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Mollie A. Scott, PharmD, BCACP, FASHP, CPP

• Regional Associate Dean
• Clinical Associate Professor, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina

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Colonies may appear flat or raised symptoms 97 jeep 40 oxygen sensor failure purchase 15 mg triamcinolone overnight delivery, smooth or rough; may pit the agar; or may hemolyze red blood cells in blood-containing agar treatment definition 40 mg triamcinolone purchase mastercard. Skilled microbiologists often have a very good idea of the identification of a microorganism based solely on its colonial appearance treatment ketoacidosis triamcinolone 15 mg order without prescription. In specimens that come from an area of the body with a resident microbiota symptoms stomach ulcer cheap triamcinolone 40 mg with visa, it is important to separate the colonies of organisms that may represent the resident microbiota from the colonies of organisms that may be pathogens treatment 21 hydroxylase deficiency triamcinolone 4 mg buy otc. In patients with suspected bacterial pneumonia, a sputum specimen may be obtained. Sputum consists of secretions coughed up from the lower airways that are expectorated through the oropharynx and submitted for culture. Because they pass through the oropharynx, sputum specimens almost always contain viridans group streptococci. The appearance of colonies produced by viridans group streptococci is very similar to that produced by A Primer on the Laboratory Diagnosis of Infectious Diseases 19 S. Bacteria are typically identified on the basis of colonial morphology, Gram stain reaction, the primary isolation media on which the organism is growing, and biochemical and serologic tests of various degrees of complexity. Yeasts are identified in much the same way that bacteria are, while molds are generally identified on the basis of the arrangement of microscopic reproductive structures called conidia. First, a patient with a "strep throat" has group A streptococci recovered from his throat. Although the organism is clearly playing a role in the illness of this patient, antimicrobial susceptibility testing is not warranted. This organism is uniformly susceptible to first-line therapy-penicillin-and is susceptible more than 98% of the time to second-line therapy-the macrolide antibiotics such as erythromycin-although recent reports suggest that erythromycin resistance is becoming more frequent in this organism. Susceptibility testing is indicated because some strains are resistant to the first-line drugs used to treat this infection-semisynthetic penicillins, including oxacillin and dicloxacillin- and the second-line drug, clindamycin. In this situation, the patient may be started on empiric antimicrobial therapy until the susceptibility of the organism is known. If the organism is resistant to the agent used for empiric therapy, then the patient should be treated with an alternative antimicrobial agent to which the organism is susceptible. However, no susceptibility testing is done by the laboratory, and this practice is acceptable to the clinician caring for the patient. If the laboratory had performed the susceptibility testing without considering that this isolate was a potential contaminant, they would be validating that the isolate was clinically significant. In this setting, the laboratory should only do susceptibility testing if instructed to by the caregiver, who is in a better position to know if this organism is clinically important. All the approaches are highly standardized to ensure that the susceptibility results will be consistent from laboratory to laboratory. Screening of selected organisms for resistance to specific antimicrobial agents is one strategy that is frequently used, especially with the emergence of resistance in three organisms: S. The E-test is a plastic strip that contains a gradient of a specific antimicrobial agent. Because of their slow growth, special susceptibility testing techniques are used for the mycobacteria. Rather, they can only grow by parasitizing living animal cells (including human cells) that are maintained by continuous tissue culture. Animals such as mice, or chicken eggs, can be inoculated in an attempt to isolate certain viruses, but this approach is rarely done. Tissue culture for Chlamydia may still be attempted, especially in situations where the detection of C. Tissue culture is still an important technique for the detection of viruses in many laboratories, though laboratories are converting to molecular methods for viral detection at an increasing rate. Herpes simplex virus can be isolated from skin and genital tract lesions, often within the first 24 hours of incubation. Another herpesvirus, varicella-zoster virus, the etiologic agent of chicken pox and herpes zoster, can also be isolated from skin lesions, but it typically requires 3 to 7 days to grow. The enteroviruses are the major etiologic agents of aseptic meningitis and can be isolated from cerebrospinal fluid, but at a significantly reduced rate compared with molecular detection. A modification of the tissue culture technique is done to detect cytomegalovirus and several respiratory viruses in clinical specimens called rapid centrifugation cultures or shell vial cultures. In this method, the specimen is centrifuged onto tissue culture cells that are growing on a round glass coverslip inside a vial referred to as a shell vial. The cells are incubated for a brief period of time (24 to 72 hours) and then stained with fluorescent antibodies to detect the virus. This technique is much more rapid and sensitive than conventional tissue culture but is still less sensitive than molecular detection. In those situations, an alternative approach is to determine if the patient has mounted an immune response against a specific agent as evidence that he or she has been infected with that agent. The immune response is generally measured by detecting antibodies in the serum of patients-thus the name serology. Depending on the target antigen against which the immune response is measured, the test can show both high sensitivity and high specificity. Compared with other techniques, these tests are relatively inexpensive and easy to perform, in part because they have been automated. As a result, they can be used to screen large numbers of specimens for selected infectious agents. Serologic tests also have several disadvantages and should be interpreted with some caution. Serum obtained from an acutely ill patient may have been taken during the window period in an infection before the patient had time to mount an immune response. Therefore, to get the most accurate result, acute and convalescent specimens should be obtained. The convalescent specimen should show a significant increase (or, in some cases, decrease) from the antibody level of an acute specimen. Because the convalescent specimen should be obtained a minimum of 2 weeks after the acute specimen, serologic diagnosis is often retrospective. Because obtaining a convalescent specimen is often difficult logistically, the only value that may be available is that from the acute specimen. Patients may have relatively high antibody levels because of previous infection with the test organism and, as a result, may have a false-positive result. Antigenic cross-reactions between the test organism and other antigens may also lead to false-positive results. Some immunocompromised patients are unable to mount a response and may never have a positive serologic test. Serologic tests can be done in combination using a screening test followed by a confirmatory test. The screening test should be highly sensitive so that all true-positive results will be detected. This test may not be highly specific, meaning that some results may be false positives. It should also be easily performed, so that large numbers of specimens can be tested fairly inexpensively. The confirmatory test needs to be highly specific so that the correct diagnosis can be applied to the patient who screens positive for the infectious agent. It tends to be much more expensive and technically complex than the screening test. In this technique, a patient is considered to be positive for the agent only if the patient has antibodies to multiple specific antigens. First, the number of microorganisms that frequently cause infection in these organs is somewhat limited. The urethra is shorter in women than in men, and straight rather than curved as in men, making it easier for microbes to ascend to the bladder. Prostatic secretions have antibacterial properties, which further protects the male. In particular, irreversible damage to reproductive organs, caused by both Chlamydia trachomatis and Neisseria gonorrhoeae, is all too common. Infections with these two organisms are almost always symptomatic in males, though the few men who do not have symptoms can be responsible for infecting many partners. By contrast, a significant number of women may be infected asymptomatically at first. They may manifest signs and symptoms of infection only when they develop pelvic inflammatory disease, which can result in sterility. Only organisms in this table should be considered in your differential diagnosis for the cases in this section. You should note that not all organisms that can be spread sexually, such as hepatitis B virus and Entamoeba histolytica, are listed. One day later she developed left flank pain, fevers, and chills and noted increased urinary frequency. Urinalysis of a cleancatch urine sample was notable for >50 white blood cells per high-power field, 3 to 10 red blood cells per high-power field, and 3+ bacteria. Briefly explain the evolution of the organism causing this infection in terms of its ability to infect the urinary tract. What virulence factors have been shown to play a pathogenic role in this infection Urine from normal individuals usually has <10 white blood cells per high-power field. The presence of bacteriuria (bacteria in urine) in this patient further supports this diagnosis. However, the presence of bacteriuria on urinalysis should always be interpreted with caution. Clean-catch urine, which is obtained by having the patient cleanse her external genitalia, begin a flow of urine, and then "catch" the flow of urine in "midstream," is rarely sterile because the distal urethra is colonized with bacteria. Therefore, if urine is not analyzed fairly quickly (within 1 hour), the organisms colonizing the urethra can divide (two to three generations per hour) if the urine specimen is left at room temperature rather than refrigerated or immediately planted on culture media. Organisms colonizing the urethra may be present in sufficient numbers to be visualized during urinalysis even when the patient is not infected. As a result of urethral contamination, essentially all clean-catch urine samples will contain a small number of organisms, so culturing urine nonquantitatively will not allow differentiation between colonization of the urethra and infection of the bladder. It should be noted that only a small number of clinical specimens other than urine are cultured quantitatively. Patients in whom the bladder is infected tend to have very large numbers of bacteria in their urine. The observation that the organism is beta-hemolytic indicates that, in all likelihood, the organism is E. Another common Gram-negative rod that is frequently beta-hemolytic is Pseudomonas aeruginosa, which is very unlikely to be the cause of community-acquired cystitis or pyelonephritis in an otherwise healthy woman. This organism is incapable of fermenting carbohydrates and should not be confused with lactose-fermenting isolates of E. One of the deleterious effects associated with the use of antimicrobial agents is the selection of antibiotic-resistant bacteria. This occurs with some degree of frequency in gut flora, where plasmids coding for resistance may be mobilized in response to antimicrobial pressure, leading to the transfer of resistance to previously susceptible organisms, such as in this E. Not only may resistance to the agent supplying the selective pressure result, but also the plasmid may contain genes that code for resistance to other antimicrobial agents, the end result being a multidrug-resistant organism. Mutations in the active site of the -lactam "extend" the activity of the -lactamases so that they are active against all penicillins and cephalosporins. Both fluoroquinolones and trimethoprim-sulfamethoxazole are widely used as empiric therapy for cystitis in women. Nitrofurantoin is not active against carbapenemase-producing strains, while fosfomycin has some degree of activity and may be useful in treating cystitis. However, fosfomycin is poorly absorbed systemically and should not be used to treat patients with pyelonephritis, such as the patient in this case, or urosepsis. It is one of the most common reasons why adolescent and adult women seek health care, resulting in ~10 million physician visits annually in the United States. Sexual activity is thought to play a significant role in the introduction of uropathogens into the urethra. However, other factors that may play a role in this gender difference have been identified. It has been observed that prostatic fluid inhibits the growth of common urinary tract pathogens in urine, providing a unique defense mechanism for men. It has also been observed that specific uropathogens bind to vaginal and periurethral epithelial cells. Binding of uropathogens to the periurethral epithelium is highest when estrogen levels reach their peak during the menstrual cycle. The clinical presentation in this patient is consistent with acute pyelonephritis. Pyelonephritis is an infection of the kidney, whereas cystitis is an infection of the bladder. The findings of fever, chills, and left flank pain, with corresponding costovertebral angle tenderness, are all consistent with pyelonephritis. Culture results would not be useful in differentiating between the two types of infections. Radiographic or cystoscopic studies would be necessary to make a definitive diagnosis of pyelonephritis, but clinical judgment is usually sufficient. The reason it is important to distinguish between pyelonephritis and cystitis is that antimicrobial treatment strategies differ. Cystitis therapy is usually brief, typically a 3-day course of trimethoprim-sulfamethoxazole unless there is a high rate of resistance to this agent in the community, while pyelonephritis therapy may be more prolonged, typically lasting 7 days to 2 weeks. The outcome of antimicrobial therapy is dependent in great part on the susceptibility of the E.

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart fail medicine bow purchase triamcinolone on line. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo medications interactions order 10 mg triamcinolone amex. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury medicine you cannot take with grapefruit cheap triamcinolone 4 mg with mastercard. Some investigations have identified a few cell/stem cell types that are promising for cardiac regeneration but many cells/stem cells are thought to be unsuitable for cardiac repair treatment regimen best 40 mg triamcinolone. While our understanding of mechanisms of certain cell-mediated or stem cell-mediated cardiac regeneration has undergone considerable evolution medications help dog sleep night 4 mg triamcinolone buy fast delivery, there are many challenges before clinical application. In this chapter, we will introduce important cell/stem cell types in cardiac regeneration; discussing common and distinct properties of these cells, advantages and limitations of animal models, assessment of the clinical investigations and therapeutic mechanisms. Key words: cardiac repair and regeneration, cell- and stem cell-based therapy, cell types, preclinical and clinical studies. Although there are many types of heart disorders, congestive heart failure serves as the final form for all cardiovascular diseases ­ a terminal stage and period for all heart diseases. It is generally accepted in the cardiovascular field that mechanical ventricular assist devices can provide benefits to improve cardiac function, but the problems such as complicated infection and blood clots remain to be further studied. However, shortage of organs, avoidance of transplant rejection and cost limit its application 63 © 2014 Woodhead Publishing Limited 64 Cardiac regeneration and repair on a larger scale. Obviously, most of the medications and interventions currently available only act to prevent further damage to the myocardium, reduce the risk of on-going cardiovascular events, raise the cardiac pumping efficiency, decrease cardiac pressure and volume burden, and lower early mortality rates; none of these treatments can regenerate or repair damaged cardiac tissue or restore heart function. Consequently, it is acceptable and agreeable to replace dead cardiac cells with young immature cells to regenerate damaged or necrotic heart myocardium. The first and most important question is what types of cells could be implanted and grown into cardiac cells with full activity. After years of hardworking research and preclinical application, researchers have selected embryonic and adult-derived stem cells for cardiac repair. Several types of stem cell or cell have been studied as possible sources for regenerating broken cardiac muscle. All of these candidate cells have been tested in animal experiments, some in smaller animal models such as mouse or rat,3­5 some in larger animal models such as pigs and sheep. Researchers have attempted to treat and prevent heart failure through cell transplantation since 1992. Because there are limited treatment methods for heart failure from a cardiovascular approach, this massive achievement is intuitively appealing to regenerative medicine, and cell transplantation therapy has contributed to a crescendo of activity in cell-based cardiac repair and will be an effective therapeutic option in the near future. Scientific research highlights a new and fundamental method to help treat heart failure by replacing the injured heart with new viable cardiac muscle tissue to restore its function. An ideal cell population for cell transplantation would fulfill the following criteria: (1) easily cultured and expanded and stored; (2) conveniently available at any time; (3) definitely differentiated into cardiomyocytes and other cells in myocardium; (4) full ability to proliferate after being implanted into cardiac muscle to repopulate large expanses of damaged cardiac tissue; (5) capability of simulating host cells or Optimal cells for cardiac repair and regeneration 65 transformed into relative cells to generate a new coronary vasculature; (6) ensured immune tolerance to avoid being ejected; (7) the minimal amount of scar tissue at the graft­host interface. It is obvious that this must be an ideal cell and no cells at present can meet all of these criteria at the same time, but key elements are starting to come together through detailed exploration and careful research. In contrast to leukemia treatment, stem cell therapy for heart failure, to regenerate damaged myocardial tissue, is more difficult; which has led researchers to thoroughly explore the application of embryonic and adult-derived stem cells for many years. Although some stem cells or cells have not been widely applied in clinical trials of cardiovascular disease, preliminary results from animal and basic experiments indicate several potential applications in the clinic. Nevertheless clinical trials to date using stem cells to repair damaged myocardium vary in terms of the treated condition, cell delivery system, and measured parameters or indices. Their availability from autologous or syngeneic origin, good proliferative ability, commitment to a myogenic lineage, and potential to withstand tissue ischemia better than other cell types have promoted their application as the initial choice among stem cell lines and they have been explored extensively for regenerating infarcted myocardium. However, it is now very clear that the answer is that myoblasts remain unchanged morphologically, stubbornly committed to form mature skeletal muscle in the heart11,19,20 with the exception of rare cell fusion events at 66 Cardiac regeneration and repair the graft­host interface. This may be because skeletal muscle cell has no potential to express gap junction proteins under normal conditions. Another study has shown that autologous skeletal muscle cell transplantation improves cardiac function in snake cardiotoxin-induced lesions in sheep and cryoinjury-induced scars in rats. In all studies myoblasts were isolated from muscle biopsies by enzymatic dispersion, then the cells were expanded for several weeks in culture using fetal bovine serum as a mitogen and finally the cells were injected into discrete akinetic and metabolically inactive scars. In four of the six studies, myoblasts were implanted at the time of coronary artery bypass grafting or left ventricular assist device implantation; in the remaining two the myoblasts were introduced through either a catheter-based endoventricular33 or a coronary sinus transvenous approach. A clinical trial34 in 2003 (n = 12) has shown that treatment with skeletal myoblasts in conjunction with coronary artery bypass is safe and feasible, just as some studies in rats and humans demonstrated that these cells can repopulate scar tissue and improve left ventricular function following cell transplantation. In this study, six patients received myoblasts at the time of left ventricular assist device implantation and four of them had their hearts retrieved during subsequent transplantation. Mature skeletal muscle was identified in the hearts, providing powerful proof that engrafted myoblasts were existing and living in human scarred myocardium, and providing evidence to support the feasibility and safety of the procedure. The major findings from the skeletal myoblast trials can be summarized as follows: Optimal cells for cardiac repair and regeneration 67 Countless myoblasts can be isolated and expanded in culture from a small muscle biopsy and subsequently transplanted into the target myocardial scar without specific procedural risks and complications under good conditions. Long-term engraftment of myoblasts occurs, featuring clusters of skeletal myofibers aligned parallel to host cardiomyocytes and embedded in scar tissue. It is expected that a large-scale, multicenter, double-blind, placebo-controlled, dose-ranging, randomized study will provide more detailed data for the feasibility and efficacy of myoblast therapy in heart failure. There are some reports focusing on a collective of bone marrow stem cells in regenerating damaged myocardium, and others on certain individually defined stem cells such as mesenchymal stem cells and mononuclear cells. These cells have the potential to generate myocardium composed of integrated cardiac cells and coronary vessels. Only 9 days after these stem cells were transplanted, the newly formed myocardium occupied nearly 70% of the broken portion of the ventricle, and survival rates of mice were greater in those receiving these cells than in those that did not. As a consequence, it was suggested that bone marrow cells have the potential to regenerate infarcted myocardium. While several subsequent studies have questioned whether these bone marrow-derived cells actually differentiate into cardiac myocytes,44,45 evidence of their ability to prevent remodeling and improve cardiac function has been provided by many laboratories. The proportional contribution of cells from bone marrow was smaller compared with non-bone marrow cells in an infarction model. Magnetic resonance imaging demonstrated that the cell therapy group had a significant improvement in left ventricular ejection fraction, without significant trends for improved end diastolic and end systolic volumes. In the 2005 American College of Cardiology meeting, it was announced in a double-blind, randomized and placebo-controlled report from Belgium49 that 32 patients received intracoronary unfractionated bone marrow cells within 24 hours of acute infarction. Magnetic resonance imaging demonstrated that bone marrow cell infusion was associated with greater infarct portion shrinkage. Catheter-based management is conventional to treat coronary heart disease, so that it is considered to be convenient to use catheter-based bone marrow cell injections to treat refractory ischemia50 and heart failure. The authors of these pilot experiments have reported striking and encouraging outcomes, but the investigated patient populations were small and there was a lack of standard control groups. The results have suggested that there is little evidence to assess the clinical effects of this treatment, Optimal cells for cardiac repair and regeneration 69 indicating a need for method standardization. Various factors should be taken into account to reduce the systemic heterogeneity, including cell dosing, cell product formulation, timing of cell transplantation and patient selection. Microvascular function was significantly restored, shown by a marked improvement in maximal vascular conductance capacity. Several points can be summarized from these preclinical trials of bone marrow for cardiac repair. It is recognized that direct injection or intracoronary infusion of bone marrow cells appears to be feasible and safe. One of the major goals for bone marrow studies will be to identify the therapeutic cell population from these complex mixtures. This effective action is apparently without relation to a myogenic pathway, which would not be evident in such an extremely brief period. Previous studies also pointed out that their limited frequency meant that the transplanted stem cell-derived cardiomyocytes were unlikely to be the main contributors to the restoration of the ischemic organs. Although there was no change in ejection fraction, there was an overall improvement in the extent of hypokinesis and dyskinesis in the treated group that was absent in the control group. Endothelial progenitor cells the endothelium is the inside layer (interior surface) of all blood vessels including the heart; it consists of a layer of specialized cells that provides an interface between circulating bloodstream and the blood vessel wall. Granulocyte colony-stimulating factor can stimulate and motivate them to come out of bone marrow into the peripheral blood pool. In this way, these cells acquired the possibility of being used in animal or human trials. The results showed elevated left ventricular ejection fraction, increased myocardial perfusion, enhanced coronary flow reserve, and lifted glucose uptake after infusion of these two types of cell. It is commonly recognized that such limited potential of endogenous repair mechanisms most likely facilitates minor repair and turnover-mediated cell replacement,17 but they are in themselves grossly insufficient to make compensation for the rapid and large-scale loss of functional cardiac cells or to restore lost myocardium or cardiac function. They first discovered the successful induction of induced pluripotent stem cells from mouse embryonic or adult fibroblasts by adding four factors (Oct3/4, Sox2, c-Myc and Klf4). These cardiopoietic cells were delivered into infarcted myocardium to give rise to new cardiac cells integrating with host myocardium and remaining tumor-free. Some of them are beyond the scope of biomedicine and must be answered and guided by people from all walks of life. Fibroblasts are cells that are responsible for synthesizing the extracellular matrix in the connective tissues. Autologous fibroblasts may be artificially manipulated to express muscle-specific transcription factors that induce differentiation into myotubes similar to those derived from skeletal myoblasts. Smooth muscle cells are Optimal cells for cardiac repair and regeneration 77 mainly present in the walls of vessels and organs. Fibroblasts and smooth muscle cells are clearly different from cardiomyocytes, and smooth muscle cells cannot contract like cardiomyocytes. Although current knowledge is insufficient, all possible beneficial mechanisms such as increasing perfusion through angiogenesis and arteriogenesis, improving the infarcted connective tissue, and enhancing myocyte or other cell survival rates must be related to paracrine effect. Combining various cell populations would allow various objectives to be dealt with. Stem cell-derived cardiomyocytes are used to target cardiomyocytes, plus endothelial progenitor donor cells to target the vascular structure. One of these concerns growth factors and other molecules released by transplanted stem cells to simulate angiogenesis or promote resident cardiac stem cells to repair tissue damage. Cardiomyocyte apoptosis is thought to underlie left ventricle remodeling and heart failure. Recent studies have demonstrated that some transplanted stem cells have this anti-apoptotic capability. Several Optimal cells for cardiac repair and regeneration 79 routes can be used to deliver transplantation cells to the myocardial wall or to the coronary bloodstream in patients, which include intravenous infusion, direct injection into the heart wall by way of transepicardial or transendocardial infusion. In preliminary studies, common approaches include intravenous injection and direct infusion into the coronary arteries through cardiac catheter in patients whose blood flow has been restored to a certain extent after a heart attack without total occlusion of arterial vessels or poor arterial flow of local myocardium. Intracoronary infusion provides the advantage of direct local delivery, which helps to increase the number of transplanted cells that reach the target tissue and increase their survival rate. The method of intravenous injection or intracoronary infusion becomes limited and less useful when the local circulation is poor or when blood vessels are almost totally occluded. This endomyocardial injection may be performed either via a catheter50 or during open-heart surgery. Patients with heart failure in the end-stage may be expected to become candidates as they are no-option patients. Transplantation cells are best transported and delivered at the time of device installation, guided by imaging techniques. After heart transplantation is finished, the cell-engrafted native heart can be studied histopathologically and pathologically by cellular, molecular and other techniques. Skeletal myoblast-originated ventricular tachycardia Although stem cells are safe in the majority of trials, an increased frequency of non-sustained ventricular tachycardia, a life-threatening form of arrhythmia, has 80 Cardiac regeneration and repair been reported in some skeletal myoblast-based trials, with a possible mechanism of lacking electrical coupling between skeletal myoblast-derived cells and host cells. Because sample sizes were not large enough to provide full evidence, larger trials should be designed to explore these issues more systematically and scientifically. Apoptosis control Results of some cell-transplant trials suggest that cell survival versus cell death after transplantation is a major limiting factor for successful engraftment and differentiation. For skeletal muscle cell, neonatal cardiomyocyte, smooth muscle cell, and bone marrow stem cell, the survival after transplantation in the infarcted heart portion varies from 4 to 28%. Interactions among different signal transduction pathways that may control donor cell death are still waiting to be further studied. As soon as stem cells have been transplanted inside the body, undesirable interactions between the host tissue and the injected cells must be limited and minimized. Animal models have shown that stem cells have the ability to rapidly diffuse from the heart to other organs such as lungs, kidneys, liver or spleen within a few hours of transplantation,158,161,162 a phenomenon observed regardless of whether the cells are injected locally into the myocardial site or not. Techniques to label and track transplanted stem cells are vital to assess their ultimate destinations and migration mechanisms. With the help of labeling techniques, research has learnt to understand how stem cells target injured tissue162 and how stem cells travel in the context of cardiac regenerative therapy. Most studies published to date have enrolled smaller samples, and different studies vary in terms of cell types, preparation methods, and delivery systems, and the transplanted cells may be autologous or allogeneic in origin. The current wide application of stem cells has made it difficult to compare and contextualize the results generated by various trials. Other nations also active in cardiac cell research include the Netherlands (Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht), France (Department of Cardiovascular Surgery B, Hôpital Bichat, Paris), Israel (Cardiovascular Research Laboratory, Department of Physiology and Biophysics, the Bruce Rappaport Faculty of Medicine, 82 Cardiac regeneration and repair Table 4. Technion-Israel Institute of Technology, Haifa), Poland (Department of Cardiology, Source University School of Medical Sciences, Pozna) and China (Division of Cardiology, Nanjing First Hospital, Nanjing University, Jiangsu). In 2000, bone marrow-derived cells were recognized as promising alternative candidates. The starting years of study for the main cell types used in recovery of heart failure are listed in Table 4. Selected stem cells have been applied in some animal models and in clinical trials for cell transplant therapy; an outline of recipient analysis of candidate cells described in this chapter has been listed in Table 4. Though many efforts and trials have been carried out, the small experimental sample size seriously limits the unification and confidence of every trial (Table 4. Fibroblast cells with the risk of myocardial fibrosis make them unsuitable candidates also. Optimal cells for cardiac repair and regeneration 87 preclinical studies and one major issue is how to maintain and scale-up production to meet clinical requirements.

Suturing Interrupted deep dermal sutures to approximate skin edges and gather any discrepancy between upper and lower flaps are advisable prior to a subcuticular suture medicine zyprexa purchase 4 mg triamcinolone. In women with excess lateral tissue treatment quadriceps pain cheap 40 mg triamcinolone with visa, it is often useful to complete the mastectomy with minimal extension of the scar laterally and then tidy this part of the scar medicine 8 iron stylings buy discount triamcinolone on-line. The easiest way to do this is to close the skin with temporary placement of skin staples medicine questions order triamcinolone with mastercard. This then allows variations of lateral scar closure to be visualised before commitment to any particular one symptoms jaw bone cancer buy triamcinolone overnight. The staples can be removed and replaced as many times as necessary to get the best and shortest scar. Final wound closure is with two layers of absorbable deep and superficial subcuticular absorbable sutures. Cases in which difficulty with the lateral tissue is predicted preoperatively can be performed either with the patient on their side (ideally) or with some degree of rotation. Women with excess lateral tissue can be challenging cases, and should be managed by those familiar with a range of flap-based surgery as well as liposuction, and be planned preoperatively. Glue provides a dressing that does not need to be changed, is waterproof (so patients can shower next day) and rarely produces skin reaction, so minimising further trauma to the skin surface around the flap edges. Goldilocks mastectomy Although it has been tradition to excise the excess skin over the breast during a mastectomy to leave a flat chest wall, other options may be considered. Skin that would normally be discarded may be deepithelialised, shaped and buried to improve the cosmetic result. This may avoid the concave appearance that often results from mastectomy and in some cases can produce a small breast mound. Skin incisions are marked as normal but the skin between the upper and lower incisions is deepithelialised. Considerations for mastectomy with immediate reconstruction Of the general issues listed above, smoking is a particular concern and the major risk factor for flap necrosis and wound problems with skin-sparing mastectomy. However, immediate breast reconstruction is enhanced by preserving most (if not all) of the breast skin. Studies assessing the safety of this procedure relative to rates of local recurrence are summarised in Table 5. Although there are several that report acceptable recurrence rates, no large randomised trial data are available. It seems sensible to apply the same principles as one would for simple mastectomy. In other words, if the cancer is close to skin such that a healthy margin of normal tissue cannot easily be excised around it, then the overlying skin should be resected. It is important to leave a skin bridge in the midline and not have a continuous scar across the chest. Undesirable scar patterns High transverse and most diagonal scars should be historical other than in salvage situations, likewise any scar that does not leave a flat surface with a contoured lateral chest wall. Transverse scars rarely leave a satisfactory result without fishtailing at the lateral end and are not recommended. Different designs of skin-sparing mastectomy can allow skin excisions at any site. This will obviously influence the scar pattern planned to facilitate the adjustment and obtain optimal symmetry of scars. This is increasingly considered an option in small breasts, particularly for prophylactic mastectomy but also in cancer cases. It can be extended easily by a lateral or inferior extension or by widening the circular skin excision. The resulting defect is replaced with skin from the flap, often with nipple reconstruction at the same time. Wise pattern this is another commonly employed technique that can be used for any ptotic breast. The design is more conservative than would be used for a standard breast reduction, and is often best planned as very conservative, with adjustment of the vertical limbs at the time of closure according to viability and tension. With division of the lateral thoracic vessels as part of the mastectomy, this often ends up as the most ischaemic part of the mastectomyflap. Tissue-based reconstruction Circumareolar this is perhaps the most commonly employed technique. Preservation of a larger section of lower flap skin until the time of closure enables the option of wider skin excision if viability is a concern or, as outlined above, deepithelialisation and double-breasting of the scar. Implant reconstruction Wise pattern this is probably the best option for the large breast and possibly any breast with some ptosis. It is particularly useful when a lower de-epithelialised flap is being used to create a partial submuscular/partial subdermal pocket. A de-epithelialised lower flap can also be combined with the use of a dermal matrix for breast reconstruction and can provide complete cover of the dermal matrix, particularly in the vulnerable area where all three scars meet. Vertical this is a good option in small breasts when a total submuscular pocket is planned. This can sometimes be combined with a de-epithelialised vertical mastopexy scar to allow repositioning of the nipple/areola. This is similarly the case for the lateral skin crease or lateral breast curvature scar. Short transverse this is sometimes a good option when a patient has a small areola that can be excised as a circumareolar incision but closed transversely. This is often prudent with skin-sparing mastectomy to allow a timely search for blue nodes and limit 78 (021)66485438 66485457 For Wise and vertical patterns the breast meridian is drawn and patients marked up as for a reduction or mastopexy but with more conservative vertical incision lines. In Wise pattern mastectomy the vertical components are usually 10 cm in length from apex to horizontal incision. The apex of the dome is on the breast meridian and can be extended to the required height. In a similar fashion to simple mastectomy, the plane is often best identified using opposing traction on the wound before skin hooks or similar retractors are applied. For incisions where access is limited, hydrodissection an adrenaline/saline solution injected using a blunt infiltration cannula is very useful. A bloodless field is essential to allow visualisation of the plane of dissection throughout and preservation of the perforators. If access is really felt to be compromising the dissection, then the incision should be extended. Once the subcutaneous plane is dissected, the submammary plane is dissected with cautery. For subcutaneous mastectomies, the nipple/areola is preserved by first bluntly dissecting the subareolar plane with scissors. It can also be valuable if a latissimus dorsi flap is being used for the breast reconstruction. This allows very restricted and, in my opinion, difficult access to the breast in all but very small breasts and compromises nipple blood supply. This is intuitive, but creates ischaemia at the skin edge, can result in a central sinus, stretches to produce an unsightly scar, and results in a scar that presents difficulties for nipple reconstruction and tattooing. Put a mark on the midline and draw a dashed line around the circumference of the breast. Wound closure the use of deep dermal interrupted sutures before subcuticular closure maximises wound quality. Often wounds can be double-breasted, with the small reinforcing de-epithelialised segment. Skin stapler this is particularly useful in Wise pattern mastectomy or any mastectomy where a skin-bearing flap is being inserted. Staples are always removed and wound closure should be with absorbable subcuticular sutures. Formal removal of all of the pectoralis major muscle is, however, rarely required and partial excisions removing the area of muscle involved with a margin of normal muscle are usually sufficient. Flap necrosis Using the principles and techniques described this should be a rarity (1% or 2% of cases). The main reasons for it are smoking, poor technique selection, poor execution of dissection, failure to preserve the intercostal perforators and too much tension of wound edges. In the circumstances where flap necrosis is encountered, early surgical debridement may allow direct re-closure and usually results in a satisfactory outcome. All have a potential role depending on the size of defect, patient fitness and suitability of donor sites. Clearing the smoke: the scientific rationale for tobacco abstention with plastic surgery. Smoking as a risk factor for wound healing and infection in breast cancer surgery. Effectof preoperative smoking intervention on postoperative complications: a randomised clinical trial. A prospective assessment of surgical risk factors in 400 cases of skin-sparing mastectomy and immediate breast reconstruction with implants to establish selection criteria. Presentation, treatment, and outcome of local recurrence after skin-sparing mastectomy and immediate breast reconstruction. Localrecurrence risk after skin-sparing and conventional mastectomy: a 6-year follow-up. Factors associated with local recurrence after skin-sparing mastectomy and immediate breast reconstruction for invasive breast cancer. Recurrence following treatment of ductal carcinoma in situ with skin-sparing mastectomy and immediate breast reconstruction. Local recurrence after skin-sparing mastectomy: tumor biology or surgical conservatism Skin-sparing mastectomy with conservation of the nipple­areola complex and autologous reconstruction is an oncologicallysafeprocedure. Local recurrence of stage 1 and 2 breast cancer after skin-sparing mastectomy and immediate breast reconstructionina15yearseries. Michael Dixon Part 1 Volume replacement techniques to improve cosmetic outcomes after breast-conserving surgery Richard M. The chances of a poor cosmetic outcome are increased still further when the tumour is in a central, medial or inferior location. Whole-breast section analysis techniques have been used to show the likelihood of complete excision of unicentric carcinomas using different margins of excision (see Chapters 4 and 15). Reconstruction at the same time as resection (breast-sparing reconstruction) is gaining in popularity. As a general rule, it is much easier to prevent than to correct a deformity that has developed as the sequela of previous surgery. Immediate reconstruction at the time of mastectomy is associated with clear surgical,17 financial18,19 and psychological20 benefits, and similar benefits are seen in patients undergoing immediate breast-sparing reconstruction after partial mastectomy. Resection defects can be reconstructed in one of two ways: (i) by volume replacement, importing volume from elsewhere to replace the amount of tissue resected; or (ii) by volume displacement, recruiting and transposing local dermoglandular flaps into the resection site. Volume replacement techniques can restore the shape and size of the breast, achieving symmetry and excellent cosmetic results without the need for contralateral surgery. However, these techniques require additional theatre time and may be complicated by donor-site morbidity, flap loss and an extended convalescence. In contrast, volume displacement techniques require less extensive surgery, can limit scars on the breast and limit donor-site problems. These procedures may be complicated by necrosis of the dermoglandular flaps and contralateral surgery is usually required to restore symmetry as volume loss is inevitable (Table 6. A number of factors need to be considered when making the choice between volume replacement and volume displacement. Volume replacement is particularly suitable for patients who wish to avoid volume loss and contralateral surgery after extensive local resections. Poor surgical technique leading to postoperative haematoma, infection or breast tissue and fat necrosis will increase the amount of scarring and retraction, and add to the risks of deformity. Moreover, the use of suction drains, inappropriate incisions and en bloc resections can worsen the cosmetic result still further. Oncoplastic techniques allow wider excision of breast cancers without risking major local deformity. This produces a bulky flap without a skin island and includes a layer of fat on its superficial surface that is used to reconstruct defects following wide excision with preservation of the overlying skin. Theatre time (hours) Convalescence (weeks) Timing 2­3 4­6 Immediate or delayed Mammographic Possibly enhanced surveillance of complications that may result in prolonged convalescence. Volume replacement is equally well suited to immediate and delayed reconstruction and is the method of choice for correcting severe deformity after previous breast irradiation. Volume displacement is less reliable in irradiated breasts, and patients need to be warned about the risk of asymmetry that may require simultaneous or subsequent contralateral surgery. Other flaps, such as the lateral thoracic adipose tissue flap, have been described24 but their clinical utility is unclear. This helps to avoid the confusing mammographic images resulting from areas of calcified fat necrosis in the vicinity of the tumour bed. The theoretical risk of tumour induction by injected stem cells remains a concern, and has led to the somewhat cautious introduction of this innovative technique into clinical practice. Non-autologous volume replacement with saline or silicone implants has been tried with mixed success. They cannot be moulded to fit the resection defect and they form localised capsules, particularly in irradiated tissues. If using implants, low height and low projection implants placed low in the treated breast combined with lipomodelling gives the best results. If there is deformity and significant nipple deviation then a myocutaneous flap is preferred.

It was thought that a stable population of cardiomyocytes slowly dwindled with advancing years and no means of myocyte renewal (Agah et al treatment type 2 diabetes discount 40 mg triamcinolone. Under this paradigm medicine 7253 triamcinolone 15 mg on line, cardiomyocytes adapted to injury by dying or enlarging while cellular integrity was maintained through continuous replenishment of intracellular organelles (Soonpaa et al treatment under eye bags purchase 15 mg triamcinolone with mastercard. At the turn of the century medicine rash generic 15 mg triamcinolone with mastercard, several studies began to document the existence of a small population of cells within the adult heart that expressed characteristic stem cells markers and were capable of re-entering the cell cycle after cardiac injury (Anversa et al medications japan buy triamcinolone 15 mg without prescription. The basis for this study was founded upon the spike in carbon-14 (14C) levels resulting from 1960s Cold War Recent advances in cardiac stem cell therapy 165 above-ground nuclear testing. Using this strategy, the authors estimated 55% of the original cardiomyocyte population remains after 50 years of life with an average turnover between 0. The degree of myocyte turnover remains a hotly debated subject with several divergent independent measures (Hosoda et al. Using this technique, the authors found that myocardial turnover approached 22% per year with an average lifespan of 8 years. This rate of turnover is significantly higher than what was described in the 14C study by Bergmann et al. This may not be valid given evidence that myocytes are formed after birth (Rakusan et al. Back of the envelope calculations suggest that if these variables were included in the calculations, the annual myocyte turnover approaches 18% (Kajstura, 2010) 8. Given the discovery of cycling cardiomyocytes, the possibility of a resident cardiac stem cell precursor was acknowledged with the search beginning to identify and isolate cells capable of creating de novo cardiomyocytes. These cells had reduced or absence of lineage markers indicative of cardiac identity and differentiated into functional cardiomyocytes when co-cultured on a feeder layer of purified mature cardiomyocytes. In this study, the authors demonstrated that these cells did not co-express the intermediate filament protein desmin, which is known to be expressed early during cardiac differentiation. Unsurprisingly, Sca-1 knockout transgenic mice have impaired myocardial and progenitor cell function (Bailey et al. Application of the murine antibody for Sca-1 to human cardiacderived cells identifies a population with characteristics suggestive of a cardiac precursor (Smits et al. However, these Sca-1+ human cells also Recent advances in cardiac stem cell therapy 167 significantly co-segregate with the c-Kit antigen suggesting that both epitopes may indicate the same population of cells (Tang et al. This trenchant finding is well taken given the observation that the human epitope of Sca-1 has yet to be identified. Tyrosine receptor kinase (c-Kit) as a marker of resident cardiac progenitor cells Twenty years of experience with hematological stem cells provided the rationale to explore the heart for resident cells expressing the tyrosine receptor kinase (c-Kit) in the hopes of identifying a population of cells capable of providing endogenous repair (Quaini et al. These studies demonstrated clusters of cells expressing c-Kit+ cells confined to areas of low cardiac stress within the atrial appendage and ventricular apex/base. Since then, clusters of c-Kit+ cells have been identified in animal models and human autopsy specimens throughout the entire lifespan of the organ (Beltrami et al. While cardiac c-Kit+ cells do not co-express lineage-associated markers (bone marrow, cardiac, neuronal, mast cells, or skeletal muscle) or transcriptional factors (Beltrami et al. Emerging evidence has demonstrated that hypoxia plays a key role in mediating this physiological response (Sanada et al. Although the function of the c-Kit receptor remains unclear, it has been shown to play a pivotal role in maintaining in vivo differentiation of cardiomyocytes within the adult myocardium (Li et al. This was suggested by the use of transgenic mice heterozygous for a deletion of the transmembrane domain of the c-Kit receptor and missense mutation that reduced the overall tyrosine kinase activity by > 95%. Prolonged pressure overload caused by aortic constriction reduced the hypertophic response presumably by eliminating the ability of c-Kit+ cells to differentiate and respond to physiological challenges. These cells were found to undergo asymmetrical cellular divisions after stimulation by spontaneous calcium ion oscillations within the developing mouse heart. After division, these cells progressively differentiated into mature cardiomyocytes, gradually losing molecular stem cell markers and the capacity for replication. The authors hypothesize that an identical hierarchy model can be applied towards c-Kit+ cells in the adult myocardium with participation in ongoing myocyte turnover and preservation of organ function. These typical environments are surrounded by supporting fibroblasts and contain c-Kit+ cell clusters capable of both symmetrical and asymmetrical cellular divisions (Urbanek et al. Finally, ex vivo proliferated subfractions of both c-Kit+ cell types were found to express typical cellular and molecular markers indicative of myogenic and vascular progenitors. The capacity of the c-Kit marker to identify multipotent adult progenitor cells has not gone unchallenged with frequent difficulty identifying c-Kit+ cells using routine human autopsy specimens (Li et al. This difficulty has led to the proposal that the c-Kit+ marker may represent proliferation of cardiac mast cells rather than genuine progenitor cells. While cellular and molecular profiling of resident c-Kit+ cells refutes this notion, studies using conditionally labeled c-Kit+ cells have suggested that these adult resident c-Kit+ cells possess vasculogenic potential (Jesty et al. Homozygous deletion of Isl-1 in transgenic animal models Recent advances in cardiac stem cell therapy 169 leads to defects in cardiac development and the speculation that Isl-1 expression denotes a cardiac progenitor population (Cai et al. Conflicting reports however have debated the existence of this cell population within the adult myocardium as their presence is rare and appears to be unaffected by acute myocardial insults (Leri et al. Despite efforts characterizing the phenotype of these various populations, little is known about the ultimate origin of each cell type. Y-chromosome-positive cells) from male recipients into transplanted female hearts (Quaini et al. This study documented chimeric organs with a significant number of recipient Y-chromosome-positive cardiomyocytes and endothelial cells within the female donor heart, suggesting that extra-cardiac stem cells may seed the transplanted heart to provide low-grade repair. Although the authors could only speculate that stem cells had contributed to the myocardial 170 Cardiac regeneration and repair renewal observed, Fransioli et al. The goal of these techniques was to provide a clinically applicable cell product capable of myocardial regeneration after an acute myocardial insult. After isolation and expansion within defined media, the authors showed that these c-Kit+ cells did not express markers of erythroid, fibroblast, lymphoid, myeloid or skeletal muscle origin. Interestingly, a modest portion of these cells (7­10%) expressed transcriptional factors associated with early cardiac commitment including Nkx2. The overall variance of transcriptional factors being expressed by this purified population of c-Kit+ cells suggests that these progenitor cells were isolated at various levels of commitment. Recent advances in cardiac stem cell therapy 171 Subsequent studies translated this technique to clinical biopsy samples by first culturing a mixed population of progenitor cells directly from plated myocardial tissue followed by antigenic selection (Beltrami et al. Most importantly, the authors were able to show that these cells were not fusing with the myocytes of the recipient heart and they were capable of electromechanically coupling with the surrounding myocardium (Beltrami et al. Using a similar purification technique other groups have demonstrated that Sca-1+ can be isolated from adult mouse whole heart digestion (Wang et al. This creates a number of limitations including complexity, cost, phenotypic drift and the possibility of malignant transformation (Rubio et al. As a result, several groups have refined a culture-guided outgrowth technique that ultimately uses a heterogeneous population of cells that spontaneously emigrates from plated tissue fragments in culture (Linke et al. When samples of minced cardiac tissue are cultured, a lawn of flat cells emigrates spontaneously from the plated tissue. Using mild enzymatic dissociation, loosely adherent cells surrounding the explant (termed cardiac outgrowth) can be serially harvested. In keeping with this finding, we and others have shown that these cells are self-renewing, clonogenic, and multipotent (Messina et al. Unfortunately, direct application of the initial cell product to larger-scale models, or the clinical setting, is limited by a constant output return to the scale of production with the amount of outgrowth collected changing in proportion to the amount of tissue plated. As such, this technique has undergone extensive refinement to progress towards clinical translation. Although application of cardiospheres has been shown to provide a dose-dependent improvement in myocardial function (Shen et al. Direct injection was thought to reduce the widespread application of this therapy to transplantation at the time of surgical procedures or needing specialized guided intramyocardial catheter delivery. These cardiosphere-derived cells have since been shown to improve myocardial function after application in models of ischemic and non-ischemic injury (Malliaras et al. These studies and others demonstrate the impact that culture techniques have upon the end cell product phenotype and the caution that should be taken when applying these results to established cell products (Shenje et al. Improvements in ventricular performance were attributed to the creation of new cardiomyocytes that were able to electromechanically couple with the surrounding myocardium through the formation of gap junctions (Beltrami et al. Interestingly, mechanical measures to enhance the acute retention were associated with improved long-term persistence and greater functional benefits. Despite the profound effects of chronic heart failure on morbidity and mortality, this patient subgroup has been enrolled in very few studies, which likely reflects the limited preclinical evidence supporting the use of current cell products. At the time of surgery, left atrial appendages were harvested and the c-Kit+ cells were isolated for expansion over 113 ± 4 days. Preliminary results did not demonstrate an increase for adverse events associated with stem cell transplantation. Twelve months after cell transplant, administration of c-Kit+ cells was associated with significant improvements in ventricular performance with a corresponding decrease in infarct size. The primary endpoint of this study will conclude after a 12-month follow-up period, in which the safety and efficacy of this combination therapy will be evaluated. The promise of these cells lies in the potential for true long-term engraftment with the generation of new working myocardium. One of the most significant barriers to this technology surrounds the regenerative capacity of these ex vivo stem cells cultured directly from patient tissue specimens ­ the very same individuals who will likely require this therapy in the future. The initial publication describing this technology focused primarily on cells cultured from the tissue donated by post-transplant patients (Smith et al. Cells from the right ventricular apex of these immunosuppressed patients did not differ significantly in crude measures of cell growth and myocardial repair/ salvage. Given that long-term engraftment was shown to be negligible, these data underscore the importance of paracrine-mediated repair using this firstgeneration stem cell product. It follows that similar modifications in the culture milieu may provide the opportunity to enhance the stem-ness and regenerative potential of cells. Direct genetic engineering of noncardiac stem cells has also been used to improve cell survival (-Akt (BockMarquette et al. Comparing these different approaches is problematic given variations in cell type (fetal myocytes, embryonic stem cells, skeletal myoblasts, mesenchymal stem cells and several cell types derived from the bone marrow) and strategies for gene transfer to cells (viral, plasmid). As expected, overexpression of Pim-1 kinase has been shown to improve acute engraftment and long-term retention in preclinical models (Fischer et al. Although modulation of Pim-1 kinase provides very good proof-of-principle evidence supporting this approach, clinical translation is expected to be problematic because of the oncogenic potential of this vector. Low acute retention of injected cells is thought to reflect a combination of mechanical extrusion, off-target disbursement and clearance from the heart through lymphatic or venous drainage. Initial attempts to improve acute retention have used biosynthetic materials to anchor transplanted cells within the myocardium upon injection. These matricellular materials provide additional trophic support to cells by providing intrinsic adhesion stimuli that increase differentiation potential, paracrine secretion of cardioprotective cytokines and early cell loss due to contact-initiated apoptosis (Zhang Y et al. Finally two studies have examined the use of platelet gels that naturally contain a rich cocktail of cytokines capable of preserving reversible damage and preventing stem cell apoptosis. These unique features open prospects for durable cardiac repair and possibly late delivery for patients with established heart failure. However, whether assessing global left ventricular ejection fraction as the primary outcome adequately reflects possible regional myocardial recovery following local cell application is questioned. Conventional measurement protocols focusing on global ejection fraction assessment fall short in addressing the quantification of changes in regional myocardial function. Clinical implementation of elaborated measurement techniques, such as strain analysis by echocardiographic speckle tracking or magnetic resonance myocardial tracking, offers new levels of accuracy in assessment of regional myocardial function. The efficacy of cardiac stem cell application may be better judged by such methods than by analyzing changes in global ventricular performance. Key words: ischemic cardiomyopathy, stem cell, regeneration, function, measurement. Among others, chronic ischemic heart disease represents the main etiology of ventricular failure. Despite established therapeutic protocols including pharmaceutical therapy, interventional and surgical revascularization procedures, assist-device implantation and finally heart transplantation, patients suffering from impaired ventricular function due to chronic ischemia exhibit a significant mid-term mortality. As intrinsic myocardial regeneration has been shown to take place but to be reduced during a normal life span (Bergmann et al. The concept is therefore still intensively discussed and serious questions arise whether it is worthwhile to continue with this strategy if a clear improvement of cardiac function cannot be achieved. On the other hand, compared with the functional results achieved by long-term pharmaceutical therapy or revascularization procedures and taking into account the fact that stem cell application adds to the effects gained with established therapeutic protocols, the functional efficacy of cardiac stem cell therapy can be considered relevant. Furthermore, possible beneficial effects of cardiac cell therapy on regional myocardial function and perfusion are likely to be insufficiently captured by routine outcome measurements (Nasseri et al. However, both represent primarily morphological measurements of ventricular wall motion and ­ if applied according to standard protocols ­ cannot adequately assess regional myocardial function or changes in regional myocardial perfusion. For a conclusive evaluation of cardiac cell therapy regarding its functional efficacy in humans the implementation of more specific imaging protocols of both global and regional ventricular function is mandatory. Offering the possibility of a simultaneous examination of right ventricular performance and valve function, as well as screening for any structural cardiac or pericardial pathology, it forms the cornerstone of non-invasive cardiological work-up. On the other hand, 2D echocardiography offers a solid imaging modality that is available in every cardiological department. Furthermore, the combination of different imaging techniques and sequences allows for an integrated assessment of global ventricular function together with myocardial perfusion and viability. These imaging techniques are based on the loss of cell membrane integrity following cell death and consecutive extracellular distribution of gadolinium-based contrast agents. The resulting increase of signal intensity in T1-weighted images defines the transmural extent of a myocardial scar following ischemia (Suzuki et al. In combination with data on regional myocardial perfusion, this technique is able to describe areas of hibernating myocardium, defined as regions of hypoperfusion but without a transmural scar. These regions are currently considered the most promising targets for myocardial stem cell application, so late enhancement imaging has sharpened the pre-procedural planning of cell injection sites to a relevant extent. Furthermore, by exploiting the high spatial resolution and tissue contrast, precise longitudinal follow-up assessments on myocardial scar size and viability following stem cell administration have become possible. Every segment is evaluated regarding wall motion and wall thickening using four semi-quantitative categories: normal function, hypokinesis, akinesis and dyskinesis.

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