Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017–6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21lo/neg cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p = 0.002) or healthy controls (5.0 ± 0.5%, p < 0.0001). While CD21lo/neg B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21lo/neg cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21lo/neg B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.
Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas. 相似文献
BACKGROUND: Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD. METHODS: We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant. RESULTS: The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984). CONCLUSIONS: Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients. 相似文献
Idiopathic membranous nephropathy has been reported rarely to develop in genetic association with certain HLA antigens. This paper describes two male siblings presenting with nephrotic syndrome with histologically proven membranous nephropathy. The younger brother maintained a normal renal function with slight proteinuria during the 3 years of follow-up, but the older one experienced a rapid decline in renal function and had to be put on maintenance hemodialysis. No clinical evidence of contributory underlying disease such as malignancy or systemic lupus erythematosus could be found. HLA typing was carried out in the two patients and in members of their family. Several HLA antigens were found to be shared by the two patients. However, the HLA antigens which have been reported to be associated with idiopathic membranous nephropathy were not found in either of them. 相似文献
A patient-centered paradigm for clinical research and medical care is presented as a solution to the problem of declining
innovation and increasing costs and development time in the pipeline for new therapies. Fundamental differences in values
and motivations among scientists, clinicians, industry sponsor, and patients in neurotherapeutics provide a framework for
analysis of ethical conflicts and the loss of public confidence in medical research. Parkinson advocates’ views on clinical
trial participation, perceived risks and benefits, placebo controls, and sham surgery are presented. These views reflect the
sense of urgency and the unique perspective that comes from living with this progressive, debilitating condition full time.
A patient-centered paradigm that includes authentic voices of patients as collaborators at every stage of development will
help to resolve conflicts, build trust, recruit trial participants, and accelerate new therapies. Key elements are adaptive
clinical trial methods and the development of information technology for the assessment of outcomes and surveillance of safety
over the life cycle of a medical product. Supported by the Parkinson’s Disease Foundation, the Parkinson Pipeline Project
is a grassroots group of Parkinson’s patients whose goal is to represent an authentic voice for patients in the treatment
development process. This group promotes education and communication between members of the Parkinson’s community and active
stakeholders in medical research, industry, and regulatory agencies. Its members are an example of a new breed of knowledgeable
consumers, armed with first-hand access to research findings and reinforced by on-line connections to like-minded peers throughout
the world. 相似文献
BACKGROUND: Studies evaluating the relationship between smoking and cancer spread are limited. METHODS: We studied the relationship between cancer stage at diagnosis (local, regional, or metastatic) and smoking history (current, previous, or nonsmoker). For lung cancer, patterns of spread were also studied. RESULTS: In a tumor registry for eastern North Dakota, northwestern Minnesota, and northern South Dakota, 11,716 cases were identified from 1986 to 2001. Current smokers (relative risk [RR], 2.11; 95% confidence interval, 1.93 to 2.32; P <.001) and previous smokers (RR, 1.56; 95% confidence interval, 1.42 to 1.72; P <.001) had an increased risk of metastatic disease at diagnosis. Current smokers (RR, 1.39; 95% confidence interval, 1.29 to 1.51; P <.001), but not previous smokers, also had an increased risk of regional disease. An increase in metastatic disease was most evident for prostate cancer (RR, 1.53; P =.003). An increase in regional disease was most evident for head and neck (RR, 3.53; P <.001), prostate (RR, 1.83; P =.030), and breast cancer (RR, 1.22; P =.005). Compared with previous smokers, current smokers with metastatic lung cancer were more likely to have involvement of the brain (33.6% v 23.0%; P =.004), bone marrow, adrenal gland, and pericardium (24.7% v 15.9%; P =.004). CONCLUSION: Previous or current smoking is a risk factor for increased cancer stage in a wide range of malignancies. Further study is required to determine whether this association is causal. 相似文献
Influenza A was cultured in 62 double rooms. The roommate was infected in 12 (19.4%). During 3,294 resident-seasons, influenza was cultured in 208 single rooms (6.3%). Those who lived in double rooms with a culture-positive roommate had a 3.07 relative risk (CI95, 1.61-5.78) of acquiring influenza. 相似文献
Sickle cell disease (SCD) is a genetic disorder that is most prevalent among those of African American and Mediterranean descent. Hemoglobin SS is the most severe form of SCD and carries an increased risk for stroke. Although the initial treatment for stroke is an exchange transfusion, the use of routine, chronic transfusion therapy (CTT) has been shown to help prevent this neurological injury. The treatment plan is rigorous and time consuming, both of which impact one's quality of life (QoL). The purpose of this study was to explore QoL, from the child's perspective, as it is affected by CTT Semistructured interviews were performed on 10 children undergoing CIT: Five themes emerged from the data: (a) pain, (b) school issues, (c) disease knowledge, (d) transfusion therapy, and (e) having a stroke. Data from this study reveal that CTT does have an impact on QoL. This information is important to share with those making CTT treatment decisions. 相似文献
In this study, ethnographic interviews were used to identify first-time fathers' experiences of the birth of their first child. Fourteen fathers were interviewed, and prenatal expectations of the experience are compared with the fathers' perceptions after the birth. Although the fathers expected to be treated as part of a laboring couple, they found that they were relegated to a supporting role. Initially the fathers were confident of their ability to support their wives, but they found that labor was more work than they had anticipated. They became fearful of the outcome, but hid these fears from their partners. Later, they found that their focus moved from their wives to their babies at the time of birth. The men all completed the experience with an enhanced respect for their wives. Fathers should be included in labor management plans and need support for their role as coach, particularly when their wives experience pain. They also need to be encouraged to eat and take a break from their wives' labor when appropriate. 相似文献