Utility of bilateral inferior petrosal sinus sampling for diagnosis and lateralization of Cushing's disease in the pediatric population: case series and review of the literature.

OBJECTS: Cushing's disease (CD) is the most common cause of ACTH-dependent hypercortisolism in children age ≥ 7. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children. We present a case series of children with ACTH-dependent hypercortisolemia and review the literature to assess the utility of BIPSS in the diagnosis and localization of CD. METHODS: We performed an IRB-approved chart review of patients aged ≤ 18 with ACTH-dependent hypercortisolism at MGH between 2000 and 2019 and collected clinical, laboratory, radiographic, BIPSS, surgical, and outcomes data. RESULTS: In our cohort (n = 21), BIPSS had a sensitivity of 93% and specificity of 100% for diagnosis of CD. Compared to surgery, successful BIPSS correctly predicted adenoma laterality in 69% of cases vs. 70% by MRI. Among patients with lesions ≥ 4 mm (n = 9), BIPSS correctly lateralized in 50% vs. 100% by MRI. In patients with subtle lesions (< 4 mm, n = 7), BIPSS correctly lateralized in 80% vs. 71% by MRI. In patients (n = 4) with CD and negative MRIs, BIPSS correctly lateralized in 75% cases. Surgical cure was achieved in 90% of patients and 95% of patients had long-term disease control. CONCLUSIONS: In our cohort (n = 21; n = 20 CD, n = 1 ectopic ACTH secretion), BIPSS was sensitive and specific for the diagnosis of CD. Compared to MRI, BIPSS was not additionally helpful for lateralization in patients with lesions ≥ 4 mm on MRI. BIPSS was helpful in guiding surgical exploration and achieving immediate postoperative remission among patients with subtle and negative MRI findings.

Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance.

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based "inflammetry" was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE.

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

A microPET study of the regional distribution of [11C]-PK11195 binding following temporary focal cerebral ischemia in the rat. Correlation with post mortem mapping of microglia activation.

BACKGROUND: Post-stroke microglial activation (MA) may have both neurotoxic and pro-repair effects, particularly in the salvaged penumbra. Mapping MA in vivo is therefore an important goal. 11C-PK11195, a ligand for the 18 kDa translocator protein, is the reference radioligand for MA imaging, but a correlation between the regional distributions of in vivo tracer binding and post mortem MA after stroke, as assessed with PET and immunohistochemistry, respectively, has not been demonstrated so far. Here we performed 11C-PK11195 microPET in a rat model previously shown to induce extensive cortical MA, and determined the correlation between 11C-PK11195 and immunostaining with the CD11 antibody OX42, so as to verify the presence of activated microglia, in a template of PET-resolution size regions-of-interest (ROIs) spanning the whole affected hemisphere. METHODS: Adult spontaneously hypertensive rats underwent 45 min distal middle cerebral artery occlusion and 11C-PK11195 PET at Days 2 and 14 after stroke according to a longitudinal design. Following perfusion-fixation at Day 14, brains were removed and coronally cut for OX42 staining. 11C-PK11195 binding potential (BPND) parametric maps were generated, and in each rat both BP(ND) and OX42 (intensity×extent score) were obtained in the same set of 44 ROIs extracted from a cytoarchitectonic atlas to cover the whole hemisphere. Correlations were computed across the 44 ROIs both within and across subjects. RESULTS: Significant BPND increases were observed in both the infarct and surrounding areas in all rats at day 14; less strong but still significant increases were present at day 2. There were highly significant (all p<0.001) positive correlations, both within- and across-subjects, between day 14 BPND values and OX42 scores. CONCLUSIONS: The correlation between Day 14 11C-PK11195 and OX42 across the affected hemisphere from the same brain regions and animals further supports the validity of 11C-PK11195 as an in vivo imaging marker of MA following stroke. The finding of statistically significant increases in 11C-PK11195 as early as 48 h after stroke is novel. These results have implications for mapping MA after stroke, with potential therapeutic applications.

Does perfusion computed tomography facilitate clinical decision making for thrombolysis in unselected acute patients with suspected ischaemic stroke?

BACKGROUND: Despite use in clinical practice and major positive trials of thrombolysis, non-contrast computed tomography (NCCT) is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how physiological imaging using CT perfusion (CTP) could add to the diagnostic utility of an NCCT and inform clinical decisions regarding thrombolysis. METHODS: Forty imaging datasets containing NCCT and CTP were retrospectively identified from a cohort of consecutive acute stroke patients. Two sets of observers (n = 6) and a neuroradiologist evaluated the images without knowledge of clinical symptoms. Inter-observer agreement was calculated using the κ statistic for identifying acute ischaemic change on NCCT: perfusion abnormalities (namely cerebral blood volume, cerebral blood flow and time to peak), and penumbral tissue on perfusion maps obtained by two image processing algorithms. RESULTS: Inter-rater agreement was moderate (κ = 0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for cerebral blood volume (κ = 0.67) and to almost perfect for time to peak (κ = 0.87) and cerebral blood flow (κ = 0.87). The agreement for qualitative assessment of penumbral tissue was substantial to perfect for images obtained using the two different perfusion algorithms. Overall, there was a high rate of decision to thrombolyse based on NCCT (81.25%). CTP strengthened the decision to thrombolyse based on NCCT in 38.3% of cases. It negatively influenced the decision in 14.6% of cases, this being significantly more common in experienced observers (p = 0.02). CONCLUSIONS: We demonstrate that the qualitative evaluation of CTP produces near perfect inter-observer agreement, regardless of the post-processing method used. CTP is a reliable, accessible and practical imaging modality that improves confidence in reaching the appropriate diagnosis. It is particularly useful for less experienced clinicians, to arrive at a physiologically informed treatment decision.

Mapping selective neuronal loss and microglial activation in the salvaged neocortical penumbra in the rat.

Rescuing the ischemic penumbra from infarction is the mainstay of acute stroke therapy. However, the rescued penumbra may be affected by selective neuronal loss (SNL) and microglial activation (MA), which may hinder functional recovery and hence represent potential new therapeutic targets. Imaging them in vivo is currently attracting considerable interest, but relevant rat models are needed to underpin methods development and validation. Although striatal SNL/MA is well described following proximal MCA occlusion (MCAo), neocortical SNL/MA is still poorly characterized, yet has greater clinical relevance. This study aimed to assess the distribution and intensity of neocortical SNL and MA in a distal clip MCAo model known to cause severe neocortical ischemia. Spontaneously hypertensive rats were subjected to 45 min distal MCAo with ipsilateral common carotid artery occlusion. At day 14, post mortem SNL and MA were mapped using NeuN and OX42 immunohistochemistry, respectively. In a separate group, cerebral blood flow (CBF) was mapped during MCAo using (14)C-iodoantipyrine autoradiography. Values for SNL, MA, and CBF were obtained in the same set of anatomical ROIs covering the cortical MCA territory. Extensive SNL and MA affected the non-infarcted MCA cortex, adopting a well-defined regional distribution and a striking patchy/pseudo-columnar pattern. Regional intensities of SNL and MA were strongly inter-correlated, and also strikingly related to occlusion CBF, showing sharp rises for CBF <40%, i.e. the penumbra threshold. This rat model may be useful in providing in vitro reference for studies aiming to validate novel imaging tracers of SNL and MA in vivo.

The relationship between motor deficit and primary motor cortex hemispheric activation balance after stroke: longitudinal fMRI study.

BACKGROUND: In the chronic stage of stroke, previous work has shown that the worse the hand motor deficit, the greater the shift of primary motor cortex (M(1)) activation towards the contralesional hemisphere (ie, unphysiological) balance. Whether the same relationship applies at earlier stages of recovery in serially studied patients is not known. METHODS: fMRI of fixed-rate auditory-cued affected index-thumb tapping was obtained at two time points (mean 36 and 147 days poststroke) in a cohort of nine patients with ischaemic stroke (age: 56+/-9 years; three women/six men; seven subcortical, one medullary and one cortical). On each fMRI day, the unaffected/affected ratio of maximal index tapping rate (IT-R) was obtained. To assess the M(1) hemispheric activation balance, the authors computed the classic Laterality Index (LI). The correlation between LI and IT-R was computed for each time point separately. RESULTS: The expected correlation between LI-M(1) and IT-R, that is, motor performance worse with more unphysiological LI, prevailed at both time points (Kendall p=0.008 and 0.058, respectively), with no statistically significant difference between the two regressions. The same analysis for the dorsal premotor cortex and the supplementary motor area showed no significant correlation at either time-point. CONCLUSION: These results from a small cohort of longitudinally assessed patients suggest that the relationship between M(1) laterality index and hand motor performance appears independent of time since onset of stroke. This in turn may suggest that attempting to restore the hemispheric balance by enhancing ipsilesional M(1) and/or constraining contralesional M(1) activity may have consistent efficacy throughout recovery.

T2*-weighted MRI versus oxygen extraction fraction PET in acute stroke.

BACKGROUND: Mapping high oxygen extraction fraction (OEF) in acute stroke is of considerable interest to depict the at-risk tissue. Being sensitive to deoxyhemoglobin, T2*-weighted MRI has been suggested as a potential marker of high OEF. METHODS: We compared T2*-weighted images from pre-contrast arrival perfusion scans against quantitative positron emission tomography in 5 patients studied 7-21 h after onset of carotid territory stroke. OEF and T2* signal were obtained in the voxels with significantly high OEF. RESULTS: All patients showed increased OEF. No significant relationship between OEF and T2*-weighted signal was found either within or between subjects. CONCLUSION: We found no indication that T2*-weighted MRI in the way implemented in this investigation was sensitive to high OEF in acute stroke.

Selective neuronal loss in rescued penumbra relates to initial hypoperfusion.

Selective neuronal loss (SNL) in the rescued penumbra could account for suboptimal clinical recovery despite effective early reperfusion. Previous studies of SNL used single-photon emission tomography (SPECT), did not account for potential volume loss secondary to collapse of the infarct cavity, and failed to show a relationship with initial hypoperfusion. Here, we obtained acute-stage computerized tomography (CT) perfusion and follow-up quantitative (11)C-flumazenil (FMZ)-PET to map SNL in the non-infarcted tissue and assess its relationship with acute-stage hypoperfusion. We prospectively recruited seven patients with evidence of (i) acute (<6 h) extensive middle cerebral artery territory ischaemia based on clinical deficit (National Institutes of Health stroke scale, NIHSS score range: 8-23) and CT Perfusion (CTp) findings and (ii) early recanalization (spontaneous or following thrombolysis) based on spectacular clinical recovery (DeltaNIHSS > or =6 at 24 h), good clinical outcome (NIHSS < or =5) and small final infarct (6/7 subcortical) on late-stage MRI. Ten age-matched controls were also studied. FMZ image analysis took into account potential post-stroke volume loss. Across patients, clusters of significantly reduced FMZ binding were more prevalent and extensive in the non-infarcted middle cerebral artery cortical areas than in the non-affected hemisphere (P = 0.028, Wilcoxon sign rank test). Voxel-based between-group comparisons revealed several large clusters of significantly reduced FMZ binding in the affected peri-insular, superior temporal and prefrontal cortices (FDR P < 0.05), as compared with no cluster on the unaffected side. Finally, comparing CTp and PET data revealed a significant negative correlation between FMZ binding and initial hypoperfusion. Applying correction for volume loss did not substantially alter the significance of these results. Although based on a small patient sample sometimes studied late after the index stroke, and as such preliminary, our results establish the presence and distribution of FMZ binding loss in ultimately non-infarcted brain areas after stroke. In addition, the data suggest that this binding loss is proportional to initial hypoperfusion, in keeping with the hypothesis that the rescued penumbra is affected by SNL. Although its clinical counterparts remain uncertain, it is tempting to speculate that peri-infarct SNL could represent a new therapeutic target.

Impairments in reinforcement learning do not explain enhanced habit formation in cocaine use disorder.

RATIONALE: Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear. Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation. OBJECTIVES: We used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD). METHODS: We re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. We used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation. RESULTS: Poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate. Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients. CONCLUSIONS: Our data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD.

Regulation of the chicken ovalbumin gene by estrogen and corticosterone requires a novel DNA element that binds a labile protein, Chirp-1.

Because induction of the chicken ovalbumin (Ov) gene by steroid hormones requires concomitant protein synthesis, efforts have focused on defining the binding site in the Ov gene for a labile transcription factor. Previous gel mobility shift studies identified one such site in the steroid-dependent regulatory element (SDRE) between -900 and -853. To ascertain whether estrogen and glucocorticoid affect the binding of this labile protein, genomic footprinting of the Ov gene was done by treating primary oviduct cell cultures with dimethyl sulfate. Several alterations that include steroid-dependent protection of guanine residues -889 and -885 and hypersensitivity of adenine residues -892 and -865 were observed. Of particular importance, the in vivo footprinting data are corroborated by two functional studies, one with linker-scanning mutations and the other with point mutations. Ten-base-pair linker-scanning mutations between -900 and -878 severely reduced the induction by estrogen and glucocorticoid. Likewise, point mutations of the protected guanine residues profoundly attenuated the response to these steroid hormones. In addition, in vitro binding activity correlated with in vivo functional activity. For example, mutant A4e shows no transcriptional activity in response to steroid hormones, and a corresponding oligomer does not bind protein in vitro. In contrast, mutant A4c is fully active in both contexts. These data support the contention that the ovalbumin gene is regulated by a steroid hormone-induced transcriptional cascade that culminates in the binding of chicken ovalbumin induced regulatory protein or protein complex (Chirp-I) to a DNA element from -891 to -878 in the SDRE.

Disrupted iron regulation in the brain and periphery in cocaine addiction.

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Quantification of index tapping regularity after stroke with tri-axial accelerometry.

OBJECTIVE: Quantifying intrinsic components of movement may help to better understand the nature of motor deficits after stroke. Here we quantify the ability of stroke patients to finger tap in rhythm with auditory cues given at physiological rate. METHODS: Using tri-axial accelerometry, we measured tapping regularity (Regularity Index) during auditory-cued index-to-thumb tapping at 1.25 Hz in 20 prospectively selected right-handed chronic stroke patients (mean age 61 yrs) and 20 right-handed healthy subjects (7 young and 13 age matched; mean age 24 and 58 yrs, respectively). With the aim to validate our method, two measures of clinical deficit, the European Stroke Scale (ESS) and the maximum number of index-thumb taps in 15s (IT-Max) were recorded on the same day. RESULTS: There was no effect of age or hand used on the Regularity Index in the control subjects. In patients, the Regularity Index of their affected hand was significantly worse compared to their unaffected hand and to age-matched controls (p<0.05 and p<0.01, respectively). The Regularity Index significantly correlated with the ESS and IT-Max in the clinically expected direction (p=0.025 and 0.001, respectively). CONCLUSION: These data indicate that our method has validity to quantify finger-tapping regularity. After stroke, there is a deficit in the ability to keep pace with auditory cues that correlates, but does not equate, with other indices of motor function. Quantifying tapping regularity may provide novel insights into the mechanisms underlying recovery of finger dexterity after stroke.

Modulation of gene expression in Syrian hamster embryo cells following ionizing radiation.

We examined the modulation of gene expression in Syrian hamster embryo (SHE) cells at various times following exposure to low doses of ionizing radiation. Early passage SHE cells were irradiated in plateau phase (greater than 95% G0-G1 cells) with 21-cGy fission-spectrum neutrons, 75-cGy X-rays, or 90-cGy gamma-rays, none of which induced more than 10% loss in cell viability. RNA harvested at various times after exposure was examined for levels of particular RNA species by dot blot and Northern blot hybridizations. Levels of beta-actin-specific RNA decreased within 15 min after exposure of the cells. The kinetics of repression of beta-actin mRNA were similar for all qualities of radiation (X-rays, gamma-rays, and neutrons) for 12 h post-irradiation. Within 1 h after neutron exposure (21 cGy), we observed a decrease in accumulation of RNA species (relative to RNA from nonirradiated cells) encoding the enzyme ornithine decarboxylase; this decrease continued for up to 12 h. Similar results were obtained with gamma- and X-rays. RNA encoding interleukin 1, however, was induced by 3 h after neutron irradiation but reduced to background levels by 7 h. Amounts of rRNA remained constant in all experiments, although total transcription on a per cell basis was reduced within 15 min following irradiation and did not return to normal until 7 h post-irradiation. No alterations, relative to untreated control cells, in overall cell viability or the rate of cell cycle progression were observed in cells either immediately or within 24 h post-irradiation. Our results demonstrate modulation of specific genes following low-dose irradiation. In addition, our findings suggest that some molecular responses to different qualities of ionizing radiation (X-rays, gamma-rays, and neutrons) may be similar.

Use of computer decision support in an antimicrobial stewardship program (ASP).

OBJECTIVE: Document information needs, gaps within the current electronic applications and reports, and workflow interruptions requiring manual information searches that decreased the ability of our antimicrobial stewardship program (ASP) at Intermountain Healthcare (IH) to prospectively audit and provide feedback to clinicians to improve antimicrobial use. METHODS: A framework was used to provide access to patient information contained in the electronic medical record, the enterprise-wide data warehouse, the data-driven alert file and the enterprise-wide encounter file to generate alerts and reports via pagers, emails and through the Centers for Diseases and Control's National Healthcare Surveillance Network. RESULTS: Four new applications were developed and used by ASPs at Intermountain Medical Center (IMC) and Primary Children's Hospital (PCH) based on the design and input from the pharmacists and infectious diseases physicians and the new Center for Diseases Control and Prevention/National Healthcare Safety Network (NHSN) antibiotic utilization specifications. Data from IMC and PCH now show a general decrease in the use of drugs initially targeted by the ASP at both facilities. CONCLUSIONS: To be effective, ASPs need an enormous amount of "timely" information. Members of the ASP at IH report these new applications help them improve antibiotic use by allowing efficient, timely review and effective prioritization of patients receiving antimicrobials in order to optimize patient care.

In the face of threat: neural and endocrine correlates of impaired facial emotion recognition in cocaine dependence.

The ability to recognize facial expressions of emotion in others is a cornerstone of human interaction. Selective impairments in the recognition of facial expressions of fear have frequently been reported in chronic cocaine users, but the nature of these impairments remains poorly understood. We used the multivariate method of partial least squares and structural magnetic resonance imaging to identify gray matter brain networks that underlie facial affect processing in both cocaine-dependent (n = 29) and healthy male volunteers (n = 29). We hypothesized that disruptions in neuroendocrine function in cocaine-dependent individuals would explain their impairments in fear recognition by modulating the relationship with the underlying gray matter networks. We found that cocaine-dependent individuals not only exhibited significant impairments in the recognition of fear, but also for facial expressions of anger. Although recognition accuracy of threatening expressions co-varied in all participants with distinctive gray matter networks implicated in fear and anger processing, in cocaine users it was less well predicted by these networks than in controls. The weaker brain-behavior relationships for threat processing were also mediated by distinctly different factors. Fear recognition impairments were influenced by variations in intelligence levels, whereas anger recognition impairments were associated with comorbid opiate dependence and related reduction in testosterone levels. We also observed an inverse relationship between testosterone levels and the duration of crack and opiate use. Our data provide novel insight into the neurobiological basis of abnormal threat processing in cocaine dependence, which may shed light on new opportunities facilitating the psychosocial integration of these patients.

Distribution of specific intermediate-filament proteins in the goldfish retina.

The intermediate-filament proteins expressed in the goldfish retina were investigated by immunohistochemistry and by immunoblotting. Polyclonal antibodies that previously had been raised against the goldfish optic nerve neurofilament (ON1 and ON2) and glial filament (ON3 and ON4) proteins were used in this study. Anti-ON1/ON2 antiserum reacted on a retinal immunoblot with two proteins having molecular weights and isoelectric points corresponding to those of ON1 and ON2. Histologically, the most pronounced anti-ON1/ON2 reactivity was observed in the ganglion cell layer of the goldfish retina. The anti-ON3/ON4 antiserum reacted with a single protein on a retinal immunoblot. This protein had a molecular weight and isoelectric point which corresponded to the goldfish optic nerve glial filament proteins. This anti-serum labeled horizontal cells in retina sections. Three previously unidentified goldfish visual-pathway intermediate-filament proteins sharing a molecular weight of 60K were observed on two-dimensional gels of retinal cytoskeletal proteins and on retinal immunoblots which were probed with a monoclonal antibody which recognizes an epitope common to all intermediate filament proteins. The possible existence of homologs of mammalian GFAP and vimentin in the goldfish retina was also explored. Antibodies directed against mammalian GFAP and vimentin labeled the Müller fibers and the cone horizontal cells, respectively. However, immunoblot analysis and a comparison of the two-dimensional gel electrophoresis patterns of goldfish retinal and rat spinal cord cytoskeletal proteins demonstrated a lack of goldfish proteins identical to the mammalian intermediate-filament proteins.

Inhibitors of cholesterol biosynthesis. 1. 3,5-Dihydroxy-7-(N-imidazolyl)-6-heptenoates and -heptanoates, a novel series of HMG-CoA reductase inhibitors.

3,5-Dihydroxy-7-(N-imidazolyl)heptanoates 4 and the corresponding heptenoates 5 were synthesized as novel classes of potent HMG-CoA reductase (HMGR) inhibitors in which members of the latter series possess enzyme inhibitory activity greater than that of lovastatin 1 and pravastatin 2. Structure-activity studies show that the 7-(N-imidazolyl)heptenoates 5 are more active than the corresponding heptanoates 4. For both imidazolyl series, the 4-fluorophenyl group is preferred at C-5, and a broad range of aryl substituents which promote widely different lipophilicities is tolerated at C-4. While the CF3 group is preferred at C-2 in the heptanoate series, the 2-(1-methylethyl) substituent is optimal in the heptenoate series. The 2-(1-methylethyl) and 5-(4-fluorophenyl) groups can be interchanged in the latter series as exemplified by 5ab. Enzyme inhibitory activity resides principally in the 3R,5S series. These potent HMGR inhibitory activities by members of the heptenoate series translated well into whole cell activities in HepG2 cells. X-ray crystallographic studies on the active enantiomer 28 reveal noncoplanarity of the heptenoate C-C double bond with the imidazole ring; this finding provides an explanation for the high acid stability of the heptenoate series.