Management of Mammographic Architectural Distortion Based on Contrast-enhanced MRI and US Correlation.

OBJECTIVE: The objective was to evaluate outcomes of mammographic architectural distortion (AD) with and without MRI and US correlates. METHODS: A retrospective review of unexplained mammographic AD with subsequent MRI from January 1, 2007 to September 30, 2017 was performed using a reader-based study design. Mammographic, MRI, and US features and outcomes were documented. Truth was based on biopsy results or minimum two-year imaging follow-up. Measures of diagnostic accuracy were calculated. RESULTS: Fifty-six cases of AD were included: 29 (51.8%) detected on 2D mammogram and 27 (48.2%) detected on digital breast tomosynthesis. Of 35.7% (20/56) with MRI correlate, 40.0% (8/20) were enhancing masses, 55.0% (11/20) were non-mass enhancement (NME), and 5.0% (1/20) were nonenhancing AD. Of eight enhancing masses, 75.0% (6/8) were invasive cancers, and 25.0% (2/8) were high-risk lesions. Of 11 NME, 18.2% (2/11) were ductal carcinoma in situ, 36.4% (4/11) were high-risk lesions, and 45.4% (5/11) were benign. Of 64.3% (36/56) without MRI correlate, 94.4% (34/36) were benign by pathology or follow-up, one (2.8%, 1/36) was a 4-mm focus of invasive cancer with US correlate, and one (1/36, 2.8%) was a high-risk lesion. Of cases without MRI and US correlates, one (3.0%, 1/33) was a high-risk lesion and 97.0% (32/33) were benign. The negative predictive value of mammographic AD without MRI correlate was 97.2% (35/36) and without both MRI and US correlates was 100.0% (33/33). CONCLUSION: Mammographic AD without MRI or US correlate was not cancer in our small cohort and follow-up could be considered, reducing interventions.

Diagnostic Utility of CT and Fluoroscopic Esophagography for Suspected Esophageal Perforation in the Emergency Department.

OBJECTIVE. We evaluated the diagnostic utility of CT in emergency department (ED) patients with suspected esophageal perforation and assessed whether subsequent fluoroscopic esophagography is necessary. MATERIALS AND METHODS. This retrospective study included consecutive adult patients presenting to an urban academic tertiary care ED from January 1, 2000, to August 31, 2017, who underwent CT and fluoroscopic esophagography within 1 calendar day (< 27 hours) of each other for suspected esophageal perforation. The use of oral or IV contrast material and the CT findings (i.e., pneumomediastinum, pleural effusion, pneumothorax, unexplained mediastinal fluid or stranding, esophageal wall air or frank esophageal wall disruption, or extraluminal oral contrast material) were documented. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Surgical or procedural intervention results or clinical follow-up results were the reference standard. RESULTS. One hundred three patients met the inclusion criteria. Sensitivity, specificity, PPV, and NPV for diagnosing esophageal perforation were 100.0%, 79.8%, 32.1%, and 100.0%, respectively, with CT and 77.8%, 98.9%, 87.5%, and 97.9% with fluoroscopic esophagography. Combining CT and fluoroscopic esophagography did not improve sensitivity, specificity, PPV, or NPV relative to using CT alone. The true-positive esophageal perforation rate was 8.7% for CT and 6.8% for fluoroscopic esophagography. When CT showed only pneumomediastinum (n = 51) or no pneumomediastinum (n = 14), the NPV of CT was 100.0%. CT with oral contrast material had a PPV of 38.5%, whereas CT without oral contrast material had a PPV of 26.7%. CONCLUSION. CT has a high NPV similar to that of fluoroscopic esophagography and has greater sensitivity than fluoroscopic esophagography for diagnosing suspected esophageal perforation. Fluoroscopic esophagrams do not provide additional information that changes clinical management beyond the information that CT provides. In ED patients with suspected esophageal perforation, CT with oral contrast material should be considered the initial imaging examination and can obviate fluoroscopic esophagography.

Adnexal mass staging CT with a disease-specific structured report compared to simple structured report.

OBJECTIVES: To assess a disease-specific structured report (dsSR) for CT staging of ovarian malignancy compared to a simple structured report (sSR). METHODS: This is a HIPAA-compliant, IRB-approved study with waiver of informed consent. An adnexal mass-specific structured reporting CT template was developed in collaboration between gynecologic oncologists and diagnostic radiologists. The study population included 24 consecutive women who had a staging CT prior to undergoing debulking surgery for a primary ovarian malignancy. Objective evaluation by radiologists for the presence of 19 key features and subjective evaluation by gynecologic oncologists were performed to assess the clarity and usefulness for procedural planning of dsSR and sSR. Accuracy, sensitivity, and specificity were assessed using operating room notes and pathology reports as the reference standard. RESULTS: Fewer key features were missing from dsSR than sSR: 0.2 ± 0.8 (range 0-2) vs.10.2 ± 1.7 (range 7-14), respectively (p < 0.0001). Compared to sSR, gynecologic oncologists deemed dsSR more helpful (4.3 ± 0.7 vs. 3.7 ± 0.8, p < 0.0001) and easier to understand (4.3 ± 0.6 vs. 3.9 ± 0.7, p = 0.0057) (on a scale 0-5, 0 not helpful/very difficult to understand; 5 extremely helpful/very clear to understand). Gynecologic oncologists reported a higher rate of potential to modify their surgical approach based on dsSR (33-42%) compared to sSR (13-17%), p = 0.004. CONCLUSIONS: Disease-specific structured reports were more reliable than simple structured reports in describing key features essential for procedural planning. dsSR was described as more helpful and easier to understand and more likely to lead to modification of the surgical approach by gynecologic oncologists compared to sSR. KEY POINTS: • Disease-specific structured report is easier to understand and more helpful for planning gynecological surgery as compared with simple structured report. • Disease-specific structured report for pre-operative evaluation of ovarian cancer provides better documentation of essential features required for surgical planning as compared with simple structured report. • Disease-specific structured report has the potential to modify the surgical approach as assessed by gynecologic oncologists.

Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.

BACKGROUND: Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice]. METHODS: We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered. RESULTS: We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens. CONCLUSIONS: These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.

Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.

BACKGROUND: Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. METHODS: We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice. RESULTS: Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. CONCLUSIONS: This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.

Deletion of striatal adenosine A(2A) receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning.

Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia, especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI) - behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice, although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning - namely, conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia.

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.

Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning.

The adenosine A(2A) receptor (A(2A)R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A(2A)R inactivation can be pro-cognitive, analyses of A(2A)R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A(2A)Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A(2A)Rs. Specifically, we evaluated the cognitive impacts of conditional A(2A)R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A(2A)R KO) or to striatum alone (st-A(2A)R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A(2A)R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A(2A)Rs as they were captured by A(2A)R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D(1), D(2), or A(1) receptor expression was found. This study provides the first direct demonstration that targeting striatal A(2A)Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies.

Endogenous adenosine is a widely distributed upstream regulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways that converge to contribute to the expression of an array of important brain functions. Over the past decade, the generation and characterization of genetic knockout models for all four G-protein coupled adenosine receptors, the A1 and A2A receptors in particular, has confirmed and extended the neuromodulatory and integrated role of adenosine receptors in the control of a broad spectrum of normal and abnormal brain functions. After a brief introduction of the available adenosine receptor knockout models, this review focuses on findings from the genetic knockout approach, placing particular emphasis on the most recent findings. This review is organized into two sections to separately address (i) the role of adenosine receptors in normal brain processes including neuroplasticity, sleep-wake cycle, motor function, cognition, and emotion-related behaviors; and (ii) their role in the response to various pathologic insults to brain such as ischemic stroke, neurodegeneration, or brain dysfunction/disorders. We largely limit our overview to the prominent adenosine receptor subtypes in brain-the A1 and A2A receptors-for which numerous genetic knockout studies on brain function are available. A1 and A2A receptor knockouts have provided significant new insights into adenosine's control of complex physiologic (e.g., cognition) and pathologic (e.g., neuroinflammation) phenomena. These findings extend and strengthen the support for A1 and A2A receptors in brain as therapeutic targets in several neurologic and psychiatric diseases. However, they also emphasize the importance of considering the disease context-dependent effect when developing adenosine receptor-based therapeutic strategies.

Dopamine D(2) receptor activation modulates perceived odor intensity.

Dopaminergic modulation affects odor detection thresholds and olfactory discrimination capabilities in rats. The authors show that dopamine D(2) receptor modulation affects odor discrimination capabilities in a manner similar to the modulation of stimulus intensity. Performance in a simultaneous odor discrimination task was systematically altered by manipulations of both odorant concentration and D(2) receptor activation (agonist quinpirole, 0.025-0.5 mg/kg; antagonist spiperone, 0.5 mg/kg). Rats' discrimination performance systematically improved at higher odor concentrations. Blockade of D(2) receptors improved performance equivalent to increasing odor concentration by 2 log units, whereas activation of D(2) receptors reduced odor discrimination performance in a dose-dependent manner. Bulbar dopamine release may serve a gain control function in the olfactory system, optimizing its sensitivity to changes in the chemosensory environment.