The Renin-Angiotensin System in Liver Disease.

The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.

Depression in Female Adolescents with Heavy Menstrual Bleeding.

OBJECTIVE: To assess the degree to which heavy menstrual bleeding is associated with depression, independent of hormonal contraception. STUDY DESIGN: We performed a retrospective cohort study of 1168 female adolescents 9-18 years old presenting to general pediatricians for heavy menstrual bleeding or well visits. Depression was the primary outcome and defined as a diagnosis in the health record. Univariable and multivariable regression models were fit to the data to identify factors associated with depression diagnosis. RESULTS: In total, 581 adolescents with heavy menstrual bleeding and 587 without heavy menstrual bleeding were included. Depression diagnoses occurred with greater frequency in youth with heavy menstrual bleeding compared with those without heavy menstrual bleeding (50.9% vs 24.2% P < .001; risk ratio 1.67, 95% CI 1.39-2.01) but did not significantly differ between those taking vs not taking hormonal contraception (risk ratio 0.99; 95% CI 0.84-1.17). Most patients with depression and heavy menstrual bleeding developed depression following or concurrent with heavy menstrual bleeding (261/296, 88%). Of these, 199 of 261 (76%) were treated with hormonal contraception, but the majority (168/199; 84%) were diagnosed with depression before initiation. CONCLUSIONS: Heavy menstrual bleeding is associated with depression diagnosis in female adolescents. The use of hormonal contraception was not associated with depression diagnosis in multivariable analysis, covarying heavy menstrual bleeding, age, body mass index, anxiety, sexual activity, and substance use. As hormonal contraception is often used to treat heavy menstrual bleeding, heavy menstrual bleeding may be partially driving previous reports of increased depression risk in those taking hormonal contraception.

IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia.

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS' function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

Line Associated Thrombosis in Pediatric Patients With NF-κB Pathway Variants.

Our report explores the complex role that nuclear factor-kappa B (NF-κB) plays in thrombosis formation, inflammation, and immunity; while additionally demonstrating that patients with NF-κB pathway pathogenic variants appear to carry a substantial thrombotic risk, particularly when secondary thrombotic risk factors are present. We propose that prophylactic anticoagulation should be strongly considered in such patients during high-risk situations and provide additional hematologic management strategies for those with NF-κB pathway alterations. We hope our work also calls to attention the potential need for a broader assessment of venous thromboembolism risk in patients with immune dysregulation to better delineate which patient populations may benefit from anticoagulation prophylaxis.

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS's novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS's DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS's regulatory effects on the PI3K oncogenic signaling pathway.

A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (D-G6PD) is an X-linked recessive disorder resulted from deleterious variants in the housekeeping gene Glucose-6-phosphate 1-dehydrogenase (G6PD), causing impaired response to oxidizing agents. Screening for new variations of the gene helps with early diagnosis of D-G6PD resulting in a reduction of disease related complications and ultimately increased life expectancy of the patients. METHODS: One thousand five hundred sixty-five infants with pathological jaundice were screened for G6PD variants by Sanger sequencing all of the 13 exons, and the junctions of exons and introns of the G6PD gene. RESULTS: We detected G6PD variants in 439 (28.1%) of the 1565 infants with pathological jaundice. In total, 9 types of G6PD variants were identified in our cohort; and a novel G6PD missense variant c.1118 T > C, p.Phe373Ser in exon 9 of the G6PD gene was detected in three families. Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice, consistent with Class I G6PD deleterious variants. Analysis of the resulting protein's structure revealed this novel variant affects G6PD protein stability, which could be responsible for the pathogenesis of D-G6PD in these patients. CONCLUSIONS: High rates of G6PD variants were detected in infants with pathological jaundice, and a novel Class I G6PD deleterious variants was identified in our cohort. Our data reveal that variant analysis is helpful for the diagnosis of D-G6PD in patients, and also for the expansion of the spectrum of known G6PD variants used for carrier detection and prenatal diagnosis.

Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic-related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant.

Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ.

Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3Kδ inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and noncovalently to the kinase. A crystal structure of idelalisib bound to the p110δ subunit of PI3Kδ furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.

Failed pneumoperitoneum for laparoscopic surgery following autologous Deep Inferior Epigastric Perforator (DIEP) flap breast reconstruction: a case report.

BACKGROUND: Laparoscopic abdominal surgery may prove difficult in patients who have undergone previous abdominal procedures. No reports in the medical literature have presented an aborted laparoscopic procedure for failed pneumoperitoneum following autologous flap-based breast reconstruction. CASE PRESENTATION: A 55-year-old woman presented with recurrent invasive lobular carcinoma of the right breast as well as a history of ductal carcinoma in situ of the left breast. The patient desired to proceed with bilateral skin- and nipple-sparing mastectomies with right axillary lymph node biopsy, followed by immediate bilateral autologous deep inferior epigastric perforator (DIEP) flap-based breast reconstruction. Preoperatively, a computerized tomography angiogram was obtained for reconstructive preparation, which revealed a left adrenal mass. Ensuing work-up diagnosed a pheochromocytoma. Given the concern for breast cancer progression, the patient elected to proceed first with breast cancer surgery and reconstruction prior to addressing the adrenal tumor. Subsequently, 3 months later the patient was brought to the operating room for a laparoscopic left adrenalectomy for the pheochromocytoma. With complete pharmacologic abdominal relaxation, the abdomen proved too tight to accommodate sufficient pneumoperitoneum and the laparoscopy was aborted. The patient was evaluated in the outpatient setting for assessment of abdominal wall compliance at regular intervals. Five months later, the patient was taken back to the operating room where pneumoperitoneum was established without difficulty and the laparoscopic left adrenalectomy was performed without complications. CONCLUSION: Pneumoperitoneum for laparoscopic surgery subsequent to autologous DIEP flap-based breast reconstruction may prove difficult as a result of loss of abdominal wall compliance. Prior to performing laparoscopy in such patients, surgeons should consider the details of the patient's previous reconstructive procedure and assess potential risk factors for difficulty with insufflation. Lastly, careful abdominal examination should be performed to indicate whether laparoscopy for elective procedures should be delayed until abdominal wall compliance normalizes.

Multidisciplinary management of advanced basal cell carcinoma: report of four cases.

BACKGROUND: Advanced basal cell carcinomas (BCC) are neoplasms with high-risk clinical characteristics that can develop as locally advanced disease or metastasis. Treatment of advanced BCC may result in significant morbidity due to the technical challenges of size and/or location or in which surgery and radiation therapy may be contraindicated. No standard of care exists for the management of advanced BCC. As such, the difficulty in managing these tumors necessitates a multidisciplinary approach to patient care. METHODS: We report four cases of advanced BCC that benefited from a multidisciplinary approach, as well as highlight treatment considerations and factors in the development of advanced BCC. RESULTS: All four complex cases of advanced BCC presented to a multidisciplinary non-melanoma skin cancer tumor board with extensive tumor involvement. Treatment of disease was effective in preventing recurrence while optimizing aesthetic outcomes. CONCLUSIONS: The multidisciplinary tumor board has a central and important role in the evaluation and management of advanced BCC.

Long-term reconstructive outcomes after expander-implant breast reconstruction with serious infectious or wound-healing complications.

INTRODUCTION: Immediate expander-implant breast reconstruction has been associated with postoperative complications, including infection and wound-healing problems. In extreme cases, these issues can lead to expander-implant loss. Little is known about the long-term reconstructive outcomes for patients who develop major complications threatening their expander-implant reconstructions. METHODS: A review of all patients who underwent mastectomy and immediate expander-implant reconstruction at University of California, San Francisco (UCSF) from 2005 to 2007 was performed. A prospective database was queried for patients who developed a major postoperative complication related to infection or wound-healing problems requiring unplanned operative intervention. Only patients who had a minimum of 3 years' follow-up were included in the study. RESULTS: Twenty-nine patients were identified who met study criteria. Mean follow-up time was 52.5 months (range, 41-71 months). Six of the 29 (20.7%) patients had received prior breast irradiation, and 9 patients (31%) underwent postoperative radiation therapy. Reasons for unplanned return to the operating room included infection (n = 11, 37.9%), expander-implant exposure (n = 5, 17.2%), nonhealing wounds without underlying exposure (n = 3, 1.3%), or >1 of these indications (n = 10, 34.5%). Unplanned operative intervention (such as wound debridement or expander-implant exchange or removal) was required once in 10 patients (34.5%), twice in 10 patients (34.5%), 3 times in 4 patients (13.8%), 4 times in 1 patient (3.4%), and 5 or greater times in 4 patients (13.8%). At the conclusion of all operative interventions, 15 patients (51.7%) had successful breast reconstruction using an expander-implant technique. Five additional patients (17.3%) ultimately achieved successful salvage reconstruction with either a transverse rectus abdominis myocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flap. Nine patients (31%) did not have successful breast reconstruction. Of these 9 patients, 5 elected to abandon reconstructive efforts after 1 unplanned return to the operating room for expander-implant removal, whereas the rest underwent at least 1 attempt at expander-implant salvage, with the overall rate of final successful reconstruction after attempt at salvage 83.3% (20 of 24 patients). CONCLUSIONS: Even when unplanned operative intervention is required to address postoperative wound-healing or infectious complications after expander-implant reconstruction, the majority of patients can achieve successful reconstructive outcomes at long-term follow-up, including those patients requiring multiple operative interventions to treat their complication.

Managing Challenging Situations in Practice: a new program developed to meet the specific needs of nursing students.

Health care workers, nurses, and nursing students face a high risk of workplace aggression and violence. Potential adverse consequences oblige health care providers and educators to protect the safety of everyone in the health care setting. It is broadly agreed that health care personnel should receive education and training in the management of work-related aggression and violence. However, there are no training programs designed to meet the specific needs of nursing students. In the absence of Irish or international policies or guidelines, an evidence-based training program for first-year undergraduate nursing students was developed. Its focus was to enable nursing students to recognize potential problems and develop the skills necessary to appropriately handle situations that may arise during their clinical nursing practice. This article outlines the development and delivery of a training program for first-year nursing students, entitled Managing Challenging Situations in Practice.

Honeycomb: a template for reproducible psychophysiological tasks for clinic, laboratory, and home use.

OBJECTIVE: To improve the ability of psychiatry researchers to build, deploy, maintain, reproduce, and share their own psychophysiological tasks. Psychophysiological tasks are a useful tool for studying human behavior driven by mental processes such as cognitive control, reward evaluation, and learning. Neural mechanisms during behavioral tasks are often studied via simultaneous electrophysiological recordings. Popular online platforms such as Amazon Mechanical Turk (MTurk) and Prolific enable deployment of tasks to numerous participants simultaneously. However, there is currently no task-creation framework available for flexibly deploying tasks both online and during simultaneous electrophysiology. METHODS: We developed a task creation template, termed Honeycomb, that standardizes best practices for building jsPsych-based tasks. Honeycomb offers continuous deployment configurations for seamless transition between use in research settings and at home. Further, we have curated a public library, termed BeeHive, of ready-to-use tasks. RESULTS: We demonstrate the benefits of using Honeycomb tasks with a participant in an ongoing study of deep brain stimulation for obsessive compulsive disorder, who completed repeated tasks both in the clinic and at home. CONCLUSION: Honeycomb enables researchers to deploy tasks online, in clinic, and at home in more ecologically valid environments and during concurrent electrophysiology.

Is abnormal gallbladder ejection fraction hokum? Retrospective chart review of gallbladder ejection fraction and subsequent postoperative symptom relief, surgical pathology, and current literature review.

The purpose of this report is to investigate the clinical importance of increased or decreased gallbladder ejection fraction (GBEF) and ultrasound findings for biliary dyskinesia by evaluating postsurgical symptom relief and surgical pathology. Single institution electronic medical record review was prepared for patients who underwent hepatobiliary iminodiacetic acid (HIDA) scan with GBEF and cholecystectomy between January 2013 and March 2020. Relevant data included patient demographics, ultrasound results, surgical pathology, HIDA with GBEF results, and postoperative symptom relief at the time of follow-up. Student's t-test was also utilized for additional statistical analysis. A total of 67 patients underwent cholecystectomy within a 1-month period of time after HIDA with GBEF. Of these patients, 97% had findings consistent with chronic cholecystitis and 3% of the patients demonstrated both acute and chronic cholecystitis surgical pathology. Fifty-seven percent of the patients demonstrated a GBEF <38%, 30% had a GBEF >80%, and 13% had a GBEF 38%-80% with a postoperative symptom resolution around 82%, 77%, and 100%, respectively. GBEF alone may not be determinative regarding gallbladder pathology or postoperative symptom relief in patients that present with typical symptoms. Regarding dyskinetic gallbladders, elevated and decreased GBEF groups were not significantly different in terms of surgical pathology or symptom relief. These patients may benefit from being treated as a single group rather than as separate entities. Elevated and decreased GBEF groups demonstrated mostly normal ultrasound results that raised concern for the utility of ultrasound as a rule out test for gallbladder inflammation.

Double and single mixed-lineage leukemia-rearranged subclones in pediatric acute myeloid leukemia: a case report.

BACKGROUND: Acute myeloid leukemia (AML) is a disease with a significant amount of cytogenetic heterogeneity including mixed-lineage leukemia (MLL) gene rearrangements. Pediatric AML commonly has genetic rearrangements which involve chromosome 11q23 in 15-20% of cases, and these genetic abnormalities have been associated with a poorer prognosis (Grimwade et al. in Blood 92:2322-2333, 1998; Raimondi et al. in Blood 94:3707-3716, 1999; Lie et al. in Br J Haematol 122: 217-225). MLL rearrangements in AML have been shown to have multiple different fusion partners (Meyer et al. in Leukemia 23:1490-1499). Heterogeneity of these cytogenetic abnormalities makes it difficult to determine how to approach patients from a treatment standpoint. This difficulty is further complicated when patients have more than a single MLL rearrangement. CASE PRESENTATION: A 10-year-old Caucasian girl presented with easy bruising and was found to have acute myeloid leukemia. Her cytogenetics showed two different MLL rearrangements, t(9;11)(p22;q23) and t(11;19)(q23;p13.3). At initial presentation she had no other cytogenetic findings. She responded well to initial therapy and achieved remission following the first induction cycle and completed four rounds of chemotherapy. She subsequently had a relapse of her AML, and her cytogenetics were consistent with a single MLL rearrangement, t(9;11)(p22;q23), in addition to monosomy 7. She was treated with reduction therapy and a haplo-identical bone marrow transplant but ultimately succumbed to her disease. CONCLUSION: MLL rearrangements are common in AML, but clinical significance continues to be elusive, and there is conflicting data on the prognostic significance. In the setting of multiple MLL rearrangements, there is concern for reduced survival, although treatment modifications are not currently done in this setting. This report details a case with multiple MLL rearrangements that initially responded to therapy but ultimately had disease progression with a selection of a leukemic clone containing a single MLL rearrangement.