A pilot study of aquatic prehabilitation in adults with knee osteoarthritis undergoing total knee arthroplasty - short term outcome.

BACKGROUND: Knee osteoarthritis (KOA) is increasingly more prevalent and significant number of patients require knee arthroplasty. Although knee arthroplasty is generally successful, it takes months to recover physical function. Preoperative physical function is known to predict postoperative outcomes and exercise can improve preoperative physical function. However, patients with KOA have difficulty exercise on land due to pain and stiffness, while water exercise can be better tolerated. We hypothesized that preoperative water exercise to improve preoperative physical function will improve postoperative outcomes after total knee arthroplasty (TKA). METHODS: We enrolled 43 participants who were scheduled for elective TKA in 4-8 weeks and scored at or below 50th percentile in mobility assessment tool-sf (MAT-sf). All enrolled participants were assessed on 1) clinical osteoarthritis symptom severity using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 2) physical function using Short Physical Performance Battery (SPPB), 3) self-reported mobility using Mobility Assessment Tool-short form (MAT-sf), 4) depression using Geriatric Depression Scale-short form (GDS-sf), 5) cognitive function using Montreal Cognitive Assessment (MoCA). Blood samples for high-sensitivity-C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were stored at - 80 °C then all samples were analyzed together. All the enrolled participants were randomly assigned to the aquatic exercise intervention (AEI) or usual care group. Sixty minute sessions of AEI was conducted three times a week for 4-8 weeks. Participants in both groups were evaluated within 1 week before their scheduled surgery, as well as 4 weeks after the surgery. RESULTS: The mean age was 67.1 (±6.2), 44% were female, 74% were White. There is no statistically significant difference in combined outcome of any complication, unscheduled ER visit, and disposition to nursing home or rehab facility by AEI. However, AEI was associated with more favorable outcomes: WOMAC scores (p < 0.01), chair-stand (p = 0.019), MAT-sf as well as improved depression (p = 0.043) and cognition (p = 0.008). CONCLUSION: 4-8 weeks of aquatic exercise intervention resulted in improved functional outcomes as well as improved depression and cognition in elderly patients undergoing TKA. A larger study is warranted to explore the role of water exercise in clinical and functional outcomes of TKA.

PENETRATING OCULAR INJURY WITH RETAINED INTRAOCULAR FOREIGN BODY FROM DRYWALL.

PURPOSE: To present a case of open globe injury and retained intraocular foreign body secondary to drywall. METHODS: Interventional case report. RESULTS: A 21-year-old man presented with corneal laceration, iris defect, and vitreous hemorrhage after hammering drywall. Computed tomography scan was negative for intraocular foreign body, but a drywall intraretinal foreign body was found on 25-gauge vitrectomy. Intraoperative findings and 6-month follow-up are presented. CONCLUSION: Intraocular foreign body must always be suspected in all cases of penetrating ocular trauma. Although magnetic resonance imaging is ideal in diagnosing nonmetallic foreign bodies, computed tomography scan with Hounsfield units should be used in an emergency setting.

Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations.

Intestinal barrier dysfunction is hypothesized to be a contributing determinant of two prominent characteristics of aging: inflammation and decline in physical function. A relationship between microbial translocation (MT), or their biomarkers (lipopolysaccharide binding protein-1 [LBP-1], soluble cluster of differentiation [sCD]-14), and physical function has been reported in healthy older adults, rats, and invertebrates. However, it is not known whether the existence of comorbidities, or clinical interventions intended to reduce comorbidities through weight loss or exercise, alters this connection. We measured inflammation, MT, and physical function in 288 overweight/obese older patients with cardiometabolic disease and self-reported mobility limitations who were enrolled in a weight loss and lifestyle intervention study. At baseline, inflammatory cytokines and LBP-1 were positively correlated after adjustment for age, gender, and body mass index. A higher LBP-1 was significantly associated with poorer physical functional after covariate adjustment. Further, even when IL-6 levels were included in the models, 400-m walk time (p = 0.003), short physical performance battery (p = 0.07), and IL-8 (p < 0.001) remained positively associated with LBP-1. Lifestyle interventions improved body mass and some functional measures; however, MT and inflammation were unchanged. MT is reliably related to inflammation, and to poorer physical function in older adults with comorbid conditions. Intestinal barrier function did not appear to improve as a result of intervention assignment, suggesting alternative strategies are needed to target this pro-inflammatory pathway in aging.

Self-reported mobility as a preoperative risk assessment tool in older surgical patients compared to the American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP®) developed a surgical risk calculator using data from 1.4 million patients and including 1557 unique Current Procedural Terminology (CPT) codes. Although this calculator demonstrated excellent performance in predicting postoperative mortality, morbidity, and six surgical complications, it was not developed specifically for use in older surgical patients who have worse surgical outcomes and additional unique risk factors compared to younger adults. We aimed to test the ability of a simple self-reported mobility tool to predict postoperative outcomes in the older surgical population compared to the NSQIP. METHODS: We used data from a prospective cohort study that enrolled 197 older surgical patients (≥ 69 years) undergoing various elective surgeries and assessed 30-day surgical outcomes. Statistical models included data from the Mobility Assessment Tool-short form (MAT-sf) alone, covariates alone, and MAT-sf data and covariates. We used leave-one-out (LOO) cross-validation of the models within our cohort and compared their performance for predicting postoperative outcomes against the NSQIP calculator based on receiver operating characteristic area under the curve (ROC AUC). RESULTS: Patients with poor self-reported mobility experienced higher rates of postoperative complications and nursing home placement. There was no difference in performance between any of our models and the NSQIP calculator (p > 0.1), with AUC between 0.604 and 0.697 for predicting postoperative complications and 0.653 and 0.760 for predicting nursing home placement. All models also predicted a length of stay (LOS) similar to the actual LOS. CONCLUSION: Mobility assessment alone using MAT-sf can predict postoperative complications, nursing home placement, and LOS for older surgical patients, with accuracy comparable to that of the NSQIP calculator. The simplicity of this noninvasive risk assessment tool makes it an attractive alternative to the NSQIP calculator that requires 20 patient predictors and the planned procedure, or CPT code to predict the chance that patients will have 15 different adverse outcomes following surgery.

Self- vs proxy-reported mobility using the mobility assessment tool-short form in elderly preoperative patients.

BACKGROUND: Mobility is fundamental to maintenance of an independent lifestyle and can predict clinical outcomes after health events among older individuals. However, certain clinical situations do not accommodate physical or self-assessments. This investigation examines whether proxy-reported assessments of function using the Mobility Assessment Tool-short (MAT-sf) form is a reliable alternative. METHODS: Sixty-six older persons (≥ age 70) and their proxies were enrolled. Proxies rated patients' mobility using the MAT-sf as did the patients. RESULTS: The mean age of patients was 78.4 yr. (±6.2); 44% were female and 86% were white. Spouses made up 55% of the proxies, while 39% were children/in-laws. The correlation coefficient between patient and proxy MAT-sf scores was 0.81 (p < 0.01); a comparison of the slope of the regression line relating patient- and proxy-reported MAT-sf to a line of identity showed disagreement (p < 0.01), with proxy reports underreporting patient responses by 8.3% in lower mobility patients. The intra-class correlation characterizing agreement between repeated proxy reports 0.81. CONCLUSION: Proxy reports of mobility in older patients have good reliability. However, in patients with poor mobility, the proxies tend to report a lower mobility than the patients.

EX VIVO MODEL FOR THE CHARACTERIZATION AND IDENTIFICATION OF DRYWALL INTRAOCULAR FOREIGN BODIES ON COMPUTED TOMOGRAPHY.

BACKGROUND: The study was inspired after the authors encountered a patient with a penetrating globe injury due to drywall, who had retained intraocular drywall foreign body. Computed tomography (CT) was read as normal in this patient. Open globe injury with drywall has never been reported previously in the literature and there are no previous studies describing its radiographic features. METHODS: The case report is described in detail elsewhere. This was an experimental study. An ex vivo model of 15 porcine eyes with 1 mm to 5 mm fragments of implanted drywall, 2 vitreous only samples with drywall and 3 control eyes were used. Eyes and vitreous samples were CT scanned on Days 0, 1, and 3 postimplantation. Computed ocular images were analyzed by masked observers. Size and radiodensity of intraocular drywall were measured using Hounsfield units (HUs) over time. RESULTS: Intraocular drywall was hyperdense on CT. All sizes studied were detectable on Day 0 of scanning. Mean intraocular drywall foreign body density was 171 ± 52 Hounsfield units (70-237) depending on fragment size. Intraocular drywall foreign body decreased in size whereas Hounsfield unit intensity increased over time. CONCLUSION: Drywall dissolves in the eye and becomes denser over time as air in the drywall is replaced by fluid. This study identified Hounsfield Units specific to intraocular drywall foreign body over time.

Hypoalbuminemia and Clinical Outcomes: What is the Mechanism behind the Relationship?

Albumin has a number of important physiologic functions, which include maintaining oncotic pressure, transporting various agents (fatty acids, bile acids, cholesterol, metal ions, and drugs), scavenging free oxygen radicals, acting as an antioxidant, and exerting an antiplatelet effect. Hypoalbuminemia in adults, defined by an intravascular albumin level of <3.5 g/dL, is associated with poor postoperative outcomes in patients undergoing surgical intervention. Although the relationship of hypoalbuminemia and poor surgical outcome has been known for many years, the pathophysiology behind the relationship is unclear. Three theoretical constructs might explain this relationship. First, albumin might serve as a nutritional marker, such that hypoalbuminemia represents poor nutritional status in patients who go on to experience poor postoperative outcomes. Second, albumin has its own pharmacologic characteristics as an antioxidant or transporter, and therefore, the lack of albumin might result in a deficiency of those functions, resulting in poor postoperative outcomes. Or third, albumin is known to be a negative acute phase protein, and as such hypoalbuminemia might represent an increased inflammatory status of the patient, potentially leading to poor outcomes. A thorough review of the literature reveals the fallacy of these arguments and fails to show a direct cause and effect between low albumin levels per se and adverse outcomes. Interventions designed solely to correct preoperative hypoalbuminemia, in particular intravenous albumin infusion, do little to change the patient's course of hospitalization. While surgeons may use albumin levels on admission for their prognostic value, they should avoid therapeutic strategies whose main endpoint is correction of this abnormality.

Body Composition and Physical Function in Older Adults with Various Comorbidities.

BACKGROUND: Lower muscle and higher fat mass are characteristics of older adults; their physical function is also characterized by slower gait speed and weaker strength. However, the association between specific body composition and physical function is unclear. METHODS: We examined the association between body composition and physical performance using combined cross-sectional data of 1,821 participants from 13 clinical studies at Wake Forest University that used a consistent battery of tests. All participants were ≥60 years old and had one of the following conditions: healthy, osteoarthritis, coronary artery disease, obesity, heart failure, at elevated risk for disability, renal transplantation candidates, heart failure with preserved ejection fraction, moderate self-reported disability, hypertension, diabetes, or coronary artery disease, at high risk for cardiovascular disease. Data at enrollment from each study using uniform tools including body mass index (BMI), dual energy x-ray absorptiometry, physical performance assessment using 4 m walk speed, five chair rise time, handgrip strength, short physical performance battery (17), and Pepper Assessment Tool for Disability were analyzed. RESULTS: Increased BMI was associated with slower walk speed, lower short physical performance battery, and higher Pepper Assessment Tool for Disability score. Increased percentage of body fat was associated with slower walk speed, lower hand grip strength, lower short physical performance battery scores, and higher Pepper Assessment Tool for Disability scores. Percent appendicular lean mass was associated with faster walk speed, higher handgrip strength, higher short physical performance battery, and lower Pepper Assessment Tool for Disability score. There were no significant discrepancies in relationship between body composition and physical function by gender except gender and BMI on chair-rise time. CONCLUSIONS: Higher BMI and percent body fat were associated with poor physical function while percent appendicular lean mass was associated with better physical function. There was no significant discrepancy in the by gender.

Patient-Reported Outcome Measures (PROM) as A Preoperative Assessment Tool.

AIM OF REVIEW: Patient-reported outcomes (PRO) on functional, social, and behavioral factors might be important preoperative predictors of postoperative outcomes. We conducted a literature review to explore associations of preoperative depression, socioeconomic status, social support, functional status/frailty, cognitive status, self-management skills, health literacy, and nutritional status with surgical outcomes. METHODS: Two electronic data bases, including PubMed and Google Scholar, were searched linking either depression, socioeconomic status, social support, functional status/frailty, cognitive status, self-management skills, health literacy, or nutritional status with surgery, postoperative complications, or perioperative period within the past 2 decades. RECENT FINDINGS: Preoperative depression has been linked to postoperative delirium, complications, persistent pain, longer lengths of stay, and mortality. Socioeconomic status associates with overall and cancer-free survival. Low socioeconomic status has also been connected to medication non- compliance. Social support can predict overall and cancer- free survival, as well as physical, social and emotional quality of life. Poor functional status and frailty have been related to postoperative complications, longer lengths of stay, post-discharge institutionalization, and higher costs. Preoperative cognitive impairment also associates with self-medication management errors, postoperative cognitive impairment, delirium, complications and mortality. In addition, a greater tendency for reduced adherence to preoperative medication instructions has been linked to health illiteracy. Preoperative malnutrition is prevalent and associates with postoperative morbidity. CONCLUSION: Efficient and effective assessments of social and behavioral determinants of health, functional status, health literacy, patient's perception of health, and preferences for self-management may improve postoperative management and surgical outcomes, particularly among vulnerable patients undergoing elective surgery who might have subtle physical, social, or psychological deficits or challenges, otherwise missed upon routine evaluation. Patient Reported Outcome Measures (PROMs) can be used to effectively and efficiently collect these factors in the preoperative period, thereby identifying areas that can be intervened preemptively. (Partially Funded by the National Institute on Aging and the Wake Forest University Claude D. Pepper Older Americans Independence Center.).

Development and Implementation of a Tool to Assess Patient-Reported Outcome Measures (PROM) in Preoperative Setting.

INTRODUCTION: Traditional preoperative assessment tools use patients' comorbidities to predict surgical outcomes, however, some functional, social and behavioral factors are known to predict surgical outcomes. Capturing functional, social and behavioral factors by incorporating patient reported measures (PROMs) into preoperative practice may be responsive to perioperative management and contribute to improved outcomes. METHODS: We developed a preoperative PROM tool to identify functional, social, and behavioral factors. We describe the development and implementation of the tool as a health system quality initiative. We also report the results of the PROMs among preoperative surgical patients. RESULTS: In our survey of 162 patients with mean age of 65, 53% were female, 29% were undergoing orthopedic surgery 12% were undergoing urologic surgery. 56% of the patients had at least one or more deficits in social or functional domain. The most common deficit was with ADLs with higher rate of deficit with advanced age. CONCLUSION: Implementation of a systematic assessment of functional and social determinants to improve processes of care in the preoperative setting is feasible. The majority of preoperative patients had at least one deficit and if identified preoperatively, appropriate interventions can be offered through well-designed intervention algorithms.

Sustained Benefits of Exercise-based Motivational Interviewing, but Only among Nonusers of Opioids in Patients with Fibromyalgia.

OBJECTIVE: Given the known side effects of opioids and their potential effects on cognition, we sought to evaluate the benefits of motivational interviewing (MI) to promote physical activity on 2 subsets of participants with fibromyalgia (FM): nonusers and users of opioids. METHODS: This was a secondary data analysis of a 36-week randomized controlled trial to assess the efficacy of MI to promote physical activity among participants with FM. Participants were randomized to 1 of 2 treatment arms: 6 phone-based MI sessions (n = 107) or 6 sessions of FM self-management instructions [attention control (AC), n = 109]. The primary outcomes were changes in physical function (Medical Outcomes Study Short Form-36), pain severity (Brief Pain Inventory), global FM symptom severity (Fibromyalgia Impact Questionnaire), and the amount of light to moderate physical activity (LMPA) from baseline to each followup visit. At study entry, subjects were categorized as opioid nonusers versus users. Repeated measures ANOVA was used to assess treatment effects adjusting for potential confounders. RESULTS: Of the 216 participants, 145 (67%) were nonusers and 71 (33%) were opioid users. Among nonusers, MI was associated with improved physical function, reduced pain severity, and global FM severity, and increased LMPA at 6-month followup. Among opioid users, there were no significant differences in any outcome measures between the MI and AC groups. CONCLUSION: Exercise-based MI was associated with sustained clinical benefits 6 months after completion of therapy, but only for those who were not taking opioids.

Self-reported Mobility in Older Patients Predicts Early Postoperative Outcomes after Elective Noncardiac Surgery.

BACKGROUND: Specific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery. METHODS: Patients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool-short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP). RESULTS: In the sample of this study (mean age, 75 ± 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge. CONCLUSIONS: Preoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events.

Early Enteral Feeding After Living Donor Liver Transplantation Prevents Infectious Complications: A Prospective Pilot Study.

Infectious complications, including bacteria, virus, and fungus, often occur after liver transplantation and are the most frequent causes of in-hospital mortality. The current study prospectively analyze the effect of early enteral feeding in patients after living donor liver transplantation (LDLT)Between January 2013 and August 2013, 36 patients underwent LDLT. These patients were randomly assigned to receive enteral formula via nasointestinal feeding tubes [enteral feeding (EN) group, n = 17] or maintenance on intravenous fluid until oral diets were initiated (control group, n = 19). All patients completed the study.The pretransplant and perioperative characteristics of patients did not differ between the 2 groups. The incidence of bacterial infection was significantly lower in the EN group (29.4%) than in the control group (63.2%) (P = 0.043). In addition, the incidence of bile duct complications in the EN group was lower than in the control group (5.9% versus 31.6%, P = 0.041). Multivariate analysis showed that early enteral feeding was closely associated with bacterial infections (odds ratio, 0.178; P = 0.041). There was no statistically significant difference in nutritional status between the 2 groups. There were no cases of in-hospital mortality.Early enteral feeding after LDLT prevents posttransplant bacterial infection, suggesting the possibility of a reduction of in-hospital mortality as a result of decreased infectious complications.

Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection.

IFN regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays a critical role in the functional maturation of microglia cells. It is induced in T cells following Ag stimulation, but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation, and IL-17 production is markedly increased in IRF8-deficient T cells. Paradoxically, loss of IRF8 in T cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE), although exacerbating colitis in a mouse colitis model. In contrast, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells, including microglial cells and a third mouse strain with targeted Irf8 deletion in T cells under direction of the nonpromiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in T regulatory cells. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise a cautionary note in the context of therapeutic targeting of IRF8.

Preoperative assessment of the older surgical patient: honing in on geriatric syndromes.

Nearly 50% of Americans will have an operation after the age of 65 years. Traditional preoperative anesthesia consultations capture only some of the information needed to identify older patients (defined as ≥65 years of age) undergoing elective surgery who are at increased risk for postoperative complications, prolonged hospital stays, and delayed or hampered functional recovery. As a catalyst to this review, we compared traditional risk scores (eg, cardiac-focused) to geriatric-specific risk measures from two older female patients seen in our preoperative clinic who were scheduled for elective, robotic-assisted hysterectomies. Despite having a lower cardiac risk index and Charlson comorbidity score, the younger of the two patients presented with more subtle negative geriatric-specific risk predictors - including intermediate or pre-frail status, borderline malnutrition, and reduced functional/mobility - which may have contributed to her 1-day-longer length of stay and need for readmission. Adequate screening of physiologic and cognitive reserves in older patients scheduled for surgery could identify at-risk, vulnerable elders and enable proactive perioperative management strategies (eg, strength, balance, and mobility prehabilitation) to reduce adverse postoperative outcomes and readmissions. Here, we describe our initial two cases and review the stress response to surgery and the impact of advanced age on this response as well as preoperative geriatric assessments, including frailty, nutrition, physical function, cognition, and mood state tests that may better predict postoperative outcomes in older adults. A brief overview of the literature on anesthetic techniques that may influence geriatric-related syndromes is also presented.

Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rß2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rß2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.

Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor α (ERα), its involvement in the epigenetic control of transcription of the ERα gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERα in ERα-positive cells but increased it in ERα-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2γ (TFAP2C) and the IFN-γ-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERα mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERα. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERα. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that the MTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer.

SOCS3 deletion in T lymphocytes suppresses development of chronic ocular inflammation via upregulation of CTLA-4 and expansion of regulatory T cells.

Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of the JAK/STAT pathway, and SOCS3 contributes to host immunity by regulating the intensity and duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3 signaling, expansion of Th1 and Th17 cells, and develop severe experimental autoimmune encephalomyelitis. Interestingly, development of the unique IL-17/IFN-γ double-producing (Th17/IFN-γ and Tc17/IFN-γ) subsets that exhibit strong cytotoxic activities and are associated with pathogenesis of several autoimmune diseases has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in the CD4 T cell compartment (CD4-SOCS3 knockout [KO]) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of experimental autoimmune encephalomyelitis in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA-4 and expansion of IL-10-producing regulatory T cells with augmented suppressive activities. We further show that SOCS3 interacts with CTLA-4 and negatively regulates CTLA-4 levels in T cells, providing a mechanistic explanation for the expansion of regulatory T cells in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-γ and Tc17/IFN-γ populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of the Th17/IFN-γ subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other autoinflammatory diseases.

A heparin-mimicking polymer conjugate stabilizes basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is a protein that plays a crucial role in diverse cellular functions, from wound healing to bone regeneration. However, a major obstacle to the widespread application of bFGF is its inherent instability during storage and delivery. Here, we describe the stabilization of bFGF by covalent conjugation with a heparin-mimicking polymer, a copolymer consisting of styrene sulfonate units and methyl methacrylate units bearing poly(ethylene glycol) side chains. The bFGF conjugate of this polymer retained bioactivity after synthesis and was stable to a variety of environmentally and therapeutically relevant stressors--such as heat, mild and harsh acidic conditions, storage and proteolytic degradation--unlike native bFGF. Following the application of stress, the conjugate was also significantly more active than the control conjugate system in which the styrene sulfonate units were omitted from the polymer structure. This research has important implications for the clinical use of bFGF and for the stabilization of heparin-binding growth factors in general.

Interleukin 27 induces the expression of complement factor H (CFH) in the retina.

Complement factor H (CFH) is a central regulator of the complement system and has been implicated in the etiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. In view of previous studies showing that reduced expression of CFH in the retina is a risk factor for developing AMD, there is significant interest in understanding how CFH expression is regulated in the retina. In this study, we have shown that the anti-inflammatory cytokine, IL-27, induced CFH expression in mouse retinal cells and human retinal pigmented epithelial cells (RPE) through STAT1-mediated up-regulation of Interferon Regulatory Factor-1 (IRF-1) and IRF-8. We further show that cells in the ganglion and inner-nuclear layers of the retina constitutively express IRF-1 and IRF-8 and enhanced CFH expression in the retina during ocular inflammation correlated with significant increase in the expression of IRF-1, IRF-8 and IL-27 (IL-27p28 and Ebi3). Our data thus reveal a novel role of IL-27 in regulating complement activation through up-regulation of CFH and suggest that defects in IL-27 signaling or expression may contribute to the reduction of CFH expression in the retina of patients with AMD.