Anthony RB Smith MD FRCOG

  • Consultant Gynaecologist, The Warrell Unit, St Mary?
  • Hospital, Manchester

Increased expression of stem cell factor and its receptor after left ventricular assist device support: a potential novel target for therapeutic interventions in heart failure herbs landscaping cheap hoodia 400 mg fast delivery. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair herbals bestellen hoodia 400mg. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction quest herbals discount 400mg hoodia with amex. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure herbals summit order hoodia 400 mg visa. Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart wonder herbals order 400 mg hoodia with visa. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction herbals wholesale discount 400mg hoodia visa, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. Identification of myocardial and vascular precursor cells in human and mouse epicardium. Vascular injury induces expression of periostin: implications for vascular cell differentiation and migration. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Periostin and periostin-like factor in the human heart: possible therapeutic targets. Plasticity of surface structures and beta(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Stem cell-mediated muscle regeneration and repair in aging and neuromuscular diseases. Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Thymosin beta-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Recently, ultrasound-mediated gene delivery has been studied as a potentially effective gene delivery method. In comparison to conventional techniques, the benefits of ultrasound-mediated gene delivery allow for the non-invasive targeted delivery of therapeutic gene vectors, minimizing adverse effects in remote organs. To date, numerous studies have been published to demonstrate the applicability and efficacy of ultrasound-mediated gene delivery in various animal models of cardiovascular diseases. This chapter will cover the fundamental topics required for the understanding of the mechanisms behind ultrasound-mediated gene delivery, review the preclinical studies of ultrasound-mediated gene delivery in the cardiovascular setting, and offer future perspectives on clinical application of this novel gene delivery method. One of the major limitations in the transfer of genes to target tissues is the delivery of genetic material across the endothelial cell barrier. Although the majority of gene delivery vectors used in clinical trials have been viral vectors, there has been increased scrutiny with respect to the immunogenicity and clinical safety issues of viral particles. While commercially available microbubble contrast agents are used as diagnostic tools to opacify the blood pool during ultrasound imaging for enhancing the delineation of tissue boundaries and assessing tissue perfusion kinetics, microbubble contrast agents have also been used to enhance targeted delivery of therapeutic agents 382 Cardiac regeneration and repair in studies in vitro14 and in vivo. This potentially allows for the use of lower concentrations of these agents systemically, and delivery only where it is required, improving the therapeutic index. This is advantageous over other methods of systemic delivery, especially when using therapeutic agents with serious systemic side effects or off-target effect in other tissues or organs. When used in combination with microbubble agents, high-powered ultrasound (mechanical index > 1. In addition to the physical changes associated with ultrasound application, microbubbles further facilitate the entry of genes into the cells and tissue. Ultrasonic insonation causes the bubbles to undergo repetitive compression and expansion in response to the peaks and depths of the acoustic wave, producing a strong backscattered signal resulting in bright contrast augmentation of the blood pool and circulation. In clinical practice, ultrasound microbubble contrast agents have shown excellent safety profiles with no specific hepatorenal toxicity, while reported adverse reactions were generally transient and mild. After circulation within the peripheral blood, microbubbles are cleared through the liver and the spleen, presumably via trapping in sinusoids in the liver, or the phagocytosis of the bubble agents by cells in the hepatosplenic reticulo-endothelial system. Optimal contrast enhancement using microbubbles requires insonation of the bubbles at their characteristic resonant frequency. This forces microbubble contraction and expansion, which varies with the acoustic power of the transmitted ultrasound. At the lower spectrum, signals produced by the microbubbles are in sync with the frequency of the incident ultrasound. With increased acoustic power, non-linear vibrations of the microbubbles occur at their resonant frequency, with signals generated at harmonic and subharmonic frequencies. Insonification of the microbubbles at even higher power leads to the destruction of the microbubbles, generating a wide-band frequency signal. The resonant frequency is dependent on many factors, such as the diameter of the microbubbles, as well as the elasticity of the microbubble shell. For charge coupling, it has been previously demonstrated that approximately 6700 plasmid particles can attach to each cationic microbubble. Their ability to bring about transient gene knockdown extends from about a week in rapidly dividing cells to about 3 weeks in non-dividing cells. The plasmid constructs have been designed and developed with sensitive reporters to overcome the issue of inefficient expression. It has been shown that CpG dinucleotide sequences in bacterial plasmids further enhance the immunogenic properties of plasmids 386 Cardiac regeneration and repair encoding antigens. The gene expression duration is also rather poor in comparison to viral gene transfer. However, augmentation/downregulation of target genes for several processes such as angiogenesis does not require persistent transgene expression. Ultrasound waves have several advantages for gene delivery including controlled application, easy focusing and deep penetration into the body. The behavior of microbubbles when insonified depends in part upon the mechanical index of the transmitted ultrasound, which is a measure of the acoustic power, and provides an approximate measure of nonthermal effects (cavitation and streaming) caused by ultrasound. It is calculated as a ratio of peak negative pressure (in Mpascal) to the root of centre frequency of the transmitted ultrasound. Taking this into consideration, safety guidelines have been proposed on the basis of mechanical index. Ultrasound, as applied in both diagnostic and therapeutic applications, can induce biological effects through two broad mechanisms: thermal and nonthermal. Lithotripsy, employing high-amplitude focused acoustic shock waves to eliminate renal calculus, is a prime example of the use of ultrasound bioeffects for therapeutic use in the clinical setting. Another such example is the use of highintensity focused ultrasound, employing ultrasound at intensities exceeding 100 W/cm2 to selectively heat tissue and induce cell death in non-invasive therapy of tumors, and for hemostasis. The hyperthermic effects generated by ultrasound have been effectively used to warm the tissues as part of physical therapy, kill cells as part of medical therapy and melt drug-containing liposomes as a part of drug delivery. The interaction of these gas-filled microbubbles with ultrasound leads to cavitation: a process involving formation and activity of gas-filled microbubbles in a medium during the oscillatory cycle. When subjected to ultrasound, these gas bodies will oscillate around equilibrium, keeping the diameter of the bubble fairly constant over repeated cycles. These acoustically driven bubble oscillations trigger a local rise in temperature, microstreaming of fluid due to pressure exerted by radiation forces. This type of cavitation, associated with production of high shear stresses and free radicals, is called inertial cavitation. Additionally, when a strong ultrasonic beam is focused through a partially absorbing liquid, a large-scale convective motion is induced in the medium. This phenomenon, known as acoustic streaming, can enhance vector transport and gene transfection. However, its applicability for in vivo models remains limited owing to the already existing rapid convection motion in vasculature. The maximal response of a bubble occurs when it is subjected to ultrasound at its resonance frequency, which depends partly on the initial size of the gas nuclei. Tissues with pre-existing gas bubbles are particularly susceptible to these acoustic bioeffects of ultrasound, but with the introduction of microbubble agents, the acoustic cavitation by ultrasound can be used in tissues that do not naturally contain gas bodies to induce the localized biological effects of ultrasound. Although bioeffects of ultrasound and microbubbles can be harnessed for therapeutic purposes, adverse effects can occur including the occurrence of hemolysis, capillary rupture and hemorrhage, and when occurring in the heart, effects on cardiac rhythm. Other chronic experimental studies have reported, however, that these potentially adverse events are transient, and have no long-term health effects. Similarly, after 388 Cardiac regeneration and repair initial safety concerns of commercially available microbubble contrast agents,58 subsequent studies have demonstrated the safety of contrast-enhanced ultrasound, at least at the doses administered clinically and ultrasound settings used in commercially available imaging systems. The cavitation of microbubbles can result in a weakened endothelial barrier, allowing for the gene transfer to occur more favorably. In addition to endocytosis, ultrasound-mediated delivery also created transient pore formation, with an influx of calcium ions and cellular release of preloaded dextrans seen after ultrasound and microbubble exposure. Diagnostic ultrasound may produce sufficiently high pulse pressure amplitude with relatively low intensity. In this respect, in vivo transfection has Ultrasound-targeted cardiovascular gene therapy 389 17. Targeted tissue transfection with ultrasound destruction of plasmid- bearing cationic microbubbles. When microbubbles were present in the circulation, the acoustic power required to induce sonoporation was significantly reduced, compared with plasmid administration without microbubbles. By monitoring and controlling the different parameters that 390 Cardiac regeneration and repair 17. Due to limited ultrasound beam width, it is generally impossible to cover the entire range of the target tissue while maintaining the probe stationary over the target. For peripheral vascular delivery, the probe is positioned transverse to the limb, and scanned along the length of the target muscle bed. As discussed in the previous section, the microbubbles in the bloodstream respond differentially to varying ultrasound parameters. They examined four parameters: (1) ultrasound triggering versus continuous ultrasound, (2) transmission frequency, (3) ultraharmonics versus power Doppler imaging, and (4) varying levels of mechanical index or acoustic power. The ratio of pulse-on to pulse-off applied over a course of treatment is referred to as the duty cycle. In addition, the optimum frequency for destruction may also vary with composition of microbubbles. Instead, they found that regardless of the number of pulses, both methods of insonation resulted in complete destruction of microbubbles and similar transfection efficiency. While viral transduction can lead to the production of exogenous therapeutic gene products for months,42 plasmid delivery has a relatively short expression profile of weeks.

Almost as soon as penicillin G was put into widespread therapeutic use komal herbals hoodia 400 mg sale, recognition of S herbs collision generic hoodia 400mg amex. New agents including penicillinase-stable penicillins (oxacillin herbal salvation discount hoodia 400mg visa, nafcillin kairali herbals order hoodia 400mg with visa, and the oral agent dicloxacillin); first- herbals on demand reviews order hoodia online, second- gayatri herbals order hoodia 400mg visa, and third-generation cephalosporins; and carbapenems were developed over the following decades. A characteristic all these drugs shared was that they were relatively stable in the presence of -lactamase-producing S. If the placements of the clindamycin (disk 7) and erythromycin (disk 8) disks are closely examined, it should be noted that they are closer together than the other disks in order to determine whether there is formation of a D-shaped zone of inhibition around the clin- Case 36 265 damycin. Expression of this methylase can be either constitutive (always on) or inducible (on only in the presence of an inducer such as erythromycin). The bacteria growing closest to the erythromycin disk are in the presence of an inducer, and therefore will be resistant to clindamycin; this resistance causes a "flattening" of the zone of inhibition in the area between the two disks, creating a characteristic D-shaped zone around the clindamycin disk. If the constitutive form of erm was present, the organism would test as resistant to clindamycin independent of the presence of erythromycin. Some studies suggest that incision and drainage is all that is necessary to clear the infection, but the physician was being cautious. Vancomycin (drug 5) is being tested using a special antimicrobialimpregnated strip called an E-test. The strip is designed to release a gradient of a specific antimicrobial agent into the agar. Their resistance is due to the acquisition of the vanA gene from Enterococcus faecium. It is a cytolytic pore-forming hexameric protein that can lyse a variety of cell types. It has particular affinity for polymorphonuclear cells and macrophages (thus the name "leukocidin"). Infections with this strain have attracted significant attention in the popular media because of outbreaks among a variety of athletic teams, day care centers, schools, and military units. More ominously, severe cases of pneumonia are being documented with increasing frequency. Typically acquired in a health care setting, these strains are often resistant to oral agents and aminoglycosides, making vancomycin the primary therapeutic option, while three newer agents, daptomycin, linezolid, and ceftaroline, are important second-line drugs. Because of its oto- and nephrotoxicity, vancomycin is complicated to give, since drug levels must be monitored to ensure that toxic levels are not accumulating. Strict adherence to hand washing is essential in preventing the spread of all health care-associated pathogens. This discussion is quite complex and is in a state of flux, so we will not attempt to cover it here. However, patients who are in isolation and on contact precautions often do not get the same level of care as patients who are not. This translates into fewer visits from health care providers, missed medicine doses, fewer assessments of vital signs, increased risks of falls, and not surprisingly, poorer satisfaction with health care. Decolonization is done by applying a topical antimicrobial, mupirocin, to the nares to eliminate nasal carriage and bathing in either dilute solutions of chlorhexidine or bleach to decrease skin colonization, including inguinal sites. Strict attention to personal hygiene, including good hand-washing practices, not sharing towels, and wiping down exercise equipment with disinfectant following use, could help reduce these infections. Methicillin-resistant Staphylococcus aureus and vancomycin: minimum inhibitory concentration matters. Two small puncture wounds were seen on the proximal phalanx of the long finger, and erythema was visible over the extensor surface of the forearm. Laboratory studies demonstrated an elevated white blood cell count of 12,000/l with a left shift (the presence of immature neutrophils in the peripheral blood). Aspiration of an abscess on her finger was sent for culture, and the patient was taken to the operating room for incision and drainage of the abscess. The organism failed to grow on MacConkey agar, and spot tests from the blood agar plate were oxidase and spot indole positive. If this patient had been scratched by a young cat rather than bitten and had subsequently developed regional lymphadenitis, what would be the likely organism Domestic animals such as cats and dogs are vaccinated against what pathogen in order to protect humans Two organisms associated with domestic animal bites that are oxidasepositive, Gram-negative bacilli and fail to grow on MacConkey agar are Pasteurella multocida and Capnocytophaga canimorsus. One point worth emphasizing is that infections following cat and dog bites are commonly polymicrobial, often including both aerobic and anaerobic bacteria, with a median of five different bacterial isolates per culture when appropriate techniques are employed for the isolation of anaerobes. Like those from cat and dog bites, human bite wound infections are typically due to a mixture of aerobic and anaerobic organisms that are part of the oral microbiota. Key organisms include facultative Gram-positive cocci in the Streptococcus anginosus group, the facultative Gram-negative bacillus Eikenella corrodens, and anaerobic Gram-negative bacilli within the genera Prevotella and Fusobacterium. Another important organism is Staphylococcus aureus, which likely arises from the skin microbiota of the injured individual. Human infection is most likely to be associated with cat bites or scratches and less likely (though still quite commonly) to be caused by dog bites. Infections following bites by other members of the cat family, including lions, have been reported to cause P. In a minority of human infections, the patients have had no known animal exposure. It is important to note that bites of domestic animals are responsible for hundreds of thousands of emergency department visits annually in the United States. If a person is bitten or scratched by a cat or dog, the wound should be thoroughly cleaned as soon as possible. The animal should also be observed for sign of rabies, especially if rabies vaccination is not well documented. In addition to soft tissue infection with rapid onset, other clinical syndromes seen with this organism following animal bites include osteomyelitis, tenosynovitis, abscess formation, and arthritis. It is speculated that the cat tooth, which is long and narrow, is more likely to cause puncture wounds that penetrate the tendon sheath (causing tenosynovitis) or periosteum (causing osteomyelitis). These infections are particularly problematic because they often occur on the hands and wrists. Because of the extraordinarily complex anatomy involved, infections of the hand and wrist, if neglected, can require complicated surgical debridement and loss of important motor function for the patient, either temporarily or permanently. Other uncommon complications include bacteremia with septic shock, meningitis, brain abscess, and peritonitis. Interestingly, there have been a fair number of reported cases of peritonitis due to P. Cat scratch disease is characterized by the development of a small lesion 1 to 2 weeks after a cat scratch, usually on the hand, wrist, or forearm. This lesion is followed 1 to 3 weeks later by regional lymphadenopathy, typically of a single or multiple nodes, most commonly in the axilla but sometimes in the cervical or epitrochlear region. The nodes may remain enlarged for several months and then resolve without treatment. Although this organism can be grown from the blood of cats, it is rarely if ever recovered from the tissue of infected individuals. Diagnosis is likely to be sought in order to rule out other potential causes of lymphadenopathy such as malignancy. There are limited diagnostic tools clinically available to diagnose cat scratch disease. Although the antibodies that are tested for when using serology cross-react with similar organisms, the detection of a 4-fold rise in titer from acute- to convalescent-phase sera is diagnostic in the appropriate clinical setting. Multiple nucleic acid amplification tests have been described in the literature, but sensitive detection from human tissue often requires culture enrichment prior to molecular amplification, and this technique remains a research tool. Although the organism can be visualized in lymph node tissue with silver staining early in the disease course, this method is nonspecific and its sensitivity is unknown. This is probably because rabies vaccination is a requirement for dog licensure, and this licensure is required in most locales in the United States. On the other hand, only one state, Rhode Island, requires cat licensure, suggesting that cats are much less likely to receive rabies vaccination. Rabies vaccination is recommended for individuals who are traveling to these regions and are likely to come in contact with dogs. More than 95% of cases that are imported into Europe and North America are due to dog bites. Of the small number of cases in the United States that are acquired in the absence of foreign travel, bats are often the source of the infection. In particular, parents are encouraged to have their children vaccinated if they may be exposed to dogs during their travels since they may be less careful about approaching these animals. The reason for this low rate is thought to be the expense of the human rabies vaccine. The importance of this vaccine is illustrated by a case of rabies obtained by a U. Unvaccinated people visiting countries where rabies is endemic should have a plan to get postexposure prophylaxis consisting of rabies immune globulin and vaccine if bitten by a dog, cat, monkey, bat, wolf, fox, or other mammal. In the industrialized world, there is not as great a need to start postexposure prophylaxis immediately, since this risk is lower, especially if the animal responsible for the exposure can be observed or tested for the presence of rabies. She had cellulitis of the right hand manifested by marked erythema, swelling, and tenderness. There were no mouth lesions, the lungs were clear, and the liver and spleen were not enlarged. Laboratory data were significant only for leukocytosis with a white blood cell count of 15,800/l with 88% neutrophils. This patient had a systemic viral infection with a complication of bacterial superinfection (cellulitis). What other causes of her skin rash should be considered in the differential diagnosis Describe the epidemiology of this viral infection and how it has changed since 1995. What complications other than bacterial superinfection (as seen in this case) can occur as a result of this viral infection How do the clinical manifestations of this reactivation infection differ from those of primary infection How do they differ in terms of vaccine composition, target population, and efficacy Varicella lesions develop in "crops" such that lesions can be seen in various stages of evolution, including vesicular, pustular, and crusted. The differential diagnosis in this case includes impetigo (group A streptococcal infection), disseminated enteroviral infection, and disseminated herpes simplex virus infection in a child with underlying skin disease Other viruses that cause "pox"-like lesions are in the Poxviridae family and include the orthopoxviruses and molluscum contagiosum virus. Molluscum contagiosum was unlikely in this case; in immunocompetent individuals, it remains localized and does not cause a sudden-onset systemic infection. However, the orthopoxviruses are important to consider, including monkeypox and smallpox. Although monkeypox is endemic in Central and West Africa and is rarely seen in the United States, there was an outbreak of monkeypox in the Midwest in 2003. This outbreak affected 72 individuals, all of whom had exposure to prairie dogs that had been housed at the same facility with imported, monkeypox-infected Gambian rats. Because of concerns about bioterrorism, the specter of smallpox must also be considered. Smallpox lesions often occur on the palms and soles of the feet and are most concentrated on the face and extremities. This is in contrast to chicken pox lesions, which are rarely on the palms and soles and are more concentrated on the torso. If the patient had recently been vaccinated against smallpox, then disseminated vaccinia should also be in the differential. Noninfectious causes of skin rashes that may be confused with varicella include contact dermatitis, drug reactions, and insect bites. In immunocompetent children, the diagnosis of chicken pox is often made on the basis of clinical findings alone. A method that combines rapidity with sensitivity is direct fluorescent-antibody staining of scrapings taken from vesicular lesions. Nucleic acid amplification tests have also been developed, including quantitative assays. Disease is more common in temperate regions, with annual epidemics in the late winter and spring in areas with low vaccination rates. The virus is spread by the respiratory route and is highly infectious, with ~90% of nonimmune household contacts and 10 to 35% of nonimmune classroom contacts becoming infected. In 1995, a live attenuated vaccine was approved in the United States for prevention of primary varicella. In the prevaccine era, there were ~4 million cases of varicella annually in the United States, which translates to 15 to 16 cases per 1,000. In the first 5 years after introduction of the vaccine, the incidence dropped 76 to 87% in the United States. Immunocompromised children and nonimmune, pregnant women also are more prone to complications with this virus than is the general population. Other complications include hepatitis, arthritis, glomerulonephritis, myocarditis, pericarditis, pancreatitis, encephalitis, and cerebellar ataxia. Primary varicella during pregnancy can also cause intrauterine infection leading to fetal loss or an infant born with congenital varicella syndrome, which may include dermatomal scarring, limb hypoplasia, ocular defects, low birth weight, and mental retardation. In addition, secondary bacterial infections of the skin lesions, as was seen in this case (cellulitis of the right hand), can also occur. These bacterial infections are most commonly caused by Streptococcus pyogenes and Staphylococcus aureus. Therefore, infants and children with febrile illnesses should not be given aspirin. There are four groups of herpes zoster complications-cutaneous, visceral, neurological, and ocular. Perhaps the most debilitating complication is the persistent pain that can occur with the rash and persist even after the lesions heal. In immunosuppressed patients, however, complicating viremia can occur, with dissemination to extradermatomal skin sites, lungs, liver, and the central nervous system. This condition, with extradermatomal sites of infection, is called disseminated herpes zoster. Patients with zoster are also infectious, although apparently not as infectious as patients with varicella.

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Humanized large-scale expanded endothelial colony-forming cells function in vitro and in vivo herbals for cholesterol purchase cheapest hoodia and hoodia. Endothelial progenitor cells as resident accessory cells for post-ischemic angiogenesis banjara herbals discount 400 mg hoodia visa. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization planetary herbals quality discount hoodia 400 mg with visa. Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance herbal viagra buy hoodia pills in toronto. Identification of the haematopoietic stem cell niche and control of the niche size zip herbals mumbai order 400 mg hoodia with visa. Hematopoietic stem cell trafficking: Regulated adhesion and attraction to bone marrow microenvironment herbs used for protection buy discount hoodia line. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Mesenchymal stem cells: Biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. Bone-marrow-derived cells for enhancing collateral development: Mechanisms, animal data, and initial clinical experiences. Nonbone marrowderived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: Role of cardiovascular lineage commitment. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Mobilization of bone marrowderived cells enhances the angiogenic response to hypoxia without transdifferentiation into endothelial cells. Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: Implications for current clinical trials. In vivo functional and transcriptional profiling of bone marrow stem cells after transplantation into ischemic myocardium. Stromal cellderived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Effect of stromalcell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy. Spliced stromal cell-derived factor-1alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction. Computational protein design to reengineer stromal cell-derived factor-1alpha generates an effective and translatable angiogenic polypeptide analog. Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy. Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1alpha angiogenic therapy for acute myocardial infarction in a murine model. Mathematically engineered stromal cell-derived factor-1alpha stem cell cytokine analog enhances mechanical properties of infarcted myocardium. Controlled release of stromal cell-derived factor-1 for enhanced progenitor response in ischemia. Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis. Surface-modified hyaluronic acid hydrogels to capture endothelial progenitor cells. Fibrin acts as biomimetic niche inducing both differentiation and stem cell marker expression of early human endothelial progenitor cells. Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: Their integration with recipient myocardium. Fibroblast sheets cocultured with endothelial progenitor cells improve cardiac function of infarcted hearts. Endothelial cell coculture within tissue-engineered cardiomyocyte sheets enhances neovascularization and improves cardiac function of ischemic hearts. Pre-vascularization of in vitro three-dimensional tissues created by cell sheet engineering. Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: A systematic review and meta-analysis. Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction: A prematurely terminated randomized study. Cell isolation procedures matter: A comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Bone marrow for cardiac repair: the importance of characterizing the phenotype and function of injected cells. Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: Comb ined consequences for cell therapy in older recipients. Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction. Sustained release of engineered stromal cell-derived factor 1-alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function following myocardial infarction. In order to function the heart needs to beat in a controlled rhythmic fashion; this process of contraction and relaxation involves numerous, biochemical, physiological and structural elements. In this chapter, we focus on the cellular components involved in the contractile part of this process, what happens following injury, current treatment options and their limitations, and new cellular strategies aimed at improving cardiac contractility by replacing damaged contractile cells, focusing primarily on replacement of the main contractile cells of the heart, the cardiomyocytes. In this chapter we explore the role of the primary contractile cells of the heart, the cardiomyocytes, the problems that occur when contractility is adversely affected by cardiomyocyte loss or dysfunction and the current in-use therapeutics used in the treatment of dysfunctional cardiac contractility. Results of cellular therapies to treat cardiac patients will also be evaluated to determine if they show any evidence of restoring cardiac contractility. Of these it is the cardiomyocytes that are the highly specialized force generating the cells of the heart primarily responsible for cardiac contraction. Concentric hypertrophy is due to chronic pressure overload, where there is an increase in wall thickness due to addition of parallel sarcomeres causing an increase in cardiomyocyte width. This allows the cardiomyocytes initially to generate more force and reduce pressure on the myocardium. However, with disease progression cardiomyocyte death occurs and cardiac fibrosis increases, leading to myocardial stiffness and cardiac dysfunction. Eccentric hypertrophy is caused by volume overload and leads to wall thinning and dilatation of the heart. The cardiomyocytes again undergo a change in shape, this time becoming elongated through the addition of sarcomeres in series. As disease progresses cardiomyocytes are lost through apoptosis, leading to wall thinning, cardiac dilatation and loss of cardiac contractility. These changes in cardiomyocyte shape are dictated by the nature of the overload process. It should also be noted that these processes are not mutually exclusive and pathological cardiac hypertrophy often progresses to dilated cardiomyopathy (Lorell and Carabello, 2000; Wakatsuki et al. Establishing the contribution of injected cells to blood propulsion from the heart remains difficult. Many studies have demonstrated that cells engrafted in the heart can contract synchronously with the heart. However, the engrafted cells were passively activated and beat after ventricular contraction. Although the skeletal myoblasts were able to form gap junctions with the host cardiomyocytes, the cells did not contribute to contractility. Therefore, demonstrating gap junctions or beating may not be sufficient to establish the contribution of engrafted cells to cardiac blood propulsion. There are few in vitro studies that have explored cardiac contractility, most having focused on expression of markers of cardiac, smooth muscle and endothelial cells, morphological characteristics, differentiation potential to cardiomyocytes, with fewer still looking at calcium signaling, electrical signaling, observation of beating of clusters of cells and ability to migrate into injured myocardium. Human embryonic derived cardiomyocytes have also been shown (in co-culture with non-contractile slices of mouse ventricle) to integrate into the mouse tissue and form beating clusters of cells that are capable of generating electrical signals and isometric forces. This force generation could be further enhanced in vitro by electrical stimulation and addition of extracellular calcium. However, the authors of this study did suggest that further maturation of these cells would be required in vitro before they would be suitable for transplantation as a cellular therapy (Pillekamp et al. One week following injury the hearts were examined to determine if the donor rat cells had engrafted and if they expressed cardiac or skeletal muscle markers. Although no in vivo functional assessments were performed in this early study, ex vivo function was looked at. Strips of tissue were taken from the injury zone of the heart and examined for muscle twitch, it was reported that the muscle could contract and relax but that it was skeletal muscle not cardiac as the grafts never expressed cardiac markers only skeletal muscle markers (Murry et al. This was based on echocardiography taken at 9 days post-transplant of the myoblasts. Moreover, this study reported that a significant amount of regeneration was possible using this bone marrow-derived cell population (Orlic et al. This was considered a leap forward because it suggested that these cells could regenerate injured myocardium to the level that caused measureable functional Cardiac cell therapy to restore contracting elements 259 improvement in cardiac performance. This improvement was attributed to better cell survival and engraftment (Li et al. There was no indication of the mechanism behind this preservation and there was no correlation with control animals that had undergone no injury or treatment. This is perhaps a limitation of this study in that even the sham-operated animals injected with saline only, showed minor scarring that might translate to reduced contractility. Another issue in terms of translating this to a cellular therapy is that cells were delivered immediately following injury; this approach may not be possible in human patients depending on the nature of their cardiac injury. One approach that may prove useful is to combine cells of interest with biomaterials. In a recent study both murine and human induced pluripotent stem cells were used to derive cardiomyocytes, which were then used in combination with collagen I and matrigel to produce an in vitro bioartificial cardiac tissue that had measureable cardiac contractility similar to that of native myocardium (Kensah et al. The clinical application of cells with the ability to become contracting cardiac constructs will very likely require biodegradable biomaterials. The resulting beating cardiac tissue constructs were then sutured on the heart of an athymic rat and demonstrated engraftment. The addition of human bone marrow mesenchymal stem cells and endothelial cells to form a tricell cardiac construct, which was also stretched in vitro, resulted in substantially greater vascularity after implantation in vivo. The combination of biomaterials and stimuli for neovascularity may provide an opportunity for the clinical translation of these contracting cardiac constructs. They found that this combination resulted in the engraftment of cellular constructs that were able to couple with the host myocardium and beat synchronously. However, enhancement of the derived cardiomyocytes offers the hope that they may be able contribute to the restoration of cardiac function in the near future. For a cellular therapy to be successful cardiac contractility needs to be improved or restored. The first cell population to be used for the treatment of cardiac patients was immature skeletal muscle cells known as skeletal myoblasts. This trial was the first randomized placebo-controlled trial to use skeletal myoblasts. The patients were divided into three groups: a high cell dose group, a low cell dose group and a placebo group. Moreover, the patients receiving the myoblast injections had a higher post-operative rate of cardiac arrhythmias than the control group. Therefore the transplantation of skeletal myoblasts failed to improve cardiac function and carried with it an elevated post-operative risk of arrhythmia. It has been suggested that this failure might be a result of the death of cells post-transplant due to the area of injury being poorly vascularized, lack of engraftment of cells or because skeletal myoblasts are lineage committed so that although they can engraft, they give rise to skeletal muscle not cardiac muscle, and are therefore not compatible with the cardiac environment in terms of electrical signaling and contractility. These small trials used a range of delivery routes, cell numbers and in some cases enriched for subpopulations of bone marrow cells, These early trials suggested that 262 Cardiac regeneration and repair the use of bone marrow cells in some cases improved global and regional heart function (Strauer and Steinhoff, 2011). It has been postulated that this improvement may be due to engraftment and differentiation of bone marrow-derived cells to cardiomyocytes or to bone marrow-derived cells having a paracrine effect and supporting resident cardiac cells that have been spared by the cardiac injury or disease.

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This explains the pressure to settle low-value claims even if defensible and a reluctance to appeal a doubtful judgment bajaj herbals pvt ltd ahmedabad order hoodia 400mg with visa. The root of the problem himalaya herbals review buy hoodia from india, however krishna herbals hoodia 400 mg discount, lies less in the complexity of the law than in the climate of defensiveness herbals for anxiety cheap generic hoodia uk. Privately financed claimants or lawyers acting on a no-win herbals for hair loss effective 400 mg hoodia, no-fee basis are therefore the burden (level) of proof In civil litigation the court determines the facts bestlife herbals purchase 400mg hoodia otc, which means that the judge makes a decision on the balance of probabilities. This means that the successful claimant will normally recover damages in full, although in one case where the claimant was held to have lost an 80% chance of cure, a deputy high court judge directed that damages should be calculated accordingly. If the court finds, however, that her chance of survival has reduced from 90% to 60%, it may award her nothing on the basis that on balance her chance of survival remains unchanged. The defendant was in breach of duty in failing to diagnose a fracture of a femoral epiphysis following a fall. The evidence was that the child had a 75% risk of developing this complication due to the accident and the trial judge and the Court of Appeal held that he was entitled to 25% of his damages for the 25% loss of a chance that prompt treatment might have prevented the complication. However, the House of Lords overturned the decision and held that on balance he was going to develop it even in the absence of negligence or, put another way, he had failed to establish that he was within the 25% who would not develop it. The Court of Appeal held that the delay had reduced his chance of survival, although this had always been less than 50%, from 42% to 25% survival at 10 years. So the burden of proof in deciding causation, for the time being at least, remains unchanged. For multifocal tumours, it can be argued that mastectomy would have been needed from the outset. With the advent of sentinel node biopsy, a claimant who has undergone axillary clearance for involved nodes may contest that earlier diagnosis at a time when her nodes were clear would have allowed less radical axillary surgery. When the patient has received chemotherapy it might be argued that this would not have been necessary if the diagnosis had been made sooner when, for example, the axillary nodes would on balance have been negative. This is a controversial area since there is public expectation, promoted over the years by health campaigners, that earlier diagnosis offers better chance of a cure. Where expert opinion is divided, the court often prefers the evidence in favour of the delay having caused a reduced survival time. A review of claims for diagnostic delay in breast cancer in Sweden over a 10-year period concluded that delays had an impact on treatment in 23% of cases and adversely affected prognosis in 11% of those patients for whom the delay was longer than 12 months. The main area of contention is where long-standing or recurrent breast nodularity coexists with an (initially) undetected lump. Relying on a negative mammogram without an expert clinical examination, ultrasound or needle biopsy may increase the risk of false reassurance. The role of triple assessment, and the circumstances in which it fails, are critical. The specialist centre is also faced with the problem that women under 35 form the majority of the diagnostic workload (66%) but the fewest number of breast cancers (3%). The mean payout was $301 000, with higher damages for longer delays and to younger patients. However, the extent to which the accuracy of these tests is reduced in younger women is not well appreciated. It has been suggested that perfection of diagnosis will require removal of every solid mass,25 but this would represent a retrograde step. The practice of defensive medicine, in place of conventional wisdom, may well be encouraged by a litigious public and diagnostic tests where the sensitivity falls below 95%. Physical examination About 70% of all breast cancers are palpable, but with tumours of 0. Cyclical changes in breast parenchyma may require repeat examination at different phases of the menstrual cycle. Coexisting benign lumps, scars and distortion from previous surgery, the ridge of tissue above the inframammary fold, changes during pregnancy and lactation, and the underlying ribs all add to the uncertainty of clinical examination. Other difficulties include: inflammatory cancers masquerading as infection; the presence of implants with an associated fibrous capsule; and the effect of hormone replacement therapy, which increases the density of breast parenchyma both clinically and radiologically. The expertise required for ultrasound examination and guided core biopsy has placed breast imaging outside the competency of the general radiologist. The breast surgeon using ultrasound in the clinic may be similarly compromised unless training in the technique can be verified. Mammography False-negative mammography is one of the principal reasons for delay in diagnosis,3,27 since it gives the clinician and patient false reassurance. The net result of medicolegal pressure on breast radiologists has been an increase in recall and biopsy rates. The false-negative rates of the three investigations have been multiplied and expressed as a percentage in Table 18. It is probable that the sensitivities of these tests are not totally independent of each other, and therefore the predicted rate that all three tests will be false negative for an individual is a conservative estimate. For a woman under 35 with breast cancer, there may be a 12% chance that all three tests will give a false-negative result. Using optimal sensitivities, the chance that all three tests will produce a false-negative result falls to approximately 1 in 1000 patients with these data skewed towards the older age groups; the likely overall rate of false-negative triple assessment in the clinic is between 1. It is possible for mammography to detect tumours as small as 2 mm, which equates to a tumour of 107 cells and about 23 doublings. Assuming a constant doubling time, early detection of breast cancer is a misnomer, since at least two-thirds of the biological life of the tumour will have been completed by the time of detection. This represents a major increase in tumour load but is a very short period in the lifespan of the tumour and it is difficult to be sure that this period of delay would have a significant effect. Lymph node status remains the most important prognostic indicator at the time of primary treatment. Tubiana and Koscielny35 suggested that breast cancer represents a continuum from slow-growing tumours with late axillary involvement and distant dissemination to the most aggressive, rapidly growing and early metastasising subtype. Assuming the growth rate of the nodal metastasis approximates to that of the primary tumour, it is possible to estimate the theoretical time at which the tumour must have metastasised, and not infrequently this would have occurred before the threshold size for detection of the primary tumour. Doubling times for breast cancers have been estimated by measuring the size of mastectomy scar recurrences36 and by serial mammographic evaluation. Although lymph node metastases are more commonly found in fast-growing tumours, it would be wrong to assume that the survival of patients was entirely a consequence of tumour doubling time. The premise that early detection of a tumour will lead to cure depends on the concept that at the time of earlier treatment the tumour has not metastasised. The period of time between the earliest possible detection of the cancer and the time at which the tumour metastasises has been described as the cancer control window. It is often argued by the claimant and her legal team that delay in treatment is the cause of metastasis rather than the inherent biology of the tumour itself. Vignettes on breach of duty the following vignettes illustrate areas of breach of duty that have arisen in medicolegal breast cases and the comments following each vignette raise issues that might be discussed in conference with counsel. The patient underwent wide local excision and axillary clearance for what subsequently proved to be a histologically benign condition. She complained of a poor cosmetic outcome and a painful swollen arm, which she had not been warned about. The patient was started on tamoxifen but was not referred for consideration of radiotherapy. From a medicolegal standpoint, an expert review of the cytology should be the first step. If experts are agreed that the cytologist acted reasonably in reporting the slides as malignant, attention will then focus on the surgeon. Histology is mandatory in the absence of a fully concordant malignant triple assessment and should have been obtained in this case. Axillary clearance for a benign condition is a potentially significant injury and it is unfortunate that this patient developed lymphoedema. Judges place most reliance on contemporaneous records and alterations to the notes are often quite obvious. Any addition to the notes must be clearly identified as such by signing and dating the record and any temptation to alter the record after the event must be firmly resisted. Vignette 3: False-negative cytology, trainees in the clinic and lobular carcinoma A 38-year-old patient was referred to a breast clinic with a breast lump. Mammography was negative and a specialist registrar found an indefinite lump of which he was not suspicious. She was discharged from the clinic but re-presented 6 months later with an invasive lobular carcinoma at the same site. Vignette 2: Failure of preoperative assessment and postoperative management A 69-year-old woman presented with a small but obvious carcinoma in the tail of the breast. Delay in diagnosis: causation issues In a case of delay in diagnosis, it is often relatively straightforward to establish whether there has been a breach of duty of care. The next hurdle to be overcome by the claimant is to satisfy the court, on the balance of probabilities, that this delay caused her harm. Expert opinion is often divided and if the experts cannot agree then the court makes a judgment. The public and the judiciary have the expectation that early diagnosis carries a better outlook. It is not surprising therefore that counter-arguments of lead-time bias and innate tumour biology tend to fall on deaf ears. Having established breach of duty, the issue of causation may include the allegation that less treatment would have been required. However, the main issue centres around whether the claimant has suffered a reduced expectation of life or, if she has died by the time the matter comes to court, whether she would have lived longer. However, if one accepts this, then for some tumours with a worse prognosis there must be a greater loss of survival. Unfortunately, he pierced the pleura and caused a pneumothorax that required hospitalisation and pleural drainage. The patient was not warned of the risk and complained of persistent chest pain over a period of many months. Were this to be a trainee, it would be necessary to establish that he or she had been properly supervised. Tumour size itself is a weak determinant of prognosis but the derived earlier tumour size is further used to calculate the likely nodal status. Assumption 3: the nodal status at the time of the breach of duty is usually unknown and often disputed by the experts. Axillary node status is invariably presumed to have been negative by the claimant, and this claim is supported by tables for tumour grade and tumour size that show the probability of positive nodes. Therefore, on balance it may often be argued that the nodes would have been negative at the earlier time when the tumour was smaller. Vignettes on causation the following vignettes illustrate some of the causation issues that have arisen once liability has been established. Delay in diagnosis remains an area of considerable uncertainty and the comments reflect our experience of differing arguments presented to the court. Vignette 5: 12-month delay in diagnosis of node-positive carcinoma A 32-year-old woman was referred to a breast clinic with a lump in the breast. She was discharged from the clinic but returned a year later with a clinical carcinoma at the same site. Liability for delay in diagnosis was admitted in failing to carry out a biopsy at the first visit. Vignette 6: 2-year delay in diagnosis of node-negative grade 1 carcinoma A 40-year-old woman presented with a lump in the breast and a triple assessment was carried out. She was discharged but 2 years later returned with a carcinoma 3 cm in diameter on histology. Review of the original cytology indicated that this had been under-reported and an expert opinion graded the slides unequivocally malignant (C5). Online50 are often used to determine the difference in outcome over the period of delay. In this particular case a record of tumour size at the first visit was available, but if no clinical measurement was recorded and there was no imaging, an approximate tumour size has to be derived by working back from the tumour volume at diagnosis using tumour doubling times. The treatment would have been the same with an earlier diagnosis and therefore the case did not succeed on causation. There was a soft-tissue opacity and the appearance was judged benign on further magnification views and ultrasound. She was returned to routine screening but 3 years later the screening films showed an obvious carcinoma at the same site. This was a 2-cm grade 2 infiltrating carcinoma with an extensive in situ component; four of 10 nodes were positive. Vignette 8: 14-month delay in the breast clinic and failure to recommend chemotherapy A 30-year-old woman was referred with a lump in the breast and was seen by a succession of specialist registrars. The patient was treated by wide local excision, axillary clearance and radiotherapy. She was not given chemotherapy or hormone treatment until she developed bone secondaries 16 months later. Breach of duty was admitted for the delay in diagnosis and the failure to give chemotherapy at the time of diagnosis. Screening by 3-yearly mammography probably reduces breast cancer deaths by up to 25%, and it is likely that a delay in diagnosis of 3 years will affect survival in a proportion of cases. At age 53 the patient now has a relatively poor prognosis but on balance is still more likely to survive 10 years (Table 18. It was agreed that when first seen the tumour would have been grade 3, 1 cm in diameter and node negative. The tumour had increased in size to 4 cm in the 14 months of delay and opinion was divided as to whether this was ever potentially curable. The experts for the claimant were far more optimistic than those for the defence but in the event the judge preferred the latter. Civil litigation rules resulted in the family winning the case but receiving none of the settlement.

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