Adverse childhood experiences (ACEs) research: A bibliometric analysis of publication trends over the first 20 years.

BACKGROUND: The relative health and robustness of a field of research can be approximated by assessing peer reviewed journal publication trends for articles pertinent to the field. To date, there have been no such assessments of the burgeoning research on adverse childhood experiences (ACEs). OBJECTIVE: The overall goal of this study was to examine ACEs research trends using bibliometric methods. More specifically, we sought to describe observed publication trends of the ACEs literature from its inception in the late 1990s. We also analyzed the nature of ACEs publications with regard to key characteristics of main outcomes, levels of analysis, and populations of primary focus. METHODS: A search was conducted using Scopus to identify English language papers on ACEs published in peer-reviewed journals between 1998 and 2018. The primary field of research was determined by having independent raters code the title of the publishing journal into distinct categories. Main research outcomes were similarly coded. RESULTS: A total of 789 articles on ACEs appearing in 351 different academic journals were published between 1998 and 2018. There was considerable growth in the number of ACEs papers published over the past several years. General medicine and multidisciplinary research were the most frequent of 12 primary fields of research characterizing ACEs research. Of 16 primary outcomes on which ACEs research focused, the most common were mental health and physical health. CONCLUSION: Significant growth in ACEs research over the past several years suggest the field is thriving. Observed publication trends and publication characteristics are discussed briefly.

A microaliquoting technique for precise histological annotation and optimization of cell content in frozen tissue specimens.

Knowledge of the exact cell content of frozen tissue samples is of growing importance in genomic research. We developed a microaliquoting technique to measure and optimize the cell composition of frozen tumor specimens for molecular studies. Frozen samples of 31 mesothelioma cases were cut in alternating thin and thick sections. Thin sections were stained and evaluated visually. Thick sections, i.e., microaliquots, were annotated using bordering stained sections. A range of cellular heterogeneity was observed among and within samples. Precise annotation of samples was obtained by integration and compared to conventional single face and "front and back"' section estimates of cell content. Front and back estimates were more highly correlated with block annotation by microaliquoting than were single face estimates. Both methods yielded discrepant estimates, however, and for some studies may not adequately account for the heterogeneity of mesothelioma or other malignancies with variable cellular composition. High yield and quality RNA was extracted from precision annotated, tumor-enriched subsamples prepared by combining individual microaliquots with the highest tumor cellularity estimates. Microaliquoting provides accurate cell content annotation and permits genomic analysis of enriched subpopulations of cells without fixation or amplification.

Expression patterns of inhibitor of apoptosis proteins in malignant pleural mesothelioma.

Inhibitor of apoptosis proteins (IAPs) comprise a family of structurally similar proteins, five of which are widely studied in the context of cancer: IAP-1/MIHC/cIAP2, IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP. IAPs are overexpressed by most neoplasms, promote tumour cell survival after a wide variety of apoptotic stimuli, and frequently have gene and/or protein expression patterns associated with a relatively poor prognosis. However, many IAPs are also expressed by normal tissues, can facilitate apoptotic cell death, and have expression patterns associated with a relatively favourable prognosis in some cases. The result is that the precise role(s) of IAPs in human tumours is not exactly known. It has been previously reported that IAP-1 is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Given the high homology of IAP family members, it is likely that other IAPs will be important in MPM. In the present study, the gene and protein expression patterns of IAP-1, IAP-2, survivin, livin, and XIAP have been determined in MPM cell lines (n=9) and a large number of MPM tumours using high-density oligonucleotide microarrays (n=40) and an MPM tissue array (n=66). Human tumours were linked to clinical data and it was found that IAP-1 and survivin mRNA expression patterns were associated with a relatively shorter patient survival, while those of XIAP and livin were associated with a relatively longer patient survival. Abundant protein for all IAPs was also detected in MPM tumours, where they were expressed primarily in the cytoplasm. Only IAP-1 and livin protein was expressed in the nucleus of MPM tumours. These results provide the rationale for additional study of this gene family in MPM and cancer in general.

Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma.

Inhibitor of apoptosis proteins (IAPs) are overexpressed by most neoplasms and promote tumour cell survival after a wide variety of apoptotic stimuli elicited via intrinsic (ie mitochondrial) and extrinsic (ie death receptor) pathways. It has previously been reported that one of these proteins, IAP-1(MIHC/cIAP2), is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Subsequent analysis in a larger number of human tumours revealed that additional IAPs (eg IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP) are also overexpressed in MPM and, with the exception of IAP-2, have expression patterns that correlate with prognosis. In the present study, potential regulatory mechanisms of IAP genes in MPM were investigated and it was found that tumour necrosis factor-alpha (TNF-alpha) can increase mRNA and protein levels of IAP-1, IAP-2, and XIAP, but not livin or survivin in MPM cell lines (n=4). It was also found that IAP gene expression levels are increased concomitantly with translocation to the nucleus of the TNF-responsive transcription factor NF-kappaB. Co-incubation of MPM cells with TNF-alpha and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, prevented TNF-mediated up-regulation of IAP gene expression levels. In survival studies, TNF-alpha was not toxic to MPM cells at any concentration examined. However, MPM cells exposed to TNF-alpha were twice as resistant to cisplatin in dose response survival assays compared with unstimulated controls and were found to have a significantly greater fraction of surviving cells at multiple cisplatin concentrations (p<0.0087). Finally, it was found that levels of circulating TNF-alpha were statistically significantly (p=0.031) (median 312.5 pg/ml) higher in MPM patients (n=6) prior to surgical tumour debulking compared with those after surgery (median 0 pg/ml). These results when combined with previous observations by our laboratory and others strongly suggest that IAPs act synergistically with TNF family members to promote survival of MPM tumour cells after exposure to cisplatin and possibly other chemotherapeutic drugs.

Noninvasive ventilation during gastrostomy tube placement in patients with severe duchenne muscular dystrophy: case reports and review of the literature.

Individuals with Duchenne muscular dystrophy may benefit from gastrostomy tube feeding due to progressive dysphagia and malnutrition. However, due to their severely impaired pulmonary function, these individuals are at risk of severe complications when they are sedated or undergo anesthesia for the procedure. We previously described a technique of noninvasive positive pressure ventilation to provide respiratory support during gastrostomy tube placement in such patients, but this technique had risks and limitations. In this case report, we examine two alternative techniques we used to provide respiratory support successfully to patients with severe muscular dystrophy and malnutrition who underwent percutaneous endoscopic gastrostomy tube placement. We then review the literature and discuss the potential benefits, risks, and limitations of the above techniques and of other options for gastrostomy placement in people with severe muscular dystrophy.

Histone deacetylation is directly involved in desilencing the expression of the catalytic subunit of telomerase in normal lung fibroblast.

The regulation of telomerase expression in normal cells is poorly understood. Moreover, the molecular mechanism underlying tumor-specific expression of telomerase remains unclear. We investigated the link between histone deacetylation and telomerase activity in normal lung and lung tumor cells. Four non-small-cell lung cancer (NSCLC) lines and one normal lung fibroblast line were tested for telomerase activity with or without Trichostatin A(TSA). The telomerase activity and the expression of telomerase associated components were determined by TRAP assay, RT-PCR analysis and Western blot analysis. All 4 NSCLC cell lines exposed to 1 microM TSA for 24 h had no change in telomerase activity or hTERT mRNA level. Telomerase activity was very low in normal lung fibroblasts (mrc-9) until exposed to 1 microM TSA for 24 h, at which time telomerase activity was readily detectable, with concomitant upregulation of hTERT mRNA (10-fold). The level of other telomerase associated components (hTER and TP1) were unaltered. Furthermore, 1 microM TSA exposure for 24 h did not alter the level of c-Myc or p21 mRNA. Immunodetection reveled that hTERT protein expression increased (approximately 6 fold) compared to c-Myc, p21, or gelsolin. The effect of TSA on hTERT expression is independent of DNA methylation as judged by 5-azacytidine (5aza) treatment. TSA effect on mrc-9 cells is unaltered even in the presence of 200 microg/ml cyclohexamide, suggesting a direct inhibition of histone deacetylation. Collectively, our study indicates that inhibition of histone deacetylation selectively regulates the transcriptional derepression of telomerase catalytic subunit in normal lung fibroblast cells compared to lung tumor cells.

Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats.

Liver regeneration after two-thirds surgical partial hepatectomy (PH) in rats treated with the pyrrolizidine alkaloid retrorsine is accomplished through the activation, expansion, and differentiation of a population of small hepatocyte-like progenitor cells (SHPCs). We have examined expression of the major liver-enriched transcription factors, cytochrome P450 (CYP) enzymes, and other markers of hepatocytic differentiation in SHPCs during the protracted period of liver regeneration after PH in retrorsine-exposed rats. Early-appearing SHPCs (at 3-7 days after PH) express mRNAs for all of the major liver-enriched transcription factors at varying levels compared to fully differentiated hepatocytes. In addition, SHPCs lack (or have significantly reduced) expression of mRNA for hepatocyte markers tyrosine aminotransferase and alpha-1 antitrypsin, but their expression levels of mRNA and/or protein for WT1 and alpha-fetoprotein (AFP) are increased. With the exception of AFP expression, SHPCs resembled fully differentiated hepatocytes by 14 days after PH. Expression of AFP was maintained by most SHPCs through 14 days after PH, gradually declined through 23 days after PH, and was essentially absent from SHPC progeny by 30 days after PH. Furthermore, early appearing SHPCs lack (or have reduced expression) of hepatic CYP proteins known to be induced in rat livers after retrorsine exposure. The resistance of SHPCs to the mitoinhibitory effects of retrorsine may be directly related to a lack of CYP enzymes required to metabolize retrorsine to its toxic derivatives. These results suggest that SHPCs represent a unique parenchymal (less differentiated) progenitor cell population of adult rodent liver that is phenotypically distinct from fully differentiated hepatocytes, biliary epithelial cells, and (ductular) oval cells.

Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury.

Retrorsine is a member of the pyrrolizidine alkaloid family of compounds whose toxic effects on the liver include a long-lasting inhibition of the proliferative capacity of hepatocytes. Despite the retrorsine-induced blockade of hepatocyte proliferation, retrorsine-exposed rats are able to reconstitute completely their liver mass after surgical partial hepatectomy (PH) via the sustained proliferation of a population of small, incompletely differentiated hepatocyte-like progenitor cells (SHPCs). The extensive proliferation of SHPCs in retrorsine-injured livers is accompanied by the progressive loss of irreversibly injured megalocytes. To study the mechanism by which retrorsine-damaged hepatocytes are removed after PH, we performed TUNEL analysis to establish apoptotic indices for hepatocytes in the livers of retrorsine-exposed and control rats up to 14 days post-PH. Apoptotic indices are highest (approximately 6.0%) in the livers of retrorsine-exposed rats at 1 day post-PH, gradually declining thereafter, yet remaining significantly elevated (approximately 1%) over control rats (<0.1%) at 14 days post-PH (P <.05). After PH, levels of the proapoptotic protein Bax are increased in livers from retrorsine-exposed rats relative to the levels observed in control livers. Similarly, levels of the antiapoptotic protein Bcl-x(L) are significantly decreased (P <.05) compared with controls at t = 0 resulting in an increased (approximately 3.5-fold) Bax/Bcl-x protein ratio that is significantly elevated (P <.05) compared with controls. Finally, increased levels of Bax protein are localized to the mitochondria of retrorsine-exposed rat livers after PH during the same time that cytochrome c is released. These observations combine to suggest that retrorsine-injured hepatocytes are removed after PH via apoptotic pathways dependent on relative levels and localization of Bax and Bcl-x(L) protein.

Induction of cytochrome P450 enzymes in the livers of rats treated with the pyrrolizidine alkaloid retrorsine.

Retrorsine is a member of the pyrrolizidine alkaloid (PA) family of naturally occurring compounds found in a large number of plant species worldwide. The cytotoxic, mutagenic, and antimitotic effects of PAs have made them targets for studies designed to determine their potential contributions to carcinogen esis and their usefulness for anticancer therapy. Evidence from the literature suggests that bioactivation of PAs by liver cytochrome P450 (CYP) enzymes is required for their toxicity. However, the specific CYP isozymes that are involved in retrorsine metabolism have not been identified. To address this issue, we administered retrorsine to a cohort of young adult male rats and examined induction or enhanced expression of mRNA and protein for widely studied hepatic CYP isoforms spanning four families together with the essential enzyme CYP reductase. The protein levels of normally expressed CYPs 1A2, 2B1/2, and 2E1 increase significantly in rat liver microsomes from retrorsine-treated rats compared to untreated control rats (P < 0. 05), but protein levels of CYP 4A3, CYP 3A1, and CYP reductase were unchanged after retrorsine treatment. In addition, CYP 1A1 mRNA and protein, which are not detectable in the livers of control rats, were induced after retrorsine exposure. The results of the present study demonstrate enhanced or induced expression of hepatic CYPs 1A1, 1A2, 2E1, and 2B1/2 in response to retrorsine exposure in rats, suggesting that one or more of these enzymes may be involved in retrorsine metabolism.

Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response.

The adult rodent liver contains at least two recognized populations of cells with stem-like properties that contribute to liver repair/regeneration under different pathophysiological circumstances: (i) unipotential committed progenitor cells (differentiated hepatocytes and biliary epithelial cells) and (ii) multipotential nonparenchymal progenitor cells (oval cells). In retrorsine-induced hepatocellular injury the capacity of fully differentiated rat hepatocytes to replicate is severely impaired and massive proliferation of oval cells does not occur. Nevertheless, retrorsine-exposed rats can replace their entire liver mass after 2/3 surgical partial hepatectomy through the emergence and expansion of a population of small hepatocyte-like progenitor cells that expresses phenotypic characteristics of fetal hepatoblasts, oval cells, and fully differentiated hepatocytes, but differ distinctly from each type of cell. The activation, proliferation, and complete regeneration of normal liver structure from small hepatocyte-like progenitor cells have not been recognized in other models of liver injury characterized by impaired hepatocyte replication. We suggest that the selective emergence and expansion of small hepatocyte-like progenitor cells observed in the retrorsine model reflect a novel mechanism of complete liver regeneration in the adult rat. Furthermore, we suggest that these cells may represent a novel progenitor cell population that (i) responds to liver deficit when the replication capacity of differentiated hepatocytes is impaired, (ii) expresses an extensive proliferative capacity, (iii) can give rise to large numbers of progeny hepatocytes, and (iv) can restore tissue mass.

Technology assessment and equipment planning in Kaiser Permanente, Northern California Region.

Hospitals face a significant challenge to select and appropriately place clinically warranted, safe, and cost-effective medical devices. To meet this challenge, the Kaiser Permanente, Northern California Region developed a comprehensive medical device technology assessment and equipment planning program. This paper discusses the structure of the program, physician leadership and accountability, the role of clinical engineers and other support personnel, and the program's influence on strategic planning and policy development.

Continuous papaveretum infusion for the control of pain in painful sickling crisis.

We describe our experience of using continuous papaveretum infusions to control pain in 24 children admitted on 45 occasions with painful sickling crisis. The children were aged from 1.7 to 14.3 years. Infusion duration ranged from one to nine days (median three days), total dose from 0.3 to 21 mg/kg (median 2.4 mg/kg), with a pronounced tendency for dosage to increase with increasing age. No respiratory depression was observed. One infusion was discontinued because of cerebral toxicity.

Hospital technology management: the Tao of clinical engineering.

Planning a profession's future is a formidable task that must be based on both what the members want to become and what is natural to the marketplace. The hospital industry, however, will not wait for clinical engineering to establish its profession. Competition will arise and push aside the unprepared. Clinical engineering's leadership has not created a clear vision of their profession's role in improving healthcare, nor have they helped others to internalize a sincere professional purpose and to share the responsibility for change. This paper examines the profession and articulates action that only clinical engineers can take to increase their value in the hospital industry.