = 0.92, 95% CI = 0.45-1.88, logrank p = .83), but did not reach statistical significance. Most culture positive infections were due to gram-positive bacteria (70%) and the most common organisms were the Staphylococcus spp (47%). There were no significant differences in the rate of SSI at 1-year (p = 1.00) and mortality (p = .33) by device type. CONCLUSIONS: The rates of infection and all-cause mortality were not different between patients who received narrow or broad prophylaxis. This highlights an opportunity for institutions to narrow their surgical infection prophylaxis protocols to primarily cover gram-positive organisms.

Guanylate-Binding Protein-1 protects ovarian cancer cell lines but not breast cancer cell lines from killing by paclitaxel.

Forced expression of the cytokine-induced large GTPase, human Guanylate-Binding Protein-1 (hGBP-1), in ovarian cancer cell lines increases resistance to paclitaxel. Elevated hGBP-1 RNA in ovarian tumors correlates with shorter recurrence-free survival. In contract, hGBP-1 is part of a gene signature predicting improved prognosis in all subtypes of breast cancers. hGBP-1 does not confer paclitaxel resistance on MCF-7 and TMX2-28 breast cancer cells. Expression of the isotype of the hGBP-1-interacting protein, PIM1, which may contribute to paclitaxel resistance when associated with hGBP-1, is different in breast and ovarian cancer cell lines. Breast cancer cell lines express the 44 kDa isoform of PIM-1, and ovarian cancer cell lines express the 33 kDa isoform.

The "Alzheimer's type" profile of semantic clustering in amnestic mild cognitive impairment.

Impairments in learning and recall have been well established in amnestic mild cognitive impairment (aMCI). However, a relative dearth of studies has examined the profiles of memory strategy use in persons with aMCI relative to those with Alzheimer's disease (AD). Participants with aMCI, nonamnestic MCI, AD, and healthy older adults were administered the California Verbal Learning Test-II (CVLT-II). Measures of semantic clustering and recall were obtained across learning and delayed recall trials. In addition, we investigated whether deficits in semantic clustering were related to progression from healthy aging to aMCI and from aMCI to AD. The aMCI group displayed similar semantic clustering performance as the AD participants, whereas the AD group showed greater impairments on recall relative to the aMCI participants. Control participants who progressed to aMCI showed reduced semantic clustering at the short delay at baseline compared to individuals who remained diagnostically stable across follow-up visits. These findings show that the ability to engage in an effective memory strategy is compromised in aMCI, before AD has developed, suggesting that disruptions in semantic networks are an early marker of the disease. (JINS, 2014, 20, 1-11).

Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain.

PURPOSE: The endocannabinoid system is known to modulate seizure activity in several in vivo and in vitro models, and CB(1) -receptor activation is anticonvulsant in the rat pilocarpine model of acquired epilepsy (AE). In these epileptic rats, a unique redistribution of the CB(1) receptor occurs within the hippocampus; however, an anatomically inclusive analysis of the effect of status epilepticus (SE)-induced AE on CB(1) receptors has not been thoroughly evaluated. Therefore, statistical parametric mapping (SPM), a whole-brain unbiased approach, was used to study the long-term effect of pilocarpine-induced SE on CB(1) -receptor binding and G-protein activation in rats with AE. METHODS: Serial coronal sections from control and epileptic rats were cut at equal intervals throughout the neuraxis and processed for [(3) H]WIN55,212-2 (WIN) autoradiography, WIN-stimulated [(35) S]GTPγS autoradiography, and CB(1) -receptor immunohistochemistry (IHC). The autoradiographic techniques were evaluated with both region of interest (ROI) and SPM analyses. KEY FINDINGS: In rats with AE, regionally specific increases in CB(1) -receptor binding and activity were detected in cortex, discrete thalamic nuclei, and other regions including caudate-putamen and septum, and confirmed by IHC. However, CB(1) receptors were unaltered in several brain regions, including substantia nigra and cerebellum, and did not exhibit regional decreases in rats with AE. SIGNIFICANCE: This study provides the first comprehensive evaluation of the regional distribution of changes in CB(1) -receptor expression, binding, and G-protein activation in the rat pilocarpine model of AE. These regions may ultimately serve as targets for cannabinomimetic compounds or manipulation of the endocannabinoid system in epileptic brain.

A molecular taxonomy of tumors independent of tissue-of-origin.

Cancer is an organism-level disease, impacting processes from cellular metabolism and the microenvironment to systemic immune response. Nevertheless, efforts to distinguish overarching mutational processes from interactions with the cell of origin for a tumor have seen limited success, presenting a barrier to individualized medicine. Here we present a pathway-centric approach, extracting somatic mutational profiles within and between tissues, largely orthogonal to cell of origin, mutational burden, or stage. Known predisposition variants are equally distributed among clusters, and largely independent of molecular subtype. Prognosis and risk of death vary jointly by cancer type and cluster. Analysis of metastatic tumors reveals that differences are largely cluster-specific and complementary, implicating convergent mechanisms that combine familiar driver genes with diverse low-frequency lesions in tumor-promoting pathways, ultimately producing distinct molecular phenotypes. The results shed new light on the interplay between organism-level dysfunction and tissue-specific lesions.

Mapping Dorsal and Ventral Caudate in Older Adults: Method and Validation.

The caudate nucleus plays important roles in cognition and affect. Depending on associated connectivity and function, the caudate can be further divided into dorsal and ventral aspects. Dorsal caudate, highly connected to dorsolateral prefrontal cortex (DLPFC), is implicated in executive function and working memory; ventral caudate, more interconnected with the limbic system, is implicated in affective functions such as pain processing. Clinically, certain brain disorders are known to differentially impact dorsal and ventral caudate. Thus, precise parcellation of caudate has both basic and clinical neuroscience significance. In young adults, past work has combined resting-state fMRI functional connectivity with clustering algorithms to define dorsal and ventral caudate. Whether the same approach is effective in older adults and how to validate the parcellation results have not been considered. We addressed these problems by obtaining resting-state fMRI data from 56 older non-demented adults (age: 69.07 ± 5.92 years and MOCA: 25.71 ± 2.46) along with a battery of cognitive and clinical assessments. Connectivity from each voxel of caudate to the rest of the brain was computed using cross correlation. Applying the K-means clustering algorithm to the connectivity patterns with K = 2 yielded two substructures within caudate, which agree well with previously reported dorsal and ventral divisions of caudate. Furthermore, dorsal-caudate-seeded functional connectivity was shown to be more strongly associated with working memory and fluid reasoning composite scores, whereas ventral-caudate-seeded functional connectivity more strongly associated with pain and fatigue severity. These results demonstrate that dorsal and ventral caudate can be reliably identified by combining resting-state fMRI and clustering algorithms in older adults.

Marked brain asymmetry with intact cognitive functioning in idiopathic Parkinson's disease: a longitudinal analysis.

OBJECTIVE: A 71-year-old (MN) with an 11-year history of left onset tremor diagnosed as Parkinson's disease (PD) completed longitudinal brain magnetic resonance imaging (MRI) and neuropsychological testing. MRI scans showed an asymmetric caudate nucleus (right < left volume). We describe this asymmetry at baseline and the progression over time relative to other subcortical gray, frontal white matter, and cortical gray matter regions of interest. Isolated structural changes are compared to MN's cognitive profiles. METHOD: MN completed yearly MRIs and neuropsychological assessments. For comparison, left onset PD (n = 15) and non-PD (n = 43) peers completed the same baseline protocol. All MRI scans were processed with FreeSurfer and the FMRIB Software Library to analyze gray matter structures and frontal fractional anisotropy (FA) metrics. Processing speed, working memory, language, verbal memory, abstract reasoning, visuospatial, and motor functions were examined using reliable change methods. RESULTS: At baseline, MN had striatal volume and frontal lobe thickness asymmetry relative to peers with mild prefrontal white matter FA asymmetry. Over time only MN's right caudate nucleus showed accelerated atrophy. Cognitively, MN had slowed psychomotor speed and visuospatial-linked deficits with mild visuospatial working memory declines longitudinally. CONCLUSIONS: This is a unique report using normative neuroimaging and neuropsychology to describe an individual diagnosed with PD who had striking striatal asymmetry followed secondarily by cortical thickness asymmetry and possible frontal white matter asymmetry. His decline and variability in visual working memory could be linked to ongoing atrophy of his right caudate nucleus.

Gray and White Matter Contributions to Cognitive Frontostriatal Deficits in Non-Demented Parkinson's Disease.

OBJECTIVE: This prospective investigation examined: 1) processing speed and working memory relative to other cognitive domains in non-demented medically managed idiopathic Parkinson's disease, and 2) the predictive role of cortical/subcortical gray thickness/volume and white matter fractional anisotropy on processing speed and working memory. METHODS: Participants completed a neuropsychological protocol, Unified Parkinson's Disease Rating Scale, brain MRI, and fasting blood draw to rule out vascular contributors. Within group a priori anatomical contributors included bilateral frontal thickness, caudate nuclei volume, and prefrontal white matter fractional anisotropy. RESULTS: Idiopathic Parkinson's disease (n = 40; Hoehn & Yahr stages 1-3) and non-Parkinson's disease 'control' peers (n = 40) matched on demographics, general cognition, comorbidity, and imaging/blood vascular metrics. Cognitively, individuals with Parkinson's disease were significantly more impaired than controls on tests of processing speed, secondary deficits on working memory, with subtle impairments in memory, abstract reasoning, and visuoperceptual/spatial abilities. Anatomically, Parkinson's disease individuals were not statistically different in cortical gray thickness or subcortical gray volumes with the exception of the putamen. Tract Based Spatial Statistics showed reduced prefrontal fractional anisotropy for Parkinson's disease relative to controls. Within Parkinson's disease, prefrontal fractional anisotropy and caudate nucleus volume partially explained processing speed. For controls, only prefrontal white matter was a significant contributor to processing speed. There were no significant anatomical predictors of working memory for either group. CONCLUSIONS: Caudate nuclei volume and prefrontal fractional anisotropy, not frontal gray matter thickness, showed unique and combined significance for processing speed in Parkinson's disease. Findings underscore the relevance for examining gray-white matter interactions and also highlight clinical processing speed metrics as potential indicators of early cognitive impairment in PD.

Proof of principle: Transformation approach alters caudate nucleus volume and structure-function associations.

Brain magnetic resonance image (MRI) registration alters structure orientation, size, and/or shape. To determine whether linear registration methods (image transformation to 6, 9, and 12° of freedom) alter structural volume and cognitive associations, we examined transformation alterations to the caudate nucleus within individuals diagnosed with Parkinson's disease (PD) and demographically matched non-PD peers. Volumes from native and six were expected be significantly different from 9 and 12° of freedom methods. Caudate nucleus volumes were expected to be associated with measures of processing speed and mental flexibility, but the strength of the association based on transformation approach was unknown. MRI brain scans from individuals with Parkinson's disease (n = 40) and age-matched controls (n = 40) were transformed using 6, 9, and 12° of freedom to an average brain template. Correlations controlling for total intracranial volume assessed expected structural-behavioral associations. Volumetric: Raw 9 and 12° transformed volumes were significantly larger than native and 6° volumes. Only 9 and 12° volumes revealed group differences with PD less than controls. Intracranial volume considerations were essential for native and 6° between group comparisons. Structural-Behavioral: The 9 and 12° caudate nucleus volume transformations revealed the expected brain-behavioral associations. Linear registration techniques alter volumetric and cognitive-structure associations. The study highlights the need to communicate transformation approach and group intracranial volume considerations.

Imaging polarimetry for high throughput chiral screening.

Imaging polarimetry was demonstrated as a highly parallel method of determining optical rotation of biochemical samples. The imaging polarimeter utilized a bright, uniform light source wavelength-filtered to near the sodium D line, a sample array flanked by inlet and analyzing polarizers, and a CCD camera fitted with an equal-perspective telecentric lens. The prototype apparatus was demonstrated to have an optical resolution better than 0.08 degrees. The potential for high throughput screening was demonstrated by imaging chiral solutions in 1536-well microtiter plates and by real-time monitoring of 30 simultaneous chiral enzymatic reactions. Improvements in polarizer and CCD technology may broadly expand the technique's applicability to fields such as directed evolution and combinatorial chemistry, where screening throughput is currently limiting for chiral applications.

ß-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner.

BACKGROUND: Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of ▵(9)-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. ß-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB(1)R effects and receptor regulation is unclear. METHODS: CB(1)R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in ß-arrestin2-knockout (ßarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [(35)S]GTPγS and [(3)H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis. RESULTS: ß-arrestin2 deletion increased CB(1)R-mediated G-protein activity in subregions of the cortex but did not affect CB(1)R binding, in vehicle-treated mice. ßarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, ßarr2-KO mice showed reduced CB(1)R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of ßarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in ßarr2-KO mice. CONCLUSIONS: ß-arrestin2 regulation of CB(1)R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB(1)Rs. The observations that ßarr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB(1)R interactions with ß-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

Antenatal maternal stress alters functional brain responses in adult offspring during conditioned fear.

Antenatal maternal stress has been shown in rodent models and in humans to result in altered behavioral and neuroendocrine responses, yet little is known about its effects on functional brain activation. Pregnant female rats received a daily foot-shock stress or sham-stress two days after testing plug-positive and continuing for the duration of their pregnancy. Adult male offspring (age 14 weeks) with and without prior maternal stress (MS) were exposed to an auditory fear conditioning (CF) paradigm. Cerebral blood flow (CBF) was assessed during recall of the tone cue in the nonsedated, nontethered animal using the ((14))C-iodoantipyrine method, in which the tracer was administered intravenously by remote activation of an implantable minipump. Regional CBF distribution was examined by autoradiography and analyzed by statistical parametric mapping in the three-dimensionally reconstructed brains. Presence of fear memory was confirmed by behavioral immobility ("freezing"). Corticosterone plasma levels during the CF paradigm were measured by ELISA in a separate group of rats. Antenatal MS exposure altered functional brain responses to the fear conditioned cue in adult offspring. Rats with prior MS exposure compared to those without demonstrated heightened fear responsivity, exaggerated and prolonged corticosterone release, increased functional cerebral activation of limbic/paralimbic regions (amygdala, ventral hippocampus, insula, ventral striatum, and nucleus accumbens), the locus coeruleus, and white matter, and deactivation of medial prefrontal cortical regions. Dysregulation of corticolimbic circuits may represent risk factors in the future development of anxiety disorders and associated alterations in emotional regulation.

Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.

Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

Successful medical management of recurrent emphysematous pyelonephritis.

Emphysematous pyelonephritis is characterized by infection and gas formation in the renal parenchyma. This rare disorder tends to occur more frequently in patients with diabetes mellitus and urinary tract obstruction. In this case report, we describe a nondiabetic patient with Hinman syndrome who developed recurrent emphysematous pyelonephritis that was successfully treated with antibiotics on both occasions.

Statistical parametric mapping applied to an autoradiographic study of cerebral activation during treadmill walking in rats.

Autoradiographs are conventionally analyzed by a region-of-interest (ROI) analysis. However, definition of ROIs on an image set is labor intensive, is subject to potential inter-rater bias, and is not well suited for anatomically variable structures that may not consistently correspond to specific ROIs. Most importantly, the ROI method is poorly suited for whole-brain analysis, where one wishes to detect all activations resulting from an experimental paradigm. A system developed for analysis of imaging data in humans, Statistical Parametric Mapping (SPM), avoids some of these limitations but has not previously been adapted as a tool for the analysis of autoradiographs. Here, we describe the application of SPM to an autoradiographic data set mapping cerebral activation in rats during treadmill walking. We studied freely moving, non-tethered rats that received injections of the cerebral blood flow tracer [14C]-iodoantipyrine, while they were performing a treadmill task (n = 7) or during a quiescent control condition (n = 6). Results obtained with SPM were compared to those previously reported using a standard ROI-based method of analysis [J. Cereb. Blood Flow Metab. 23(2003) 925]. The SPM method confirmed most areas detected as significant using the ROI approach. However, in the subcortex, SPM detected additional significant regions that, because of their irregular structures, fell short of statistical significance when analyzed by ROI. The SPM approach offers the ability to perform a semi-automated whole-brain analysis, and coupled with autoradiography, provides an effective means to globally localize functional activity in small animals.