Commonly used Latin terms and their anglicized counterparts are provided in Appendix 7 generic kamagra soft 100mg on-line erectile dysfunction herbal treatment options. Although the notation system proposed by Van Praagh (3) is not emphasized in this chapter generic kamagra soft 100 mg line erectile dysfunction doctors in atlanta, it is favored at some institutions and warrants summarization. The situs (sidedness) is determined separately for the atria, ventricles, and great arteries. Ventricular situs is solitus or D- loop (D), inversus (I) or L-loop (L), or ambiguous (X). Great arterial situs is designated as solitus (S), inversus (I), D-transposition/malposition (D), L-transposition/malposition (L), or ambiguous or anterior transposition/malposition (A). Abbreviations are listed within the parentheses, with the ventriculoarterial arrangement included before the parentheses and any atrioventricular malalignments or other anomalies stated after the parentheses. Sequential Segmental Analysis For evaluating patients with suspected congenital heart disease, it is helpful to consider the heart as a segmented structure represented by three regions—atria, ventricles, and great arteries (3,4,5,6). Each region, in turn, is partitioned into two components, usually right-sided and left-sided. Atrioventricular valves serve as connectors between atria and ventricles, and semilunar valves join the ventricles to the great arteries. There is only a limited number of possible connections between the three major regions, regardless of their spatial orientations. In practice, each region is evaluated independently, following the direction of blood flow: (a) systemic and pulmonary veins, (b) atria, (c) atrioventricular valves, (d) ventricles and right ventricular outflow tract (infundibulum or conus), (e) semilunar valves, and (f) great arteries. In a systematic manner, right-sided and left-sided structures at each level are evaluated according to their morphology; their relative positions; their connections to proximal and distal segments; and the presence and location of shunts, obstructions, and valvular regurgitation (7). Before applying this method, however, it is important to determine the cardiac position and the visceral situs (sidedness). Cardiac Position and Apical Direction With regard to the position of the heart in the chest, two questions arise that can be answered independently: Where is the heart located, and what is the direction of the cardiac apex? Unfortunately, the terms levocardia, dextrocardia, and mesocardia are commonly used to answer both questions, thus imparting an element of ambiguity (3,4). Although the approach described below is not universally accepted, it does provide clarity by defining the cardiac location and apical direction separately and by avoiding the ambiguous Latin terms. Location in the Chest Within the thorax, the heart can be described positionally as left-sided (normal), right-sided, or midline. This designation is particularly useful radiographically, before a patient has been evaluated by other imaging techniques. The position of the heart in the mediastinum is affected not only by underlying cardiac malformations but also by abnormalities in adjacent structures. It can be displaced by conditions that distort the shape of the thorax, such as severe scoliosis or an elevated diaphragm, or that alter the size of thoracic structures, such as a hypoplastic lung or diaphragmatic hernia. Rightward displacement of the heart constitutes dextroposition, a leftward shift represents levoposition, and shifts toward the midline are called mesoposition. In rare instances, sternal or diaphragmatic defects exist and are associated with an extrathoracic heart, or ectopia cordis (ectopic heart). This condition may be partial or complete and can be further categorized as cervical, thoracocervical, thoracic, thoracoabdominal, or abdominal. Orientation in the Chest The direction in which the ventricles are aligned defines the base–apex axis of the heart and may be leftward, rightward, or midline (Figs. Leftward ventricles represent the normal state and are characterized by an apex that is directed leftward, anteriorly, and somewhat inferiorly. The extent of these three directions is variable and is influenced by age, body build, and the level and functional state of the diaphragm. In contrast, midline ventricles are often box-shaped and exhibit two apices that are directed anteriorly and inferiorly (7). For example, a patient with a hypoplastic right lung could have a right-sided heart, owing to dextroposition, and still exhibit a leftward apex (Fig. Thus, the presence of a leftward apex does not necessarily imply normal sidedness (situs solitus), and a right-sided apex does not always coincide with mirror- image sidedness (situs inversus). A midline apex, on the other hand, usually is associated with cardiac isomerism (situs ambiguus). Visceral Sidedness (Situs) All major organ systems begin their embryologic development as midline structures with bilateral mirror-image symmetry. However, three organ systems (cardiovascular, respiratory, and digestive) later acquire asymmetry and are thereby characterized by sidedness (situs or handedness), which is genetically determined. Right isomerism indicates bilateral right-sidedness, whereas left isomerism denotes bilateral left-sidedness. Isomerism and Splenic Anomalies The relationship between isomerism and splenic anomalies is intriguing (8). The splenic anlage, rather than originating as a midline structure, appears to be left-sided from its inception. Thus, when right isomerism exists, the spleen is usually absent (asplenia syndrome). Left isomerism, in contrast, is generally associated with multiple spleens (polysplenia syndrome) that are confined to only one side of the vertebral column. Occasionally, subjects with asplenia or polysplenia have normal hearts, and, rarely, those with atrial isomerism have normal spleens. Abnormalities may affect the entire body, as in total mirror images sidedness (situs inversus totalis), or can involve individual organ systems. Although the term atriovisceral situs enjoys common usage, it does not always allow an accurate description of sidedness in the asplenia and polysplenia syndromes. Consequently, it is recommended that the sidedness of cardiovascular, respiratory, and digestive systems be designated separately (7). A: The three types are shown schematically and are independent of cardiac position or situs. B: The ventricular apex is leftward (arrow), even though a hypoplastic right lung has caused dextroposition of the entire heart. B, C: Congenitally corrected transposition of the great arteries, showing a box-shaped midline apex (B) and a rightward apex (C. Cardiac Sidedness (Situs) Cardiac sidedness is determined by the position of the morphologic right P. It is not determined by the direction of the cardiac apex, the positions of the ventricles or great arteries, or the sidedness of noncardiac viscera. The morphologic right atrium is normally right-sided but is left- sided in situs inversus (mirror-image sidedness). Bilateral right atria define right cardiac isomerism, and bilateral left atria constitute left cardiac isomerism (Fig. In some cases of polysplenia, one chamber represents a left atrium, but the other has a hybrid appearance that is morphologically neither left nor right; this constitutes indeterminate cardiac sidedness. In practice, an accurate determination of cardiac sidedness depends on an accurate distinction between right and left atrial morphology, as discussed in this chapter and in Chapter 6. Although all investigators agree on the concept of normal and mirror-image cardiac sidedness, some have questioned the existence of atrial isomerism (9).
Careful examination of the entire heart is necessary to remove concurrent sites of myxomatous tissue buy kamagra soft visa low libido erectile dysfunction treatment. The use of echocardiography to facilitate a surgical approach has been proposed (184) by preoperatively defining tumor size purchase kamagra soft 100mg amex erectile dysfunction drugs for heart patients, location, point of attachment, and the presence of concurrent site involvement. Patients require continual reevaluation for recurrence of disease and for later development of peripheral arterial aneurysms (137,143,146,149,153,167,182). The approximate incidence of recurrence is 4% to 7% in most large series (169,171,185,186). Familial occurrence of cardiac myxomas is well established (137,138,143,144,187,188) and accounts for 7% of all myxomas. Cardiac myxomas often are seen in children and adolescents with multiple lentigines syndromes (164) and may be associated with nonneoplastic endocrine abnormalities (Fig. Recent nosology aggregates these conditions under the broader category of Carney complex, which consists of (a) myxomas in other locations (breast or skin), (b) spotty pigmentation (lentigines, pigmented nevi, or both), and (c) endocrine overactivity (pituitary adenoma, primary pigmented nodular adrenocortical disease, or testicular tumors). The precise gene defects remain unknown (189); however, certain investigators have mapped these syndromes to two loci, on chromosome 2p (190) and chromosome 17q (191). Intrapericardial Teratomas Despite their rare occurrence, intrapericardial teratomas constitute another major subgroup of primary pediatric cardiac tumors (Table 72. These rare tumors previously were associated with a high mortality rate (193,194,195,196,197). More recently, increased survival is emerging as a result of earlier diagnosis and improvements in surgical care (136,193). Intrapericardial tumors are seldom malignant or recurrent; therefore, surgery is considered curative for such life-threatening illness. Intrapericardial teratomas are single, encapsulated, grayish tan, bosselated tumors attached to the base of the heart (197,198,199). Often a broad-based stalk or narrow pedicle firmly attaches the tumor to the root of the aorta or pulmonary artery (193,196,197). The tumor capsule itself can be firmly attached to the aorta (194,195,196,197,198,199,200,201,202,203,204,205,206,207,208) or to pulmonary artery adventitia (195,197,199,205,208). The tumor has been reported to adjoin the superior vena cava (199), right atrium (195,197,199), right ventricle, left atrium, and left ventricle (197). The tumor blood supply usually emanates as nutrient vessels from the aortic vasa vasorum (195,197,205,206). Single blood vessels from the vicinity of the coronary arteries (198) or multiple small blood vessels from the superior mediastinum also may supply the tumor (199). Intrapericardial teratomas may be three to four times the size of the newborn or infant heart (194,197,207); however, the tumor may be relatively small in asymptomatic older children and adolescents. Critically ill newborns and babies almost always have a large pericardial effusion (196,197,205). Obstruction and compression of the heart develop due to an essentially solid tumor mass contained within a restrictive fibrous pericardium (196,197,206). In newborns and infants, the tumor is most frequently right sided, attached to the ascending aorta, and wedged between the aorta and superior vena cava (195,196,203,204,205,206,207,208). These right-sided tumors rotate the heart, on a vertical axis, to the left and posteriorly (197,200,206). The tumors also may compress the right atrium and right ventricle (86,194,195,196,197,208,209,210). Less frequently, the tumor is left sided, attached to the aorta, overlying the left atrium and left ventricle (197,200,206). Left-sided intrapericardial teratomas rotate the heart anteriorly and to the right (197,200,206). Intrapericardial teratomas also can occur concomitantly with other congenital heart defects (197,198). These intracardiac teratomas cause findings similar to those for the intramural and intracavitary tumors described above. Intracardiac teratomas are rarely malignant in young infants and children (86,209). Intrapericardial teratomas consist of tissue derived from all three embryonic germinal layers (Fig. This allows serologic levels of alpha-feto protein to be used to track recurrences (211). Mesodermal tissue includes smooth and striated muscle, hyaline, and elastic cartilage. Endodermal tissue consists of respiratory bronchial, pancreatic, intestinal, and salivary glands; ectodermal neuroepithelial structures include choroid plexus and eyes. Intrapericardial teratomas are rarely malignant, particularly in infants and newborns (193,196,200,203). Intrapericardial bronchogenic cysts have the same gross appearance and clinical manifestations as intrapericardial teratomas (195,200,202,203,207). These two intrapericardial tumors can be differentiated only by histologic examination. Intrapericardial bronchogenic cysts consist predominantly of respiratory and gastrointestinal tissue. They do not have the neuronal tissue elements that can be found in intrapericardial teratomas (195,200,202). The true incidence of intrapericardial teratomas remains somewhat unclear because earlier reports may have included intrapericardial bronchogenic cysts (195,200). Half of all intrapericardial teratomas are diagnosed in newborns and infants younger than 1 month of age and two-thirds in infants younger than 1 year of age (200,206). Critically ill newborns and infants have a distinct clinical presentation consisting of respiratory distress, pericardial effusion, and direct cardiac compression by the tumor mass as well as cardiac tamponade (193,194,195,196,197,198,199,200,201,202,203,204,205,206,207). Direct compression of pulmonary parenchyma may contribute to the extreme respiratory distress in the newborn or infant (195,199,206,207). Sudden deaths occurred in two-thirds of pediatric patients who had intrapericardial teratomas (196). These events were attributed to acute rupture of cysts into the pericardial space with sudden tamponade (210), severe encroachment by the tumor on the heart and great vessels (196,199), and infectious pericarditis (199). Signs and symptoms of severe disease may not be apparent in the rare situation in which an infant does not have an associated significant pericardial effusion (197,200,206). Patients older than 3 months of age are usually asymptomatic or have findings of a chronic pericardial effusion (197,200,206). Intrapericardial teratomas can be diagnosed in the asymptomatic older child during evaluation of an abnormal chest radiograph or as an incidental finding at autopsy (197,200,206). Heart sounds are distant or muffled, murmurs are inaudible, and the precordial impulse conspicuous for its absence in the newborn or infant who has impending tamponade (193,197,200,204,207). The patient may have marked hepatomegaly and diminished peripheral pulses (193,200,206). Stenotic murmurs may be heard when the tumor mass compresses cardiac chambers or great vessels (203,206). The newborn may present with cyanosis from compression of the pulmonary parenchyma (193,207) or from right-to-left atrial shunting (203). In critically ill patients, a markedly enlarged cardiac silhouette is seen on chest radiographs (193,194,195,196,197,198,199,200,201,202,203,204,205,206,207).
Ideally cheap kamagra soft online mastercard erectile dysfunction pump surgery, one would like to be assured that any differences in outcomes were solely attributable to the interventions being compared kamagra soft 100 mg low price erectile dysfunction while drunk. Differences in baseline characteristics can be minimized if the subjects are randomly allocated to intervention groups, hence eliminating selection bias. Random allocation gives the best chance that baseline differences will be minimized, including differences in both measured and unmeasured characteristics. The greater the number of subjects randomized, the greater the likelihood that there will be few important differences in characteristics between the groups. One can also test the success of randomization, by comparing the measured baseline characteristics between assigned intervention groups and by looking for both potentially relevant and statistically significant differences. In analyses of outcome comparisons, one has the opportunity for applying statistical adjustment for any or all baseline characteristics. Valid randomization can only be achieved if it is performed and applied properly, as noted in Table 81. Use of blocks with simple randomization ensures that the number of subjects in each group is equal at the start of the intervention throughout the study. Cluster randomization is used when subjects fall into natural groups where there might be contamination between individuals within the groups if they were to receive different interventions, such as an educational or behavioral intervention. Some randomization variations are employed to ensure that there are no chance differences between groups regarding specific baseline characteristics that have an important influence on the outcomes, and included stratified randomization and pair matching. Controversial variations of randomization include unequal allocation and adaptive randomization. Unequal allocation entails allocating more subjects to one group than another, usually in a specific ratio other than 1:1, creating groups of unequal sizes. It may be used to evaluate multiple treatment groups against a single control group, with relatively larger numbers allocated to control. Increased allocation to an intervention group may be desired to detect rare outcomes and adverse effects specific to that intervention. It may be used to increase recruitment when it is known that subjects have a greater chance of being allocated to a desirable intervention. Conversely, it may be used to limit allocation to an intervention that is expensive or of limited availability. This type of allocation reduces statistical power, complicates consent, and remains controversial as to validity. Adaptive randomization entails changing the probability of allocation for the next subject based on the characteristics of those subjects previously randomized. This can be used as the allocation proceeds to correct for imbalances regarding baseline characteristics (covariate adaptive) or differences in group sizes (treatment adaptive). It may also be used to preferentially assign subjects to the “best” intervention based on the outcomes of preceding subjects, allowing more subjects to be given the potentially beneficial intervention, or fewer subjects to be given a potentially harmful or ineffective intervention. Adaptive allocation requires continuous tracking of characteristics and outcomes, often precludes effective blinding, and reduces statistical power and validity. Cointerventions and Blinding A significant factor that may alter, or confound, the results of a clinical trial is cointervention, a phenomenon that occurs when potentially outcome-altering interventions (other than the study intervention) are administered to some subjects, but are not specified in the study protocol. Cointerventions may be introduced into the study intentionally or unintentionally, and are often allocated to subjects by nonrandom means. For example, if investigators believe the study intervention to be effective, they may (consciously or unconsciously) give compensatory care to those not receiving the intervention in the control group. Conversely, subjects in the study intervention group may take extra steps to supplement or augment any intervention effect, to increase the likelihood of an anticipated outcome. Such behavior results in uneven distribution of cointervention across trial groups, and subsequent confounding of the trial outcome. Blinding or masking can minimize both cointervention and ascertainment bias in clinical trials. When blinding, either the study subjects, investigators, or both are made unaware of the intervention assignments until the end of the trial, as outlined in Table 81. Triple blinding adds blinding to any data analyses, whereby those performing or reviewing interim and final analyses for either safety or for efficacy are unaware of the meaning of the groups, that is, the groups are labeled A and B. Regardless of the degree of blinding of subjects and investigators, any individual charged with measuring the primary outcome of a trial should always be blinded to the greatest extent possible. This includes any laboratory personnel analyzing study samples, as well as clinical staff charged with interpreting any data susceptible to significant interobserver variability, as outlined in Table 81. Trial subjective judgment on diagnosis based on should be blinded to the greatest the part of an observer. Nonsubjective Ascertainment does not Mortality as a study end Low risk of ascertainment bias. Placebos are an inert or sham intervention designed to mimic the study intervention in all but biologic effect, and would be administered to the control or comparison group of a clinical trial. Placebo controls serve to make the study interventions indistinguishable to both subjects and investigators, maintaining blindness to individual group assignments. Placebos should, therefore, be matched to the study intervention in as many dimensions as possible. Studies evaluating surgical interventions Performance of sham surgeries on the control group may be unethical, due to high risk and invasiveness. Consent issues Subjects must be made fully aware of the likelihood of assignment to placebo, which may not be feasible with certain types of interventions. Difficulty in intervention matching Due to properties of the active intervention; e. Since such circumstances often evolve suddenly, safety measures should be put in place to allow for quick and accurate unblinding in the case of such an event. Such measures might include distribution of a 24-hour emergency telephone number to all subjects through which their care providers may access immediate unblinding. One can often unblind to the treating care provider without disclosure to the subject or investigators. Success of blinding throughout a trial can be evaluated at the end of a study by a simple survey, asking subjects and investigators to make guesses on group assignments. If >50% of guesses are correct for either subjects or investigators, then the blindness of the study may have been compromised. Sample Size and Power A pivotal component of clinical trial design is an estimation of the number of completing study subjects needed in order to reliably achieve the study aim and confidently answer the research question. If too few subjects are studied, the possibility of erroneous conclusions is increased; if too many subjects are studied, there is greater cost and loss of efficiency. The required number of subjects who completed participation in the trial and had valid outcome assessment is a subset of the subjects who were enrolled and allocated to the study interventions, which is a subset of accessible subjects who were deemed potentially eligible, which is a subset of the target population to whom one wishes to generalize the trial results. One would like to be confident that one can infer that the results of the study as performed in the participating subjects are a reasonable reflection of the results had the study been performed perfectly with the entire target population, and hence, are the truth. The calculation of sample size is always based on a number of assumptions, and must, therefore, be viewed as an estimation. The necessary components to calculate sample size are hypotheses that include an estimation regarding an anticipated and clinically relevant effect size and its variation, and specification of tolerance limits for making potentially erroneous conclusions, as outlined in Table 81.
It remains to be seen whether this and other potential age-related effects cost of kamagra soft erectile dysfunction cholesterol lowering drugs, including Dolly’s death cheap kamagra soft 100 mg mastercard erectile dysfunction medication for high blood pressure, are a result of the nuclear transfer process. This means that the effects of aging and genetic inheritance have not been fully assessed. In two independent studies, animals cloned from one cell type became obese in adult life (Tamashiro et al. The technique of nuclear transfer by which Dolly was produced has been replicated or modiﬁed to produced clones from adult cells using a variety of other farm animals, e. In early 2003, news reports suggested that the ﬁrst cloned human child had been born. Although such claims have not been scrutinized scientiﬁcally, it seems inevitable that a cloned human will be produced at some stage. The difﬁculties encountered with cloned animals described above should serve as a warning to anyone considering the procedure. The temptation to replace a dead or dying child with an ‘exact copy’ may be more than some parents can bear, but the potentially disastrous consequences should not be underestimated. Chromosome replication is bidirectional, which means that replication begins at a replication origin and simultaneously moves out in both directions from the replica- tion origin. Chromosome replication begins at speciﬁc nucleotide sequences located throughout the chromosome called replication origins. The stability of the replication fork is maintained by single-stranded binding proteins. Dna A protein recognizes the replication origin and opens up the double helix at that site forming a replication bubble. Type I topoisomerase introduces negative supercoiling (or relaxes positive su- percoiling). The chemotherapy drugs irinotecan and topotecan inhibit Type I topoisomerase in cancer cells. Reverse gyrase is a variant of Type I topoisomerase found in hyperthermophilic bacteria. If the 5 end of the lagging strand is not lengthened, a chromosome would get progressively shorter as the cell goes through a number of cell divisions. If the U is not corrected back to a C, then upon replication instead of the occurrence of a correct C-G base pairing, a U-A base pair- ing will occur. Clinical features include: ionizing radiation hypersensitivity; cerebellar ataxia with depletion of Purkinje cells; progressive nystagmus; slurred speech; oculocu- taneous telangiectasia (permanent dilation of preexisting small blood vessels cre- ating focal red lesions) initially in the bulbar conjunctiva followed by ear, eyelid, cheeks, and neck; immunodeﬁciency; and death in the second decade of life. A high frequency of structural rearrangements of chromosomes 7 and 14 is the cyto- genetic observation with this disease. Figure 2-4 (top) shows the appearance of telangiectasia of the bulbar conjunctiva. Clinical features include: onset of colorectal cancer at a young age, high fre- quency of carcinomas proximal to the splenic ﬂexure, multiple synchronous or metachronous colorectal cancers, and presence of extracolonic cancers (e. Meiosis is a specialized process of cell division (contrasted with mitosis which occurs in somatic cells; see Chapter 10: Cell Cycle) that occurs only in the production of the gametes (i. In female meiosis, each chromosome has a homologous partner whereby the two X chromosomes synapse and crossover just like the other pairs of homol- ogous chromosomes. In male meiosis, there is a problem because the X and Y chromosomes are very different. The pair- ing of the X and Y chromosomes is an end-to-end fashion (rather than along the whole length as for all the other chromosomes) which is made possible by a 2. Crossover introduces one level of genetic variability among the gametes and occurs by a process called general recombination. Alignment refers to the condition whereby the 46 homologous dupli- cated chromosomes align at the metaphase plate. Disjunction refers to the separation of the 46 maternal and paternal homolo- gous duplicated chromosomes from each other into separate secondary game- tocytes (Note: the centromeres do not split). However, the choice of which maternal or paternal homologous duplicated chromosomes enters the secondary gametocyte is a random distribution. It is important to understand that both the “single chromosome” state and “duplicated chromosome” state will be counted as one chromosome 18. The “duplicated chromosome” is often referred to as consisting of two sister chromatids (chromated 1 and chromatid 2). Only one pair of homologous chromosomes is shown (white maternal origin and black paternal origin). There are 2 possible ways the maternal and paternal homologous duplicated chromosomes can be combined. This random distribution of maternal and paternal homologous duplicated chromosomes introduces another level of genetic variability among the gametes. Cell division: two secondary gametocytes (23 duplicated chromosomes, 2 N) are formed. Disjunction: 23 duplicated chromosomes separate to form 23 single chromosomes when the centromeres split. An important example of general recombination occurs during crossover when 2 homologous chromosomes pair during the formation of the gametes. The human nuclear genome consists of 24 different chromosomes (22 autosomes; X and Y sex chromosomes). The fact that the 30,000 genes make up only 2% of the human nuclear genome means ● Figure 4-1 Pie chart indicating the or- ganization of the human nuclear genome. To fully understand how heritable traits (both normal and disease related) are passed down, it is important to understand three aspects of the human nuclear genome which include the following: 1. For decades, protein-coding genes were enshrined as the sole repository of heritable traits. A mutation in a protein-coding gene caused the for- mation of an abnormal protein and hence an altered trait or disease. Exons (expression sequences) are coding regions of a gene with an average size of 200 bp. Introns (intervening sequences) are noncoding regions of a gene with a huge variation in size. A classic gene family is a group of genes that exhibit a high degree of sequence homology over most of the gene length. A gene superfamily is a group of genes that exhibit a low degree of sequence homology over most of the gene length. Examples of gene superfamilies include the immunoglobulin superfamily, globin superfamily, and the G-protein receptor super- family. Genes can be organized as a tandem repeated array with close cluster- ing (where the genes are controlled by a single expression control locus) and com- pound clustering (where related and unrelated genes are clustered) all on a single chromosome. Genes can be organized in a dispersed fashion at two or more differ- ent chromosome locations all on a single chromosome. Genes can be organized in multiple clusters at various chro- mosome locations and on different chromosomes.
N. Shakyor. Emporia State University. 2019.
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