Texas Tech University Health Science Center at Houston
El Paso, Texas
Cellular proliferation was assessed 3 by cell counting erectile dysfunction heart attack order 90 mg priligy amex, incorporation of [ H]-thymidine erectile dysfunction at 65 purchase 30mg priligy mastercard, protein expression (as assessed by Western blots) erectile dysfunction age young purchase priligy master card, and apoptosis erectile dysfunction treatment hyderabad purchase priligy online now. A concomitant decrease in cell viability was not observed (>95% cell viability at concentrations up to 9 g/L [150 mmol/L]) erectile dysfunction ear generic 30 mg priligy overnight delivery. Additionally erectile dysfunction treatment options uk priligy 90 mg cheap, urea was shown to significantly stimulate macrophage proliferation at concentrations ranging from 0 erectile dysfunction treatment on nhs priligy 90 mg online. At 8 weeks of age erectile dysfunction 5x5 best order priligy, mice were divided into two groups, uremic (8 males and 14 females) and nonuremic control (6 males and 19 females). Chronic renal failure was initiated to induce uremia by cauterizing the right kidney cortical region of mice in the uremic group and then performing a total nephrectomy of the left kidney 2 weeks later. The authors noted that all procedures were conducted in accordance with National Institutes of Health guidelines for the care and use of experimental animals. Areas of athermanous and medial calcification in uremic animals were larger than in nonuremic animals. Assessment of the composition of the lesions in uremic animals indicated increases in collagen (control mice: 12. Urea was shown to produce mechanical and electrical alterations in isolated papillary muscles and in Langendorff perfused rat hearts (Abaurre et al. The left ventricle papillary muscles were obtained from one group while isolated rat hearts were obtained from the other two groups and perfused according to the Langendorff technique at a constant pressure of 75 mm Hg. A balloon mounted on the tip of a plastic tube was placed in the left ventricle and used to modify the diastolic pressure. Papillary muscles were exposed to test media containing 17 mM urea because it is similar to the concentration of plasma urea (1 g/L) in patients with severe renal insufficiency. Contraction recordings in papillary muscles were taken before exposure, during exposure (30 minutes), and after washout of the test chemical. Additionally, urea was shown to decrease isovolumic systolic pressure (33% of control; p < 0. Biochemical studies indicated that urea reduces calcium binding to the glycocalyx outside the sarcolemma, which is proposed to decrease contraction force. An additional foreign language article, which had an accompanying English summary, discussed cardiotoxic effects of exogenous urea (Cuparencu et al. The authors suggested that the hypertension was induced by a vasoconstrictor reflex of the veins while the hypotension might have been caused by an exocrine vasoactive substance. Pituitary Effects Okada and Kobayashi (1989) showed that short-term administration of urea produced alterations in intermediate cells of the mouse pituitary. Urea produced significant (p-value not provided), dose-dependent increases in protein synthesis (287. Dermal Toxicity A 24-hour dermal exposure study on skin penetration enhancers evaluated their potential to induce skin irritation (Lashmar et al. The test chemical was filled into a polyvinyl chloride cup and fastened to the dorsum of the animal using surgical tape and Superglue then left in contact with the skin for 24 hours. Animals were sacrificed and specimens of the exposed area and an adjacent untreated skin area were taken for histological examination. Tissues were fixed in formalin, paraffin-embedded, and stained with hematoxylin and eosin. Treated skin samples from each animal were randomly selected and microscopically examined and scored using a standard scoring system. The authors reported that urea did not cause any significant change in skin histology after the 24-hour exposure period. Intracranial and Intraocular Effects Intravenous urea (30% concentration) has been used to lower the intracranial and intraocular pressure in humans (Javid and Anderson, 1958). Javid and Anderson (1958) investigated these effects in adult female rhesus monkeys to determine the optimal rate of administration of a lower urea concentration and the effect of s. Urea Toxicity in Ruminants and Non-Laboratory Animals Case reports of probable urea toxicity are primarily reported in ruminants, although other species can be affected. Urea readily degrades to ammonia in water and therefore, urea or urea based fertilizers mixed with water can be a biological hazard (Raidal and Jaensch, 2006; Zarnke and Taylor, 1982). Urease produced by bacteria in the rumen converts urea to ammonia, which then combines with ketoacids formed by the bacteria to produce amino acids. If too much urea is present, ammonia will still be formed, but there will be insufficient amounts of ketoacids to prevent the absorption of ammonia (Decker, 1996). However, if that safeguard is overwhelmed, acute ammonia toxicity results (Ortolani et al. In simple stomach animals, such as humans, nonhuman primates, rodents, and pigs, ingested urea is primarily absorbed into the blood in the upper gastrointestinal tract and excreted by the kidneys. Some nonruminant mammals, such as rabbits, guinea pigs, and horses, have a sizable fermentation sac, the cecum (which does not have that function in humans), which digests roughage such as grasses. Most ingested urea is absorbed before reaching the cecum and any ammonia generated would readily enter the portal vein and be detoxified by the liver. Diets containing 1?2% urea and supplemented with amino acids have been shown to increase the rate of weight gain in growing pigs (Kornegay et al. Neurological Effects Neurological complications of uremia can include seizures, lethargy, jerking movements, and stimulus-sensitive myoclonus. Sprague-Dawley rats (n = 6 for highest dose group, number of rats for lower dose groups not provided; sex not specified) were administered 0. Animals were monitored for stimulus-induced (auditory, tactile, and air puffs) and spontaneous behavioral changes. Minimal observed neurological changes (exaggerated sensitivity to stimuli) were reported in animals that received 10 injections of 0. Three injections of 2 g/kg (total of 6 g/kg) produced jerking movement and spontaneous myoclonus 1 and 1. Four injections of 2 g urea/kg produced spontaneous moderate intensity myoclonus that lasted for 30?50 minutes. The rats then appeared cyanotic and exhibited decreased locomotor activity before convulsions occurred and death followed. No information was provided on animal behavior when more than four injections were given at any of the noted doses. Brain and plasma urea concentrations were evaluated at the peak of myoclonus in rats given four i. Six rats each in the control and treated group were sacrificed by decapitation 45 minutes after the last injection. Cervical blood, the medulla, frontal cortex, and spinal cord were evaluated for urea concentrations. Studies showed that urea concentrations in the brain tissues were 5?8-fold higher than control values and plasma urea concentrations were 18-fold greater than control values (p < 0. Control and urea-treated rats exhibited similar glycine levels in whole or crude synaptosomal fractions of the medulla. In a separate set of experiments, the affinity of urea for a variety of receptors in rat medulla and spinal cord membrane preparations was evaluated (Chung et al. Mannitol was used as a positive 44 control in order to determine if the inhibitory effect of urea was due to its hyperosmotic action. To assess whether urea binding was due to its hyperosmotic action, the authors evaluated the 3 3 effect of mannitol on [ H]-strychnine and [ H]-diazepam binding. However, 10?100 mM mannitol 3 significantly decreased [ H]-diazepam binding (p < 0. The authors proposed that the 3 inhibition of [ H]-strychnine binding is not likely related to the osmotic action of urea, while it 3 may play a role in its affinity for [ H]-diazepam binding sites. In vivo studies, similar to those described above, with 6 g mannitol/kg (equimolar concentration to 2 g urea/kg) injected i. Comparison of the effects produced by 50 g strychnine and 40?800 g urea after stereotaxic injection into the nucleus gigantocellularis showed that while strychnine produced moderately intense generalized myoclonus, urea produced tremors that were induced by stimuli or voluntary movements. Based on the results of the above study, the authors conclude that accumulation of urea produces the generalized stimulus-sensitive myoclonus in experimental animals. Mechanistically, it appears that urea inhibits glycine action at the receptor site producing a reversible allosteric change in the strychnine binding sites on the glycine receptor complex similar to strychnine. Thus, urea may produce myoclonus by blockades of glycine receptors in the medullary reticular formation. Time-course studies indicated that the protein is present 30 minutes after the addition of urea and the response was maximal after 10 hours (9. Similar responses were not observed with other chemicals tested (mannitol, NaCl, or glycerol) at equivalent osmolalities. In addition to upregulation of Hsp72, urea induced carbamylation of proteins in a time-dependent manner. The authors suggested that urea induces cellular stress via its ability to produce cyanate, which may carbamylate cellular proteins. It was proposed that this carbamylation may induce the observed heat shock response. Since the cells seemed to recover after approximately 10 hours, the authors further proposed that these cells may be able to adapt to the effects of urea. The potential neuroexcitatory effect of 17 candidate neurotoxins associated with uremia was studied in dissociated mouse spinal cord neurons (D?Hooge et al. Whole cell recordings were made using a single-patch pipette with a resistance of 3?5 Ohms. Urea 45 (300 mg/L [5 mmol/L]) was used as a reference and at this concentration did not produce an effect. Together, these studies suggest that urea may produce some of the observed neurological effects. Binding and modulation of these ion channels by urea may affect neurotransmission. Additionally, modification of proteins through carbamylation likely plays a general role in the effects produced by urea. The putative function of P-gp is to pump hydrophobic drugs out of cells, decreasing their intracellular concentrations and their toxicity. Oxidative damage to protein was measured by detection of protein carbonyl content after urea exposure (0?300 mM). The authors noted that plasma urea concentrations observed during uremia range from 20 to 80 mM (normal plasma concentrations are 5 mM). Time course studies showed that protein carbonylation occurred rapidly (300 mM increased protein carbonylation within 5 minutes) (data provided in a figure in Zhang et al. The authors proposed that carbonylation at higher urea concentrations may decrease because available carbonyl groups may oxidize to carboxylic acids. Urea did not cause protein carbonylation directly as evidenced by the lack of protein carbonylation when 300 mM urea was added for 15 minutes to cell homogenates (data not provided). Furthermore, carbonylation was not an effect secondary to protein carbamylation because direct addition of cyanate, which is formed from urea under physiological conditions and causes carbamylation, did not cause carbonylation (data provided in a figure in Zhang et al. Extensive protein carbonylation was also detected in the inner medulla of the normal mouse kidney but not in the renal cortex (data provided in a figure in Zhang et al. These results suggest that hyperosmolality as a result of urea exposure can cause oxidative stress in renal medullary cells in vitro and in vivo via protein carbonylation. Wistar rats (200 g, n = 18) were subjected to surgical removal of 2/3 of one kidney under diethyl ether anesthesia. Urine was collected noncontinuously every week in a metabolic chamber under water deprivation conditions from the first stage of the subtotal nephrectomy. The animals were divided into three groups (n = 6): Group 1 rats received a diet with at least 40% protein, Group 2 rats received a diet with 4?5% protein and 0. The remaining kidney was fixed in formalin; paraffin sections were prepared and stained with hematoxylin and eosin, chromotrope, and periodic acid-Schiff stain. Histological changes were observed in the glomerulus, renal tubules, and interstitium. Serum urea concentrations were significantly lower in control animals (Group 3) when compared to Group 1 and Group 2 rats; serum urea concentrations did not differ between Group 1 and Group 2 rats (results provided in a figure). A similar pattern was observed in the evaluation of the proteinuria index and serum creatinine concentrations. Control values of serum creatinine concentrations were also lower than those of Groups 1 and 2 (control: 0. The text states serum concentrations while the figure states plasma 47 concentrations. Observable protein cylinders in the lumen of the proximal tubules were absent in control and Group 2 rats, but were marked in Group 1 rats. Markers of intraglomular hypertension were associated with increased size of the glomerulus, proliferation of mesangium, and an increase in mesangial matrix in the test rats and scarcely noted in the control rats. Cohen and Gullans (1993a) evaluated a proposed growth-promoting effect of urea on renal epithelial cells. In these studies, a variety of confluent, growth suppressed cell types were exposed for 24 hours to urea at concentrations ranging from 0 to 300 mM (concentrations that 3 are typically found in the renal medulla), and [ H]-thymidine uptake was evaluated. By comparison, 100 mM NaCl inhibited [ H]-thymidine uptake by 57%, glycerol 3 produced no effect, and 10% serum increased [ H]-thymidine uptake by 34%. Endpoints evaluated included urea effects on pyruvate kinase and glutathione reductase 48 32 activities, reduced glutathione concentration, uptake of [ P]-orthophosphate, methemoglobin 42 concentration, Heinz body formation, [ K] uptake, and autohemolysis. Urea also increased 32 [ P]-orthophosphate uptake after a 4-hour incubation (7,053 counts/300 seconds vs. Urea did not trigger methemoglobin production and had no effect on the osmotic fragility of the cells, but it induced ring forms with abnormally crenated and distorted cells after 2 hours. Gene Expression Studies Urea exposure results in many changes in gene expression in renal medullary cells. How urea activates or depresses these signaling pathways is an area of active investigation (reviewed by Burg et al. Overall, the authors concluded that renal epithelial cells can increase expression of c-fos and Egr-1 through transcriptional activation in response to hyperosmotic urea. Urea treatment has been shown to be associated with increased oxidative stress and the stress-responsive transcription factor Gadd153 (Zhang et al. Intracellular reduced glutathione content, a biochemical indicator of oxidative stress, was decreased in urea-treated cells within 15 minutes of exposure. Compared to basal conditions (where approximately 5% of the immunoprecipitable Ras was activated), urea (12 g/L [200 mM]) increased Ras activation to 15. A stably transfected cell line with an expression plasmid containing a dominant-negative N17Ras mutation was used to further characterize the intracellular signaling pathway (defined as N17Ras-B7 cells). N17Ras induction inhibited urea inducible Egr-1 and Gadd153 transcription, indicating a role for wild-type Ras signaling in response to urea (data not provided). Overexpression of N17Ras also had no effect on urea-inducible apoptosis (400 mM urea) (data provided in a figure in Tian et al. Together, these studies suggest that Ras signaling may play a role in renal epithelial cell responses to urea-induced oxidative stress. Shc activation and recruitment of Grb2 (as assessed by immunoblots) were also observed after urea treatment (200 mM) (data provided in a figure in Zhang et al. The authors noted that 400 mM, but not 200 mM, urea increased caspase-3 activity (data not provided) and that this effect was increased by 266% after pretreatment of wortmannin (100 nM). Urea induced annexin V binding (a biochemical marker of apoptosis) increased 178% (compared to control) after pretreatment of wortmannin. Pretreatment with urea can protect renal medullary cells, but not 3T3 cells, from the proapoptotic effect of NaCl (Zhang et al. This was exemplified by using two biochemical indices of apoptosis, caspase-3 activation and annexin V binding. However, when urea was applied before NaCl treatment, a 61% inhibition of the NaCl-induced caspase-3 activation and a 63% inhibition of the NaCl-induced annexin V binding were observed (p < 0. Urea also was shown to block the proapoptotic effects of mannitol (data not provided). Urea treatment by itself decreased annexin V binding by 18%, which was statistically not significant. The proapoptotic effect (as evaluated by caspase-3 activation) was not observed when fibroblastic 3T3 cells were used (data provided in a figure in Zhang et al. Urea exposure resulted in downregulation of approximately 6% of 12,000 genes on the Murine Genome U74A GeneChip (Affymetrix) array, whereas 0. Of the upregulated genes, only 21 were upregulated significantly (threefold or more) in response to urea. In contrast, NaCl (100 mM) upregulated approximately 4% of the genes evaluated; 71 genes were upregulated sevenfold or more. Additionally, NaCl downregulated expression of approximately 12% of the 12,000 transcripts studied. These data supported earlier speculation that hyperosmotic urea and NaCl have different signaling mechanisms (Cohen and Gullans, 1993b). Urea pretreatment for 30 minutes partially restored genes affected by hypertonic NaCl stress to basal levels of expression. The authors suggested that urea may play a cytoprotective role in response to hypertonicity induced by other substances. Genotoxicity the genotoxic effects of urea have been studied in a variety of short-term test systems, in vitro (bacteria and mammalian cells) and in vivo (mouse bone marrow). A summary of the results from these genotoxicity studies are discussed in the following section and presented in Table 4-5. Genotoxicity and mutagenicity of urea from in vitro and in vivo studies Results Species/ Test system Exposure Metabolic activation cell line (strain/species) (dose/concentration) S9 +S9 Reference In vitro Bacterial systems Salmonella Reverse mutation 0?10,000 g/plate Mortelmans et al. Genotoxicity and mutagenicity of urea from in vitro and in vivo studies Results Species/ Test system Exposure Metabolic activation cell line (strain/species) (dose/concentration) S9 +S9 Reference In vivo Mammalian rodent Bone marrow Chromosomal 0. Studies have been conducted in different mammalian cells using various genotoxicity assays.
Syndromes
Tumors
Senile cardiac amyloid
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Nephrotic syndrome
Oleandrin
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Burns
Chest x-rays
Spinal cord tumor
A single amino acid substitution weanling mice previously immunized against this epitope (54) erectile dysfunction in a young male purchase priligy online. Weiss erectile dysfunction treatment south florida order priligy with paypal, unpub resistance to a monoclonal antibody mapping to the receptor lished data) (see Fig erectile dysfunction drugs cost comparison order priligy 30 mg fast delivery. Furthermore erectile dysfunction bp meds order cheap priligy on line, mutations within S1 but rather by background genes erectile dysfunction treatment raleigh nc buy 30mg priligy otc, again encoded in the 3 end of may also affect host range; 21 amino acid substitutions and a genome (Iacono et al drugs for erectile dysfunction ppt buy priligy with paypal. During serial passage in cul protein is believed to have functions in host interactions erectile dysfunction young male purchase priligy now. There are early data both recombinant viruses with N erectile dysfunction age 50 purchase priligy 60 mg with amex, O, or no glycosylation demonstrated supporting and arguing against this hypothesis. The ability to upregulate transcription of this gene Replicase Proteins maps to the nucleocapsid gene and correlates with the devel the replicase proteins could affect tropism and pathogenesis opment of fulminant hepatitis (77, 230). For example, recently a one-amino the coronavirus E protein is an integral membrane protein acid substitution in nsp14 (ExoN or p59), a protein with exo (365). Along with the M protein, E plays an important role in nuclease activity, was shown to drastically reduce the virulence viral assembly (324). E protein, when expressed alone or when of a recombinant A59 without affecting the in vitro replication; expressed together with M, forms virus-like particles. Apart from its role in virus assembly, E protein vice versa, demonstrated that the replicase is not an important has additional functions during infection. While the role of this is rather the 3 portion of the genome that is responsible for activity is as yet unknown, the E protein ion channel could pathogenic properties (Navas-Martin and Weiss, unpublished function at the site of budding to enhance viral morphogenesis data). It has been speculated that, in analogy to their cellular plasmic reticulum and Golgi network (227). It is found in virus gene 7 is not essential for replication; however, a recombinant particles, and in infected Vero E6 cells it is localized to pe virus in which the expression of gene 7 was abrogated displays rinuclear regions as well as the plasma membrane and with reduced virulence with less virus replication in the lung and intracellular virus particles. For example, there are reports that in the show an attenuated phenotype in the cat. In fact, other than dif wild-type virus in tissue culture, demonstrating that neither of ferences in spike gene sequences, this was the most striking the two proteins encoded in gene 5 is essential for replication difference observed between the genomes of animal and hu and that these are candidate accessory proteins (34). While it is tempting to and also in a Chinese ferret-badger (Melogale moschata) (122). The sequence information demonstrated that this was a antigenic stimulation that results in the observed serological previously unrecognized coronavirus (267, 287). Infected individuals have slightly decreased platelet transmission and wildlife reservoirs are not a new ideas for counts, prolonged coagulation pro? Although the route of transmission ruses are antigenically related and may even be host range has not been clearly established, airborne droplets from in mutants derived from a common ancestor. Furthermore wild and domestic carnivores such route of transmission for one index case (252). In range of domestic and wild mammals in Guangdong Province contrast, spike protein from the severe 2002 to 2003 outbreak were examined. Rather it tients may also exhibit gastrointestinal symptoms (313) and has been suggested that apoptosis of uninfected lymphocytes splenic atrophy and lymphadenopathy (79). Some macaques became lethargic from 3 days postinfec and Golden Syrian hamsters have been experimentally infected tion (p. Taking all the data together, those authors present in the lumens of alveoli and bronchioles. In contrast Three other labs have attempted to develop nonhuman pri to the previous studies (216, 268), Qin et al. It is worth noting that the utility of the cynomol macaques for a longer period (60 days p. Interestingly, the lesions in the lung, caques develop a mild self-limited respiratory infection very although milder than the histopathological changes observed different from that observed in humans. All animals developed multifocal casional areas of intra-alveolar edema, interspersed with nor mononuclear cell interstitial pneumonitis, accompanied by mal lung histology. There was no evidence of syncytia or alve multinucleated syncytial cells, edema, and bronchiolitis in most olar damage, as has been reported for humans. The virus was infection to prevent reinfection was evaluated in African green isolated from nasal swabs on days 4 and 6 p. In contrast with previous studies, macaques were followed for a 60-day period postinfection. Histopathological changes of interstitial pneumonia were the ferret (Mustela furo) is been exploited as an animal found in the lungs during the 60 days after inoculation. Both strains of mice developed ferrets were totally asymptomatic although they supported bronchiolitis and patchy interstitial pneumonia. First, a mouse model, if successful, would be less expensive than a macaque model. However, mice did not administration, is more robust in hamsters than in mice or develop clinical signs and even continued to gain weight. Interestingly, primary infection con / served in mice (not even in the Stat1 mice). One of the avenues that require more investigation protected against viral replication. It should be emphasized that organ for which there was an increase in the number of positive these animals (in particular mice and macaques) are currently samples with increasing time after infection. These authors pointed out antibodies that block receptor binding and virus entry in cell that although their results need to be further investigated, they culture (94, 128, 303, 307, 345). Treat various cell lines (183, 186, 281, 328, 342, 374), as well as in the ments have been based on the administration of antibacterials macaque model with promising results (183). The use of antiviral antibodies (dis be more immune mediated rather than directly virus induced. Characterization of have provided possible targets for which to evaluate potential the Ld-restricted cytotoxic T-lymphocyte epitope in the mouse hepatitis drug therapies. Localization of a T-cell epitope within the nucleocapsid protein of avian coronavirus. We apologize to any investigators whose work we have in glycoprotein, extended at the carboxy terminus with green? The primary structure and expression of the of apoptosis in murine coronavirus-infected cultured cells and demonstra second open reading frame of the polymerase gene of the coronavirus tion of E protein as an apoptosis inducer. Coronaviruses from pheasants (Phasianus colchicus) are genetically pathogenic in vivo. Murine is targeted to the Golgi complex and directs release of virus-like particles. Mapping of linear antigenic infected cells and lung tissue of severe acute respiratory syndrome patients sites on the S glycoprotein of a neurotropic murine coronavirus with syn and inhibits growth of Balb/c 3T3 cell line. Viral replication in the nasopharynx is associated with nation determinants map to the spike glycoprotein gene of coronavirus diarrhea in patients with severe acute respiratory syndrome. Cytokine capacity of the virus in vitro and its ability to replicate in the liver but not responses in severe acute respiratory syndrome coronavirus-infected mac the brain. A single immunization with a rhab deletion, by reverse genetics, is attenuating in the natural host. Virology dovirus-based vector expressing severe acute respiratory syndrome corona 296: 177?189. Phillips, and hepatitis virus encodes a structural protein that is not essential for viral G. The clinical pathology of coronavirus associated with respiratory disease in humans. Association between a novel human coronavirus and Kawasaki respiratory syndrome coronavirus phylogeny: toward consensus. Evidence of a novel human coronavirus that is associated with respiratory Thomas, Jr. A novel coronavirus associated with tonitis virus infection in feline alveolar macrophages and human monocyte severe acute respiratory syndrome. Coronaviridae: the viruses and their replication, acids of the murine coronavirus spike protein. Angiotensin-converting enzyme 2 is a functional of severe acute respiratory syndrome. Antibody prevents virus reactivation within the central action between the carboxy termini of the membrane and nucleocapsid nervous system. Amino acid substitutions changes in the viral glycoprotein M affect induction of alpha interferon by within the leucine zipper domain of the murine coronavirus spike protein the coronavirus transmissible gastroenteritis virus. Vi respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 rology 166: 415?422. A major outbreak of severe acute respiratory syndrome in Hong navirus neurovirulence. Receptor-induced conformational analysis reveals extensive polymorphism and evidence of deletions within changes of murine coronavirus spike protein. Cytotoxic T cell-resistant variants are selected in a virus-induced demyelin 220. Murine coronavirus tion, and virus-induced immunopathology in the central nervous system. Bgp2, a new member of the aetiology, origins, and diagnosis of severe acute respiratory syndrome. Lan carcinoembryonic antigen-related gene family, encodes an alternative re cet Infect. The 5 end sequence of the murine coronavirus genome: impli hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein cations for multiple fusion sites in leader primed transcription. Diamond, recombinant polymerase and coronaviruses have a history of host-shifting. Prior infection and murine coronavirus spread in vitro and in the mouse central nervous sys passive transfer of neutralizing antibody prevent replication of severe acute tem. The S protein respiratory syndrome by an animal study, epitope mapping, and analysis of of bovine coronavirus is a hemagglutinin recognizing 9-O-acetylated sialic spike variants. Itamura, bly of coronavirus-like particles by co-expression of viral envelope protein K. Human and bovine coronaviruses: evidence for polymorphism on the pepolmer glycoprotein, coronaviruses recognize sialic acid-containing receptors similar to those of E2. Conformational changes in the spike glycoprotein of murine corona vecchia, and G. Biosynthesis, structure, and biological activities of envelope protein gp65 of 374. Cover: Reconstruction of pre-operative computed tomography scan on a patient with previously ablated tumours and present tumours to be ablated. The liver is the most common metastatic site and liver metastases are detected in 25-30% of all patients. A quarter of these patients are amenable for liver resection that results in a five-year survival exceeding 50%. The indications for liver resection continue to broaden and are no longer limited by number and size of liver metastases nor the presence of extrahepatic metastases. Currently liver resection is indicated when macroscopic tumour clearance can be achieved with preservation of a sufficient future liver remnant. Failing to do so may result in suboptimal management and patients that could be resected are not necessarily offered curative-intended treatment. As a result of this there are known regional differences in the treatment of patients with liver metastases that may affect survival. For patients not suitable for resection, either due to the metastatic burden or comorbidity omitting extensive surgery, local ablation is an option. The feasibility and safety of the procedure as well as local recurrence rate was recorded. Overall and disease-free survival in the ablated group was compared with results from two historic cohorts from Study I, one treated palliatively and the other resected. Descriptive statistics were used to evaluate the accuracy of antenna placement, the number of antenna readjustments, safety and radiation dose. Liver and lung metastases were more often diagnosed in hindgut (splenic flexure to rectum) compared with midgut cancer (caecum to splenic flexure) (28. Eighteen patients had recurrence in the liver, 11 had extrahepatic recurrence and 10 out of 20 treated patients were alive at a median follow-up of 25 months. Colorectal cancer liver metastases a population-based study on incidence, management and survival J. The impact of a liver specific multidisciplinary assessment in patients with colorectal cancer liver metastases a population-based study J. A multiple microwave ablation strategy in patients with initially unresectable colorectal cancer liver metastases A safety and feasibility study of a new concept Engstrand J, Nilsson H, Jansson A, Isaksson B, Freedman J, Lundell L, Jonas E. In Sweden, 4000 new cases of colon cancer are diagnosed annually and 2000 new cases of rectal cancer. The incidence of rectal cancer is higher in men and that of colon cancer is slightly higher in women (4). Five-year survival has improved over the last few decades and the five-year survival for Swedish patients with colon and rectal cancer diagnosed between 2005-2009 was 61% for men, and 65% and 64% for women, respectively (6). The five-year stage-specific relative survival in colon cancer is presented in Table 1. Surveillance, Epidemiology and End Results Program data for five-year stage-specific relative survival rates in colon cancers based on sixth edition of the American Joint Committee on Cancer Staging Manual for colon and rectal cancer. There are two main pathways involved in the progression from adenoma to carcinoma in the colon and rectum, namely the adenoma-carcinoma sequence and the serrated adenoma pathway (9), Figure 2. It describes the gradual progression from normal mucosa to adenoma and then to carcinoma due to a series of genetic changes such as mutation and gene amplification. This is thought to in part explain why screening colonoscopy is more effective in preventing left-sided cancer (12). Lately, research has focused on interactions of hormones, energy balance, intestinal flora and inflammation to explain different epidemiological associations (13). This pathway comprises an imbalance in the chromosome number, aneuploidy, and loss of heterozygosity. Identifying biomarkers that predict sensitivity and resistance to chemotherapy is of major clinical importance. The exact effects of these risk factors have been difficult to establish and whether they influence the risk differently depending on gender and for development of colon versus rectal tumours. Preventive factors established in epidemiological studies are physical activity (23), oral contraceptive use (24), aspirin use (25) and endoscopy with removal of pre-cancerous adenomas (26), Table 2. Relative risks are greatest for relatives of patients diagnosed young, (relative risk 3. Tumour grading into high-grade and low-grade is based on the proportion of tumour composed of glands relative to solid areas. T1 tumours are sub-classified into sm1, sm2, and sm3, invading the superficial, middle and deep one-thirds of the submucosa, respectively. Total mesorectal 5 excision is the optimal surgical treatment for low or mid-rectal cancer (31). Surgical resection is undertaken in all patients unless the tumour is deemed locally unresectable, if there is a medical contraindication to surgery or in patients with asymptomatic primary tumours in the presence of incurable disseminated disease. Since the turn of the century, two new cytotoxic agents have been introduced: a topoisomerase inhibitor named irinotecan (Campto) and oxaliplatin (Eloxatin), a third-generation platinum compound (32). Adjuvant treatment for six months after radical excision of colon cancer reduces the risk of relapse and enhances the chance for long-term survival. Factors that increase the risk of relapse include T4 disease, the presence of vessel invasion, <10 examined lymph nodes, poorly differentiated tumours and emergency surgery. The indications for radiation in rectal cancer are to reduce the risk of local recurrence and to shrink locally advanced tumours 6 to facilitate successful resection. In a Cochrane review it was concluded that pre-operative radiotherapy reduces the risk of local recurrence compared with surgery alone and overall mortality is marginally improved (39). Patients with right-sided tumours are more often females, are slightly older and more often present with advanced (T3/T4) tumours (42). Patients with right-sided tumours often present with more subtle signs such as microcytic anaemia and weight loss while left-sided typically present with rectal bleeding and alterations in bowel habits (43). The caecum, ascending colon and proximal two-thirds of the transverse colon originate from the midgut while the remaining segments to the upper anal canal derive from the hindgut. Branches of the superior mesenteric artery supply the proximal colon, while the distal colon gets its blood supply from the inferior mesenteric artery (44). Nearly all venous blood from the colon flows into the portal vein and the liver capillaries are the first capillaries encountered by portal blood-borne cancer cells. Advanced left-sided cancers also benefit more from bevacizumab than advanced right-sided cancers (47). The incidence of detection of metastases at the time of diagnosis of the primary tumour is rising, probably due to better imaging practices and improved imaging techniques (53). Five and 10-year cumulative incidences of metachronous metastases are reported to be 14. Around 85% of liver metastases are diagnosed within one year, 94% within two years and 97. The time-point of diagnosis of the primary tumour, the time of operation of the primary tumour and a variation of time intervals related to these time-points have been used. The definition of synchronous detection most commonly used today is the detection of liver metastases either before or during the surgical procedure for the primary tumour (55). Patients who present with synchronous liver metastases tend to have a more locally advanced primary tumour and present with a greater metastatic burden compared with those who develop metachronous metastases (56). In a German study as well as a United States-based study, colon cancer more often caused haematogenous spread to the liver (56, 58). In a Norwegian study, left-sided colon cancer was found to be associated with an increased risk of metastatic spread to the liver (60). More recently, the hypothesis has expanded to the concept of pre-metastatic niche formation.
Potential adverse impact of ovariectomy on physical and psychological function of younger women with breast cancer erectile dysfunction natural shake order cheap priligy on line. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy fast facts erectile dysfunction cheap priligy 90 mg on line. Orchiectomy can be associated with psychological Testicular volume by Prader testicular radiation and/or distress related to altered body image erectile dysfunction 35 buy discount priligy 90mg. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer erectile dysfunction causes agent orange order priligy 90 mg line. Orchiectomy can be associated with psychological to induce puberty (or immediately for post distress related to altered body image erectile dysfunction over 70 cheap generic priligy uk. Gonadal function and fertility in patients with bilateral testicular germ cell malignancy herbal erectile dysfunction pills canada generic priligy 60 mg with amex. Testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction erectile dysfunction acupuncture buy priligy 60 mg overnight delivery. See also Section 122 Retroperitoneal node Nocturia dissection Abnormal urinary stream Considerations for Further Testing and Intervention Extensive pelvic dissection Yearly Urologic consultation for patients with dysfunctional voiding or erectile dysfunction treatment pdf 90 mg priligy with amex. Long-term functional sequelae of sacrococcygeal teratoma: a national study in the Netherlands. Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma. Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop. Medical Conditions Considerations for Further Testing and Intervention Hypogonadism Urologic consultation in patients with positive history and/or physical exam fndings. Long-term sequelae after cancer therapy-survivorship after treatment for testicular cancer. Long-term effects on sexual function and fertility after treatment of testicular cancer. Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Sexual function in teenagers after multimodal treatment of pelvic rhabdomyosarcoma: A preliminary report. Sexual and psychological functioning in women after pelvic surgery for gynaecological cancer. Also counsel regarding risk associated Blood culture with malaria and tick-borne diseases if living in or visiting When febrile T? Discuss with dental provider potential need for antibiotic prophylaxis based on planned procedure. The prevention and management of infections in children with asplenia or hyposplenia. Pulmonary consultation for patients with abnormal results or progressive with symptomatic pulmonary dysfunction; Infuenza and pulmonary dysfunction pneumococcal vaccinations. Thoracic wall reconstruction for primary malignancies in children: short and long-term results. Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. Expression of sodium iodide symporter in the lacrimal drainage system: implication for the mechanism underlying nasolacrimal duct obstruction in I(131)-treated patients. Depressed mood Yearly, consider more frequent screening Considerations for Further Testing and Intervention during periods of rapid growth Endocrine consultation for medical management. Primary hypothyroidism as a consequence of 131-I-metaiodobenzylguanidine treatment for children with neuroblastoma. High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during (131)I-metaiodobenzylguanidine treatment in children with neuroblastoma. Improved radiation protection of the thyroid gland with thyroxine, methimazole, and potassium iodide during diagnostic and therapeutic use of radiolabeled me taiodobenzylguanidine in children with neuroblastoma. Long-term follow-up results in children and adolescents treated with radioactive iodine (131I) for hyperthyroidism. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Females who are sexually active may still beneft from vaccination through protection against strains to which they have not been exposed. Considerations for Further Testing and Interventions Gynecology and/or oncology consultation as clinically indicated. Information from the frst adenomatous polyps or colonoscopy will inform frequency of follow-up testing. Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Computed tomography screening for lung cancer: review of screening principles and update on current status. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. Prostate Cancer Early Detection National Comprehensive Cancer Network Clinical Practice Guideline V. American Cancer Society guideline for the early detection of prostate cancer: update 2010. No studies were found that evaluated whether screening improves the outcomes of these cancers. Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study. Even in the absence of screening, the current treatment interventions provide very favorable health outcomes. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. In addition, certain subpopulations require screening for lipid disorders, sexually transmitted diseases, and diabetes mellitus. Others require counseling regarding the prevention of cardiovascular disease, osteoporosis, and other disorders. Hypermobility syndromes occur frequently, but the wide spectrum of possible symptoms, coupled with a relative lack of awareness and recognition, are the reason that they are frequently not recognized, or remain undiagnosed. It aims to create better awareness of hypermobility syndromes among health professionals, including medical specialists, and to be a guide to the management of such syndromes for patients and practitioners. The book will be of interest to patients with hypermobility syndromes and their families, as well as to all those healthcare practitioners who may encounter such syndromes in the course of their work. This book is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non Commercial License 4. Hypermobility syndromes often are characterised by extra-articular signs and symptoms that often go unrecognised or are only recognized at a late stage. The ultimate goal was to improve care for patients with hypermobility syndromes, and this proved to be a great success. Realising that this book indeed filled a gap in the health care system, some years ago the idea arose to publish an international multidisciplinary book on hypermobility syndromes with the help of international authors, with the same aims as those for the Dutch book. This has proven not to be a simple endeavour, but we think we eventually have succeeded. To make this book easily accessible to patients and health care workers, we decided to publish it as a freely available e book. Financial support was given by many organisations (see the acknowledgements on the next page), for which we are very grateful. Genetics and testing of Ehlers-Danlos syndrome and of differential diagnostic diseases. Generalised joint hypermobility and joint hypermobility syndromes: the clinical perspective. Gastrointestinal complications of Ehlers-Danlos syndromes and hypermobility spectrum disorders. Neurological complications of Ehlers-Danlos syndromes and hypermobility spectrum disorders. Ehlers-Danlos syndrome, generalised joint hypermobility and the masticatory system. Gynaecological and obstetrical problems and management dilemmas in women with Ehlers-Danlos syndrome. Ehlers-Danlos syndrome, generalised hypermobility and ethics: reflections from the ethics of care. Stretched beyond the limit: well-being and functioning in patients with Ehlers-Danlos syndrome and other hypermobility syndromes. Clinical profiling and tailored non-pharmacological treatment in hypermobility spectrum disorders/hypermobile Ehlers-Danlos syndrome. Considerations, precautions and measures in case of surgery in patients with Ehlers-Danlos syndrome. Historyand introduction Generalised hypermobility has been known since ancient history; for instance Peruvian ceramic figures of 1200?200 B. This will probably take place during international congresses, such as that in New York City May 2016. In contrast with these developments and the relatively frequent occurrence of hypermobility syndromes is the relative lack of awareness and recognition of these syndromes in daily clinical practice with underdiagnosis as result. Although as said therapeutic options are meagre, recognition and diagnosis of a hypermobility syndrome in a patient are beneficial, ending an often year long quest for the cause of signs and symptoms and guiding management. When the quest ends, finding a way of coping for patient and because of the genetic nature of these syndromes also for his/her family can start. For hypermobility syndromes with the risk of life-threatening complications, recognition and diagnosis might even be life-saving. This book is not meant as a reference book for basic research or the newest developments; it is meant for usage in daily clinical practice, with a practical, clinical scope, as much as possible in a reading level of text, health care worker or educated patient can understand, without compromise to the scientific content. Bearing our purpose in mind, we believe this book should be widely available, which we have attempted to achieve by publishing it as an E book. Patients with hypermobility syndromes, having a wide spectrum of signs, symptoms, manifestations and complications, often get to deal with a wide array of medical specialists and other health care providers, who each have a special interest in and knowledge about a specific organ or physical system. The description of these symptoms by only one person with one specialism is bound to be a bit one-dimensional (see figure). We would welcome development of multidisciplinary outpatient clinics for patients with hypermobility syndromes. Both a case manager and a multidisciplinary outpatient clinic should take the whole spectrum of possible manifestations into account. This is the reason we chose for our book the scope and vision from different specialisms on the subject, trying to describe the whole spectrum of manifestations, as much as possible at the persons level, rather than at the organ level. The drawback of this choice is some heterogeneity in the medical level and length of chapters, and some overlap between chapters, which we accepted. The outline of the book is as follows: first there are chapters on classifications and genetics, then chapters on individual types, organ (system) manifestations and complications, and at the end ethics and therapeutic strategies, with an appendix on (precautions at) surgery. In May 2016 in New York an international symposium of the Ehlers-Danlos Society took 6 place, with propositions of changes regarding classification and nosology. Given the fast developments in research, particularly in genetic testing through the widespread introduction of next generation sequencing, it might be that criteria sets, classifications and genetic tests, will be further updated in the near future. However, we feel that for the purpose of the book this is not a major obstacle, and can update the text, given this is an e-publication. So, if our book leads to earlier recognition of patients with hypermobility syndromes and better management, and functions as a practical guide for patients and their families and friends in daily practice, we feel we have met our aim. New clinical and molecular data required another revision, which was initiated during the Ehlers Danlos Society International Symposium in New York, May 2016, the results of which have been published in the March 2017 issue of the American Journal of Medical Genetics Part C, Seminars in Medical Genetics. The hypermobile 6 type by far the most common and the classical type comprise more than 90% of all cases. Classification and nosology 5 the New York classification is based on clinical, biochemical and molecular data. In clinical practice, the clinical manifestations guide the choice for further investigations. In young children it is difficult to assess hyperextensibility due Classification and nosology of Ehlers-Danlos syndrome 7 to the abundance of subcutaneous fat. Skin hyperextensibility can also be assessed at the 0 dorsal aspect of the elbow in 90 flection, where the upper limit of normal is 3 cm. In the New York nosology, a score of 5/9 or more defines generalized hypermobility in both sexes, though it is known that joint mobility depends, apart from age, family and ethnic background, also on gender. Not infrequently, the Bulbena mobility score is also used (table 2-4), in which a score of 5/10 or more defines generalized hypermobility in females and 4/10 or more in males. Generalised hypermobility is not 8,9 rare: 5-10% of mainly female secondary school age Caucasian children is hypermobile. Easy bruising is seen as spontaneous ecchymoses, frequently recurring in the same bodily regions, of which long-term signs are often visible as brownish discoloration (haemosiderin), in particular on knees and shins. If it is the predominant presenting sign, child abuse and bleeding disorders need to be considered first. Tissue fragility is manifested in the skin as easy bruising and impaired wound healing with dystrophic scars, which are usually found over pressure points like forehead, chin, elbow, knee and shin and which may have a wide and papyraceous appearance. Internal organs like arteries, lungs, intestines, liver, spleen and uterus may also show fragility, predominantly in the vascular type. Some features are regularly observed, but are not criteria of generalised hypermobility 10 syndromes. In table 2-5 the major and minor diagnostic criteria are shown, minimal criteria for diagnosis and how to verify the diagnosis. A minor criterion is a sign of lesser diagnostic specificity, but its presence supports the diagnosis. However, in the absence of major criteria, minor criteria are not sufficient for a given diagnosis. Minimal diagnostic criteria are the presence of skin hyperextensibility and atrophic scars, plus either generalized joint hypermobility and/or 3 minor criteria (see table 2 11 12 5). It is inherited in an autosomal dominant fashion (see glossary), implying that each child (be it a boy or a girl) of an affected parent (be it father or mother) has a chance of 50% (=? Once the causative mutation has been found in a proband (see glossary), mutation analysis in relatives of the proband is possible. Also, in mild cases of the classical type (partial expression), differentiation from the hypermobile type might be difficult, if not impossible. It is characterised by generalized hypermobility, with a remarkable laxity of finger joints. In contrast with the classical type, its inheritance is autosomal recessive, so most cases are sporadic and some occur in sibships. Diagnosis in children is difficult, particularly in the absence of a family history. Arterial rupture is the most common cause of sudden death and has its peak rd th incidence in the 3 or 4 decade. Acute abdominal and flank pain is a common presentation of an arterial or intestinal rupture and needs urgent investigation and treatment. For women with the vascular type, pregnancy and delivery pose specific risks, which warrant 19 pre-conceptional counselling with an experienced obstetrician and clinical geneticist. As said above, when extensive bruising is the initial presentation and the only sign/symptom, bleeding disorders and child abuse have to be considered. As said, the new diagnostic criteria are more strict than those of the Villefranche criteria and the Brighton criteria (see table 2-5 and chapter 5). Basically, there is no confirmative laboratory test for the hypermobility type, meaning that it is a pure clinical diagnosis. Also, a changing phenotype from one diagnosis into the other in one individual and in some pedigrees 26 the occurrence of both diagnoses argued for this statement. Larsen syndrome, which also features congenital luxations, should be in the differential diagnosis. It is one of the rarest of all types and since only very few cases have been described, possibly this type is characterised by other as yet unrecognised features. The mode of inheritance is autosomal recessive (see glossary), whereby both parents of a patient are healthy carriers and the recurrence risk for siblings is 25% (=? Laboratory tests should start with measurement of the urinary lysyl and hydroxy-lysyl pyridinoline ratio. Because of severe hypotonia, patients very often undergo a full scale neuromuscular work-up, including a muscle biopsy before the diagnosis is established. The differential diagnosis comprises all other causes of severe hypotonia, including neonatal Marfan syndrome. Minimal diagnostic criteria are thin cornea with or without rupture plus either at least one other major criterion and/or 3 minor criteria (see table 2-5). The urinary lysysl and hydroxylysyl pyridinoline ratio is moderately increased (to approximately 1 compared to normal values of ~ 0. Minimal diagnostic criteria are congenital muscle hypotonia and/or muscle atrophy that improves with age plus either one other major criterion and/or three minor criteria. Among these, one finds not surprisingly other heritable connective tissue disorders like cutis laxa, osteogenesis imperfecta, Stickler syndrome (see chapter 5), Loeys-Dietz syndrome and Marfan syndrome, but also skeletal dysplasias, inborn errors of metabolism, neuromuscular disorders, chromosomal abnormalities and syndromes like Larsen syndrome, Fragile X syndrome and Langer-Giedion syndrome. Like always in clinical practice, the results of history taking, including a family history, and physical examination are the basis for planning additional investigations and finally reaching a diagnosis. This is already standard routine diagnostic practice in some laboratories and will become routine in all in the near future (see chapter 3).
Using the examples of Ireland erectile dysfunction performance anxiety 30mg priligy mastercard, Italy and by different peoples around the world towards the human embryo erectile dysfunction jacksonville fl purchase 30mg priligy mastercard. Canada erectile dysfunction after radical prostatectomy treatment options discount priligy 60mg mastercard, how many factors can you think of For example erectile dysfunction more causes risk factors buy priligy us, a recent survey of nine European countries showed that might have played a part in shaping the that views varied considerably erectile dysfunction psychological treatment techniques 60 mg priligy free shipping. For countries who wish to encourage research erectile dysfunction doctors in connecticut generic priligy 60 mg on line, there are Such views are often although not always refected in the programmes which try to assist the sharing of materials best erectile dysfunction pills side effects discount priligy line. This resource was set up to act creation and importation of embryos for research purposes (and as a central reserve for high-quality research materials and also the production of cloned and hybrid embryos erectile dysfunction statistics nih discount priligy 30mg online, Ireland does not to help reduce the number of embryos that would have to be allow either use and is generally strongly opposed to any uses created and destroyed in the name of research. Another example is the European about this kind of research, the creation of embryos is illegal but Human Embryonic Stem Cell Registry which exists to help the free their importation and use is allowed; examples include Germany fow of information and to foster international co-operation. Many countries in Europe and elsewhere, such as Canada and Denmark, only allow embryos to be used for stem cell research when they were originally created for fertility treatment (but not implanted). Some fear that a consequence of this No one really knows how much it will cost to bring stem cell will be that research in this area will go to other countries where therapy to patients. A good guess, however, would put the bill there is no such rule and that this could have a negative impact on at over? Once again, should the law have a role to play in answering these In small groups, discuss the pros and cons of the European Parliament directive. They expect a As a group, design, write and conduct an decent proft from their work. One of the best ways to secure a anonymous poll of your classmates as to whether proft is by taking out a patent on any new invention, and this is or not they feel patents of embryonic stem cell also true for medical inventions. The problem is that while no one is likely to die if they do not get their hands on the latest i-phone, this could very well be International considerations true of new medicines. Indeed, should patents be granted over embryonic stem cell lines when these have involved the. In other words, should profts be allowed stem cell research and commercialisation? There have been attempts to reach international agreement Once again, we see different attitudes in different countries. The European Convention on Human Rights and Biomedicine (1997) the European Parliament directive and the legal protection of states in Article 18 that: The creation of human embryos for biotechnological conventions (1998) says that a patent should not research purposes is prohibited. This means that patents are unlikely to be given for than half of these countries have done so. Member States were to push for called on to adopt all measures necessary to prohibit all forms of international human cloning inasmuch as they are incompatible with human agreement in this dignity and the protection of human life. This text at least leaves it to each country to argue that its own measures are compatible with human dignity. But it is far from an international agreement on how we should proceed in this area. Key messages in this chapter the law serves many purposes and can help shape There are no international laws regarding stem society for the better. There are international laws cell research but many differing national laws and and national laws. This act has been modifed consideration must be given as to who will pay for twice since its inception. There have been attempts to reach international agreement on stem cell research and commercial exploitation but so far this has not been successful. Review of the Human Fertilisation and Embryology Act: A public [Reference/webpage no longer available December 2016] consultation. Chapter 3 Stem Cells: ethical issues 35 Chapter 3 Stem Cells: ethical issues but know there is only one tragic outcome. Many people feel that we should not make the status of embryos a constraint on finding a way that might address so much suffering. For me, stem cells show how important it is to consider what wider Many people, however, fall somewhere in between these opposite human values are affected, as science poles. They see the human need, but they think the human embryo is more than just nameless cells, and yet it is not the same digs ever deeper into human biology. Later, we will also look at some other ethical questions like cloned embryos, Introduction animal-human hybrid cells, producing human sperm from stem cells, and using stem cells to test future pharmaceutical drugs for Few people doubt the medical potential of stem cell research. As with other new areas of medical research, there are issues like proving the effectiveness and minimizing the risks, personal questions about the status of the early human embryo donation and consent, and social issues like whether everyone can afford the therapies and how much health service resources they Do early embryos fall into the same class as people, or are they a would consume. But what makes this area especially contentious is ball of cells and nothing more? Or does the answer lie somewhere the source of the cells, and in particular the use of human embryos. Different European countries vary greatly in their laws about stem cell research, reflecting the deep ethical conflicts which exist No moral status at the blastocyst stage about the nature of the human embryo, and what are, or are not, permissible uses. One pole of the argument emphasises a scientific way of viewing the embryo in terms of its composition, properties and functions. At this stage, it the Old Town feature among their scary tales the deeds of Burke could split to produce twins, so we cannot yet say for sure that and Hare in the early nineteenth century, who murdered people this is a single individual. The and sold their bodies as anatomical specimens to the medical mother would not yet be aware that she is pregnant. Most people would recoil at the idea of killing another the scientific case, a philosophical judgment is made that at this human being in cold blood in order to provide spare parts or cells stage the embryo has no moral significance. Yet, some people consider that this is what we are human person; it is just a ball of cells. Some even say it is a moral duty Others are equally deeply troubled that concerns about the status of humanity, if it provides a potential means to fnd treatments for of a few cells in the earliest stage of human development should otherwise serious and incurable suffering. Only at some later stage be allowed to hold back the prospect of what can be done to of development, perhaps where certain human characteristics are treat terminal disease and chronic human suffering. This is doctors and nurses can offer only temporary relief for people they a yes provided? position. The opposite view says that we should not judge the status of the Philosophy can be defined as a study and investigation of embryo by its state of development, but by what it will become, questions about ethics and existence. We have a special duty However, can you define the difference between morals to protect the most vulnerable of the human community, and and ethics? One moral might person, the beneft of the doubt and protect it as one would a be; It is right to tell the truth. They are all about how you apply your morals to a situation, and, as such, your Those that hold this view believe that no research should therefore morals and ethics affect each other. For example, some be allowed that is not for the beneft of that particular embryo. Once a human life has been created, even in an embryo, it is not Can you think of any examples where that might happen? Those holding this position advocate only the use of stem cells derived from adult tissue or placental cord blood. Although it is perhaps best known as the formal position of the Catholic and Orthodox churches, and of some (but by no means all) Protestant Christians, it is not a view shared by all religions. People with the second view criticise the frst view as reducing the being? of the embryo to a scientifc description. The latter criticise the second position as giving a signifcance to the embryo for which, at that stage, there is no scientifc basis. For these two polar positions, their ethical responses to embryonic stem cells are straightforward: all or nothing. Intermediate views But many people think that neither of these radically opposed views do justice to the complexity of the developing embryo. They may recognise 37 purposes of which could be achieved by the use of other animals or in some other way? [1]. But they would not agree that this is as who hold an under no circumstances? position would agree with much status as we would give to a new-born baby in position two. Some ethical questions about limited embryo research Some people make a distinction between those embryos which lead to a successful pregnancy, and the majority of conceptions 14 day rule in which the body spontaneously aborts at a fairly early stage. Whereas it is unreasonable to ascribe human status to those After what point in the development of an embryo should no conceptions which never succeeded, successful embryos would research be allowed? But legally a line has to be drawn somewhere between conception and the upshot is that there would be limited circumstances under birth, unless you hold the view that human embryos should which research on human embryos might be allowed. After seriousness of certain medical conditions would justify the consulting professional medical bodies, the Warnock Committee action. Many Jews, Muslims and Protestant Christians fall broadly recommended 14 days, because at about this time there are within this category, and also many non-religious people. Shortly after influential statement of this way of thinking was the 1984 Warnock this the primitive streak? begins to appear, which will make Report on fertility and embryo research, which argued that the the three germ layers including the cells that will become the embryo of the human species ought to have a special status and central nervous system, which in turn will lead to consciousness that no one should undertake research on human embryos the and sensory feeling. After this, twinning is no longer normally 38 possible, so we know that it is indeed one particular individual. Some see an important moral significance to this beginning of the physical the following group task will help you consolidate and further relationship between mother and the eventual baby. These flms were produced by the EuroStemCell network which Using embryos as a means to an end? Watch A stem cell story? at the following web address: to make replacement body cells is treating the embryo as just. Embryonic stem cell research takes a purely utilitarian view of the embryo, as a means to an. The two views differ on for burns patients, neurons for testing possible whether respect for an embryo is measured by what you do not drug treatments for neurological diseases and allow to be done to it, or the uses to which it is put. Now watch Conversations: ethics, science, stem cells? also available online at. What would you say if you were interviewed for this You must ask if this is justified bearing in mind it involves the use flm? Some have expressed concern that any sense of special status? for the early human 4. Or maybe they will turn out to be Those objecting think that to create an embryo just for research essentially the same. For those who consider embryos to have stem cells no moral status until 14 days or later, to stop embryo research would never be an option. There were several may become a real question sooner than we expect, so it is worth reasons in favour. It was thought that this could be done by frst making a cloned embryo using cells from the patient. If these embryos would not now have any chance to develop into babies, because the couple who created them does not wish to attempt further pregnancies, why not use them for potentially very beneficial medical research? Many European countries allow this Neurons (green) derived from embryonic stem cells. New ethical challenges in stem cell research Using cloned embryos in stem cell research drew much criticism, notably in a vote of the European Parliament and a non-binding Deriving sex cells (sperm and eggs) from human recommendation of the United Nations General Assembly. A embryonic stem cells House of Lords Select Committee, set up to clarify such issues in 2002, said cloned embryos?should not be created for research purposes unless there is a demonstrable and exceptional need Some research groups have claimed to have made human which cannot be met by the use of surplus embryos? [5]. Firstly, it would again involve the would welcome this, if it gave us a better understanding of what deliberate creation of an embryo simply to use as a resource for sometimes goes wrong in male fertility. Secondly, there are widespread some time if it could work well enough to enable an infertile man ethical and safety objections to reproductive human cloning. Some consider it embryo of himself created, say, from some of his skin cells, to make unwise to produce cloned embryos for research, in the absence of the stem cells and thus the sperm. Is there a Animal-human mixed (hybrid) cells contradiction if he creates and sacrifces a cloned embryo to create an ordinary? one? In a highly politicised campaign, proved frst time and every time, that everything had worked. How proponents argued that the shortage of donated human eggs could that be done without doing a procedure which treats the was holding up stem cell research and potential treatments. This is quite different animal eggs was hardly different from human eggs but would from a dying patient consenting to take the risk of an experimental avoid pressures on women to donate. These examples illustrate some of the on ethical grounds for mixing reproductive cells, and on scientifc dilemmas coming from new areas of stem cell research. Some observers consider that the real issue was not hybrids but the freedom of science. But having created an embryonic stem cell line, say for intended drugs anyway, but if they could use embryonic stem cells diabetes research, can the same cells be used for purposes which for the rapid screening of chemicals, it would reduce the time and would have been refused a licence, like drug screening or even cost of testing. Using human others disagree because they were created by destroying a human cells instead of animals may give a more reliable test, but would embryo, arguing that the same limits on what the embryo can it be better ethically? Both animal research and embryo stem cell be used for must apply also to whatever uses the cells would research oblige the researcher to look for an alternative. It is also possible that scientists would replace one ethically controversial process (using animals) by sometimes need to use fresh human embryos to create stem cell another ethically controversial process (using cells derived from lines for drug or chemical testing. If this indeed becomes the frst major use, has the public been kept in the dark? By law, pharmaceutical companies have to test all Stem cells isolated from human bone marrow. Ethics and the scientist Does it matter that he is destroying the cloned embryo of himself to create a new embryo? The society, whose taxes and on the basis of diabetes for testing the toxic effects of investments provide the research funds and infrastructure for pharmaceutical drugs, or cosmetic products, given that a scientifc endeavour, now demands more accountability for what license would not have been granted for these directly? This is especially so in the area of stem cells because it touches on some very basic beliefs about what a Other ethical issues about stem cells human being is, when human life begins, and what is permissible in research in pursuit of medical treatments. As a result, not only this summary of ethical issues has focused primarily on the special the public but also funders of research now expect scientists to features relating to stem cells and embryos. There are other issues be able to show they are aware of, and understand, the ethical relating to stem cells which are common to other areas involving and social dimensions of their work. These have not been covered in this increasingly recognising that ethics is not just a matter for booklet, however they are listed below as suggestions for further society as a whole, but is something they need to think about for study for readers: themselves. Scientists are enthusiastic about their discoveries and also want to secure further funding. European Group on Ethics in Science and New Technolo donating eggs, embryos or tissues, there are issues of gies (2000), Opinion 15: Ethical Aspects of Human Stem informed consent, non-directive counselling, understanding Cell Research and Use, 14 November 2000, European Commission, Brussels. Human Fertilisation and Embryology Act, 2008, the Sta the Bioethics Education Project supports students in learning to tionery Office, London. European Group on Ethics in Science and New Technolo-gies (2002), Opinion 16: Ethical Aspects of. Two ways in which embryos are created for research is through the generation of animal this section suggests three viewpoints regarding human hybrid embryos and through using nuclear the moral status of human embryos. An important aspect of being a scientist involves engaging with the social and ethical dimensions of research. Society and scientists alike must be involved in the discussions regarding using human embryos in stem cell research. Wellbeing (safety, Autonomy Justice the spaces in the scientists? row as if you were a scientific researcher using the ethical matrix (designed by Professor Ben Mepham, Centre for embryonic stem cells. Interest Groups welfare and health) (freedom and choice) (fairness) Applied Bioethics at the University of Nottingham) is a tool to help 4. Once everyone has completed the ethical matrix consider these people analyse an ethical issue and make informed choices. It can questions: aid reflection and discussion about a topic and here it is used to . Discuss your but it should be noted that there can be some crossover between decision-making. In the blank ethical matrix below the three reasons are interested in this issue), patient groups. Now consider if your analysis would change if you issues for wider society you apply these three ethical principles in order to consider and then were discussing a specifc use or a specifc research project. Working in groups, give each person a photocopy of the blank Dr Kate Millar, Department of Ethical Engagement Methods developed by staff at the Centre for ethical matrix. When completing each row remember that you should do it as if you Autonomy is concerned with the interests of an individual. Scientists people working in stem cell research and developing stem cell therapies to treat patients. Society issues for wider society such as social priorities, research and medical priorities and how money should be allocated. Asymmetric division Cell division resulting in two daughter cells with different properties. Atrophy A wasting or decrease in size of a body organ, tissue or part, owing to disease, injury, or lack of use. Beta cell A cell type found in the pancreas (specifically in the islets of Langerhans) that produces the hormone insulin. Blastocyst A ball of around 250 cells formed around five days after fertilisation. The formation of blood cells (red blood cells, white blood cells and platelets) occurs in the bone marrow. Cancer Any malignant growth or tumour caused by abnormal and uncontrolled cell division. The cells are placed in a petri dish and given a mixture of nutrients so that they can survive and divide. Cell line A population of cells all carrying the same genes, grown in the laboratory through many cycles of growth and division over many generations of cells. Cell replacement therapy the replacement of cells damaged by disease or injury, with new healthy ones derived from stem cells. The ability of stem cells to self-renew and differentiate into particular cell types offers the potential to culture stem cells in the lab to become replacements.
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