Benjamin Hibbert, MD, FRCPC

• Vascular Biology Lab Research Fellow
• Department of Biochemistry and Division of Cardiology
• University of Ottawa Heart Institute
• Ottawa, Ontario, Canada

In patients with medically refractory symptoms during pregnancy erectile dysfunction causes premature ejaculation discount levitra oral jelly 20 mg otc, balloon aortic valvuloplasty can be considered [18 erectile dysfunction age 21 purchase 20mg levitra oral jelly mastercard,49] benadryl causes erectile dysfunction order levitra oral jelly with a mastercard. Surgical aortic valve replacement can be considered in severely symptomatic patients not responding to medical therapy and who are not candidates for valvuloplasty impotence vacuum pump demonstration cheap levitra oral jelly on line, with careful consideration of maternal and fetal morbidity erectile dysfunction see a doctor levitra oral jelly 20 mg cheap. Transcatheter aortic valve replacement may be an option in pregnant women but the clinical experience with this approach is extremely limited [18] erectile dysfunction in young males causes buy cheap levitra oral jelly 20mg on-line. However, surgery should be considered pre-pregnancy for exercise-induced symptoms (like shortness of breath, chest pain, dizziness), drop in blood pressure, or left ventricular dysfunction [18]. In bicuspid aortic valve disease, ascending aortic diameters should be assessed before, during, and after pregnancy to rule out worsened dilation. Surgical treatment of severe left-sided regurgitation is rarely indicated during pregnancy [52]. Balloon pulmonic valvuloplasty during pregnancy is typically for medically refractory symptoms [57,60]. However, scoring systems are not an absolute method to ascertain risks for all patients [63]. The risk associated with each pregnancy is derived from the specific underlying cardiac diagnosis and comorbidities, making each patient distinctive. Pregnancy planning Patient decides to avoid risks of pregnancy: Offer access to safe and appropriate contraception Offer information on the safe termination of undesired pregnancy Offer information about adoption or surrogate pregnancies Patient decides to continue with pregnancy: Consultation with cardiology, maternal-fetal medicine, and anesthesiology as pregnancy heart team Determine whether the patient needs preconception intervention based on guidelines Perform preconception counseling with pregnancy heart team Adjust medications to avoid teratogenicity Arrange schedule of follow-up visits with pregnancy heart team Determine location of care based on specialization needed Determine location and mode of delivery (see Table 11. A multidisciplinary team of experienced physicians should ascertain the risk using the medical history, general cardiac assessments, and diagnostic tools specific to the lesion. In contrast, bioprosthetic use at a younger age risks structural valve deterioration during the reproductive years of life. Dysfunctional bioprosthetic valves have comparable risks during pregnancy as native diseased valves [18]. If possible, this should be a longitudinal conversation beginning early in her reproductive years. For patients with congenital heart disease, it has been shown that by starting conversations in adolescence, girls have a significantly better understanding of their disease, their need for lifelong monitoring, and that they should have their condition evaluated before becoming pregnant [73]. Preconception counseling should include a review of contraception compatible with individual comorbidities, based on individual preferences, efficacy, the risk/benefit of each method, and cost [74]. A patient-centered approach to Bioprosthetic versus Mechanical Valves For patients who must undergo valve replacement prior to pregnancy, preconception counseling may include discussion of bioprosthetic vs. Part of preconception counseling is considering whether to carry out an intervention before the pregnancy, or if the patient can tolerate the hemodynamic changes that occur during pregnancy and peripartum. This conversation should include a list of symptoms that may signify deterioration in their clinical status. If experiencing pregnancy poses too great a risk, other options may be appropriate to discuss, such as adoption and surrogacy. European Society of G, Association for European Paediatric C, German Society for Gender M. Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa. Quantitative cardiovascular magnetic resonance in pregnant women: Cross-sectional analysis of physiological parameters throughout pregnancy and the impact of the supine position. Combined Doppler and echocardiographic measurement of cardiac output: Theory and application in pregnancy. Global cardiac risk assessment in the Registry of Pregnancy and Cardiac disease: Results of a registry from the European Society of Cardiology. Maternal hemodynamic effects of uterine contractions by M-mode and pulsed-Doppler echocardiography. Echocardiographic evaluation of hemodynamic changes in left-sided heart valves in pregnant women with valvular heart disease. Recommendations for noninvasive evaluation of native valvular regurgitation: A Report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance. Recommendations for the echocardiographic assessment of native valvular regurgitation: An executive summary from the European Association of Cardiovascular Imaging. Clinical and echocardiographic assessment of pregnant women with valvular heart diseases-Maternal and fetal outcome. Pregnancy outcomes in women with rheumatic mitral valve disease: Results from the Registry of Pregnancy and Cardiac Disease. Heart rate response during exercise and pregnancy outcome in women with congenital heart disease. Cardiopulmonary variables during exercise predict pregnancy outcome in women with congenital heart disease. Percutaneous balloon aortic valvuloplasty during pregnancy: Use of the Inoue balloon and the physiologic antegrade approach. Cardiovascular effects of intravaginal misoprostol in the mid-trimester of pregnancy. Non-cardiac complications during pregnancy in women with isolated congenital pulmonary valvar stenosis. National trends and in-hospital outcomes in pregnant women with heart disease in the United States. Incidence and predictors of obstetric and fetal complications in women with structural heart disease. Educational needs of adolescents with congenital heart disease: Impact of a transition intervention programme. The cardiomyopathies are a diverse group of disorders characterized by structural abnormalities of the heart muscle, many of which have a genetic component. Abnormalities may be anatomic (dilatation, thickened, or stiff musculature), histologic (manifested by fiber disarray, fibrofatty dysplasia, or fibrosis) or functional (systolic or diastolic dysfunction). Nonischemic cardiomyopathies have several phenotypes that include dilated, hypertrophic, restrictive, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy commonly presents in the third and fourth decade of life, which underscores concerns during reproductive years [5]. Pregnancy-related alterations in hemodynamic, hormonal, and autonomic systems lead to atrial and ventricular stretch, which may increase arrhythmia burden when combined with the normal increased heart rate during pregnancy [9]. The precise frequency of cardiomyopathy during pregnancy is not known and varies with geographic location, population, and specific cardiomyopathy. Cancer patients receiving chemotherapy, especially anthracyclines, or chest radiation therapy are at risk of ventricular dysfunction. Thirty-nine percent of pregnancies were associated with at least one adverse maternal event. Sixteen-month event-free survival was worse in women who had a pregnancy than in women who did not [22]. Maternal prognosis is variable but may be better than many other forms of cardiomyopathy [16,37,38]. Most women improve in the first 6 months postpartum but delayed recovery has also been reported [38,39]. There is a wide variation in published outcomes ranging from 2% in a German registry to 13% in a recent South African study [16,38]. Most are transmitted as autosomal dominants, although all inheritance patterns are described. Bromocriptine stimulates hypothalamic dopaminergic receptors inhibiting prolactin production suggesting a potential role in therapy [49]. A randomized trial in 20 South African women showed improved ventricular recovery as proof in concept [50]. Further interest has been stimulated by a multicenter trial in 63 women with ejection fractions less than 35% who were randomized to 1 week versus 8 weeks of bromocriptine, finding a nonsignificant trend toward greater recovery in the 8-week therapy group, but both groups improved. No women required advanced interventions, right ventricular function improved, and there were no deaths at 6 months [51,52]. In the United States, the incidence is strikingly higher in African Cardiomyopathies in Pregnancy with bromocriptine, and loss of the ability to lactate have dampened enthusiasm for use in the United States in the absence of a larger placebo-controlled trial [16,53]. European guidelines have recommended consideration of bromocriptine in addition to guideline directed medical therapy [54]. A retrospective internet survey noted improved recovery in the two-thirds of women who breastfed [58]. Some women may have subnormal cardiac reserve even in the setting of improved function. Additional risk stratification might be considered using dobutamine or exercise stress prior to proceeding [63,64]. Most believe full recovery is associated with improved outcomes and lower mortality with a subsequent pregnancy, but all patients have a risk of deterioration [38,59,61]. Elevated scores should prompt additional evaluation with biomarkers or transthoracic echocardiography. The hypertrophy is often asymmetric with wall thickness >15 mm, but multiple patterns of hypertrophy have been described [67]. Arrhythmia risks include atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Recurrence risk estimations are derived from retrospective analysis of women with subsequent pregnancies. In the largest study, deterioration was seen in 21% of gravidas with recovered function in comparison with 112 variable expression and age-related penetrance. Symptomatic patients may present with fatigue, dyspnea, chest pain, palpitations, pre-syncope, or syncope. Left ventricular outflow obstruction may be dynamic and worsen with exercise or reduced systemic vascular resistance of pregnancy; however, this may be offset by the increased volume of pregnancy. Left atrial enlargement or increased filling pressure can worsen mitral regurgitation and exacerbating arrhythmias such as atrial fibrillation. Restrictive Cardiomyopathy Restrictive cardiomyopathies are characterized by the presence of "restrictive filling pattern in the presence of normal or reduced diastolic volumes, normal or reduced systolic volumes, and normal wall thickness" and may represent various pathologies rather than a distinct entity [2]. Primary restrictive cardiomyopathy may be inherited due to genetic mutations in cardiac proteins, such as troponin, or non-inherited, such as in infiltrative disorders including hemochromatosis, amyloidosis, or sarcoid or radiation exposure [2]. Disruption of normal myocardium increases electrical instability, so arrhythmias are a prominent problem [73]. Preterm delivery and cesarean rates were low, but premature sudden death was seen in five children before age 25 (10%) [74]. This allows for estimation of maternal and fetal risk, assessment of potential transmission to offspring for heritable conditions, and modifications of medications compatible with pregnancy. Baseline exercise tolerance and functional status may be estimated by stress testing 7. Pregnancy heart team/multidisciplinary team should be identified consisting of a cardiologist, obstetrician/maternal-fetal medicine specialist, and obstetric anesthesiologist versed in management of heart disease in pregnancy. Other members may include neonatologist, geneticist, electrophysiologist, or cardiothoracic surgeon. Beta-blockers are generally considered safe with the caveat that fetal growth should be monitored. Fluid and sodium restriction is recommended for all patients, and loop diuretics for symptomatic relief of pulmonary congestion or significant edema. Serial echocardiograms, serial measurement of natriuretic peptides, and fetal ultrasounds should be followed during pregnancy [54]. Otherwise timing of delivery should be determined by obstetric factors, such as fetal growth or development of preeclampsia, using a team approach [38,54]. Conclusion the cardiomyopathies encompass a wide spectrum of diseases with genetic and phenotypic overlap. Goals of therapy are maintenance of normal volume status, treatment of arrhythmias, and prevention of thromboembolic complications. Pre-pregnancy counseling should be performed when possible focusing on maternal functional status and ventricular function and optimization of medical therapy. When a genetic etiology is known, patients should be informed about the risk of transmission to offspring based on the inheritance pattern. Transthoracic echocardiography and measurement of plasma natriuretic peptides, along with careful history and frequent reassessment, are the mainstays of follow-up during pregnancy and the puerperium. During delivery, noninvasive telemetry monitoring is useful to assess for arrhythmias, point-of-care echocardiogram can give information about volume status, and arterial line pulse wave analysis may provide information on cardiac output and stroke volume variation. Placement of a Swan-Ganz catheter remains the gold standard for measuring cardiac output and filling pressure but has not been shown to have mortality benefit and is not frequently used during delivery, although may be used for patient stabilization and assessment. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Classification of the cardiomyopathies: A position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Current diagnostic and treatment strategies for specific dilated cardiomyopathies: A scientific statement from the American Heart Association. Pregnancy-related cardiovascular deaths in California: Beyond peripartum cardiomyopathy. Temporal trends in incidence and outcomes of peripartum cardiomyopathy in the United States: A nationwide population-based study. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution.

The flaviviruses responsible for causing ocular manifestations are shown in green whereas specific ocular tissue pathology is highlighted in red [11] erectile dysfunction trimix buy generic levitra oral jelly 20 mg on-line. It is generally believed that measures like such as vaccination of at-risk individuals impotence kit buy genuine levitra oral jelly, quarantine of diseased persons erectile dysfunction clinic raleigh generic 20 mg levitra oral jelly mastercard, and acute and timely treatment help to control all the epidemics newest erectile dysfunction drugs purchase levitra oral jelly paypal. The people who may be resistant to the disease may be so because of previous exposure to viruses with similar structures encore erectile dysfunction pump buy levitra oral jelly 20 mg without prescription, resulting in the development of immune responses that are adequate for multiple pathogens erectile dysfunction pills images cheap levitra oral jelly 20mg free shipping. They might also be resistant due to superior health, including age, nutritional status, and occupational advantages. The virus might eventually be faced with a population that is completely resistant to the infection. Weather changes, including temperature and humidity fluctuations, may significantly influence the survival or propagation of a virus outside the body. Elimination of reservoirs that carry pathogens including animals, insects, food, or water, by chance or design, may disrupt the cycle of propagation. Such elimination of infection is less likely to occur within an epidemic because of diverse factors and geographical areas involved. This theory reflects the similarity between retention of particulate matter during filtration based on density of sand particles, which can be compared to pathogens within a population based on population density. Dengue virus infection outbreak Chapter 3 21 Most epidemics are composed of diseases that require close contact between diseased and healthy individuals for continued propagation of pathogens. Unlike natural disasters, such as hurricanes, floods, volcanoes, and changes in climate that exist independent of population density, epidemics depend upon population density, a feature shared with reproduction rates, migrations, and predation. After population density reduces below a critical limit, such contact may not be available enough for continued propagation of pathogens. Review of the factors modulating Dengue virus infection transmission Understanding of factors, which play important role in Dengue virus infection transmission, is very important for planning more effective strategies for prevention and control of this disease [7]. Relations among rainfall, vector density, and Dengue virus infection incidence A positive association between rainfall or larval density and Dengue viral illness incidence has been reported by few studies but it only hold true for countries just above and below the equator. For example, Dengue virus infection epidemics have been recorded in regions where rainfall or larval indices were unusually low or where due to availability of piped water, water jars/wells were rare. In northeastern Thailand in 1987, Dengue hemorrhagic fever epidemic happened in dry and hot season and was over before the rainy season. It is important to note that Dengue hemorrhagic fever incidence was highest in that region of the country [7]. Temperature Blanc and Caminopetros reported that Aedes aegypti mosquitoes can only transmit the Dengue virus at temperature above 20 C. For example, the Dengue virus infection epidemics ceased when the temperature dropped to 14e15 C in winter. As Aedes aegypti mosquitoes infect mostly domesticated species, as a result outdoor temperature may not always affect their distribution. That is why it was not surprising to have Dengue virus infection outbreak in Mexico at an altitude of 1700 m [7]. The validity of using the minimum vector density to access the success of programs directed toward Dengue virus infection has been questioned [7]. Vector movement Flight range the flight range for Aedes aegypti mosquito has been variable from as long as 2. In one study conducted in an African village, the majority of marked mosquitos remained in the house when they were recaptured. In addition, the house entering behavior of mosquito is genetically controlled [7]. Transport of vectors Three important modes of vector transmission are: water, land, and air. Before, the advent of air travel, ships were considered to be the principal source for transmission of Dengue virus infection from Africa to Asia and Americas. Latter on development of efficient highways and other means of ground transportation lead to infestation by the Aedes aegypti mosquito in towns located along the roads and railways. Similarly, an extensive list of records showing aircraft bringing Aedes aegypti mosquitoes to Dengue-free countries is available [7]. Mosquito-related factors Density (number) of Dengue viruseinfected adult female mosquitos per residence is an important factor in transmission but is not the only factor. For example, in an isolated Dengue virus infection outbreak in a school in Malaysia, only three A. Other factors include proportion of engorged females mosquitoes per residence, number of virus infected females, and multiple feedings (bites). Multiple feeding per mosquito is considered to be an important factor for exponential spread of Dengue virus infection epidemic, but it is also not the only factor. It depends if the first human bitten had neutralizing antibody which could result in neutralizing of virus from a viremic person to a noninfected person, provided the second bite Dengue virus infection outbreak Chapter 3 23 is within 6 h after first bite. Human factors More than one person per household increases the chance of transmission of Dengue virus infection epidemic. Transmission occurs if same mosquito infects other susceptible member of the household or an uninfected female mosquito feeds on first victim who is still in viremic stage of illness. Thus multiple infections in a single household accelerate the spread of infection in the community. Vector-infested places: schools, commercial establishments, churches or temples, offices, military bases, factories, hospitals, prisons, and theaters facilitate the Dengue virus infection spread [7]. Herd immunity With respect to role of protective antibody, it is difficult to determine the exact levels of immunity required against a specific serotype for all age groups in secondary infection. In one study in Singapore, despite the low levels of mosquito density, low levels of herd immunity was likely responsible for continuous spread of Dengue hemorrhagic fever in children under age 10 years. Thus it was reported that intense vector control program in Singapore brought the opposite effects with increase in outbreaks of Dengue fever as a result of declining herd immunity. For some viral diseases such as measles and rubella, levels of immunization required for disease prevention range from 84 to 96%. Thus knowing levels of herd immunity required for Dengue virus infection prevention is vitally important [7]. Breast milk as a possible route of Dengue virus infection vertical transmission Barthel et al. They reported a case report where patient presented to hospital in preterm labor and gave birth to a premature but healthy baby. On day 2 after birth, infant was fed on expressed breast milk after which both mother and baby experienced nonsevere acute Dengue infection with fever and severe thrombocytopenia but no signs of hemorrhage or plasma leakage. Dengue virus was tested in breast milk and as result breast feeding was stopped on day 4. Breast feeding transmission has been reported in other flaviviruses such as West Nile virus and Yellow fever virus. Therefore, recommendations have been made to stop 24 Dengue Virus Disease breast feeding during the acute viremic phase after using a live attenuated virus vaccine [8]. Dengue, Zika, and Chikungunya viruses: emerging arboviruses in the new world Dengue, Chikungunya, and Zika viruses are all three arboviruses, which in recent years have expanded across the globe with large outbreaks in Western Hemisphere territories in close proximity to the United States. The increase in globalization led to spread of these infections to populations with no native immunity. These mosquitoes are aggressive bitters during the day time but can also bite at night too. These mosquitos lay eggs in standing water in things like buckets, bowls, animal dishes, flower pots, and vases [9]. Zika virus Zika virus is named after an Ugandan forest in which it was first discovered and is closely related to Dengue virus. For decades, it was of a little concern for clinicians, until recently when a correlation between Zika virus infection and fetal microcephaly was discovered in 2016 and World Health Organization officially declared it a "Public Health Emergency of International Concern. Subsequent outbreaks occurred across the Pacific Islands until 2015 when Brazil reported the first case of Zika virus infection in the America. Other possible mechanisms other than mosquito biting are sexual transmission and blood borne transmission likely during the viremia stage. Zika virus has also been isolated from urine, saliva, and breast milk of infected individuals but no transmission has been documented from these sources yet. During viremia, a mild disease consisting of fever, nonpurulent conjunctivitis, a maculopapular rash, arthritis/arthralgias, headache, and vomiting occurs. Zika virus infection has not been shown to cause the severe capillary leak syndrome or hemorrhagic fever. Since symptoms are clinically indistinguishable from Dengue virus infection initially, aspirin, nonsteroidal antiinflammatory drugs, and steroids should be avoided as they may increase the severe hemorrhage in cases of Dengue infection. Due to potential risk of fetal birth defects in pregnant women due to Zika virus infection, it is strongly recommended by Centers for Disease Control and Prevention to avoid travel to endemic areas. If the travel cannot be avoided, strict mosquito protection measures should be taken. Pregnant women with Zika virus infection should undergo serial ultrasounds every 3e4 weeks throughout the pregnancy. In addition, there is also Dengue virus infection outbreak Chapter 3 25 a concern for possible correlation between Zika virus infection and GuillaineBarre syndrome. Some occurrences have been reported by several countries in the western Pacific and Americas [9]. Chikungunya virus Chikungunya virus was first isolated 1953 from a febrile patient in Tanzania. Chikungunya, an alphavirus of the Togaviridae family is a mosquito-spread virus and cause the symptoms similar to Dengue and Zika virus infections. Viremia and other symptoms occur after an incubation period of 1e12 days (typically 3e7 days). Arthralgia almost occurs in all the cases with common joints involved are ankles, wrists, and fingers. Arthralgia is worse in the morning, improves with mild exercise but worsens with strenuous exercise. Similar to Dengue and Zika viral infections, management of Chikungunya viral infections is supportive. Acetaminophen is preferred for pain and fever control over nonsteroidal antiinflammatory drug due to risk of possible misdiagnosis of Dengue virus infection [9]. Dengue and other emerging flaviviruses More than 70 flaviviruses have been identified [10], almost half of them cause disease in humans and only few are of major importance. There are three clinical syndromes caused by the flaviviruses: fever-arthralgia-rash, viral hemorrhagic fever with or without hepatitis, or central nervous system diseases. There are no antiviral drugs against the flaviviruses but vaccines do exist against a few of them. Mosquito-borne viruses tend to occur in warm while the tick-borne viruses in cooler climates. Examples are mosquito-borne Japanese encephalitis virus occurs in southern and eastern Asia but tick-borne encephalitis virus occurs in Europe and Commonwealth of Independent States (the former Soviet Union). In addition, mosquito-borne viruses have shorter life cycles due to the fact that mosquito have shorter life cycles than ticks. As a result, mosquito-borne viruses are evolving rapidly to fill in the ecological niches in new geographical areas. As humans do not produce high viremia, therefore act as a dead end hosts for them. Most of the flavivirus infections produce a mild disease with the exception of few diseases [10]. Yellow fever virus Epidemics compatible with yellow fever virus have been described in West Indies, Central and South America and, West Africa since 15th century. In the 26 Dengue Virus Disease early 1900s, a team demonstrated that yellow fever was caused by a filterable agent (a virus), transmitted by mosquitoes. Yellow fever occurs in jungle and urban cycles in West and South America, transmitted to forestry and agricultural workers when bitten by mosquitoes. Due to high and prolonged viremias in humans, infected individuals will carry the disease to populated areas where Aedes mosquitoes transmit the virus to cause "urban Yellow Fever. Yellow fever vaccine was one of the first live attenuated vaccines with conferring immunity up to 10 years or more. Other effective measures included removal of breeding sites, treatment of stored water, and ultralow volumes spraying [10]. Japanese encephalitis Japanese encephalitis is the most important viral encephalitis worldwide with 50,000 cases and 10,000e15,000 deaths. The disease was recognized since epidemics of encephalitis in Japan in 1870s onwards and virus was isolated from a fatal case in 1930s. Virus gets transmitted between birds and animals by Culex mosquitoes, especially Culex tritaeniorhynchus and humans get infected due to close proximity with this enzootic cycle. Serological studies have shown that almost all individuals living in rural Asia get infected with Japanese encephalitis during the childhood but only 1 in 300 become symptomatic. Japanese encephalitis virus infections cause variable clinical presentation ranging from headache, cough, and coryza but in some cases these febrile prodromes are followed by coma and convulsions. About 20%e30% patients die and more than half of the survivors are left with severe neuropsychiatric sequelae. Cerebrospinal fluid analysis will likely show lymphocytic pleocytosis but can be normal and computer tomography and magnetic resonance imaging shows damage in thalamus, basal ganglia. Japanese encephalitis vaccine is available for 30 years now and strongly recommended for residents of endemic areas and travelers planning to visit the endemic areas for more than 3 weeks. Other important preventive measures include insect repellents; bed nets to avoid mosquitoes biting; and keeping pigs, chickens, and other potential animals away from human dwellings [10]. West Nile encephalitis West Nile virus, first isolated in 1930s, was considered benign until recently and is mostly found in much of Africa, much of Asia, Southern Europe, and recently in North America.

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Introduction In the 21st century skin diseases and ailments are on the rise erectile dysfunction doctor in delhi buy levitra oral jelly online pills, affecting millions on a day-to-day basis. Skin troubles may be benign or fatal and are usually caused by inflammation or diseasecausing pathogens [1]. Generally, infections are found to be responsible for these skin-related issues and there has been unsatisfactory advancements in treatments. These therapies are based on a number of factors, namely: pathogen type, medical condition of the person, patient skin condition/layers, and their integrity [2]. The competent remedy of skin disorders like psoriasis needs appropriate identification, dealing with the pathogen by a systematic therapy. This is brought about by administration of the therapeutic moiety via a suitable administration route. Knowledge about skin morphology and barrier characteristics, along with target information, will surely accelerate the development of better and specific treatments [3]. The aim of this chapter is to evaluate nanocarrierbased delivery systems which enhance drug uptake in the skin and show promising therapeutic potential in the treatment of psoriasis. Psoriasis is an inflammatory skin condition, with the cause remaining not completely understood. It is distinguished by scaly, dry, and itchy patches on the knees, scalp, and elbows. Psoriasis is a noncontagious disease with genetic factors responsible for its emergence. Psoriasis therapy varies, depending on the severity, ranging from small and local patches on skin. Systemic and topical antipsoriasis medications are available for the symptomatic treatment of psoriasis. Nanocarriers for topical delivery in psoriasis the main challenge here is to overcome this barrier and ensure an optimal drug amount reaches the deepest skin layer. Therefore, in this direction novel therapies have been developed which are composed of specific ingredients to improve drug delivery yet maintain the safety profile [5]. Conventional treatment of psoriasis usually includes immune system suppressors, ultraviolet light. In the past years, the evolution of new drugs has become inadequate to ensure progress in the overall drug treatment. The primary reasons for this are extensive distribution, metabolism, and therapeutic moiety insoluble in formulations [6]. The advantages of nanocarriers are reduced dosage, improved safety profile, and efficient targeting potential [3]. Skin Skin serves as the outermost barrier protecting the body from the external environment. It is the largest organ of the body, averting the entry of external pathogens and chemicals. This goes hand in hand with its numerous functions including vitamin D metabolism, perception as a sense organ, as well as being the main site for topical drug delivery [7]. Its three main layers include the outermost epidermis, the middle dermis, and the innermost hypodermis. The epidermis is devoid of blood vessels and therefore essential nutrients have to diffuse across the dermaleepidermal junction. The epidermis is in direct contact with the outside environment, which is responsible for its main purpose as a barrier. Therefore, pathogens and drugs are restricted from entering into and also water from exiting the body. This distinctive disposition helps in the prevention of entry of molecules larger than 500 Da. The viable epidermis, on the other hand, is made up of Langerhans cells, Merkel cells, and keratinocytes at different phases of differentiation [8]. Melanin synthesis is also a major function of viable epidermis along with immunology and sensory perception. Percutaneous transport of drugs through lipophilic skin is due to the presence of phospholipids, cholesterol, and its esters [9]. Passive diffusion is mainly responsible for the transport of substances and is possible by three routesdintercellular, transcellular, and appendageal [10]. The intercellular pathway is taken up by tiny molecules also referred to as penetrants. The volume, molecular weight, hydrophilicity, and lipophilicity are some of the factors that control the diffusion process. Active transport of drugs may be facilitated via numerous protein transporters of the skin. The location and presence of tight junction proteins may also change in skin disorders like psoriasis [10]. These assist in removing cancerous cells, particulate matter of a solid nature, and any foreign bodies [12]. The middle layer of the skin dermis is composed of collagen fibrils, which play a role in its flexible nature and mechanical support. The dermis serves as an essential location for fluid and cellular exchange between the blood, lymph, and skin. It is primarily made up of fibroblasts that create connective tissue constituents, melanocytes, nerves, and mast cells. Below the dermis is the inner subcutaneous tissue, also referred to as the hypodermis, which acts as an energy deposit. The dermis also serves as a connecting link for the skin to the blood vessels and nerves. There is also the presence of various appendages impaling the skin, such as hair follicles, and sweat and sebaceous glands arising from the dermis [13]. Their association with mast cells, specific T lymphocytes, and keratinocytes is a critical prerequisite for this activity [14]. The barrier role of the skin in its diseased condition must be considered while developing nanocarriers. The delivery of nanoparticles by penetration through the diseased skin is usually done topically for local action. Since the existing data on this aspect is limited, the effect of the skin barrier in its various ailments on nanocarrier transport is unfamiliar. The latter is an autoimmune chronic skin condition that shows excess keratinocyte growth, differentiation, and enhanced dermal vascularity [2]. In 1841 a Viennese dermatologist Ferdinand von Hebra used the term "psoriasis" as a chronic human skin disorder. This medically debilitating condition affects 2%e3% of the worldwide population [15]. It has a peak between the ages of 20e30 years and the onset is usually before 40 years [16]. Psoriasis results in a decrease in mental faculties and physical functioning equivalent to that seen in chronic diseases like hypertension, cancer, diabetes, etc. Quality of life of patients is hampered by its presence at both physical and emotional levels due to social isolation. Clinically, psoriasis is classified into the following five types, namely pustular, inverse, erythrodermic, guttate, and psoriasis vulgaris. The type of therapy along with dose regimen depends upon the severity of the disease and so varies between individuals [17]. Psoriasis leads to increased chances of morbidity since patients are apprehensive about the side effects of medicines used along with their physical appearances. These patients have a high Different types of psoriasis based on the clinical manifestations. The area of the body covered with plaques varies widely from patient to patient Multiple small, red spots, usually seen on the trunk and limbs Scale-free lesions that appear in the folds of skin. This may be localized to a particular area or cover the entire body this is a rare and dangerous form of psoriasis that causes patients to lose excessive amounts of heat through the skin. The body is found to be covered with severe skin redness over large part of the body 78 4. Nanocarriers for topical delivery in psoriasis occurrence of metabolic syndromes, depression, and psoriatic arthritis. Generally, psoriasis shows the presence of certain skin deformities like inflammation, erythema, modified epidermis differentiation, and excess multiplication of keratinocytes. Clinically delineated and uniform erythematous plaques with clingy silvery scalps are seen. Untimely keratinocyte maturity with epidermis hyperproliferation is the cause of these scalps. Along with the scalp, other body sites affected by the disorder include elbows, cutaneous sites, and knees. Environmental factors and climate influence the clinical course of psoriatic arthritis and cutaneous psoriasis. Lesions or skin eruptions were found to subside during the summer season and were aggravated in winter [20]. The skin of a psoriatic patient shows the presence of keratosis, which is the growth of keratin on the skin and mucous membranes. There may be orthokeratosis manifestations in which hyperkeratosis exists but without nucleus in cells [21]. Psoriasis is a huge public health problem, with 125 million people affected worldwide. Vitamin D levels and exposure to external pathogens may be responsible for this "equator effect. Psoriasis is caused due to the hyperproliferation of the keratinocytic layer in the skin. This is brought about by an amalgamation of environmental, genetic, and immunological agents. Psoriasis skin shows an enhanced mitotic rate of basal keratinocytes in the epidermis. This rate is much higher in psoriatic patients as compared to normal healthy individuals. The keratinocytes show migration from the basal layer to the surface of the epidermis in a quick manner. This leads to a decreased cell cycle for the keratinocytes, thereby making their mitotic rates faster [23]. It is an immunologically mediated autoimmune disorder due to induction of T lymphocytes activated by superantigens. The T-cell receptor for a particular T-cell identifies an antigen on the major histocompatibility complex by the antigenpresenting cells. The adjacent endothelial cells at the location of inflammation are traversed by the process of extravasation as seen in leukocytes as well. This sequence of steps culminates in the generation of a psoriatic plaque via keratinocytic proliferation and relocation of inflammatory messengers [26]. The level of inflammatory cytokines and their subset provides an insight into psoriatic lesions and their severity. The treatment for the same may be known based on the specific cytokines responsible for the skin condition. Therefore, the approach of therapy has also shifted to focus on targeting the cytokines involved in psoriasis [30,31]. Conventional treatments Managing psoriasis through skin therapy depends upon the type of psoriasis, i. In localized psoriasis almost <10% of the body surface area is usually dealt with by topical medications. Conventional preparations like ointments, creams, and lotions are used for topical action. These cytokines lead to inflammation and accumulation of macrophages at the site of inflammation by vasodilation. Accumulation of macrophages leads to further production of cytokines and activation of keratinocytes. Activated keratinocytes undergo proliferation and lead to scale formation, it also produces cytokines, which leads to inflammation of skin and increased macrophage accumulation by the formation of new blood vessels. Biologics inhibit cytokines which are responsible for keratinocyte proliferation and inflammation. Emerging landscape in psoriasis management: from topical application to targeting biomolecules. Nanocarriers for topical delivery in psoriasis A high-concentration layer of therapeutic moiety is created due to the formulation partitioning upon their application to skin. The stickiness, greasiness, and unpleasant odor of ointments have gone a long way in decreasing patient compliance. Since these delivery systems exhibit low efficiency, a huge amount of drugs are loaded with vehicles resulting in allergies and irritation [32].

In the early 1970s erectile dysfunction rates age order levitra oral jelly amex, the eradication program was stopped which led to the reinvasion of the infection in the countries from where it was already eradicated [20 erectile dysfunction age at onset purchase levitra oral jelly 20 mg mastercard,21] erectile dysfunction doctors albany ny cheap levitra oral jelly 20mg visa. During this time erectile dysfunction labs generic 20mg levitra oral jelly overnight delivery, the American region was facing the major Dengue viral illness epidemics that had been free of the disease for the past 100 years [19 causes of erectile dysfunction in 60s levitra oral jelly 20 mg with mastercard,20 erectile dysfunction pills review buy cheap levitra oral jelly 20mg online,22]. Similar to the Southeast Asian region, the development of hyperendemicity due to the peaked epidemic activity in the American region also led to the emergence of epidemic Dengue hemorrhagic fever. In Africa, the sporadic cases of Dengue hemorrhagic fever occurred more commonly than having major epidemics. This is due to the remarkable increase in the Dengue fever epidemic in the past 25 years in this region leading to severe disease. Until the 1980s, very little was known about the spread of Dengue fever disease viruses in Africa. Since then, major Dengue fever epidemics have occurred in both the Western and Eastern parts of Africa [18,24], which involved all four viral strains. Presently, this virus is responsible for causing more morbidity and mortality than any other arbovirus illness in humans. Due to these epidemics, every year approximately 100 million cases of Dengue fever and many hundred thousands of Dengue hemorrhagic fever occur [23,25,27]. Factors responsible for increased incidence Dengue fever and Dengue hemorrhagic fever outbreaks have been global public health problems over the past 17 years. Although a number of factors are responsible for the significant resurgence and emergence of these outbreaks but still the precise determination of these factors is complex and not well understood. Nevertheless, over the past 50 years [18,23,24] this resurgence seems to be narrowly linked with the demographic and societal changes. Following are the four major factors responsible for the increase in incidence: 1) One of the major factors has been the extraordinary growth of the global population. This population growth has been the main driving force for the uncontrolled and unplanned urbanization, particularly in tropical countries. In this regard, the substandard housing, overcrowding of cities, and decline in sewer, water, and waste management systems are aiding to provide an ideal environment for the increased transmission of vector-borne diseases. Since the past 25 years, spraying the spaces with insecticides to kill the mosquitoes is being used but it has proven to be ineffective over time [20,28,29]. In addition to that, because of the augmented amount of mosquito larval habitations, the population density and terrestrial distribution of A. Air travel provides an ideal way for the transportation of viruses like dengue and other urban pathogens among different population centers of the world [23,24]. Scarcity of resources has led to an overwhelming shortage of qualified physicians who can propose and Dengue virus disease; the origins Chapter 2 15 develop effective prevention and control programs for the mosquito and other vector-borne diseases. In summary, the societal and demographic changes, lack of effective mosquito control programs, scarce resources for the vector-borne disease prevention and control, and alterations in the public health program have all led to the increased Dengue epidemic activity, the hyperendemicity development, and the incidence of Dengue hemorrhagic fever epidemic. As of 2019, the global burden of Dengue viral illness is truly immense affecting approximately 2. According to World Health Organization, there are anywhere from 50 to 100 million cases every year with staggering 22,000 deaths due to the Dengue viral illness. Dengue and dengue hemorrhagic: its history and resurgence as a global public health problem. Origins of dengue Type 2 viruses associated with increased pathogenicity in the Americas. An account of the bilious remitting fever: as it appeared in philadelphia, in the summer and autumn of the year 1780. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem. Aedes aegypti and Aedes aegypti-borne disease control in the 1990s: top down or bottom up. Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. The global pandemic of dengue/dengue haemorrhagic fever: current status and prospects for the future. Emergence of epidemic dengue/dengue hemorrhagic fever as a public health problem in the Americas. New treatment strategies for dengue and other flaviviral Diseases: Novartis Foundation Symposium 277, vol. Chapter 3 Dengue virus infection outbreak: comparison with other viral infection outbreak Mohammad Rauf A. About 40% world population live in areas with high risk of Dengue virus transmission. There are about 100 countries in Asia, the Pacific, the Americas, Africa, and the Caribbean where Dengue virus infection is endemic [2]. Dengue virus infection is caused by any of the four narrowly related serotypes: Dengue viruses 1e4. In fact it increases the risk for Dengue hemorrhagic fever and Dengue shock syndrome [3]. The four serotypes originated in monkeys and independently made a cross over to humans in Africa or South East Asia about 100e800 years ago [4]. Dengue virus infection can be asymptomatic or a self-limited, varying in severity, classical form is characterized by high fever, headache, stomach ache, rash, myalgia, and arthralgia. Dengue hemorrhagic fever and Dengue shock syndrome are severe forms of Dengue virus infection, accompanied by thrombocytopenia, vascular leakage, and hypotension [1]. Mechanisms underlying the severe form of disease are still not well understood despite the intensive research. The lack of understanding is partly due to lack of appropriate animal models of infection and disease. Due to lack of vaccine and antiviral drugs, only control measure is limiting the Aedes mosquito vectors spread [1]. Epidemic versus pandemic Epidemic and pandemic are primarily different in terms of spread of contagious, infectious, or viral illness. In simple words, when epidemics falls short in describing the scale of a problem, it is better to use pandemic [5]. Common features of epidemics According to our previous work on Ebola virus infection epidemic by Qureshi et al. Tooth necklace pattern It constitutes where the disease is eradicated from the population, but pathogen species is kept alive under controlled circumstances for preparation of vaccines and biological studies. While the escape of pathogen from confinements of laboratories has been the subject of numerous conspiracy theories, vaccination with live attenuated viruses is more likely to be the string to maintain the continuity. Like Japanese encephalitis, West Nile encephalitis transmitted by Culex mosquitoes and humans are dead hosts. Virus will cause fever-arthralgia-rash syndrome mostly with conjunctivitis and lymphadenopathy. Clinically, West Nile encephalitis is similar to Japanese encephalitis in Dengue virus infection outbreak Chapter 3 27 terms of causing coma, convulsions, and mixture of causing upper and lower motor neuron signs: flaccid paralysis of limb and respiratory muscles. Meningoencephalitis is considered a rare complication of West Nile virus infection. A large outbreak occurred in Romania, in 1960s in which about 600 people had the neurological disease but no one with rash or lymphadenopathy. Poor plumbing and sewerage under the apartments was considered to cause the outbreak as it lead to explosive increase in population of Culex pipiens. All age of people were affected but the attack rate and mortality was higher in older adults [10]. Other mosquito-borne flaviviruses Other important mosquito-borne flaviviruses include Murray Valley encephalitis virus, Kunjin virus, Saint Louis encephalitis virus, and Rocio virus. Murray Valley encephalitis virus was the cause of polio like encephalomyelitis in Australia in 20th century. The virus gets transmitted by Culex annulirostris, water birds, cattle, and some marsupials. St Louis encephalitis virus was an important neurotropic flavivirus in United States with first epidemic reported in 1930s. Though most of the areas of United States, Canada, and Mexico are affected by this disease at some point in time, sporadic cases still occur. Rocio virus was first isolated from the brain of a fatal case from an outbreak in Sao Paulo State of Brazil in 1975 and is transmitted by Psorophora mosquitoes [10]. Tick-borne flaviviruses Tick-borne flaviviruses are less important in humans compared to animals as ticks preferentially feed on animals compared to humans. Viruses are transmitted by Ixodidae (hard ticks): Dermacentor and Hemophysalis species. Other important routes of transmission are ingestion of infected milk, and direct transmission from infected animal carcasses. Tick-borne encephalitis mostly circulate among the small wild animals like rodents and transmitted to human by ingestion of goat milk in addition to tick bites. Up to 70% of the patients remember the tick bite with tick-borne encephalitis presenting 1e2 weeks after the high grade fever, headache, malaise, and myalgia. In latter cases, it can progress to flaccid paralysis of upper limb and shoulder girdle. Respiratory muscles and bulbar (brain stem) involvement can lead to respiratory failure and death [10]. Ocular manifestations of emerging flaviviruses and the blood-retinal barrier Flaviviruses, despite causing many systemic complications, has been documented to cause multiple ocular abnormalities such as conjunctivitis, retinal 28 Dengue Virus Disease hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies [11]. Eyes are protected from the systemic infections by presence of bloode retinal barriers. Flaviviruses modulate the retinal innate response and penetrates the blooderetinal barriers to cause the ocular pathologies [11]. Seroepidemiology of Dengue, Zika, and Yellow Fever viruses among children in the democratic republic of the Congo the public health importance of arthropod-borne viruses is growing tremendously as they cause millions of infections in humans annually with physical manifestations ranging from birth defects, hemorrhage, shock, encephalitis, and even death. In 2015, Zika virus infection in Latin America became an international public health emergency due to its adverse effects on developing fetus when expecting mothers were infected. The epidemiology of Dengue virus infection and Zika virus infection in Asia and America better described compared with Africa. Finding Dengue and Zika virus infections in travelers returning from Africa suggests that prevalence of these viral infections in African population is largely underestimated. A recent outbreak of yellow fever virus in 2016 in Angola and surrounding countries despite the existence of an effective vaccine since the 1930s represents a constant threat for yellow fever virus epidemic [12]. At least 42 deaths were reported in Democratic Republic of the Congo when the Angolan outbreak crossed country orders. Risk of Yellow fever virus outbreaks in the Democratic Republic of the Congo and lack of data on other flavivirus infections such as Dengue virus and Zika virus prompted Willcox et al. They found that children despite the documented proof of receiving the Yellow fever virus vaccine, failed to show the evidence of seroconversion. Evidence of low rate of seroconversion among children has been previously reported but it consistently reported to be more than 80%. The other possible reason could be that majority of children had administration of Measles vaccine with Yellow fever virus vaccine. It has been demonstrated that coadministration of measles vaccine with yellow fever vaccine decreases its immunogenicity [12]. Other reasons include malnutrition in children and insufficiency of sensitivity of enzyme-linked immunosorbent assay and neutralization assays to detect the low levels of antibodies that are sufficient for protection. Despite the possibility of above mentioned reasons, the fact remains that Democratic Republic of the Congo continues to experience major yellow fever outbreaks which questions the effectiveness of efforts to integrate yellow fever vaccine into routine childhood vaccination programs. In addition, the study found that Dengue, Zika, and yellow fever viruses are circulating in the Democratic Republic of the Congo. Recommendations were made to Dengue virus infection outbreak Chapter 3 29 conduct more studies to explore the detailed reasons for low rates of seroconversion observed in vaccinated Congolese children and considering flavivirus infection as an important etiology of acute febrile illness especially in patients who test negative for malaria [12]. Viremia and clinical presentation in Nicaraguan patients infected with Zika virus, Chikungunya virus, and Dengue virus All the three viruses cocirculate in Nicaragua. Study was conducted to compare the clinical presentation and quantify the levels of viremia. Out of 263 patients tested positive: 192 tested positive for a single virus infection, 71 for two, and 2 for all the three viral infections (coinfections). Viremia levels were lower in Zika virus infections compared with Chikungunya virus or Dengue virus. Zika virus infected patients were likely to develop rash but less likely to be febrile or hospitalized compared to chikungunya virus or Dengue viruseinfected patients. Due to lot of similarity in clinical presentation, it becomes difficult to make accurate clinical diagnosis where the patient may be infected with any of three viral infections. This supports the use of testing protocol for sensitive, accurate, multiplex diagnostics for clinical care, disease research, and epidemiological surveillance of Zika, Chikungunya virus, and Dengue virusesuspected cases [13]. Concurrent outbreaks of Dengue, Chikungunya and Zika virus infectionsdan unprecedented epidemic wave of mosquito-borne viruses in the pacific 2012e14 About 28 new documented outbreaks and circulation of Dengue, Chikungunya, and Zika virus infections have been reported between January 2012 and 17 September 2014 and about 120, 000 people were affected in the Pacific region. These outbreaks put extra burden on preexisting healthcare system in Pacific Islands. First could be due to low immunity as Dengue virus serotype 3 had been absent in this region since 1995. Secondly, in addition to Aedes aegypti and Aedes albopictus mainly in this region, local mosquitoes such as Aedes polynesiensis or Aedes hensilli can also transmit these viruses and thirdly, the large population mobilization and airline travel facilitate the spread [14]. The important factor for long-distance spread of 30 Dengue Virus Disease infectious disease is increased human mobility. Outbreaks were caused by infected persons coming from endemic and epidemic areas, acting as a Trojan horse for these germs. After the virus was incorporated in the new area, other factors like climate change, virus evolution, lack of vector control, sociodemographic changes, and environmental changes i.

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