Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts.

Chronic kidney disease (CKD) is accompanied by cardiac fibrosis, hypertrophy, and dysfunction, which are commonly referred to as uremic cardiomyopathy. Our previous studies found that Na/K-ATPase ligands or 5/6th partial nephrectomy (PNx) induces cardiac fibrosis in rats and mice. The current study used in vitro and in vivo models to explore novel roles for microRNA in this mechanism of cardiac fibrosis formation. To accomplish this, we performed microRNA profiling with RT-qPCR based arrays on cardiac tissue from rats subjected to marinobufagenin (MBG) infusion or PNx. The analysis showed that a series of fibrosis-related microRNAs were dysregulated. Among the dysregulated microRNAs, microRNA (miR)-29b-3p, which directly targets mRNA of collagen, was consistently reduced in both PNx and MBG-infused animals. In vitro experiments demonstrated that treatment of primary cultures of adult rat cardiac fibroblasts with Na/K-ATPase ligands induced significant increases in the fibrosis marker, collagen protein, and mRNA expression compared with controls, whereas miR-29b-3p expression decreased >50%. Transfection of miR-29b-3p mimics into cardiac fibroblasts inhibited cardiotonic steroids-induced collagen synthesis. Moreover, a specific Na/K-ATPase signaling antagonist, pNaKtide, prevented ouabain-induced increases in collagen synthesis and decreases in miR-29b-3p expression in these cells. In conclusion, these data are the first to indicate that signaling through Na/K-ATPase regulates miRNAs and specifically, miR-29b-3p expression both in vivo and in vitro. Additionally, these data indicate that miR-29b-3p expression plays an important role in the formation of cardiac fibrosis in CKD.

CT of acute perianal abscesses and infected fistulae: a pictorial essay.

Computed tomography (CT) is an effective, readily available diagnostic imaging tool for evaluation of the emergency room (ER) patients with the clinical suspicion of perianal abscess and/or infected fistulous tract (anorectal sepsis). These patients usually present with perineal pain, fever, and leukocytosis. The diagnosis can be easy if the fistulous tract or abscess is visible on inspection of the perianal skin. If the tract or abscess is deep, then the clinical diagnosis can be difficult. Also, the presence of complex tracts or supralevator extension of the infection cannot be judged by external examination alone. Magnetic resonance imaging (MRI) is the best imaging test to accurately detect fistulous tracts, especially when they are complex (Omally et al. in AJR 199:W43-W53, 2012). However, in the acute setting in the ER, this imaging modality is not always immediately available. Endorectal ultrasound has also been used to identify perianal abscesses, but this modality requires hands-on expertise and can have difficulty localizing the offending fistulous tract. It may also require the use of a rectal probe, which the patient may not be able to tolerate. Contrast-enhanced CT is a very useful tool to diagnose anorectal sepsis; however, this has not received much attention in the recent literature (Yousem et al. in Radiology 167(2):331-334, 1988) aside from a paper describing CT imaging following fistulography (Liang et al. in Clin Imaging 37(6):1069-1076, 2013). An infected fistula is indicated by a fluid-/air-filled soft tissue tract surrounded by inflammation. A well-defined round to oval-shaped fluid/air collection is indicative of an abscess. The purpose of this article is to demonstrate the usefulness of contrast-enhanced CT in the diagnosis of acute anorectal sepsis in the ER setting. We will discuss the CT appearance of infected fistulous tracts and abscesses and how CT imaging can guide the ER physician in the clinical management of these patients.

Association between obesity and statin use on mortality and hospital encounters in atrial fibrillation.

Background: Obesity increases risk of atrial fibrillation (AF) at least in part due to pro-inflammatory effects, but has been paradoxically associated with improved mortality. Although statins have pleiotropic anti-inflammatory properties, their interaction with obesity and clinical outcomes in AF is unknown. We explored the relationship between BMI, statin use, and all-cause mortality and AF/congestive heart failure (CHF)-related encounters, hypothesizing that statin exposure may be differentially associated with improved outcomes in overweight/obesity. Methods: This was a single center retrospective cohort study of adults with AF diagnosed between 2011-2018. Patients were grouped by body mass index (BMI) and statin use at time of AF diagnosis. Outcomes included all-cause mortality and ED or inpatient encounters for AF or CHF. Results and Conclusions: A total of 2503 subjects were included (median age 66 years, 43.4 % female, median BMI 29.8 kg/m2, 54.6 % on baseline statin therapy). Increasing BMI was associated with decreased mortality hazard but not associated with AF/CHF encounter risk. Adjusting for statin-BMI interaction, demographics, and cardiovascular comorbidities, overweight non-statin users experienced improved mortality (adjusted hazard ratio [aHR] 0.55, 95 % CI 0.35-0.84) compared to statin users (aHR 0.98, 95 % CI 0.69-1.40; interaction P-value = 0.013). Mortality hazard was consistently lower in obese non-statin users than in statin users, however interaction was insignificant. No significant BMI-statin interactions were observed in AF/CHF encounter risk. In summary, statin use was not differentially associated with improved mortality or hospitalization risk in overweight/obese groups. These findings do not support statins for secondary prevention of adverse outcomes based on overweight/obesity status alone.

Vitamin d and the risk of uterine fibroids.

BACKGROUND: Uterine leiomyomata (also known as fibroids) are benign tumors of uterine smooth muscle that are characterized by overproduction of extracellular matrix. Fibroids are the leading indication for hysterectomy in the United States. The active metabolite of vitamin D has been shown to inhibit cell proliferation and extracellular matrix production in fibroid tissue culture and to reduce fibroid volume in the Eker rat. No previous study has examined whether vitamin D is related to fibroid status in women. METHODS: The National Institute of Environmental Health Sciences Uterine Fibroid Study enrolled randomly selected 35- to 49-year-old women who were members of an urban health plan during 1996-1999. Fibroid status was determined by ultrasound screening of premenopausal women (620 blacks, 416 whites). Vitamin D status was assessed in stored plasma by radioimmunoassay of 25-hydroxyvitamin D (25(OH)D) and questionnaire data on sun exposure. Associations were evaluated with logistic regression, controlling for potential confounders. RESULTS: Only 10% of blacks and 50% of whites had levels of 25(OH)D regarded as sufficient (>20 ng/ml). Women with sufficient vitamin D had an estimated 32% lower odds of fibroids compared with those with vitamin D insufficiency (adjusted odds ratio [aOR] = 0.68, 95% confidence interval [CI] = 0.48-0.96). The association was similar for blacks and whites. Self-reported sun exposure ≥ 1 hour per day (weather permitting) was also associated with reduced odds of fibroids (aOR = 06. [0.4-0.9]), with no evidence of heterogeneity by ethnicity. CONCLUSIONS: The consistency of findings for questionnaire and biomarker data, the similar patterns seen in blacks and whites, and the biological plausibility provide evidence that sufficient vitamin D is associated with a reduced risk of uterine fibroids.

Evaluation of exposures to healthcare personnel from cisplatin during a mock demonstration of intra-operative intraperitoneal chemotherapy administration.

UNLABELLED: Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In 2006, the National Cancer Institute released an announcement supporting the use of intraperitoneal (IP) chemotherapy in advanced ovarian cancer. It remains unanswered how many cycles of IP chemotherapy are required to maintain a survival advantage. There may be a benefit with as few as three IP cycles and possibly as few as one IP chemotherapy cycle. OBJECTIVE: In preparation for a clinical trial in which chemotherapy would be administered intra-operatively, the question of exposure to healthcare personnel arose, therefore, the purpose of this study was to perform an evaluation of healthcare personnel exposure to cisplatin during a mock demonstration of intraperitoneal chemotherapy administration. MATERIALS AND METHODS: The National Institute of Occupational Safety and Health (NIOSH), the Women's Cancer Center of Nevada, and the staff of the University Medical Center, Las Vegas, participated in this mock demonstration. Employees wore personal protective equipment recommended by NIOSH. Wipe, area, and breathing zone air samples were taken from the pharmacy and operating room, and during sterilization of equipment. RESULTS: All samples were negative for cisplatin, except for one surface wipe from the floor of the operating room (OR) after the mock procedure. Upon sanitization of the OR, no cisplatin was detected on the floor. CONCLUSION: This was the first study evaluating the exposure of healthcare personnel to the administration of cisplatin intra-operatively. NIOSH endorsed this practice so long as the employees adhere to using the recommended personal protective equipment.

The use of argon beam coagulation in treating vulvar intraepithelial neoplasia III: a retrospective review.

UNLABELLED: Argon beam coagulation (ABC) has unique properties which make it suitable for the local treatment of superficial epithelial disorders such as vulvar intraepithelial neoplasia (VIN III). OBJECTIVE: To evaluate argon beam coagulation in treating multifocal VIN III. METHODS: Argon beam coagulation was used in twenty-nine patients. ABC was set at 80 W, 7 L/min. All patients were given 1% silvadene cream to apply to vulva. Patients had follow-up appointments two weeks and six weeks postoperatively. Patients were followed every three to six months for the subsequent year. RESULTS: 2 of 29 (6.8%) experienced moderate pain within the first two weeks postoperatively requiring prescriptions for perocet. 2 of 29 (6.8%) had yeast infection requiring diflucan. Mean follow-up time was 34.9 months (11.7-37.4). 15 of 29 (51.7%) had no recurrence within the follow-up period. 14 of 29 (48.3%) recurred within the follow-up period. The mean time to recurrence is 23.2 months. CONCLUSION: This small retrospective review is the first to evaluate argon beam coagulation in treating multifocal VIN III. This review indicates that ABC is comparable to other vulva organ conserving therapies. ABC retains cosmesis, and form of the vulva. This is a major advantage over surgery. Repeat treatments are also possible, which is important in a condition such as VIN, which tends to be multifocal and recurrent.

Biodegradable photo-crosslinked alginate nanofibre scaffolds with tuneable physical properties, cell adhesivity and growth factor release.

Nanofibrous scaffolds are of interest in tissue engineering due to their high surface area to volume ratio, interconnected pores, and architectural similarity to the native extracellular matrix. Our laboratory recently developed a biodegradable, photo-crosslinkable alginate biopolymer. Here, we show the capacity of the material to be electrospun into a nanofibrous matrix, and the ability to enhance cell adhesion and proliferation on these matrices by covalent modification with cell adhesion peptides. Additionally, the potential of covalently incorporating heparin into the hydrogels during the photopolymerisation process to sustain the release of a heparin binding growth factor via affinity interactions was demonstrated. Electrospun photo-crosslinkable alginate nanofibrous scaffolds endowed with cell adhesion ligands and controlled delivery of growth factors may allow for improved regulation of cell behaviour for regenerative medicine.

Management of Pulmonary Mucormycosis After Orthotopic Heart Transplant: A Case Series.

Invasive pulmonary mucormycosis is a potentially fatal infection that can occur in immunosuppressed patients such as those who have undergone orthotopic heart transplant (OHT). High-dose intravenous antifungal agents, including amphotericin B, are generally accepted as the first-line medical treatment, with prompt surgical resection of lesions if feasible. The body of evidence guiding treatment decisions, however, is sparse, particularly regarding adjustment of immunosuppression during acute infection and long-term recovery. We present 2 cases of patients with pulmonary mucormycosis occurring within the first 6 months after OHT, both of whom successfully recovered after appropriate medical and surgical treatment, and we highlight differences in immunosuppression management strategies for this life-threatening condition.

Microgel encapsulated nanoparticles for glucose-responsive insulin delivery.

An insulin delivery system that self-regulates blood glucose levels has the potential to limit hypoglycemic events and improve glycemic control. Glucose-responsive insulin delivery systems have been developed by coupling glucose oxidase with a stimuli-responsive biomaterial. However, the challenge of achieving desirable release kinetics (i.e., insulin release within minutes after glucose elevation and duration of release on the order of weeks) still remains. Here, we develop a glucose-responsive delivery system using encapsulated glucose-responsive, acetalated-dextran nanoparticles in porous alginate microgels. The nanoparticles respond rapidly to changes in glucose concentrations while the microgels provide them with protection and stability, allowing for extended glucose-responsive insulin release. This system reduces blood sugar in a diabetic mouse model at a rate similar to naked insulin and responds to a glucose challenge 3 days after administration similarly to a healthy animal. With 2 doses of microgels containing 60 IU/kg insulin each, we are able to achieve extended glycemic control in diabetic mice for 22 days.

Uterine leiomyomata in relation to insulin-like growth factor-I, insulin, and diabetes.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and insulin stimulate cell proliferation in uterine leiomyoma (fibroid) tissue. We hypothesized that circulating levels of these proteins would be associated with increased prevalence and size of uterine fibroids. METHODS: Participants were 35-49-year-old, randomly selected members of an urban health plan who were enrolled in the study in 1996-1999. Premenopausal participants were screened for fibroids with ultrasound. Fasting blood samples were collected. Associations between fibroids and diabetes, plasma IGF-I, IGF binding protein 3 (BP3), and insulin were evaluated for blacks (n = 585) and whites (n = 403) by using multiple logistic regression. RESULTS: IGF-I showed no association with fibroids in blacks, but in whites the adjusted odds ratios (aORs) for both mid and upper tertiles compared with the lowest tertile were 0.6 (95% confidence intervals [CI] = 0.3-1.0 and 0.4-1.1, respectively). Insulin and diabetes both tended to be inversely associated with fibroids in blacks. The insulin association was with large fibroids; aOR for the upper insulin tertile relative to the lowest was 0.4 (0.2-0.9). The aOR for diabetes was 0.5 (0.2-1.0). Associations of insulin and diabetes with fibroids were weak for whites. Binding protein 3 showed no association with fibroids. CONCLUSIONS: Contrary to our hypothesis, high circulating IGF-I and insulin were not related to increased fibroid prevalence. Instead, there was suggestion of the opposite. The inverse association with diabetes, although based on small numbers, is consistent with previously reported findings. Future studies might investigate vascular dysfunction as a mediator between hyperinsulinemia or diabetes and possible reduced risk of fibroids.

The correlation between elevated cardiac troponin I and pulmonary artery obstruction index in ED patients with pulmonary embolism.

OBJECTIVES: The aim of this study is to investigate the correlation between cardiac troponin I (cTnI) values and the pulmonary artery obstruction index assessed with spiral computed tomography (CT) scan in emergency department (ED) patients with pulmonary embolism (PE). METHODS: This is a retrospective cohort study of all 179 ED patients diagnosed with PE between December 2004 and January 2007. Study population consisted of 104 (58.1%) of 179 patients with PE in whom both cTnI was measured and a contemporaneously performed CT scan was available for review. In these patients, the levels of cTnI measured in the ED were correlated with the degree of pulmonary vascular obstruction determined by applying the modified Computed Tomography Obstruction Index to the spiral CT scan performed in the ED. RESULTS: Troponin values were elevated in 20 (19.2%) of 104 patients (95% confidence interval [CI], 11.6-26.8) with a mean cTnI concentration of 0.38 +/- 0.44 microg/L. Elevated cTnI value had a significant correlation with main pulmonary arteries involvement using the modified Computed Tomography Obstruction Index score (P = .0001). Elevated ED cTnI value had 53.8% (95% CI, 37.6-66) sensitivity and 92.3% (95% CI, 87-96.4) specificity, 70% (95% CI, 49-86) PPV, and 85.7% (95% CI, 80.7-90) NPV for predicting main pulmonary artery obstruction on CT. Increased cTnI values were highly correlated to intensive care unit admission of patients with PE (RR, 12.83; 95% CI, 3.87-42.4). CONCLUSIONS: Measuring cTnI value might be considered in ED patients who are suspected of having PE. Elevated cTnI should raise the clinician's concern for the possibility of central pulmonary vascular obstruction.

Ultrasound of the scrotum.

Ultrasound is a vital adjunct to clinical examination in diagnosing scrotal disease, as a number of different processes may present similarly. Potential applications range from the acute emergency to long-term screening as well as cases in which a distinct scrotal abnormality may or may not be palpable. Differentiating acute epididymitis/epididymoorchitis from testicular torsion is possible sonographically, thereby guiding appropriate medical or surgical management. Distinguishing between cystic, solid, or complex scrotal masses is readily performed with this modality. It clearly depicts simple versus complex hydroceles and determines the presence of underlying testicular or epididymal disease. Not only is ultrasound the best imaging modality for longitudinal screening in patients (testicular microlithiasis, cryptorchidism) at risk for testicular tumors, it also provides valuable information in the infertile male by documenting the presence or absence of a varicocele.

The diagnostic challenge of the sequelae of acute pancreatitis on CT imaging: a pictorial essay.

PURPOSE: The purpose of the study was to present a pictorial review of the long-term sequelae of acute pancreatitis on CT imaging as these findings can cause diagnostic confusion in the absence of a proper clinical history and/or prior CT imaging. METHODS: We retrospectively identified 81 patients who had an episode of acute pancreatitis with diagnostic findings on CT and also underwent one or more follow-up CT scans at least 1 month beyond the acute episode. The residual findings on all follow-up CT scans were tabulated, including the time interval since the initial bout of acute pancreatitis. RESULT: Residual inflammatory changes were present in 19.8% of cases, with a median time period lasting 86 days since the initial episode of acute pancreatitis. Residual fluid collections were seen in 27.2% and persisted for a median of 132 days. Three patients had residual solid-appearing inflammatory masses, which could be mistaken for neoplasms. Other long-term sequelae were also tabulated, including pancreatic ductal dilatation, pancreatic atrophy, new or increased pancreatic calcifications, biliary tract dilatation, central portal venous occlusion, and pseudoaneurysm formation. These residual findings and long-term complications are presented as a pictorial essay. CONCLUSION: Recognizing the spectrum of residual findings of acute pancreatitis, some of which can be long term, is important in the correct interpretation of a pancreatic CT. These findings can mimic acute pancreatitis or a pancreatic/peripancreatic neoplasm and often cause diagnostic confusion, especially in the absence of prior CT imaging.

Macrophages with cellular backpacks for targeted drug delivery to the brain.

Most potent therapeutics are unable to cross the blood-brain barrier following systemic administration, which necessitates the development of unconventional, clinically applicable drug delivery systems. With the given challenges, biologically active vehicles are crucial to accomplishing this task. We now report a new method for drug delivery that utilizes living cells as vehicles for drug carriage across the blood brain barrier. Cellular backpacks, 7-10 µm diameter polymer patches of a few hundred nanometers in thickness, are a potentially interesting approach, because they can act as drug depots that travel with the cell-carrier, without being phagocytized. Backpacks loaded with a potent antioxidant, catalase, were attached to autologous macrophages and systemically administered into mice with brain inflammation. Using inflammatory response cells enabled targeted drug transport to the inflamed brain. Furthermore, catalase-loaded backpacks demonstrated potent therapeutic effects deactivating free radicals released by activated microglia in vitro. This approach for drug carriage and release can accelerate the development of new drug formulations for all the neurodegenerative disorders.

CT findings in duodenal diverticulitis.

OBJECTIVE: Duodenal diverticulitis is a rare complication of duodenal diverticulosis. It is often clinically misdiagnosed because it has no pathognomonic signs or symptoms and its CT findings may mimic other intraabdominal processes. We describe two patients with duodenal diverticulitis who presented with abdominal pain, nausea, and leukocytosis. At the time of initial presentation, only one of the two patients was diagnosed correctly. In the first case, which was initially misdiagnosed as acute pancreatitis, the correct diagnosis was evident only after the disease process had become more quiescent and a follow-up CT scan using orally and i.v.-administered contrast agents was performed. In the second case, the coronal reformatted images confirmed the diagnosis suggested by the axial images. CONCLUSION: Duodenal diverticulitis can be a difficult CT diagnosis to make; however, maintaining it in the differential diagnosis of duodenal and pancreatic inflammatory processes and masses as well as defining the anatomy with nonaxial imaging including coronal images may be helpful in confirming the diagnosis.

The role of ultrasound in renal insufficiency: the essentials.

Sonography is the best screening modality to evaluate patients presenting with renal insufficiency. Ultrasound findings can be normal in patients with renal disease, especially in prerenal azotemia and acute parenchymal renal disease. Echogenic kidneys indicate the presence of parenchymal renal disease; the kidneys may be of a normal size or enlarged. Small kidneys suggest advanced stage chronic kidney disease. Uncommonly, cystic disease of the kidney, especially adult type polycystic kidney disease may be the cause of the patient's renal insufficiency with bilaterally enlarged kidneys containing multiple cysts of various sizes. If hydronephrosis is present, the level and cause of the obstruction should be sought. When ultrasound cannot diagnose the level and cause of obstruction, other imaging modalities, including CT and MRI may be useful. When renovascular disease (arterial stenosis or venous thrombosis) is suspected, spectral and color Doppler can be useful in detecting abnormalities.

Spatial control of cell gene expression by siRNA gradients in biodegradable hydrogels.

The extracellular environment exposes cells to numerous biochemical and physical signals that regulate their behavior. Strategies for generating continuous gradients of signals in biomaterials may allow for spatial control and patterning of cell behavior, and ultimately aid in the engineering of complex tissues. Short interfering RNA (siRNA) can regulate gene expression by silencing specific mRNA molecules post-transcriptionally, which may be valuable when presented in a continuous gradient for regenerative or therapeutic applications. Here, a biodegradable hydrogel system containing a gradient of siRNA is presented, and its capacity to regulate protein expression of encapsulated cells in a spatially continuous manner is demonstrated. Photocross-linkable dextran hydrogels containing a gradient of siRNA have been successfully fabricated using a dual-programmable syringe pump system, and differential gene silencing in incorporated cells that is sustained over time has been shown using green fluorescent protein as a reporter. This platform technology may be applied in tissue engineering to spatially control biologically relevant cellular processes.

Self-reported heavy bleeding associated with uterine leiomyomata.

OBJECTIVE: To characterize the relationship between self-reported bleeding symptoms and uterine leiomyoma size and location. METHODS: The leiomyoma status of a randomly selected sample of women aged 35-49 in the Washington, DC, area was determined using abdominal and transvaginal ultrasound to measure size and location of leiomyomata found at screening. Women were asked about symptoms of heavy bleeding (gushing-type bleeding, long menses, pad/tampon use) in a telephone interview. Using multivariable regression, we examined the relationships between leiomyoma characteristics and heavy bleeding symptoms among 910 premenopausal women. RESULTS: Women with leiomyomata (n = 596) were more likely to report gushing-type bleeding than women without leiomyomata; risk increased with leiomyoma size. Adjusted relative risks with 95% confidence intervals (CI) for women in each leiomyoma size category compared with the reference category (women without leiomyomata) were as follows: adjusted relative risk of 1.4 (95% CI 1.1, 1.9) for diffuse only, adjusted relative risk of 1.4 (95% CI 1.1, 1.8) for small leiomyomata (less than 2 cm), adjusted relative risk of 1.6 (95% CI 1.3, 2.0) for medium leiomyomata (2-5 cm), and adjusted relative risk of 1.9 (95% CI 1.5, 2.5) for large leiomyomata (greater than 5 cm). Reported use of eight or more pads/tampons on the heaviest days of menstrual bleeding increased with leiomyoma size, with a nearly 2.5-fold risk for women with large leiomyomata compared with women without leiomyomata (adjusted relative risk of 2.4; 95% CI 1.8, 3.1). Nonsubmucosal leiomyomata were associated with essentially the same increase in heavy bleeding as submuscosal leiomyomata of similar size. CONCLUSION: Small leiomyomata were associated with increased risk of heavy bleeding, and risk increased with size. Contrary to published articles, nonsubmucosal leiomyomata were associated with heavy bleeding to the same extent as submucosal leiomyomata.

Ultrasound of the acute female pelvis.

Ultrasound is the most valuable imaging modality in evaluating the premenopausal female presenting with acute pelvic pain. The appropriate interpretation of the ultrasound study requires correlation with the patient's clinical history and laboratory values. This is especially true of the serum beta-hCG, where ultrasound relies on this test to make the diagnosis of ectopic pregnancy. When the serum test for pregnancy is negative and the patient has an adnexal mass this could be secondary to a complicated ovarian cyst (hemorrhage, rupture), ovarian torsion or pelvic inflammatory disease. The ultrasound image can usually make the diagnosis in conjunction with the clinical papameters, however, this is most difficult in patients with ovarian torsion.