Experimental Demonstration of Hadron Beam Cooling Using Radio-Frequency Accelerated Electron Bunches.

Cooling of beams of gold ions using electron bunches accelerated with radio-frequency systems was recently experimentally demonstrated in the Relativistic Heavy Ion Collider at Brookhaven National Laboratory. Such an approach is new and opens the possibility of using this technique at higher energies than possible with electrostatic acceleration of electron beams. The challenges of this approach include generation of electron beams suitable for cooling, delivery of electron bunches of the required quality to the cooling sections without degradation of beam angular divergence and energy spread, achieving the required small angles between electron and ion trajectories in the cooling sections, precise velocity matching between the two beams, high-current operation of the electron accelerator, as well as several physics effects related to bunched-beam cooling. Here we report on the first demonstration of cooling hadron beams using this new approach.

Endocervical glandular involvement is associated with an increased detection rate of high-grade squamous intraepithelial lesions on the Papanicolaou test.

INTRODUCTION: Although The Bethesda System for Reporting Cervical Cytopathology does not mandate reporting of endocervical glandular involvement (EGI) in Papanicolaou test specimens with high-grade squamous intraepithelial lesions (HSIL), several studies have suggested that EGI diagnosed on surgical specimens is associated with higher rates of residual or recurrent dysplasia. When suspected, EGI is reported for Papanicolaou test specimens at our institution, but the performance of this diagnosis has not been assessed. MATERIALS AND METHODS: The archives were queried for Papanicolaou test specimens with a diagnosis of HSIL-EGI (2006-2017). All follow-up surgical pathology specimens within a year of the Papanicolaou test diagnosis were evaluated for cytologic-histologic correlation. This same query was repeated for all surgical pathology specimens with a diagnosis of HSIL-EGI. All preceding Papanicolaou test diagnoses within a year were assessed for cytologic-histologic correlation. Twenty Papanicolaou test specimen glass slides were reviewed by 6 observers to assess for interobserver variability. RESULTS: Patients with HSIL-EGI on surgical specimens were more likely to have a preceding Papanicolaou diagnosis of HSIL and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (32.3% versus 25.5%, P = 0.03, and 16.7% versus 11.8%, P = 0.04, respectively). Patients with an HSIL-EGI diagnosis on a Papanicolaou test were significantly more likely to have HSIL-EGI detected on a follow-up histology (41.6% versus 24.0%, P < 0.001). Interobserver concordance was poor for the assignment of EGI in Papanicolaou test specimens. CONCLUSIONS: Overall, the diagnosis of HSIL-EGI on Papanicolaou test specimens is complicated by poor sensitivity and interobserver concordance.

Insulinoma-associated protein 1 immunostaining on cytology specimens: an institutional experience.

Neuroendocrine tumors (NETs) are epithelial neoplasms with prominent neuroendocrine differentiation. Cytologic examination and utilization of immunohistochemical (IHC) markers are important diagnostic tools for the evaluation of these tumors. Herein we report our experience with the application of INSM1 in cytology samples. We searched our pathology system for cytologic specimens with INSM1 IHC performed from 2017 to 2018. Patients' demographics were recorded, and cytology materials were reviewed including all neuroendocrine IHC markers performed. A total of 134 (67 male, 67 female) specimens with INSM1 IHC were identified. Specimens included 91 (68.2%) NETs or tumors with neuroendocrine features (TNEFs), 33 (24.3%) nonneuroendocrine lesions (non-NET), and 10 (7.5%) nonneoplastic diagnoses. INSM1 was positive in 90 (99%) of the NET/TNEFs and negative in 32 (97%) non-NETs. CD56 was positive in 42 (95.5%) of the NET/TNEFs and negative on 9 (69.2%) of the non-NETs. The sensitivity of INSM1 was 99% and specificity was 97%, whereas the sensitivity of CD56 was 95.5% and specificity was 69.2%. Chromogranin had the lowest sensitivity (82.5%), and synaptophysin had the lowest specificity (66.7%). Both positive and negative predictive values of INSM1 were higher than CD56 (99% versus 91.3% and 97% versus 81.8%, respectively). INSM1 is a sensitive and specific marker for detection of NETs in cytology samples independent of primary site.

Variability among observers utilizing the CellSolutions BestCyte Cell Sorter imaging system for the assessment of urinary tract cytology specimens.

INTRODUCTION: Image analysis systems are not currently commonly used for evaluating urinary cytology specimens. We evaluated whether the BestCyte Cell Sorter (CellSolutions, Greensboro, NC) imaging system can reliably identify atypical cells in urinary cytology specimens. METHODS: Fifty-three consecutive urine cytology specimens underwent 2 preparations: one slide using SurePath (SP; BD Diagnostics, Sparks, MD)™ for routine clinical evaluation, and a second slide using the CellSolutions F50 system for analysis by the BestCyte Cell Sorter (BCCS) scanning system. Eight observers reviewed atypical cells flagged by BCCS and assigned a BCCS diagnosis to each of the 53 specimens. The observers also blindly reviewed the SP preparation (when available) and assigned an SP diagnosis. The SP diagnoses given by one "expert" observer was considered as a reference diagnosis. RESULTS: There was fair-to-moderate agreement among observers for identifying any atypia and high-grade atypia (Fleiss kappa: 0.417 and 0.338, respectively) using BCCS. Review of SP preparations had slightly better agreement (Fleiss kappa: 0.558 and 0.564, respectively). Intraobserver agreement between the two methods varied greatly between individuals (Cohen's kappa range: 0.260 to 0.647). When a consensus diagnosis could be reached among the observers for cases with surgical follow-up, the consensus diagnosis was concordant in 11 of 12 instances, with one instance being a one-step discrepancy. CONCLUSIONS: Specimen review by BCCS resulted in slightly greater interobserver variability than review of routine SP preparations. This may have been due to variations in observer experience and comfort with the use of a digital imaging system, which is further suggested by the wide range of intraobserver agreement among individuals.

Paraganglioma: Cytomorphologic features, radiologic and clinical findings in 12 cases.

BACKGROUND: The cytologic diagnosis of paraganglioma can be challenging because of its rarity, wide anatomic distribution, and variable cytomorphological features. DESIGN: The Johns Hopkins Hospital pathology archives were searched for fine-needle aspiration (FNA) specimens confirmed as paraganglioma on histology (2003-2015). RESULTS: Twelve specimens from 10 patients (6 males and 4 females) with an age range of 16-81 years (mean = 47) were included. Anatomic location included neck (n = 4), paraspinal (n = 2), retroperitoneum (n = 2), and peripancreatic (n = 2). Cellularity of cytological specimens ranged from scant to hypercellular. The cells were arranged in clusters (n = 7), single cells (n = 6), acini (n = 3), and syncytium (n = 1). Plasmacytoid (n = 5) and spindled cells (n = 6) were often present. Nuclear details included anisonucleosis (n = 8), marked pleomorphism (n = 8), scattered binucleation and/or multinucleation, nuclear knobbing (n = 2), speckled (n = 3), coarse (n = 2), hyperchromatic chromatin (n = 3), nuclear grooves (n = 6), intranuclear pseudoinclusions (n = 2), prominent nucleoli (n = 1), naked nuclei (n = 7), and rare nuclear streaking artifact (n = 2). Cytoplasm was delicate, abundant, and granular (n = 9). Necrosis (n = 1) was rare. Synaptophysin, chromogranin, CD56, and S100 (only in sustentacular cells) were positive in tested cases. Three cases showed loss of Succinate Dehydrogenase Subunit B (SDHB). Two patients developed metachronous lesions at different sites. Three patients developed recurrence at the surgical site. Metastatic paraganglioma to the lymph nodes (n = 2), bone (n = 1), and lung (n = 1) also occurred. CONCLUSION: An accurate diagnosis of paraganglioma on FNA specimens is crucial for proper treatment. SDH status should be considered for all patients with paraganglioma as it may be important for patients' lifelong follow-up as well as for familial considerations. Paraganglioma is a rare entity with wide age and anatomic distribution and variable cytomorphological features that often overlap with those of malignant neoplasms. Possible aggressive behavior such as recurrence and metastasis to lymph nodes, bone, and lung as well as Succinate Dehydrogenase complex mutations warrant an accurate diagnosis on aspirated material for appropriate clinical management.

Fine-needle aspiration of a pancreatic neuroendocrine tumor with prominent rhabdoid features.

Pancreatic neuroendocrine tumors (PanNETs) are uncommon neoplasms that conventionally possess architectural and cytomorphological features seen in neuroendocrine neoplasms found at other sites. When present, these features often allow rapid identification of neuroendocrine differentiation and an accurate diagnosis. Here, we report the cytologic findings seen on fine-needle aspiration (FNA) of a PanNET with distinct rhabdoid features. This morphology is rare in PanNETs and has been reported in only two case series examining surgical resection specimens and has not been described on FNA. It is important to recognize this morphology as this variant appears to portend an aggressive clinical course. Furthermore, unfamiliarity with this morphologic variant may lead to a larger initial differential and thus delay final diagnosis.

When words matter: A "suspicious" urinary tract cytology diagnosis improves patient follow-up among nonurologists.

BACKGROUND: Urinary tract cytology (UTC) specimens diagnosed using high-risk indeterminate categories such as "atypical urothelial cells, cannot exclude high-grade urothelial carcinoma" (AUC-H) or "suspicious for high-grade urothelial carcinoma" (SHGUC) have a high rate of detection of high-grade urothelial carcinoma on subsequent biopsy. Although urologists are familiar with such terminology, it is unclear whether patients receive appropriate follow-up when UTC is ordered by nonurologists. In the current study, the authors investigated whether the use of AUC-H versus SHGUC altered patient management among nonurologists. METHODS: Specimens signed out as AUC-H or SHGUC were identified from the archives of the study institution, which included periods of time before the use of the standardized Johns Hopkins Hospital template, during use of the Johns Hopkins Hospital template, and after institution of The Paris System for Reporting Urinary Cytology. RESULTS: Approximately one-half of the specimens diagnosed as AUC-H were not investigated further when ordered by nonurologists. Patients with specimens diagnosed as AUC-H received fewer subsequent biopsies (14% vs 53%; P < .001) when the specimens were ordered by nonurologists versus urologists, despite having similar rates of high-grade urothelial carcinoma on follow-up biopsy (67% vs 66%). When specimens ordered by nonurologists were diagnosed as SHGUC, these patients received more follow-up (100%) compared with those whose specimens were diagnosed as AUC-H (44%; P < .001). Patients with specimens ordered by nonurologists also received more follow-up biopsies when these were diagnosed as suspicious (60%) compared with patients whose specimens were diagnosed as AUC-H (14%; P < .001). CONCLUSIONS: Use of the word "suspicious" for the high-risk indeterminate category results in greater follow-up among nonurologists ordering UTC specimens. Cancer Cytopathol 2018;126:282-8. © 2018 American Cancer Society.

Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

BACKGROUND: The lack of effective short-course therapies for treatment of the adult stage of filarial worms is a major limitation in the global effort to eliminate lymphatic filariasis. Studies using current small mammal models of lymphatic filariasis are limited by difficulties in quantifying adult worm numbers and in assessing lymphatic anatomy and function. METHODOLOGY/PRINCIPAL FINDINGS: Here, we re-established Brugia malayi infection of ferrets as a model for lymphatic filariasis and demonstrated parasitological, immunological, and histological parallels with human infection. Subcutaneous injection of L3 larvae into a hind-footpad resulted in a mean of 18 adult worms recovered 16 weeks post-infection, primarily from the draining inguinal and femoral lymphatics of the injected limb. Infected ferrets developed microfilaremia, with patency lasting from 12-26 weeks post-infection. Quantitative PCR assessing cytokine transcription by antigen-stimulated lymph node cells demonstrated a mixed Th1/Th2 response occurring during early infection. Immunoregulation with production of down-regulatory cytokine IL-10 occurred just prior to peak microfilaremia. Histological analysis revealed progressive inflammation of the lymphatic vessel walls, with intimal thickening and disorganization of collagen fibers. Inflammation was observed as early as 8 weeks post-infection and extended into the perivascular and subcutaneous tissues by 16 weeks post-infection. Finally, we developed a novel ferret PET/CT lymphoscintigraphy method demonstrating substantial changes in lymphatic anatomy and function as early as 3 weeks post-infection, with progression over the course of infection. CONCLUSIONS/SIGNIFICANCE: B. malayi infection of ferrets is a robust model of human lymphatic filariasis that can be utilized to study efficacy of novel antifilarial agents against adult worms residing within lymphatic vessels. In conjunction with PET/CT lymphoscintigraphy, this model can also be used to investigate pathogenesis of lymphatic dysfunction in lymphatic filariasis and efficacy of medications aimed at reversing lymphatic dysfunction after clearance of adult worms.

Safety and diagnostic accuracy of dipyridamole-thallium imaging in the elderly.

The noninvasive diagnosis of coronary artery disease in the elderly can occasionally be difficult. Intravenous dipyridamole-thallium imaging is a potentially useful diagnostic test to determine presence and severity of coronary disease; however, the safety of the procedure has not been determined in an older population. The side effect profile and frequency of severe ischemic responses after 0.56 mg/kg of intravenous dipyridamole were compared in 101 patients greater than or equal to 70 years old and 236 patients less than 70 years old. There were no side effects in 64% and 62% of patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). Among the 337 patients tested, there were no complications of myocardial infarction or death. The most common cardiac side effect was chest pain, which occurred in 21 (21%) of the 101 patients aged greater than or equal to 70 years and in 64 (27%) of the 236 patients less than 70 years (p = NS). Aminophylline was required to reverse cardiac or noncardiac side effects in 15 (15%) and 36 (15%) of the patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). A severe ischemic response occurred in 2% and 2.5% of patients greater than or equal to 70 and less than 70 years old, respectively (p = NS). The sensitivity of intravenous dipyridamole-thallium imaging for obstructive coronary artery disease was 86% (25 of 29) and 83% (68 of 82) in older and younger patients, respectively (p = NS); the specificity was 75% (6 of 8) and 70% (16 of 23), respectively (p = NS). Thus, intravenous dipyridamole-thallium imaging is a safe noninvasive method for assessment of older patients with obstructive coronary disease; its side effect profile and diagnostic accuracy are similar to those seen in younger patients. The technique is associated with severe ischemic responses in only a small minority of patients.

Digitalis use in a retirement community.

Complex medical problems of older patients demand that particular care be taken with their use of digitalis. Although accounting for more than 5% of the top ten prescribed drugs in the United States, studies have suggested that digitalis use might be discontinued in some patients without harm. To assess the potential impact of these observations, a survey was conducted to evaluate the extent of digitalis use in a retirement community in Florida. The community under study consisted of approximately 5600 persons, mean age 72.6 years; 97% were over age 55. The sample of 463 telephone respondents reflected the local census. Digitalis preparations had been taken by 11.4% of the sample, of whom 60% (or 6.9% of the total sample) were currently taking them. Persons taking digitalis tended to be older (P less than .002) and reported worse overall health status than those not taking the drug (P less than .025). Seventeen percent of those who had stopped use of digitalis claimed adverse symptoms or "complications." Of Florida's 10 million population, 23% are over age 60, a proportion increasing yearly. This survey suggests that digitalis use in the elderly is widespread and a potentially important area for investigating management of cardiac problems in the elderly.

Selective cardiovascular effects of stress and cigarette smoking in young women.

In an earlier study, we found that men who smoked a cigarette and then engaged in a mildly stressful activity (video game) evidenced pronounced increases in heart rate and blood pressure, which were approximately equal to the sum of the effects produced by either smoking alone or stress alone. In the present study, a 2 (smoke vs. sham smoke) X 2 (stress vs. no stress) factorial design was used to evaluate the impact of stress and smoking on the cardiovascular responses of young women. The results revealed that the combination of stress and cigarette smoking produced blood pressure and heart rate responses that were larger than the additive effects of smoking and stress taken separately.

An analysis of the relationship between cardiac deceleration and correct performance under conditions of constant task difficulty.

Previous analyses of the relationship between cardiac deceleration and correct performance suffered from a confounding of task difficulty with performance accuracy. The present analysis indicates that the relationship between these variables still holds and is, in fact, more general under conditions which control difficulty of the task at a constant level.

Cardiac deceleration as an indicator of correct performance.

A within-subjects experiment involving 10 subjects was performed to examine the relationship between the accuracy of judgment of position and cardiac deceleration. The results supported the hypothesis that accurate (correct) performance is accompanied by greater cardiac deceleration than inaccurate performance for those subjects (9 out of 10) who exhibited cardiac deceleration to stimulus onset. The data indicated, however, that the relationship varied with time. Part of this variability appears related to the initial exploratory behavior in which subjects engaged and later reported during the post-experiment interview.

Pre- and postpartum sex steroids in female marmosets (Callithrix kuhlii): is there a link with infant survivorship and maternal behavior?

Recent studies in primates have suggested that pre- and peripartum sex steroid hormones may be important determinants of maternal behavior and motivation, since higher levels of prepartum estrogen are associated with maternal competency and infant survivorship. To test the cross-species generality of this finding, we monitored excreted profiles of estradiol (E(2)), progesterone metabolites (pregnanediol glucuronide; PdG), and E(2):PdG ratios throughout pregnancy in black tufted-ear marmosets (Callithrix kuhlii). Additionally, we wanted to determine the extent to which variability in maternal carrying effort was related to hormonal factors and relative levels of maternal experience. For six females, hormonal profiles were determined by enzyme immunoassay for two pregnancies, one in which infants survived at least 2 weeks postpartum and one in which infants did not survive. Our within-subjects analyses revealed significant differences in mean prepartum E(2) levels for females in the different infant survival conditions. In contrast to previous findings, however, females exhibited significantly higher prepartum E(2) levels when their infants did not survive a minimum of 2 weeks postpartum, relative to when their infants did survive. Maternal carrying effort was also negatively and significantly correlated with prepartum E(2) levels. Unlike previous reports in callitrichid primates, then, our data suggest that high concentrations of prepartum E(2) in callitrichid primates are not necessarily associated with competent maternal behavior and may instead be associated with poor infant survivorship and inadequate maternal care. Further, our results appear to be convergent with research focusing on human mothers and may represent a common underlying mechanism linking prepartum estrogen and postpartum affect and behavior in some primates.

Interactions among paternal behavior, steroid hormones, and parental experience in male marmosets (Callithrix kuhlii).

Male black tufted-ear marmosets (Callithrix kuhlii) contribute to the rearing of their offspring. Here we evaluated predictions of hypotheses suggesting that (1) T and E2 influence infant-care behavior in male marmosets, (2) levels of T and E2 are modulated by paternal experience, and (3) paternal behavior and levels of T and E2 in male marmosets covary with stress. We observed the behavior of marmosets in their family groups following the birth of infants and evaluated urinary concentrations of T, E2, and the stress hormone cortisol (CORT) among fathers before and after the birth of young. Urinary levels of T, E2, and CORT were lower among males who carried infants at high rates than males who carried at low rates, and T and CORT levels were negatively correlated with carrying rates across all males. Males had significantly lower T levels while carrying the second compared to the first litter and slightly lower rates of infant-carrying, possibly due to assistance provided by offspring of the first litter. There were increases in CORT levels of fathers after the birth of the first litter, but decreases in CORT after the birth of the second. Our results suggest a relationship in C. kuhlii between paternal behavior, hormones, and paternal experience. Rates of infant-carrying appear to be linked to hormone levels, and hormone levels in turn are affected by experience caring for young. Our data also suggest that T, E2, and CORT have synergistic influences on infant-carrying behavior or alternatively that associations between T and E2 and rates of infant-carrying are influenced by stress or other glucocorticoid-related variables. Finally, we propose a hypothesis suggesting that experience-related changes in hormones reinforce the commitment of males to successful breeding partnerships.