In silico Mechanics of Stem Cells Intramyocardially Transplanted with a Biomaterial Injectate for Treatment of Myocardial Infarction.

PURPOSE: Biomaterial and stem cell delivery are promising approaches to treating myocardial infarction. However, the mechanical and biochemical mechanisms underlying the therapeutic benefits require further clarification. This study aimed to assess the deformation of stem cells injected with the biomaterial into the infarcted heart. METHODS: A microstructural finite element model of a mid-wall infarcted myocardial region was developed from ex vivo microcomputed tomography data of a rat heart with left ventricular infarct and intramyocardial biomaterial injectate. Nine cells were numerically seeded in the injectate of the microstructural model. The microstructural and a previously developed biventricular finite element model of the same rat heart were used to quantify the deformation of the cells during a cardiac cycle for a biomaterial elastic modulus (Einj) ranging between 4.1 and 405,900 kPa. RESULTS: The transplanted cells' deformation was largest for Einj = 7.4 kPa, matching that of the cells, and decreased for an increase and decrease in Einj. The cell deformation was more sensitive to Einj changes for softer (Einj ≤ 738 kPa) than stiffer biomaterials. CONCLUSIONS: Combining the microstructural and biventricular finite element models enables quantifying micromechanics of transplanted cells in the heart. The approach offers a broader scope for in silico investigations of biomaterial and cell therapies for myocardial infarction and other cardiac pathologies.

Using machine learning to characterize heart failure across the scales.

Heart failure is a progressive chronic condition in which the heart undergoes detrimental changes in structure and function across multiple scales in time and space. Multiscale models of cardiac growth can provide a patient-specific window into the progression of heart failure and guide personalized treatment planning. Yet, the predictive potential of cardiac growth models remains poorly understood. Here, we quantify predictive power of a stretch-driven growth model using a chronic porcine heart failure model, subject-specific multiscale simulation, and machine learning techniques. We combine hierarchical modeling, Bayesian inference, and Gaussian process regression to quantify the uncertainty of our experimental measurements during an 8-week long study of volume overload in six pigs. We then propagate the experimental uncertainties from the organ scale through our computational growth model and quantify the agreement between experimentally measured and computationally predicted alterations on the cellular scale. Our study suggests that stretch is the major stimulus for myocyte lengthening and demonstrates that a stretch-driven growth model alone can explain [Formula: see text] of the observed changes in myocyte morphology. We anticipate that our approach will allow us to design, calibrate, and validate a new generation of multiscale cardiac growth models to explore the interplay of various subcellular-, cellular-, and organ-level contributors to heart failure. Using machine learning in heart failure research has the potential to combine information from different sources, subjects, and scales to provide a more holistic picture of the failing heart and point toward new treatment strategies.

Multiscale characterization of heart failure.

Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 µm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure. STATEMENT OF SIGNIFICANCE: Heart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse heart failure.

Effect of intra-myocardial Algisyl-LVR™ injectates on fibre structure in porcine heart failure.

Recent preclinical trials have shown that alginate injections are a promising treatment for ischemic heart disease. Although improvements in heart function and global structure have been reported following alginate implants, the underlying structure is poorly understood. Using high resolution ex vivo MRI and DT-MRI of the hearts of normal control swine (n = 8), swine with induced heart failure (n = 5), and swine with heart failure and alginate injection treatment (n = 6), we visualized and quantified the fibre distribution and implant material geometry. Our findings show that the alginate injectates form solid ellipsoids with a retention rate of 68.7% ±â€¯21.3% (mean ±â€¯SD) and a sphericity index of 0.37 ±â€¯0.03. These ellipsoidal shapes solidified predominantly at the mid-wall position with an inclination of -4.9°â€¯±â€¯31.4° relative to the local circumferential direction. Overall, the change to left ventricular wall thickness and myofiber orientation was minor and was associated with heart failure and not the presence of injectates. These results show that alginate injectates conform to the pre-existing tissue structure, likely expanding along directions of least resistance as mass is added to the injection sites. The alginate displaces the myocardial tissue predominantly in the longitudinal direction, causing minimal disruption to the surrounding myofiber orientations.

Endothelial cells on an aged subendothelial matrix display heterogeneous strain profiles in silico.

Within the artery intima, endothelial cells respond to mechanical cues and changes in subendothelial matrix stiffness. Recently, we found that the aging subendothelial matrix stiffens heterogeneously and that stiffness heterogeneities are present on the scale of one cell length. However, the impacts of these complex mechanical micro-heterogeneities on endothelial cells have not been fully understood. Here, we simulate the effects of matrices that mimic young and aged vessels on single- and multi-cell endothelial cell models and examine the resulting cell basal strain profiles. Although there are limitations to the model which prohibit the prediction of intracellular strain distributions in alive cells, this model does introduce mechanical complexities to the subendothelial matrix material. More heterogeneous basal strain distributions are present in the single- and multi-cell models on the matrix mimicking an aged artery over those exhibited on the young artery. Overall, our data indicate that increased heterogeneous strain profiles in endothelial cells are displayed in silico when there is an increased presence of microscale arterial mechanical heterogeneities in the matrix.

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American­European Consensus Group (AECG) criteria, a model-based "gold standard"obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

The effects of cidofovir on progressive multifocal leukoencephalopathy: an MRI case study.

MRI was used to study the effects of introducing cidofovir (HPMPC, Vistide) to the antiretroviral therapy of a 33-year-old white man diagnosed as having progressive multifocal leukoencephalopathy (PML) secondary to AIDS. In response to combined cidofovir and antiretroviral therapy he showed significant clinical improvement. MRI showed a decrease in extent of existing lesions, without new ones. Blood chemistry information obtained indicated some involvement of immunologic mechanisms: the CD4:8 ratio showed improvement from an average of 0.08 before treatment to 0.13 during therapy.

[Necrotizing enterocolitis: a historical and current review]. / Darmbrand (Enteritis necroticans). Eine historische und aktuelle Ubersicht.

Enteritis necroticans, locally called "Darmbrand", is a severe and life threatening infectious disease which was epidemic in Northern Germany after World War II. Darmbrand had a limited appearance, occurring only for a few years. In Lübeck many cases were diagnosed in 1946/1948 and the book "Darmbrand, Enteritis necroticans" was published in 1949 by clinicians and pathologists. Enteritis necroticans is also known as a tropical cause of bloody diarrhea and is caused by Clostridium perfringens Type C (type beta-toxin). The disease is related to pig feasts in Papua New Guinea. Although necrotizing enterocolitis is now a rather rare disease we must be aware of the appearance of this fulminant entity. This paper represents a review on the historic and current aspects of enteritis necroticans and discusses the epidemiology, pathogenesis and treatment of this disease.

The impaired immune response to diphtheria vaccination in elderly chronic hemodialysis patients is related to zinc deficiency.

Zinc deficiency causes abnormalities of the immune response. In chronic hemodialysis therapy abnormalities in zinc metabolism as well as an impaired immune response to vaccination have been reported. Therefore we performed a vaccination study against diphtheria and hypothesized that the response to diphtheria vaccination is related to serum zinc deficiency in hemodialysis patients. Serum zinc concentrations were assayed in 16 chronic hemodialysis patients (10 male, 6 female; mean age 65 years) without a documented vaccination history against diphtheria. Nine of these patients were triple immunized against diphtheria while seven received a single vaccination. The response to diphtheria vaccination was measured by ELISA detecting specific antibodies to diphtheria-toxoid. Seroconversion 6 and 12 months after vaccination was defined as the doubling of antibody titers in patients > or = 0.1 IU/ml prior to vaccination or as titers > 0.1 IU/ml in all other patients. Only 6/16 hemodialysis patients responded to immunization against diphtheria by specific antibody production (> 0.1 IU/ml). Twelve months after the single injection 3/7 patients seroconverted while six months after the triple vaccination 3/9 patients responded to immunization. This was not age-dependent, whereas in non-responders we detected significantly decreased serum zinc levels. In contrast, responders showed similar serum zinc levels as age-matched controls. Furthermore, we measured a decreased alpha 2-macroglobulin concentration only in the responders amongst the hemodialysis patients. Protection against diphtheria and the immune response to diphtheria vaccination in hemodialysis patients is poor. The failure to respond to active diphtheria vaccination is related to a significantly decreased serum zinc concentration in hemodialysis patients.

When to try COX-2-specific inhibitors. Safer than standard NSAIDs in some situations.

COX-2-specific inhibitors, by sparing COX-1 enzyme and its physiologic functions, are a safer option than regular NSAIDs in patients who are at risk for gastrointestinal bleeding (e.g., patients with a history of peptic ulcer disease, gastritis, alcoholism, concomitant corticosteroid or anticoagulant use). They have been approved for use in arthritis, and their efficacy is comparable to that of other NSAIDs. Further clinical data are needed to establish the long-term safety profile of these newly introduced drugs.

[POEMS syndrome with chronic renal failure]. / POEMS-Syndrom mit Niereninsuffizienz.

CASE HISTORY AND CLINICAL FINDINGS: A 43-year-old male was admitted to the hospital because of subfebrile temperatures since 3 months, weight loss of 9 kilogramms and lateral foot pains with bilateral leg edema. Over the last years, the patient had consulted a doctor several times for upper respiratory infections, orchitis and a spinal neck syndrome. At the physical examination, we found a temperature of 37.4 degrees C, no rales, no crackles at auscultation of the lung, bilateral ankle edema and livid, pressure-dolent skin changes at the lateral margins of both feet. The blood pressure was 170/100 mmHg. EXAMINATIONS: The following pathologically laboratory results were found: erythrocyte sedimentation rale (ESR) 35/55 mm n. W., C-reactive protein (CRP) up to 39 mg/l, leucocytes up to 13.5/nl, LH and FHS were elevated corresponding to hypergonadotropic hypogonadism, renal failure with at the beginning a selective glomerular proteinuria, as well as a monoclonal IgG-gammopathy. The bone marrow aspiration as well as the bone marrow biopsy revealed neither plasmocytoma nor a malignant systemic disease. The ultrasound examination showed enlarged liver, spleen, and kidneys. TREATMENT AND FOLLOW-UP: After excluding a connective tissue disease and an infection and with the missing proof of a malignant tumor treatment was started with parenteral methylprednisolon 500 mg on 3 consecutive days under the hypothesis of classic panarteriitis nodosa, even when multiple biopsies were negative. Under the treatment, the elevated inflammatory parameters and renal failure improved, but deteriorated quickly after discontinuation of the corticosteroid medication. The second kidney biopsy showed a chronic scaring glomerulopathy of the hemolytic uremic syndrome type. In the follow-up the renal insufficiency was improved by corticosteroids. With the manifestation of a bilateral sensory polyneuropathy in January 1994, the diagnosis of a POEMS syndrome was most likely. CONCLUSION: According to the literature, up to 50% of the cases with POEMS syndrome reveal renal failure. Most times a glomerular microangiopathy is shown histologically. A treatment trial with corticosteroids is justified.

Defective immune response to tetanus toxoid in hemodialysis patients and its association with diphtheria vaccination.

The incidence of infectious diseases is increased in patients with chronic renal failure. This is thought to be due to an impaired T cell stimulation by antigen presenting cells. Immunization programs are of great significance in the prevention of infections in immunocompromised individuals. However, the immune response to various vaccinations is impaired in patients with chronic renal failure. So far only few studies have focused on seroresponse to tetanus toxoid. Therefore we measured the levels of antitetanus toxoid antibodies in 71 hemodialysis patients with unknown vaccination history. The antibody levels were detected prior to and twelve months after a single "Td" or "Td-d-d" vaccination. Initially only 31 (44%) of the patients had a sufficient protection against tetanus. Of the unprotected patients 15 (38%) seroconverted after immunization, while 25 (63%) did not respond. We found a high association (p < 0.04, Fisher's exact test) between the efficacy of vaccination against diphtheria and tetanus. Out of 38 initially unprotected patients 27 (71%) showed a similar response to both vaccines: 9 (24%) individuals seroconverted, while 18 (47%) did not. Our data clearly demonstrate the need for frequent monitoring of antibody levels after immunization against tetanus and diphtheria in hemodialysis patients.

Adherence of Staphylococcus aureus isolated in peritoneal dialysis-related exit-site infections to HEp-2 cells and silicone peritoneal catheter materials.

BACKGROUND: Peritoneal catheter exit-site infections cause a relevant morbidity in peritoneal dialysis patients and are frequently caused by Staphylococcus aureus. We tested the hypothesis that adherence of exit-site-derived S. aureus to epithelial cells and peritoneal catheter silicone tubes discriminates virulent and less virulent strains. METHODS: The binding of isolated S. aureus to an epithelial cell line (HEp-2) and to silicone tubes was analyzed using light-microscopy or radioactive labeling of bacteria. RESULTS: Of 378 exit-site swabs, 99 (26%) were positive for microbial growth. S. aureus was cultured in 25 of 99 positive swabs; three of 13 swabs taken in exit-site infections grade 3 and 4 that had tested positive for S. aureus. Adherence of S. aureus from exit-site infections grade 2, 3 and 4 to Hep-2 cells did not differ from adherence of bacteria isolated from asymptomatic or moderately inflamed catheter exit sites (grade 0-2). However, binding of S. aureus to silicone tubes was enhanced in grade 0/1 compared with grade 2-4 exit-site isolates. CONCLUSIONS: Staphylococcus aureus is an important pathogen in CAPD-related exit-site infection being isolated in about 6.6% of all exit-site swabs (and in 25% of all positive swabs). Silicone-adhesive strains may be of more clinical significance in peritoneal dialysis patients since adhesion to silicone was increased in S. aureus strains isolated in more severe exit-site infections.

The difficulties of differentiating vasculitis from its mimics.

The signs and symptoms of vasculitis are not specific, and tests for confirming the diagnosis can be misleading. Thus, when considering a diagnosis of vasculitis, physicians need to keep an open mind. With a case vignette, the author illustrates some of the difficulties in diagnosing "vasculitis."

Laparoscopic nephrectomy: comparison of dialysis and non-dialysis patients.

BACKGROUND: Laparoscopy is believed to result in possible clinical benefits for the patient. We report our experience with renal laparoscopy in dialysis patients and compare the results with those from non-dialysis patients. METHODS: Between December 1994 and April 1997, 19 dialysis patients underwent laparoscopic nephrectomy or nephroureterectomy at our hospital. The group consisted of 11 female and eight male patients (mean age 45 years). In nine patients the indication for nephrectomy was chronic pyelonephritis. Nephroureterectomy for vesicoureteral reflux with recurrent episodes of pyelonephritis or analgesic nephropathy for exclusion of transitional cell carcinoma of the upper urinary tract was considered in nine other patients. Laparoscopic bilateral nephrectomy for drug-resistant hypertension was performed in one patient. In comparison, a consecutive group of non-dialysis patients who had undergone renal laparoscopy was reviewed. RESULTS: In the dialysis group, one patient had to be converted to open nephrectomy due to bleeding. Six dialysis patients required blood transfusions compared with none in the non-dialysis group. There were four complications in the dialysis group and two in the non-dialysis group. Both groups had comparable results for operative times, analgesic consumption, postoperative start of oral intake and mobilization, and duration of hospitalization and convalescence. CONCLUSIONS: Laparoscopic nephrectomy in dialysis patients has acceptable results. The higher transfusion rate is probably due to a lower preoperative haemoglobin and is not aggravated by possible affects of the clotting system in patients with chronic uraemia.

Treatment of posttransplant hypertension by laparoscopic bilateral nephrectomy?

BACKGROUND: Hypertension is an important risk factor for the development of chronic graft failure and decreased graft and patient survival after renal transplantation. METHODS: Between September 1994 and August 1996, 14 patients underwent laparoscopic bilateral nephrectomy for treatment of drug-resistant hypertension after successful renal transplantation. Common causes of hypertension were largely excluded before bilateral nephrectomy. A scoring system was developed for comparison of different antihypertensive regimes. In this system, points were given according to type and dosage of each antihypertensive drug. RESULTS: At 6-month follow-up, all patients showed well-controlled blood pressure (median of mean arterial pressure: 104 vs. 130 mmHg preoperatively, P<0.001, n=14), and significantly fewer antihypertensive drugs were needed according to the scoring system (48.9+/-20.9 points vs. 105.9+/-23.5 points preoperatively, P<0.001, n=14). During laparoscopy, three conversions to open surgery were necessary. Postoperatively, four complications occurred. After laparoscopy, immunosuppression and other oral medication were given continuously. The hospital stay ranged between 3 and 6 days (median: 5 days). CONCLUSIONS: The results indicate that bilateral nephrectomy using the laparoscopic technique can be an effective alternative method for a selected group of patients with severe hypertension, which is unresponsive to conservative management after successful renal transplantation with regard to improving the long-term graft survival.

Serum erythropoietin and creatinine concentrations as predictive factors for response to recombinant human erythropoietin treatment in anaemic tumour patients on chemotherapy.

Recent studies have shown that recombinant human erythropoietin (rHuEPO) is effective in correcting anaemia in about 50% of tumour patients. Predictive parameters for the response to rHuEPO still need to be established. In the present prospective study, rHuEPO therapy was scheduled in 22 patients with solid tumours for 12 weeks (3x10,000 U rHuEPO/week s.c.). If response was not achieved within 4 weeks, the dose was increased to 3x20,000 U rHuEPO/week. All patients received combined chemotherapy (ifosfamide, carboplatin, etoposide) before and during rHuEPO therapy. 10 of the 22 patients responded to rHuEPO and did no longer need blood transfusions. In 8 of the 10 responders and in 2 of the 12 non-responders serum creatinine concentration was increased before rHuEPO therapy was started. In addition, the endogenous serum EPO concentrations were significantly lower in the responders versus the non-responders. We conclude that rHuEPO is primarily effective in patients with chemotherapy-induced renal impairment. The rate of the response to rHuEPO is high when the baseline serum EPO level is <75 U/l and the serum creatinine concentration is greater than normal (or the estimated creatinine clearance <60 ml/min).