scholarly journals Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4694-4698 ◽  
Author(s):  
P. K. Epling-Burnette ◽  
Lubomir Sokol ◽  
Xianhong Chen ◽  
Fanqi Bai ◽  
Junmin Zhou ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Clinical Manifestations ◽  
Erythroid Differentiation ◽  
Pulmonary Artery Hypertension ◽  
Large Granular Lymphocyte ◽  
Receptor Signaling ◽  
Pulmonary Endothelial Cells ◽  
First Case ◽  
Nk Receptor ◽  
Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.

scholarly journals A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3226-3234 ◽  
Author(s):  
Xianghong Chen ◽  
Fanqi Bai ◽  
Lubomir Sokol ◽  
Junmin Zhou ◽  
Amy Ren ◽  
...  
Keyword(s):  
T Cells ◽  
Pulmonary Artery ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Pulmonary Artery Hypertension ◽  
Dominant Negative ◽  
Large Granular Lymphocyte ◽  
Ligand Interactions ◽  
First Results ◽  
Natural Killer Receptors

Abstract Large granular lymphocyte (LGL) leukemia, or LGLL, is characterized by increased numbers of circulating clonal LGL cells in association with neutropenia, anemia, rheumatoid arthritis, and pulmonary artery hypertension (PAH). Emerging evidence suggests that LGLL cells with a CD8+CD28null phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared with CD8+CD28null T cells from healthy controls, CD8+CD28null T cells from LGLL patients have acquired the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. Here, we show that LGLL cells from patients possess enhanced cytotoxic characteristics and express elevated levels of activating natural killer receptors as well as their signaling partners, DAP10 and DAP12. Moreover, downstream targets of DAP10 and DAP12 are constitutively activated in LGLL cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. These are the first results to show that activating NKR-ligand interactions play a critical role in initiating the DAP10 and DAP12 signaling events that lead to enhanced lytic potential of LGLL cells. Results shown suggest that inhibitors of DAP10 and DAP12 or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of LGLL and other autoimmune diseases and syndromes.

scholarly journals Hospital Outcomes of Surgical Closure of Patent Ductus Arteriosus: 19 Years Experience at Shahid Gangalal National Heart Center

2020 ◽  
Vol 18 (2) ◽  
pp. 30-35
Author(s):  
R. Koirala ◽  
N. Panthee ◽  
S. Pradhan ◽  
N. Rajbhandari ◽  
D.K. Shrestha ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Patent Ductus Arteriosus ◽  
Ductus Arteriosus ◽  
Main Pulmonary Artery ◽  
Pulmonary Artery Hypertension ◽  
Hospital Outcomes ◽  
Descending Aorta ◽  
Surgical Closure ◽  
First Case ◽  
Patent Ductus

Background Ductus arteriosus is a vascular structure which connects the roof of main pulmonary artery near the origin of the left branch pulmonary artery to the proximal descending aorta. Patent ductus arteriosus (PDA) closure is indicated for any patient who is symptomatic from left to right shunting. Objective To investigate the hospital outcomes of surgical closure of patent ductus arteriosus over last 19 years starting from the very first case of our center. Method This is a retrospective analysis of all patent ductus arteriosus treated surgically from August 2001 to July 2019. Patients who underwent isolated surgical closure of patent ductus arteriosus were included. Data have been presented in three different eras (Era 1: 2001-2007, Era 2: 2008-2013, and Era 3: 2014-2019) to see the trend of evolution of this surgery. Result A total of 901 patients aged 8.67±8.76 years under went patent ductus arteriosus surgical closure over last 19 years. Patients in the initial era 2001-2007 were significantly older compared with other 2 eras (p=0.000). Males accounted for 35.5% of all cases. Twenty percent had severe pulmonary artery hypertension. Duration of mechanical ventilation was 3.57±9.64 hours with ICU stay of 1.55±1.53 days, and hospital stay of 3.9±2.3 days. Overall in hospital mortality was 0.8%; for isolated patent ductus arteriosus diagnosis, mortality was 0.2%. Chylothorax was noted in 0.4%. Conclusion This is the first report to analyze surgical outcomes of patent ductus arteriosus ligation in our center. We have discussed the evolution of patent ductus arteriosus surgery in our center, and have shown favorable outcomes in terms of morbidity and mortality.

scholarly journals Association between RNF213 c.14576G>A Variant (rs112735431) and Peripheral Pulmonary Artery Stenosis in Moyamoya Disease

2021 ◽  
pp. 1-6
Author(s):  
Dan Ozaki ◽  
Hidenori Endo ◽  
Ryosuke Tashiro ◽  
Koichiro Sugimura ◽  
Shunsuke Tatebe ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Moyamoya Disease ◽  
Clinical Manifestations ◽  
Pulmonary Artery Hypertension ◽  
Artery Stenosis ◽  
Vascular Lesions ◽  
Pulmonary Artery Stenosis ◽  
Surgical Indications ◽  
Retrospective Case ◽  
Predisposing Factor

<b><i>Background:</i></b> Moyamoya disease (MMD) and peripheral pulmonary artery stenosis (PPAS) are relatively rare and demonstrate steno-occlusive vascular lesions in different organs. Genetic studies identified <i>RNF213</i> polymorphism c.14576G&#x3e;A (rs112735431) as a susceptibility variant for East Asian MMD. <i>RNF213</i> polymorphism c.14576G&#x3e;A is further associated with various vascular lesions of other organs. In this study, we aimed to clarify the incidence and clinical manifestations of PPAS in MMD patients and analyze the correlation between <i>RNF213</i> genotype and PPAS. <b><i>Methods:</i></b> This retrospective case-control study investigated the association between <i>RNF213</i> polymorphism and PPAS in 306 MMD/quasi-MMD patients, reviewing the medical charts and imaging records of consecutive patients with MMD admitted from January 2015 to December 2020. <b><i>Results:</i></b> PPAS was observed in 3 MMD/quasi-MMD patients (0.98%, 3/306). <i>RNF213</i> polymorphism c.14576G&#x3e;A was determined for all 306 MMD/quasi-MMD patients. The incidence of PPAS in <i>RNF213</i>-wildtype, <i>RNF213</i>-heterozygote, and <i>RNF213</i>-homozygote MMD/quasi-MMD patients was 0% (0/101), 0.5% (1/200), and 40% (2/5), respectively. The association between PPAS and homozygote polymorphism of <i>RNF213</i> c.14576G&#x3e;A was statistically significant in MMD/quasi-MMD patients (<i>p</i> = 0.0018). In all cases, pulmonary artery hypertension due to PPAS was evident during their childhood and young adolescent stages. Surgical indications for MMD were discouraged in 1 case due to her severe cardiopulmonary dysfunction. <b><i>Conclusions:</i></b> The homozygote variant of <i>RNF213</i> polymorphism c.14576G&#x3e;A can be a potential predisposing factor for PPAS in MMD/quasi-MMD patients. Despite the relatively rare entity, PPAS should be noted to determine surgical indications for MMD/quasi-MMD patients.

scholarly journals Upbeat vertical nystagmus after brain stem cavernoma resection: a rare case of nucleus intercalatus/nucleus of roller injury

2020 ◽  
Vol 267 (10) ◽  
pp. 2865-2870
Author(s):  
Torstein R. Meling ◽  
Aria Nouri ◽  
Adrien May ◽  
Nils Guinand ◽  
Maria Isabel Vargas ◽  
...  
Keyword(s):  
Rare Case ◽  
Vascular Malformations ◽  
Clinical Manifestations ◽  
Neurological Injury ◽  
Medial Longitudinal Fasciculus ◽  
Blurred Vision ◽  
Complete Excision ◽  
First Case ◽  
Vertical Nystagmus ◽  
Upbeat Nystagmus

Abstract Introduction CNS cavernomas are a type of raspberry-shaped vascular malformations that are typically asymptomatic, but can result in haemorrhage, neurological injury, and seizures. Here, we present a rare case of a brainstem cavernoma that was surgically resected whereafter an upbeat nystagmus presented postoperatively. Case report A 42-year old man presented with sudden-onset nausea, vomiting, vertigo, blurred vision, marked imbalance and difficulty swallowing. Neurological evaluation showed bilateral ataxia, generalized hyperreflexia with left-sided predominance, predominantly horizontal gaze evoked nystagmus on right and left gaze, slight left labial asymmetry, uvula deviation to the right, and tongue deviation to the left. MRI demonstrated a 13-mm cavernoma with haemorrhage and oedema in the medulla oblongata. Surgery was performed via a minimal-invasive, midline approach. Complete excision was confirmed on postoperative MRI. The patient recovered well and became almost neurologically intact. However, he complained of mainly vertical oscillopsia. The videonystagmography revealed a new-onset spontaneous upbeat nystagmus in all gaze directions, not suppressed by fixation. An injury of the rarely described intercalatus nucleus/nucleus of Roller is thought to be the cause. Conclusion Upbeat nystagmus can be related to several lesions of the brainstem, including the medial longitudinal fasciculus, the pons, and the dorsal medulla. To our knowledge, this is the first case of an iatrogenic lesion of the nucleus intercalatus/nucleus of Roller resulting in an upbeat vertical nystagmus. For neurologists, it is important to be aware of the function of this nucleus for assessment of clinical manifestations due to lesions within this region.

scholarly journals Facial cleft? The first case of manitoba‐oculo‐tricho‐anal syndrome with novel mutations in China: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuchen Gu ◽  
Yimin Khoong ◽  
Xin Huang ◽  
Tao Zan
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Manifestations ◽  
Sporadic Case ◽  
Facial Cleft ◽  
Ocular Manifestations ◽  
First Case ◽  
Whole Exome ◽  
Chinese Girl ◽  
Low Prevalence

Abstract Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing. Case presentation A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established. Conclusions We discovered the first sporadic case of MOTA syndrome according to clinical manifestations and genetic etiology in the Chinese population. We have identified 2 novel stop-gain mutations in FREM1 gene which further expands the spectrum of mutational seen in the MOTA syndrome. Further research should be conducted for better understanding of its mechanism, establishment of an accurate diagnosis, and eventually the exploitation of a more effective and comprehensive therapeutic intervention for MOTA syndrome.

scholarly journals 369. Clinical Characteristics of the First 177 Patients Admitted with COVID-19 at a Bronx Community Hospital

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S254-S254
Author(s):  
Victoria Bengualid ◽  
Maria Martinez ◽  
Zhenisa Hysenaj ◽  
Debra M Willner ◽  
Judith Berger
Keyword(s):  
Oxygen Saturation ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Gastrointestinal Symptoms ◽  
Retrospective Chart Review ◽  
Patient Characteristics ◽  
Altered Mental Status ◽  
Channel Blockers ◽  
First Case ◽  
Overall Mortality

Abstract Background The first case of COVID-19 was admitted on March 15th 2020 to our community based hospital in the Bronx, NY. The aim of this study is to describe the clinical characteristics and outcome of these first COVID-19 patients. Patient Characteristics and Outcome Methods IRB approved retrospective chart review study of all COVID-19 patients admitted during March 2020 focusing on patient characteristics, co-morbidities, clinical manifestations and outcome. Results A total of 177 patients were admitted during March 2020: 57% African American 23.1% Hispanic and 16.9% White. 44.9% female, average age 60 years, and 90% had at least one comorbidity. Outcome was available on all patients except for one who was transferred to another institution for ECMO. Overall mortality was 33%. Clinical presentation: 69.4% presented with cough or shortness of breath, 15.8% with diarrhea, nausea, vomiting or abdominal pain, and 14.6% with myalgia, dizziness or altered mental status. 6.2% presented only with fever. However 59.8% of patients presented with fever and respiratory or gastrointestinal symptoms. Mortality The table compares patients who died vs discharged (either home or to a short term facility). Those that were 65 years or older, hypertensive or presented to the ER with an oxygen saturation of 94% or lower, were more likely to die. Ventilated patients: 31.6% of patients were intubated with a mortality rate of 77%. 22% of these patients were intubated in the first 24 hours. Compared to non-intubated patients, there was no difference in BMI, diabetes, hypertension, COPD/Asthma, use of statins, aspirin or calcium channel blockers. Intubated patients older than 64 years had significantly higher mortality rates (p=0.0001). Conclusion This cohort of COVID-19 patients is unique as almost all received Hydroxychloroquine and Azithromycin. Only 9% received steroids and even fewer received an interleukin-6 inhibitor, convalescent plasma or Remdesivir. African Americans and Hispanics accounted for 80% of patients. Greater than 90% received Medicaid. Overall mortality was 33%. The most common presentation was respiratory followed by gastrointestinal symptoms. The overall mortality was 33% but increased to 77% in intubated patients. Age, hypertension, and ER oxygen saturation correlated with mortality. Disclosures All Authors: No reported disclosures

scholarly journals The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

2021 ◽  
Vol 22 (9) ◽  
pp. 4980
Author(s):  
Inés Roger ◽  
Javier Milara ◽  
Paula Montero ◽  
Julio Cortijo
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Clinical Manifestations ◽  
Different Types ◽  
Artery Remodeling ◽  
Stat Pathway ◽  
Pulmonary Artery Remodeling

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

Sign in / Sign up

Export Citation Format

Share Document