Evaluation of Urinary Renal Biomarkers for Early Prediction of Acute Kidney Injury Following Partial Nephrectomy: A Feasibility Study.

BACKGROUND: Partial nephrectomy (PN) is the gold standard for the treatment of small renal masses. Urinary biomarkers (UBMs) may serve as early indicators of acute kidney injury (AKI) following PN. OBJECTIVE: To evaluate the timing, specificity, and sensitivity of several candidate UBMs after PN to determine the most promising UBMs in this setting. We hypothesize that some UBMs will have utility as early markers of AKI. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two patients undergoing on-clamp robotic or open PN underwent paired urine collection via ureteral catheterization of the affected kidney and Foley catheterization for the unaffected kidney obtained preoperatively, after anesthesia, and at several points in time after renovascular occlusion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Measured UBMs included albumin, α-glutathione S-transferase, B2M, calbindin, clusterin, cystatin C, epidermal growth hormone, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, osteoactivin, osteopontin, total protein, trefoil factor 3, uromodulin, and vascular endothelial growth factor. RESULTS AND LIMITATIONS: The largest fold changes in UBM levels were observed between the baseline values and just prior to vascular occlusion (time "0"). Albumin, clusterin, and calbindin were among the most consistently and significantly increased UBMs. After vascular occlusion and subsequent reperfusion, some UBMs, most notably albumin, calbindin, and total protein, continued to increase in the affected kidney, peaking at 60-90min, followed by decrease to time "0" measurements after 1 d and to baseline levels 14-42 d after surgery. No striking association of UBMs with parameters such as duration of surgery, ischemia time, and tumor complexity was observed. CONCLUSIONS: The most significant UBM increases were observed when comparing samples obtained at preoperative visit and after anesthesia, but before clamp time. Albumin, clusterin, and calbindin were the most consistently and significantly altered UBMs; further investigation will be necessary to determine whether UBMs can identify AKI earlier in nephrectomy patients. PATIENT SUMMARY: Factors (biomarkers) measured in the blood or urine can indicate the presence and amount of kidney injury. We evaluated 15 different biomarkers at several points in time prior to, during, and after surgery for kidney cancer. We found that three of these biomarkers were most consistently elevated in patients undergoing partial nephrectomy. Interestingly, the largest increases were observed when comparing samples obtained prior to surgery with those obtained just after anesthesia.

The effect of antipsychotic medications on acoustic startle latency in schizophrenia.

Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p=0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p=0.04) and the SGA subjects (p=0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p=0.03), the SGA group (p=0.02) and the FGA group (p=0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON.

Declarative memory and WCST-64 performance in subjects with schizophrenia and healthy controls.

The Wisconsin Card Sorting Test (WCST) is a set-switching task used extensively to study impaired executive functioning in schizophrenia. Declarative memory deficits have also been associated with schizophrenia and may affect WCST performance because continued correct responding depends on remembering the outcome of previous responses. This study examined whether performance in visual and verbal declarative memory tasks were associated with WCST performance. Subjects comprised 30 patients with schizophrenia or schizoaffective disorder (SCZ) and 30 demographically matched healthy controls (CON) who were tested on the WCST, the Benton Visual Retention Test (BVRT), the California Verbal Learning Test (CVLT), and the Continuous Performance Test (CPT). SCZ subjects showed significant correlations between visual and verbal declarative memory and performance on the WCST-64 that were in the hypothesized direction such that worse memory performance was associated with worse performance on the WCST. CON subjects did not show a significant relationship between visual or verbal memory and WCST-64 performance. Fisher's r to z transformations indicated that the associations between declarative memory and WCST-64 performance in the SCZ subjects differed significantly from those of CON subjects. The findings suggest that interpretations of WCST-64 scores for subjects with schizophrenia should be considered in light of their declarative memory functioning.

Lack of relationship between acoustic startle and cognitive variables in schizophrenia and control subjects.

Measures of acoustic startle such as prepulse inhibition (PPI) and startle latency have been found to be impaired in schizophrenia, and are commonly thought to be related to cognitive deficits in this disease. However, findings about the relationship between startle variables and cognitive performance have been equivocal. In this study, we examined correlations between startle measures (baseline startle magnitude, latency, habituation and PPI) and cognitive performance (using the Benton Visual Retention Test, Conner's Continuous Performance Test, California Verbal Learning Test, Finger Tapping Test, and Wisconsin Card Sort Test) in 107 schizophrenia patients and 94 healthy controls. Overall, there was a lack of any significant relationship between these constructs in both populations when correcting for multiple comparisons. This suggests that alterations in startle measures seen in schizophrenia may not reflect elements of information processing that cause cognitive deficits in the disease.

Altered engagement of attention and default networks during target detection in schizophrenia.

Recent studies have implicated inappropriate engagement of functional brain networks in schizophrenia. This fMRI study examined task-induced activations and deactivations in 10 schizophrenia patients with prominent negative symptoms and 10 healthy controls during a simple target detection task. Group comparison revealed recruitment of distinct attentional networks during this task, with schizophrenia subjects activating the dorsal attention system and controls activating the executive network. Further, schizophrenia patients failed to deactivate posterior cingulate regions during the task, supporting recent studies of altered default mode processing. These findings support theories of dysfunctional recruitment of large-scale brain networks in schizophrenia.

Heritability of acoustic startle magnitude, prepulse inhibition, and startle latency in schizophrenia and control families.

Prepulse inhibition (PPI) is an acoustic startle paradigm that has been used as an operational measure of sensorimotor gating. Many patients with schizophrenia have impaired PPI, and several lines of evidence suggest that PPI may represent a heritable endophenotype in this disease. We examined startle magnitude and latencies in 40 schizophrenia patients, 58 first-degree relatives of these patients, and 100 healthy controls. After removing low-startlers, we investigated PPI and startle habituation in 34 schizophrenia patients, 43 relatives, and 86 control subjects. Heritability analyses were conducted using a variance-component approach. We found significant heritability of 45% for PPI at the 60-ms interval and 67% for startle magnitude. Onset latency heritability estimates ranged between 39% and 90% across trial types, and those for peak latency ranged from 29% to 68%. Heritability of startle habituation trended toward significance at 31%. We did not detect differences between controls and either schizophrenia patients or their family members for PPI, startle magnitude, or habituation. Startle latencies were generally longer in schizophrenia patients than controls. The heritability findings give impetus to applying genetic analyses to PPI variables, and suggest that startle latency may also be a useful measure in the study of potential endophenotypes for schizophrenia.

Timing of extinction relative to acquisition: a parametric analysis of fear extinction in humans.

Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction occurs within minutes of acquisition. However, a limited number of human extinction studies have shown that short interval extinction does not prevent the return of fear. For this reason, we performed an in-depth parametric analysis of human fear extinction using fear-potentiated startle. Using separate single-cue and differential conditioning paradigms, participants were fear conditioned and then underwent extinction either 10 min (Immediate) or 72 hr (Delayed) later. Testing for spontaneous recovery occurred 96 hr after acquisition. In the single cue paradigm, the Immediate and Delayed groups exhibited differences in context, but not fear, conditioning. With differential conditioning, there were no differences in context conditioning and the Immediate group displayed less spontaneous recovery. Thus, the results remain inconclusive regarding spontaneous recovery and the timing of extinction and are discussed in terms of performing translational studies of fear in humans.

Differences in startle reflex and prepulse inhibition in European-Americans and African-Americans.

The acoustic startle reflex and its modulation by a prepulse are psychophysiological phenomena that are commonly studied to evaluate various aspects of information processing. Recent reports in human populations suggest that subjects from disparate racial backgrounds may have significant differences in the startle response. To determine if this pattern could be observed in our subject population and whether it extended to prepulse inhibition (PPI), we evaluated baseline startle parameters and PPI in 53 African-Americans (AA) and 38 European-Americans (EA). In AA compared to EA, mean startle magnitude and probability of blink response were lower, with no difference in habituation. PPI was greater in AA than EA when groups were matched on baseline startle magnitude. These findings support the idea of racial differences in startle response. Implications for study design are highlighted, and possible environmental and genetic influences are considered.

An fMRI study of the interaction of stress and cocaine cues on cocaine craving in cocaine-dependent men.

Acute stress is associated with relapse in cocaine addiction, possibly through the activation of craving-related neural circuitry. Neural responses to cocaine cues and acute stress were investigated in an fMRI study. Ten male participants mentally re-enacted personalized scripts about cocaine use and a neutral experience both with and without a stressor present (anticipation of electrical shock). Interaction analysis between script type and stress condition revealed greater activation of the posterior cingulate cortex and of the parietal lobe during the cocaine script in the presence of the stressor. These data suggest that stress may precipitate relapse in cocaine addiction by activating brain areas that mediate reward processing and the attentional and mnemonic bias for drug use reminders.

Relative risk of glucose elevation during antipsychotic exposure in a Veterans Administration population.

Concern is mounting that atypical antipsychotics cause disturbance in glucose regulation ranging from reversible hyperglycemia to diabetic ketoacidosis and death. It is difficult, however, to know what the level of risk of hyperglycemia might be for an individual patient on a particular medication of this class. We conducted a retrospective nonrandomized cohort analysis of glucose measurements in 18,764 patients receiving outpatient prescriptions for olanzapine, risperidone, or typical antipsychotics from 1 October 1998 to 30 June 2003 at six Veterans Affairs Medical Centers in the southeast United States. In patients without a random plasma glucose measurement > or =160 mg/dl before medication exposure (n=1394), treatment with index medications was associated with an incidence of new diabetes-level hyperglycemia of 78.7 cases per 1,000 individuals exposed per year. Olanzapine exposure was associated with a greater rate of developing at least one glucose measurement > or =200 mg/dl than risperidone (odds ratio=2.14, P=0.003). Olanzapine exposure was also associated with a greater rate of development of at least one fasting glucose measurement > or =126 mg/dl than risperidone. Typical antipsychotics were associated with risk intermediate between the two atypicals. These data indicate that patients with no previously observed glucose elevations develop diabetes-level hyperglycemia during antipsychotic treatment, particularly in patients receiving olanzapine.