An ultrathin membrane mediates tissue-specific morphogenesis and barrier function in a human kidney chip.

Organ-on-chip (OOC) systems are revolutionizing tissue engineering by providing dynamic models of tissue structure, organ-level function, and disease phenotypes using human cells. However, nonbiological components of OOC devices often limit the recapitulation of in vivo-like tissue-tissue cross-talk and morphogenesis. Here, we engineered a kidney glomerulus-on-a-chip that recapitulates glomerular morphogenesis and barrier function using a biomimetic ultrathin membrane and human-induced pluripotent stem cells. The resulting chip comprised a proximate epithelial-endothelial tissue interface, which reconstituted the selective molecular filtration function of healthy and diseased kidneys. In addition, fenestrated endothelium was successfully induced from human pluripotent stem cells in an OOC device, through in vivo-like paracrine signaling across the ultrathin membrane. Thus, this device provides a dynamic tissue engineering platform for modeling human kidney-specific morphogenesis and function, enabling mechanistic studies of stem cell differentiation, organ physiology, and pathophysiology.

Design and Development of a Novel System for Remote Control of Stationary Oxygen Concentrator Flow Rate.

Purpose: Long-term oxygen therapy involves utilizing stationary oxygen concentrators to allow patients with respiratory illnesses to attain sufficient blood oxygenation via supplemental oxygen. Disadvantages of these devices include their lack of remote adjustability and domiciliary accessibility. To adjust oxygen flow, patients typically walk across their homes - a physically taxing activity - to manually rotate the knob of the concentrator flowmeter. The purpose of this investigation was to develop a control system device that allows patients to remotely adjust the oxygen flow rates on their stationary oxygen concentrator. Methods: The engineering design process was used to develop the novel FLO2 device. The two-part system is composed of 1) a smartphone application and 2) an adjustable concentrator attachment unit that mechanically interfaces with the stationary oxygen concentrator flowmeter. Results: Product testing indicates that users successfully communicated to the concentrator attachment from a maximum distance of 41m in an open field, suggesting usability from anywhere inside a standard home. The calibration algorithm adjusted oxygen flow rates with an accuracy of ±0.019 LPM and a precision of ±0.042 LPM. Conclusion: Initial design testing suggests the device as a reliable and accurate method of wirelessly adjusting oxygen flow on a stationary oxygen concentrator, but further testing should be performed on different stationary oxygen concentrator models.

Evaluating Thera-101 as a Low-Volume Resuscitation Fluid in a Model of Polytrauma.

Traumatic brain injury (TBI) and hemorrhage remain challenging to treat in austere conditions. Developing a therapeutic to mitigate the associated pathophysiology is critical to meet this treatment gap, especially as these injuries and associated high mortality are possibly preventable. Here, Thera-101 (T-101) was evaluated as low-volume resuscitative fluid in a rat model of TBI and hemorrhage. The therapeutic, T-101, is uniquely situated as a TBI and hemorrhage intervention. It contains a cocktail of proteins and microvesicles from the secretome of adipose-derived mesenchymal stromal cells that can act on repair and regenerative mechanisms associated with poly-trauma. T-101 efficacy was determined at 4, 24, 48, and 72 h post-injury by evaluating blood chemistry, inflammatory chemo/cytokines, histology, and diffusion tensor imaging. Blood chemistry indicated that T-101 reduced the markers of liver damage to Sham levels while the levels remained elevated with the control (saline) resuscitative fluid. Histology supports the potential protective effects of T-101 on the kidneys. Diffusion tensor imaging showed that the injury caused the most damage to the corpus callosum and the fimbria. Immunohistochemistry suggests that T-101 may mitigate astrocyte activation at 72 h. Together, these data suggest that T-101 may serve as a potential field deployable low-volume resuscitation therapeutic.

A Biomimetic Electrospun Membrane Supports the Differentiation and Maturation of Kidney Epithelium from Human Stem Cells.

Podocytes derived from human induced pluripotent stem (hiPS) cells are enabling studies of kidney development and disease. However, many of these studies are carried out in traditional tissue culture plates that do not accurately recapitulate the molecular and mechanical features necessary for modeling tissue- and organ-level functionalities. Overcoming these limitations requires the design and application of tunable biomaterial scaffolds. Silk fibroin is an attractive biomaterial due to its biocompatibility and versatility, which include its ability to form hydrogels, sponge-like scaffolds, and electrospun fibers and membranes appropriate for tissue engineering and biomedical applications. In this study, we show that hiPS cells can be differentiated into post-mitotic kidney glomerular podocytes on electrospun silk fibroin membranes functionalized with laminin. The resulting podocytes remain viable and express high levels of podocyte-specific markers consistent with the mature cellular phenotype. The resulting podocytes were propagated for at least two weeks, enabling secondary cell-based applications and analyses. This study demonstrates for the first time that electrospun silk fibroin membrane can serve as a supportive biocompatible platform for human podocyte differentiation and propagation. We anticipate that the results of this study will pave the way for the use of electrospun membranes and other biomimetic scaffolds for kidney tissue engineering, including the development of co-culture systems and organs-on-chips microphysiological devices.

Comparative evaluation of mesenchymal stromal cell growth and osteogenic differentiation on a shape memory polymer scaffold.

Trauma-induced, critical-size bone defects pose a clinical challenge to heal. Albeit autografts are the standard-of-care, they are limited by their inability to be shaped to various defect geometries and often incur donor site complications. Herein, the combination of a "self-fitting" shape memory polymer (SMP) scaffold and seeded mesenchymal stromal cells (MSCs) was investigated as an alternative. The porous SMP scaffold, prepared from poly(ε-caprolactone) diacrylate (PCL-DA) and coated with polydopamine, provided conformal shaping and cell adhesion. MSCs from five tissues, amniotic (AMSCs), chorionic tissue (CHSCs), umbilical cord (UCSCs), adipose (ADSCs), and bone marrow (BMSCs) were evaluated for viability, density, and osteogenic differentiation on the SMP scaffold. BMSCs exhibited the fastest increase in cell density by day 3, but after day 10, CHSCs, UCSCs, and ADSCs approached similar cell density. BMSCs also showed the greatest calcification among the cell types, followed closely by ADSCs, CHSCs and AMSCs. Alkaline phosphatase (ALP) activity peaked at day 7 for AMSCs, UCSCs, ADSCs and BMSCs, and at day 14 for CHSCs, which had the greatest overall ALP activity. Of all the cell types, only scaffolds cultured with ADSCs in osteogenic media had increased hardness and local modulus as compared to blank scaffolds after 21 days of cell culture and osteogenic differentiation. Overall, ADSCs performed most favorably on the SMP scaffold. The SMP scaffold was able to support key cellular behaviors of MSCs and could potentially be a viable, regenerative alternative to autograft.

Ruptured Emphysematous Liver Abscess: An Unusual Presentation in Kochs.

Gas forming liver abscess (GFLA) though rare is seen in diabetic patients. Rupture of such abscesses usually requires surgical intervention. These cases are associated with high morbidity and mortality due to sepsis. Tuberculous liver abscesses are more often silent in presentation. GFLA formed in the background of a tuberculous liver abscess is rare. We present a case of ruptured GFLA with underlying tuberculous pathology in a normoglycemic patient. The abscess was managed by image guided intervention. A brief case report along with review of literature is presented.

Transcorneal Electrical Stimulation Reduces Neurodegenerative Process in a Mouse Model of Glaucoma.

Glaucoma is a neurodegenerative disease in which the retinal ganglion cell axons of the optic nerve degenerate concomitant with synaptic changes in the retina, leading finally to death of the retinal ganglion cells (RGCs). Electrical stimulation has been used to improve neural regeneration in a variety of systems, including in diseases of the retina. Therefore, the focus of this study was to investigate whether transcorneal electrical stimulation (TES) in the DBA2/J mouse model of glaucoma could improve retinal or optic nerve pathology and serve as a minimally invasive treatment option. Mice (10 months-old) received 21 sessions of TES over 8 weeks, after which we evaluated RGC number, axon number, and anterograde axonal transport using histology and immunohistochemistry. To gain insight into the mechanism of proposed protection, we also evaluated inflammation by quantifying CD3+ T-cells and Iba1+ microglia; perturbations in metabolism were shown via the ratio pAMPK to AMPK, and changes in trophic support were tested using protein capillary electrophoresis. We found that TES resulted in RGC axon protection, a reduction in inflammatory cells and their activation, improved energy homeostasis, and a reduction of the cell death-associated p75NTR. Collectively, the data indicated that TES maintained axons, decreased inflammation, and increased trophic factor support, in the form of receptor presence and energy homeostasis, suggesting that electrical stimulation impacts several facets of the neurodegenerative process in glaucoma.

Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.

BACKGROUND: No study has evaluated current scoring systems for their accuracy in predicting short and long-term outcome of alcoholic hepatitis in a US population. METHODS: We reviewed electronic records for patients with alcoholic liver disease (ALD) admitted to Parkland Memorial Hospital between January 2002 and August 2005. Data and outcomes for 148 of 1,761 admissions meeting pre-defined criteria were collected. The discriminant function (DF) was revised (INRdf) to account for changes in prothrombin time reagents that could potentially affect identification of risk using the previous DF threshold of >32. Admission and theoretical peak scores were calculated by use of the Model for End-stage Liver Disease (MELD). Analysis models compared five different scoring systems. RESULTS: INRdf was closely correlated with the old DF (r (2) = 0.95). Multivariate analysis of the data showed that survival for 28 days was significantly associated with a scoring system using a combination of age, bilirubin, coagulation status, and creatinine (p < 0.001), and an elevated ammonia result within two days of admission (p = 0.012). When peak values for MELD were included, they were the most significant predictor of short-term mortality (p < 0.001), followed by INRdf (p = 0.006). CONCLUSION: On admission, two scoring systems that identify a subset of patients with severe alcoholic liver disease are able to predict >50 % mortality at four weeks and >80 % mortality at six months without specific treatment.

Personal derived health information: a foundation to preparing the United States for disasters and public health emergencies.

BACKGROUND: In the days following a disaster/public health emergency, there is great effort to ensure that everyone receives appropriate care and lives are saved. However, evacuees following a disaster/public health emergency often lack access to personal health information that is vital to receive or maintain quality care. Delayed treatment and interruptions of medication regimens often contribute to excess morbidity and mortality following a disaster/public health emergency. This study sought to define a set of minimum health information elements that can be maintained in a personal health record (PHR) and given to first responders/receivers within the first 96 hours of a disaster/public health response to improve clinical health outcomes. METHODS: A mixed methods approach of qualitative and quantitative data gathering and analyses was completed. Expert panel members (n = 116) and existing health information elements were sampled for this study; 55% (n = 64) of expert panel members had clinical credentials and determined the health information. From an initial set of 6 sources, a step-wise process using a Likert scale survey and thematic data analyses, including interrater reliability and validity checks, produced a set of minimum health information elements. RESULTS: The results identified 30 essential elements from 676 existing health information elements, a reduction of approximately 95%. The elements were grouped into 7 domains: identification, emergency contact, health care contact, health profile -past medical history, medication, major allergies/diet restrictions, and family information. CONCLUSIONS: Leading experts in clinical disaster preparedness identified a set of minimum health information elements that first responders/receivers must have to ensure appropriate and timely care. If this set of elements is used as the fundamental information for a PHR, and automatically updated and validated during clinical encounters and medication changes, it is conceivable that following large-scale disasters clinical outcomes may be improved and more lives may be saved.

Transferred and delayed care of patients with colorectal cancer in a safety-net hospital system--manifestations of a distressed healthcare system.

BACKGROUND: Safety-net hospital systems provide care to a large proportion of United States' under- and uninsured population. We have witnessed delayed colorectal cancer (CRC) care in this population and sought to identify demographic and systemic differences in these patients compared to those in an insured health-care system. DESIGN, PATIENTS, AND APPROACH/MEASUREMENTS: We collected demographic, socioeconomic, and clinical data from 2005-2007 on all patients with CRC seen at Parkland Health and Hospital System (PHHS), a safety-net health system and at Presbyterian Hospital Dallas System (Presbyterian), a community health system, and compared characteristics among the two health-care systems. Variables associated with advanced stage were identified with multivariate logistic regression analysis and odds ratios were calculated. RESULTS: Three hundred and eighteen patients at PHHS and 397 patients at Presbyterian with CRC were identified. An overwhelming majority (75 %) of patients seen at the safety-net were diagnosed after being seen in the emergency department or at an outside facility. These patients had a higher percentage of stage 4 disease compared to the community. Patients within the safety-net with Medicare/private insurance had lower rates of advanced disease than uninsured patients (25 % vs. 68 %, p < 0.001). Insurance status and physician encounter resulting in diagnosis were independent predictors of disease stage at diagnosis. CONCLUSIONS: A large proportion of patients seen in the safety-net health system were transferred from outside systems after diagnosis, thus leading to delayed care. This delay in care drove advanced stage at diagnosis. The data point to a pervasive and systematic issue in patients with CRC and have fundamental health policy implications for population-based CRC screening.

Physician knowledge and appropriate utilization of computed tomographic colonography in colorectal cancer screening.

GOALS: To assess physician understanding of computed tomographic colonography (CTC) in colorectal cancer (CRC) screening guidelines in a pilot study. BACKGROUND: CTC is a sensitive and specific method of detecting colorectal polyps and cancer. However, several factors have limited its clinical availability, and CRC screening guidelines have issued conflicting recommendations. STUDY: A web-based survey was administered to physicians at two institutions with and without routine CTC availability. RESULTS: 398 of 1655 (24%) participants completed the survey, 59% was from the institution with routine CTC availability, 52% self-identified as trainees, and 15% as gastroenterologists. 78% had no personal experience with CTC. Only 12% was aware of any current CRC screening guidelines that included CTC. In a multiple regression model, gastroenterologists had greater odds of being aware of guidelines (OR 3.49, CI 1.67-7.26), as did physicians with prior CTC experience (OR 4.81, CI 2.39-9.68), controlling for institution, level of training, sex, and practice type. Based on guidelines that recommend CTC, when given a clinical scenario, 96% of physicians was unable to select the appropriate follow-up after a CTC, which was unaffected by institution. CONCLUSIONS: Most physicians have limited experience with CTC and are unaware of recent recommendations concerning CTC in CRC screening.

Management of small polyps detected by screening CT colonography: patient and physician preferences.

BACKGROUND: Management of small polyps found on computed tomography (CT) colonography is controversial and critical to both cancer outcomes and cost. Patient and physician behavior are influenced by personal beliefs and prior experience. Thus, we aimed to understand patient and physician preferences after finding polyps on CT colonography. METHODS: Patients were given a validated handout and survey asking for their preference for evaluation of a "pea-sized" polyp found on CT colonography. By using an Internet survey, physicians were asked how they would manage a 5-mm, 8-mm, or 12-mm polyp, or three 5-mm polyps found by CT colonography in a hypothetical 52-year-old patient of average colorectal cancer risk. Survey reliability was assessed using Cronbach's coefficient alpha. RESULTS: Of the 305 patient respondents, 95% wanted to know if the polyp found on CT colonography was precancerous, 86% stated they would request endoscopic evaluation, and 85% wanted polypectomy. Of the 277 primary care physicians, 71% would refer a 5-mm sigmoid polyp for endoscopy, 86% would refer an 8-mm polyp, 97% would refer a 12-mm polyp, and 91% would refer three 5-mm polyps. Of the 461 gastroenterologists, 83% would refer a 5-mm sigmoid polyp for endoscopy, 96% would refer an 8-mm polyp, 97% would refer a 12-mm polyp, and 93% would refer three 5-mm polyps. Overall, 75% of physicians indicated the fear of missing a precancerous lesion would prompt referral for colonoscopy. CONCLUSION: Both patients and physicians overwhelmingly preferred to follow up small polyps identified by CT colonography with endoscopy, suggesting that population-based CT colonography screening programs in which polyps are not removed might require significant patient and physician education before implementation.

Purulent pericarditis: report of 2 cases and review of the literature.

Purulent pericarditis, a localized infection within the pericardial space, has become a rare entity in the modern antibiotic era. Although historically a disease of children and young adults, this is no longer the case: the median age at the time of diagnosis has increased by nearly 30 years over the past 6 decades. Despite advances in diagnostic and treatment modalities, purulent pericarditis remains a life-threatening illness. Unfortunately, the diagnosis is made postmortem in more than half the cases. Thus, a high index of clinical suspicion is crucial. We present 2 cases of purulent pericarditis, and provide an updated review of other case series published over the past 60 years.

Yersinia pestis TonB: role in iron, heme, and hemoprotein utilization.

In Yersinia pestis, the siderophore-dependent yersiniabactin (Ybt) iron transport system and heme transport system (Hmu) have putative TonB-dependent outer membrane receptors. Here we demonstrate that hemin uptake and iron utilization from Ybt are TonB dependent. However, the Yfe iron and manganese transport system does not require TonB.