RNA tape sampling in cutaneous lupus erythematosus discriminates affected from unaffected and healthy volunteer skin.

OBJECTIVE: Punch biopsy, a standard diagnostic procedure for patients with cutaneous lupus erythematosus (CLE) carries an infection risk, is invasive, uncomfortable and potentially scarring, and impedes patient recruitment in clinical trials. Non-invasive tape sampling is an alternative that could enable serial evaluation of specific lesions. This cross-sectional pilot research study evaluated the use of a non-invasive adhesive tape device to collect messenger RNA (mRNA) from the skin surface of participants with CLE and healthy volunteers (HVs) and investigated its feasibility to detect biologically meaningful differences between samples collected from participants with CLE and samples from HVs. METHODS: Affected and unaffected skin tape samples and simultaneous punch biopsies were collected from 10 participants with CLE. Unaffected skin tape and punch biopsies were collected from 10 HVs. Paired samples were tested using quantitative PCR for a candidate immune gene panel and semi-quantitative immunohistochemistry for hallmark CLE proteins. RESULTS: mRNA collected using the tape device was of sufficient quality for amplification of 94 candidate immune genes. Among these, we found an interferon (IFN)-dominant gene cluster that differentiated CLE-affected from HV (23-fold change; p<0.001) and CLE-unaffected skin (sevenfold change; p=0.002), respectively. We found a CLE-associated gene cluster that differentiated CLE-affected from HV (fourfold change; p=0.005) and CLE-unaffected skin (fourfold change; p=0.012), respectively. Spearman's correlation between per cent area myxovirus 1 protein immunoreactivity and IFN-dominant mRNA gene cluster expression was highly significant (dermis, rho=0.86, p<0.001). In total, skin tape-derived RNA expression comprising both IFN-dominant and CLE-associated gene clusters correlated with per cent area immunoreactivity of some hallmark CLE-associated proteins in punch biopsies from the same lesions. CONCLUSIONS: A non-invasive tape RNA collection technique is a potential tool for repeated skin biomarker measures throughout a clinical trial.

Impact of Task-Oriented Role Assignment on Neonatal Resuscitation Performance: A Simulation-Based Randomized Controlled Trial.

OBJECTIVE: Task-oriented role assignment (TORA) is the assignment of a specific role, a list of tasks, and a location to stand to each resuscitation team member. We performed this study to examine the impact of TORA training during a Neonatal Resuscitation Program (NRP) course on neonatal resuscitation team technical performance and behavioral skills. STUDY DESIGN: Participants were cluster randomized into either a standard NRP course (control) or an NRP course with TORA training. Both technical and behavioral skills were evaluated using standardized simulations. The simulations were video recorded and then scored by two blinded reviewers using previously validated instruments. RESULTS: A total of 65 participants (62 resident physicians and 3 nurses) participated in 108 simulations (48 controls, 60 TORA). Technical skill scores were similar between the two groups (control = 77.6% [±8.4] vs. TORA = 78.1% [±8.1]; p = 0.74). The TORA group had higher behavior skill scores in 8 of the 10 NRP key behavioral skills and had higher overall behavioral skill scores (control = 30.1 [±7.2] vs. TORA = 34.9 [±4.8]; p < 0.001). CONCLUSION: In resuscitation teams comprising mostly resident physicians, TORA training resulted in better behavioral skills during simulated neonatal resuscitation. Further study on the impact of TORA training on actual resuscitation performance in interdisciplinary teams is warranted.

Serratia Chorioamnionitis and Culture Proven Sepsis in a Preterm Neonate: A Case Report and Review of the Literature.

BACKGROUND: Serratia marcescens is a well-known cause of nosocomial infectious outbreaks in the neonatal intensive care unit, with a high mortality rate in the vulnerable preterm population. However, it is not typically associated with neonatal sepsis secondary to intrapartum vertical transmission. We present the case of a preterm male born at 25 weeks and 4 days of gestation in Okinawa, Japan with culture-proven S. marcescens chorioamnionitis and sepsis, as well as a review of the previously published literature. METHODS: We conducted a literature search utilizing MeSH indexing with the headings [chorioamnionitis], [Serratia], and [infant, newborn] limited to "humans" with a publication date range between 1950 and 2020. RESULTS: All reported cases of preterm S. marcescens chorioamnionitis occurred in coastal locations. The majority of cases resulted in spontaneous abortion, and we found no published reports of confirmed S. marcescens chorioamnionitis in conjunction with viable preterm delivery and positive neonatal cultures. In the case presented herein, S. marcescens chorioamnionitis with associated neonatal sepsis was confirmed by positive placental and blood cultures. Bacterial clearance was achieved following an antibiotic course consisting of 5 days of gentamicin and 14 days of meropenem therapy. CONCLUSIONS: S. marcescens is an uncommon cause of chorioamnionitis that can have devastating neonatal consequences, especially in the at-risk preterm population.

Advancing the Science of Healthcare Service Delivery: The NHLBI Corporate Healthcare Leaders' Panel.

There is a growing gap between available science and evidence and the ability of service providers to deliver high-quality care in a cost-effective way to the entire population. We believe that the chasm between knowledge and action is due to a lack of concerted effort among all organizations that deliver health care services across the life span of patients. Broad participation is needed and necessitates a far more explicit and concerted public-private partnership focused on large-scale transformation. In this context, the National Heart, Lung, and Blood Institute convened a panel made up of leaders of corporate health care entities, including academic health centers, and government agency representatives to inform contemporary strategic partnerships with health care companies. This article provides insights from the meeting on how to execute a transformative innovation research agenda that will foster improvements in health care service delivery by leveraging the translation of biomedical research evidence in real-world settings.

Use of External Quality Control Material for HIV-1 RNA Testing To Assess the Comparability of Data Generated in Separate Laboratories and the Stability of HIV-1 RNA in Samples after Prolonged Storage.

The National Institute of Allergy and Infectious Diseases (NIAID) AIDS Clinical Trials Group (ACTG) stores specimens from its clinical trials in a biorepository and permits the use of these specimens for nonprotocol exploratory studies, once the studies for the original protocol are concluded. We sought to assess the comparability of the data generated from real-time HIV-1 RNA testing during two clinical trials with the data generated from the retesting of different aliquots of the same samples after years of storage at -80°C. Overall, there was 92% agreement in the data generated for 1,570 paired samples (kappa statistic = 0.757; 95% confidence interval [CI], 0.716 to 0.797), where samples were tested in one laboratory using the microwell plate (MWP) version of the Roche HIV-1 Monitor test within 1 to 37 days of collection and retested in another laboratory using the Cobas version of the assay after a median of 6.7 years of storage (range, 5.7 to 8.6 years). Historical external quality control data submitted to the NIAID Virology Quality Assurance program (VQA) by client laboratories using the same two versions of the Monitor assay were used to differentiate between systematic differences in the assays to evaluate the stability of HIV-1 RNA in the stored samples. No significant loss of RNA was noted in samples containing either a low concentration (<50 copies/ml) or a high concentration (≥50 copies/ml) of HIV-1 RNA (P = 0.10 and P = 0.90, respectively) regardless of the time in storage. These data confirm the quality of the plasma samples in the ACTG biorepository following long-term storage.

Association of peripheral microvascular dysfunction and erectile dysfunction.

PURPOSE: Increasing evidence of a link between erectile dysfunction and cardiovascular disease suggests a shared vascular etiology with endothelial dysfunction as a plausible underlying biological mechanism. To our knowledge whether this association is different for large arterial endothelium compared to microvascular endothelium has not yet been established. We investigated the association of erectile dysfunction with macrovascular and microvascular endothelial function. MATERIALS AND METHODS: A sample of 390 men with a mean age of 55.5 years was recruited from the BACH survey, a population based survey of urological symptoms. Erectile dysfunction was assessed using IIEF-5. The percent of brachial artery flow mediated dilatation, a measure of macrovascular function, and hyperemic flow velocity in cm per second, a measure of microvascular function, were assessed by ultrasound. Linear regression was used to assess the association of erectile dysfunction and endothelial function, and adjust for potential confounders. RESULTS: Reactive hyperemia was lower in men with vs without erectile dysfunction (mean ± SE 97.1 ± 2.5 vs 106.0 ± 1.6 cm per second, p = 0.003). However, the difference in flow mediated dilatation between men with vs without erectile dysfunction was statistically nonsignificant (mean 6.6% ± 0.33% vs 7.2% ± 0.24%, p = 0.147). The association of erectile dysfunction with reactive hyperemia was attenuated but it remained statistically significant in men with moderate to severe erectile dysfunction (IIEF-5 less than 12) after adjusting for traditional cardiovascular risk factors (p = 0.038). CONCLUSIONS: These results provide evidence of greater microvascular than macrovascular endothelial dysfunction as a potential contributor to erectile dysfunction and an underlying mechanism linking erectile dysfunction and cardiovascular disease.

Incidence of lower urinary tract symptoms in a population-based study of men and women.

OBJECTIVE: To report the incidence of lower urinary tract symptoms (LUTS) in a racially and ethnically and age-diverse U.S. population-based sample of men and women. MATERIALS AND METHODS: We conducted a prospective cohort study with 5 years of follow-up. A stratified 2-stage cluster random sampling method was used to recruit 5502 Boston residents aged 30-79 years of black, Hispanic, or white race or ethnicity. Of these, 4144 (1610 men and 2534 women) completed the follow-up protocol. The American Urological Association Symptom Index was used to define moderate-to-severe LUTS. RESULTS: Of the 3301 men and women with no or mild LUTS at baseline, the 5-year incidence of moderate-to-severe LUTS (American Urological Association Symptom Index ≥8) was 11.4% overall and was higher for women than for men (13.9% vs 8.5%, P = .02). Although the incidence increased with age (P <.001), it had a plateau among women aged 50-70 years and then doubled to 35.0% among women aged ≥70 years. White men had a distinctly lower incidence (7%) than all other sex and race subgroups (13%). CONCLUSION: Approximately 1 in 10 adults had newly developed LUTS at 5 years follow-up of in our study, with differences by sex and race or ethnicity, indicating a greater occurrence of urologic problems among black and Hispanic participants and women.

Intake of caffeinated, carbonated, or citrus beverage types and development of lower urinary tract symptoms in men and women.

Evidence to substantiate recommendations for restriction of caffeinated or acidic beverages as self-management for lower urinary tract symptoms (LUTS) is limited. We examined longitudinal and acute associations between beverage intake and LUTS in the Boston Area Community Health (BACH) cohort (n = 4,144) between 2002 and 2010. Multivariable models tested associations between baseline intakes and progression of LUTS at 5-year follow-up, between follow-up intakes and International Prostate Symptom Scores at follow-up, and between 5-year intake changes and LUTS progression. Greater coffee or total caffeine intake at baseline increased the odds of LUTS progression in men (coffee: >2 cups/day vs. none, odds ratio = 2.09, 95% confidence interval: 1.29, 3.40, P-trend = 0.01; caffeine: P-trend < 0.001), particularly storage symptoms. Women who increased coffee intake by at least 2 servings/day during follow-up (compared with categories of decreased or unchanged intakes) had 64% higher odds of progression of urgency (P = 0.003). Women with recently increased soda intake, particularly caffeinated diet soda, had higher symptom scores, urgency, and LUTS progression. Citrus juice intake was associated with 50% lower odds of LUTS progression in men (P = 0.02). Findings support recommendations to limit caffeinated beverage intake for LUTS, and in men, they suggest benefits of citrus juice consumption. Further clinical research is warranted, particularly of the precise role of sodas containing artificial sweeteners in bladder sensations and urological function.

IMPROVE trial: a randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies.

BACKGROUND: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. PURPOSE: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. METHODS: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. RESULTS: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. LIMITATIONS: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. LESSONS LEARNED: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. CONCLUSIONS: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

Red blood cell alloimmunization in sickle cell disease: prevalence in 2010.

BACKGROUND: Transfusion of red blood cells (RBCs) is frequently required for care of individuals with sickle cell disease (SCD). Alloimmunization rates are high and may be reduced by matching for RBC antigens that can cause alloimmunization. STUDY DESIGN AND METHODS: During the PROACTIVE Feasibility Study, patients with SCD age 2 years or older admitted for pain without acute chest syndrome were enrolled for possible randomization to preventive blood transfusion or standard care. Transfusion and antibody histories were obtained at each site, and antibody screening was done, to assess transfusion burden and alloimmunization prevalence. Participating sites were surveyed regarding antigen matching practice. RESULTS: A total of 237 patients (169 SS, 42 SC, 15 Sß(0) -thalassemia, 11 Sß(+) -thalassemia), 118 males and 119 females, were enrolled. Mean age was 19.3 years (range, 2.0-68.0); there were 122 children and 115 adults. A total of 75.8% had received at least a single transfusion of RBCs before the study. Thirty-four patients (14.4%) had a history of at least one alloantibody and 17 of these had more than one. When surveyed, 19 sites (83% of responders) reported antigen matching to at least include C, E, and K for transfusion of all patients with SCD. CONCLUSION: Though antigen typing before transfusion of people with SCD and providing antigen-negative units is now widely employed by sickle cell centers, the alloimmunization rate remains quite high in contemporary sickle cell populations and may be due in large part to transfusions received at institutions not providing extended matching.

Cross-platform analysis of HIV-1 RNA data generated by a multicenter assay validation study with wide geographic representation.

HIV-1 RNA quantitation continues to be extremely important for monitoring patients infected with HIV-1, and a number of assays have been utilized for this purpose. Differences in assay performance with respect to log(10) recovery and HIV-1 subtype specificity have been well documented for commercially available assays, although comparisons are usually limited to one or two assay platforms. Two new FDA-approved assays, the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test (RT) and the Abbott RealTime HIV-1 assay (AR), that utilize real-time PCR have replaced previous HIV-1 RNA platforms. Inadequate detection of some strains of HIV-1 resulted in the addition of a new primer/probe set and the introduction of a second version of the RT assay. In this study, comparisons of assay performance between the different FDA-approved HIV-1 RNA assay platforms (both new and existing) were performed by using validation data that included both well-characterized virus stock and locally collected clinical samples. Laboratories across diverse geographical regions performed the validation testing and submitted data to the Virology Quality Assurance program (VQA) for analysis. Correlation values for clinical sample testing varied across the assay platforms (r = 0.832 to 0.986), and average log(10) recoveries for HIV-1 RNA controls (compared to the nominal value) ranged from -0.215 to 0.181. These data demonstrate the need for use of one assay platform for longitudinal patient monitoring, but the data also reinforce the notion that no one assay is superior and that testing across platforms may be required for discordance reconciliation.

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE).

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.

Inpatient management of sickle cell pain: a 'snapshot' of current practice.

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain.

Application of quantitative 19F and 1H NMR for reaction monitoring and in situ yield determinations for an early stage pharmaceutical candidate.

Quantitative NMR spectrometry (qNMR) is an attractive, viable alternative to traditional chromatographic techniques. It is a fast, easy, accurate, and nondestructive technique which allows an analyst to gain quantitative information about a component mixture without the necessity of authentic reference materials, as is the case with most other analytical techniques. This is ideal for the synthesis of active pharmaceutical ingredients (API) that are in the early stages of development where authentic standards of the analytes may not be available. In this paper, the application of (19)F and (1)H qNMR for reaction monitoring and in situ potency determinations will be discussed for an early stage pharmaceutical candidate with several analytical challenges. These challenges include low UV absorption, low ionization, thermal instability, and lack of authentic reference standards. Quantitative NMR provided quick, fit-for-purpose solutions for process development where conventional separation techniques were limited.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI­higher demand dose with low constant infusion or LDHI­lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

Split-plot designs for robotic serial dilution assays.

This article explores effective implementation of split-plot designs in serial dilution bioassay using robots. We show that the shortest path for a robot to fill plate wells for a split-plot design is equivalent to the shortest common supersequence problem in combinatorics. We develop an algorithm for finding the shortest common supersequence, provide an R implementation, and explore the distribution of the number of steps required to implement split-plot designs for bioassay through simulation. We also show how to construct collections of split plots that can be filled in a minimal number of steps, thereby demonstrating that split-plot designs can be implemented with nearly the same effort as strip-plot designs. Finally, we provide guidelines for modeling data that result from these designs.

Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions.

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.

Cells in midline thalamus, central amygdala, and nucleus accumbens responding specifically to antipsychotic drugs.

RATIONALE: Determining brain regions in which neuroleptic drugs of different types produce similar effects, especially where these effects are not shared with drugs lacking antipsychotic efficacy, provides evidence as to how and where the clinical effects of neuroleptic drugs are mediated. OBJECTIVE: For this study, the pattern of expression of the protein Fos, a marker of cellular activation, was compared after administration of the typical neuroleptic haloperidol, the antipsychotic drug clozapine, and the atypical neuroleptic olanzapine, as well as the sedative drug diphenhydramine and the anxiolytic lorazepam. METHODS: Animals (Sprague-Dawley rats, three per cohort) received intraperitoneal injections of haloperidol (1 mg/kg), clozapine (20 mg/kg), olanzapine (5 mg/kg), diphenhydramine hydrochloride (1 mg/kg), lorazepam (5 mg/kg) or vehicle (2% lactic acid, 1 ml/kg). Two hours after drug administration, animals were killed. Patterns of activated cells were observed by immunohistochemistry for Fos-like antibodies in regions previously suggested as responding to all antipsychotic drugs, including nucleus accumbens, central amygdala, and central medial thalamus. Cells staining for Fos were counted by semi-automated methods. RESULTS. A very similar pattern and number of Fos positive cells in nucleus accumbens, central amygdala, and central medial thalamus followed administration of each antipsychotic drug. The numbers of apparently activated cells were much greater following antipsychotic drug administration than after vehicle, with differences between each drug and vehicle being highly statistically significant in each region. Lorazepam produced apparent activation of cells of the central amygdala similar in degree and location but not identical in distribution to that of antipsychotic drugs. Diphenhydramine produced no apparent activation of cells in any of the sites tested. CONCLUSION: Typical and atypical antipsychotic drugs shared a distinctive pattern of robust activation of cells in nucleus accumbens, central medial thalamus, and central amygdala. Antipsychotic drug-induced activation of amygdala was shared by lorazepam, but activation of thalamus and nucleus accumbens was much greater following antipsychotic drugs than following lorazepam. The pattern of activated cells may be relevant to the therapeutic actions of antipsychotic drugs.