Mark Corson

By F. Uruk. Indiana University of Pennsylvania.

Aer 24 and 48 weeks of Elaprase infusions discount super avana 160 mg line erectile dysfunction drugs prostate cancer, liver and spleen volumes were À1 signicantly reduced in the overall treated population cheap super avana 160 mg on line erectile dysfunction medicine for heart patients. Normalisation of liver volumes occurred in six of nine patients (67%) with hepatomegaly at baseline 160mg super avana otc injections for erectile dysfunction. All seven patients with splenomegaly at baseline had normal spleen volumes following 48 weeks of Elaprase treatment. Aer 48 weeks of treatment, patients in the mid- and high-dose groups had increases in walking distance of 17. Pooled results across the three dose groups at 48 weeks showed an increase in walking distance of 14. Following 48 weeks of treatment, there also appeared to be a reduc- tion in le ventricular mass across all three dose levels. Finally, the study results also suggested improvements in some patients with sleep apnoea as well as certain joint range of motion measurements (e. Infusion reactions occurred in patients receiving the mid- and high-dose levels; all patients were able to continue treatment by slowing the infusion rate (infu- sion time was extended from 1 to 3 hours) and by pre-medication with antihistamine and corticosteroids. No infusion reactions were associated with elevations of tryptase or complement activation. Some patients at the higher dose levels developed IgG antibodies to Elaprase aer exposure to three to six infusions. The induction of these antibodies did not appear to have an impact on either the biological or clinical activity of Elaprase. The study examined every other week infusions of three different dose levels of Elaprase in the blinded phase and all patients continued in the open-label extension. Infusion reactions were successfully managed by the combination of slowing the infusion rate and pre-medication. Demonstration of clear clinical benet was more difficult, however, owing to the small sample size of the study and the heterogeneity of the disease of the patients, the latter resulting in variable treatment View Online 176 Chapter 7 responses. Nonetheless, there was evidence of clinical benet as many patients showed improvements in walking distance, pulmonary function and sleep apnoea, as well as a reduction in le ventricular mass. Moreover, regulatory approval would be based on the results of a single pivotal trial, requiring the trial to be conducted robustly and to provide rm evidence of safety and efficacy. The biodistribution studies in mice and rats, however, showed Elaprase to have a tissue half-life of 1–2 days, indicating that it would be eliminated from the tissues by the second week aer the infusion. The weekly administration would test the importance of having active enzyme continuously present in the tissues. The demon- strated efficacy of weekly administered Aldurazyme also supported this decision. Other end points, including sleep apnoea, and liver and spleen size, were considered for the primary composite score but were eventually not used. Measurement of joint range of motion was also highly variable and responsiveness to therapy was difficult to show. Liver and spleen size and joint range of motion were, however, included as secondary outcomes; sleep studies were not performed during the study. The two-component composite end point was clinically justied as it captured the effect of Elaprase treatment on respiratory function and physical functional capacity as measured by walking ability. The primary statistical analysis of the composite end point was performed by the global non-parametric rank-sum test as described by O’Brien. The primary comparison of the composite variable was between the weekly Elaprase-treated group and the placebo group. A sample size calculation was difficult to perform for the study due to the composite nature of the primary efficacy end point. The proposed sample size of 90 patients represented as large a number of patients as was feasible for the study. Based on this sample size, coupled with the composite score and its analysis for the primary efficacy end point, the power of the study was assumed to be sufficient and high. Because of its direct impact on responsiveness to treatment, a signi- cant concern was a potential imbalance in disease severity between treatment groups. It was hoped that this would improve the efficiency of the comparisons for a small study. These sites also administered study drug, but because of the burden of administering weekly infusions of study drug to 90 patients, other centres were recruited to perform study drug infusions but not clinical testing. The primary end point showed the greatest statistically signif- icant difference between the weekly Elaprase-treated group and the placebo group (p ¼ 0. It was also evident that the weekly dosing regimen was superior to the every other week dosing regimen of Elaprase. In contrast, the every other week dosing regimen did not reach statistical signicance for any of these outcomes. In terms of joint range of motion, only an improvement in elbow mobility was detected between the weekly Elaprase and placebo groups. Infusions of Elaprase were generally well tolerated, with no patients withdrawing from the 1 year study due to an infusion-related reaction. Although certain patients in the Elaprase-treated groups developed IgG antibodies to Elaprase during the course of the study, there was no mean- ingful correlation of these antibodies with adverse events or clinical assessments. View Online Discovery and Clinical Development of Idursulfase 179 The percentage of patients developing antibodies to idursulfase has ranged from 51% to 68%, with a proportion having antibodies that neutralise either the uptake of idursulfase into cells or enzymatic activity. Antibody-positive patients appear to have a higher incidence of hypersensitivity reactions and a reduced systemic exposure to idursulfase.

Guidance may be sought from the patient order super avana 160mg without a prescription erectile dysfunction medication injection, who is likely to know the contact’s individual circumstances generic super avana 160 mg with mastercard erectile dysfunction code red 7, and can alert the health adviser to potential pitfalls (For example: “Ring him on his mobile cheap super avana 160 mg with amex erectile dysfunction and prostate cancer, he works away” “Don’t send anything through the post in case her husband sees it- 32 ring her during the day” “Send her a hospital letter so she knows its not a wind-up”). Negotiating a back-up plan An alternative approach might be agreed, in case the first choice fails. It may be necessary to arrange to speak to the index patient again, should more information be needed. Clarifying the boundaries of confidentiality The patient would be reassured that the contact would not be given any information that could expose his or her identity: this includes name, gender, area of residence, date of exposure and type of relationship. The patient would also be aware that the contact’s subsequent diagnosis is also confidential. However, if the health adviser fails to find the contact, the patient may to be informed so s/he can reconsider patient referral and/or avoid re-exposure. Preparing the index patient to manage the possible consequences Consideration would normally be given to the likelihood that the contact might guess the index patient’s identity. Provider referral is a hazardous choice for current regular partners, who may feel betrayed and humiliated to be informed by a third party. It is important to ensure the patient has considered the consequences, and is equipped to manage any resulting difficulties. The index patient may be confronted subsequently by a contact claiming to ‘know’ they instigated provider referral. The patient can avoid being tricked into confession if s/he is prepared for this, and is confident in the confidentiality of the service. Equally, a contact may notify the index patient in future, unaware that they have already attended: preparing the patient for this possibility may help them to maintain composure and respond appropriately. Most people will be able to give a first name, estimated age, physical description and say where they met; others may even know the area where they live, or occupation. Even if this is not enough to trace the contact, it may allow the person to be recognised and managed appropriately if they attend spontaneously. Incomplete data can also be useful if several index patients give different pieces of identifying or locating information for the same contact: eventually the person may be traced on aggregated data. Sometimes patients have substantial details about the contact, including full name and/or date of birth, but believe they need to provide a full address 33 before action can be taken: the health adviser may explain this can be obtained from other medical records. Where details are insufficient, the patient may be willing to seek more information from mutual acquaintances. The patient believes the contact is not involved The patient may have a fixed view on who is the likely source of infection and be unwilling to notify previous contacts within the look-back period. The danger of infected contacts being overlooked may be avoided by emphasising the difficulty of being certain about the duration of the infection. The risk of exposure despite condom use, due to unprotected genital contact, would also be outlined. If the patient cannot be persuaded to inform a regular partner, it is worth advising repeat tests if unprotected sexual contact is resumed. The patient is afraid of the consequences Partner notification is not without risk for the index patient, who may fear loss of relationship, verbal abuse, a damaged reputation or even physical violence. Some fears - that the contact will know who gave their name; be angry; end the relationship or tell others - can be examined and possibly challenged: for example, confidence may be enhanced by reassurances about confidentiality, or by considering the possibility that the contact may be more grateful than angry. The patient may be able to reduce the risk of angry confrontation by selecting an appropriate time and place, speaking calmly, resisting blame or guilt and focusing on the need for medical care rather than speculating about the source. Sometimes there are fears that the patient or a regular partner may come face to face with another contact, thereby compromising confidentiality and risking confrontation. The healthy adviser may be able to prevent this by booking appointments personally, at ‘safe’ intervals. Where there is risk of violence, delaying provider referral until the patient is in a place of safety, or the contact is in prison, may be acceptable. For example, the index patient may become re-infected, or may eventually be confronted by a contact who has realised s/he could have been notified earlier, thus preventing complications and further transmission. The patient is hostile towards the contact Unwillingness to inform a contact may be rooted in anger or resentment, particularly if the infection has brought an infidelity to light. If the patient is given the opportunity to ventilate and explore these feelings with the support and understanding of the health adviser, anger may eventually dissipate sufficiently for the patient to reconsider. Equally, the patient may assume the 34 infection has been recently acquired, and that therefore a partner has been unfaithful. Emphasis upon the serious consequences of untreated infection may stir enough concern or conscience to override anger. If the patient is still not ready to co-operate, further discussion may be postponed. The patient is uninterested in the contact’s welfare Indifference is often a barrier, particularly towards casual partners where there is insufficient familiarity or sense of connection to provoke empathy, concern or obligation. The first is to build some sense of familiarity by ‘re-visiting’ the contact and making that person as real and three dimensional as possible. This may be done by asking a series of questions that move from the superficial (age, appearance) towards some speculation of circumstances, personality, values and aspirations. The second technique is to encourage a sense of relationship by focussing on the interactions between them (how they met, what attracted them to each other, how they got on, how they parted). A third approach involves strengthening a sense of connectedness by identifying social connections through mutual acquaintances. Finally, empathy can be encouraged asking the patient to imagine how they would feel if the situation were reversed and the contact failed to let them know.

Serum liver enzymes may be elevated with serum peri- cardial effusion regardless of the cause buy 160 mg super avana visa impotence organic. Diagnosis Although the clinical signs of traumatic pericarditis usu- ally are sufficient for diagnosis buy super avana 160mg visa erectile dysfunction treatment australia, definitive diagnosis in the field can be accomplished by two-dimensional echocardiography generic 160 mg super avana mastercard erectile dysfunction doctors in south jersey, pericardiocentesis, or both proce- dures. Fluid and fibrin in the pericardial sac are easily visu- Figure 3-16 alized with two-dimensional echocardiography. Heavy accumulation of fibrin coats the epicardium and vis- “Scrambled egg” appearance of epicardium and pericar- dial sac of an adult cow with pericarditis. This fibrin frequently has the appearance of “scrambled eggs” when seen on postmortem examination (Figure 3-16). Pericardiocentesis can be performed with an Bacteria are easily detected in the gram-stained smears 18-gauge, 8. Following clipping and standard prep of The major reason for pericardiocentesis is diagnostic the left thorax, a skin puncture is performed with a differentiation of traumatic pericarditis from diseases scalpel in the fifth intercostal space just dorsal to the that may create similar signs. If continuous drainage is desired, a 20-French cardial involvement and fluid accumulation is the major chest trochar and catheter may be introduced into the differential diagnosis. The fluid ob- nonseptic pericarditis have been documented, in which tained is purulent and fetid. Fibrin clots frequently the clinical signs are very similar to those documented obstruct flow of the fluid through finer gauge needles with septic pericarditis, but the fluid tends to be a sterile or catheters. The purulent fluid greatly exceeds normal hemorrhagic transudate with low to moderate numbers values for pericardial fluid (normal protein 2. Cytology of pericardial fluid would clearly are the major cellular component rather than the differentiate between these diseases. Usually the be better following drainage and antiinflammatory ther- wire is mostly or completely in the thorax and would be apy than for pericarditis associated with sepsis or neo- difficult or impossible to remove through rumenotomy. The presence of flocculent, mixed echogenicity However, we have observed patients with acute reticulo- fluid with gas shadowing within the pericardium on ul- peritonitis and acute traumatic pericarditis from a single trasound is also characteristic for septic pericarditis. These pa- plications include pneumothorax, fatal arrhythmia, car- tients had clinically detectable pericardial effusions and diac puncture leading to hemorrhage or death, and radiographic evidence of foreign body penetration of the leakage of pericardial material into the thorax, resulting pericardium. Some, but not all, of these complications systemic antibiotics are sometimes sufficient treatment can be mitigated by performing the procedure using of peracute or acute pericarditis in such cases. Leakage into the pleural space is ditis worsens despite systemic antibiotics and rumenot- possible because most pericarditis patients do not have omy to retrieve the foreign body, thoracotomy may then attachment of the fibrous pericardium to the parietal be considered. Pericardiocentesis performed on one of the au- in acute cases for which it is hoped that some portion of thor’s patients yielded only gas from the needle and was the metallic foreign object remains in the reticulum. Postmortem examination confirmed benefit of radiographs, and although indicated in the that neither hemorrhage nor cardiac injury had oc- field, an unsuccessful rumenotomy may further compro- curred. The routine adminis- pericarditis, pericardiocentesis is a worthwhile risk to tration of a magnet to heifers of breeding age and bulls confirm the diagnosis before salvaging a cow suspected before 2 years of age should be part of routine disease to have the disease. Treatment of nonseptic pericarditis includes drainage Treatment of the pericardial fluid, systemic antimicrobial therapy, Treatment of traumatic pericarditis in dairy cattle usu- and administration of 5 mg of dexamethasone with or ally is hopeless. Medical therapy with systemic antibiot- without 100,000 units of sodium penicillin into the ics and drainage of the pericardial sac rarely, if ever, pericardial space. Thoracotomy and Cor Pulmonale pericardiectomy or pericardiotomy have been performed in many fashions in an effort to provide drainage, Etiology search for the foreign body, and prevent fluid or later Conditions of right heart dilatation, hypertrophy, and constrictive damage to the heart. Sporadic case reports subsequent failure caused by pulmonary hypertension and third-hand stories attest to the occasional success of and increased pulmonary vascular resistance often is pericardiectomy and fifth rib resections, but success is referred to collectively as cor pulmonale. Authors recommending rib-splitting tho- tion is uncommon and sporadic in dairy cattle. Most racotomy and pericardiectomy reported that five of nine cases of cor pulmonale occur in cows known to have clinical patients recovered. Results from our clinic, as chronic pneumonia, bronchiectasis, and pulmonary reported by Ducharme and co-workers, are much more abscesses secondary to bacterial bronchopneumonia, pessimistic with only one of seven surviving thoracic consolidated anteroventral lung lobes from previous surgery. Severe chronic in- may result in clinical improvement with prolongation terstitial pulmonary disease, although rare, may also of life to reach a short-term goal like calving. Despite a result in cor pulmonale in mature cattle with diffuse poor prognosis, surgery remains the treatment of choice pulmonary fibrosis. Chronic should be performed as early in the course of the disease hypoxia and pulmonary hypertension in cattle may as possible. Cattle with severe ventral edema and obvi- provoke hypertrophy of medial smooth musculature ous heart failure are not good candidates for surgery. We have treated Chapter 3 • Cardiovascular Diseases 59 one adult Holstein cow that had primary pulmonary abscesses, or diffuse pulmonary fibrosis. This disease can occur in dairy cattle, and in fact Treatment Holsteins have been reported to be particularly sensi- In cattle affected with primary chronic pulmonary dis- tive. However, on a practical basis, to our knowledge, ease, treatment of the primary lung disease coupled few dairy cattle in the United States are at risk because with furosemide therapy may be beneficial. Brisket disease known to have had pneumonia in the past and mild but may be seen at elevations of 1600 m (5249 ft) above sea persistent chronic respiratory signs thereafter may ben- level and tends to have increasing incidence at eleva- efit from a tracheal wash to establish cytologic and cul- tions above 1600 m. Definite genetic resistance or sus- tural aids to antibiotic treatment of the chronic lung ceptibility is documented, and affected cattle must be problem. Baermann’s technique should be performed if returned to low altitudes early in the course of the dis- chronic lungworm infestation is suspected. Concurrent ingestion of certain plants high altitude suspected to have brisket disease should such as Astragalus sp. Although digoxin may be considered Pulmonary hypertension secondary to pulmonary in these cases, those cattle that require digoxin require and bronchial arteritis recently was observed as an en- hospitalization and incur extreme expense. If digoxin is required lar sclerosis and vasculitis were identified pathologi- for a select case, the recommended dosage is 0. Although unconfirmed, monocrotaline, a pyrrolizidine alkaloid, was suspected as the cause by Arrhythmias the authors.

Human immunodeficiency virus type 1 neutralization is deter- mined by epitope exposure on the gp120 oligomer super avana 160mg generic impotence zinc. Antibody cross-competition analysis of the human immunodefi- ciency virus type 1 gp120 exterior envelope glycoprotein buy super avana 160mg overnight delivery erectile dysfunction medication canada. Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells generic super avana 160mg fast delivery erectile dysfunction low testosterone. Antigen-specific inhi- bition of effector T cell function in humans after injection of immature dendritic cells. Humoral, mucosal, and cellular immunity in response to a human immunodeficiency virus type 1 immunogen expressed by a Venezue- lan equine encephalitis virus vaccine vector. Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. However, the nature of the rela- tionship between strong humoral responses and control of infection has not been estab- lished. Passive immunization with pathogen-specific antibodies is protective against infec- tion with a number of other organisms. These include rabies virus (10), respiratory syn- cytial virus (11), cytomegalovirus (12), hepatitis A and B viruses (13,14), varicella-zoster virus (15), poliovirus (16), measles virus (17), rubella virus (18), and mumps virus (19). In addition, this form of treatment has proved effective in the man- agement of established infections with respiratory syncytial virus (11), cytomegalovirus (20), parvovirus B19 (21), hepatitis B virus (22), and Junin arenavirus (Argentine hem- orrhagic fever) (23), as well as pneumococcal pneumonia (24), meningococcal menin- gitis (23), and Hemophilus influenzae meningitis (23). The knowledge learned from these interventions contributed to the successful development of effective vaccines against many of these infectious agents (23). However, in its natural state on the surface of the virus as a trimer, conformational From: Immunotherapy for Infectious Diseases Edited by: J. Various envelope sites are also heavily glycosylated, further affecting virus-antibody interactions (25). The gp41 glycoprotein, a transmembrane element non-covalently bound to gp120, is involved in virus-cell fusion and also serves as a neutralization target (27). Recent evidence suggests that the transient envelope structures arising during cell binding and fusion may be more susceptible to antibody neutralization and could serve as targets for immunization strategies (28). Neutralization Epitopes It has long been known that the V3 loop contains neutralizable epitopes (29,30). Antibodies to this region of the viral envelope are produced early in the course of infec- tion (31) and are associated with delayed progression of disease (32) and reduced maternal-infant transmission of infection (33). They appear to function by inhibiting coreceptor binding and virus-cell fusion (34). Several anti-V3 monoclonal antibodies have been created (Table 1), but the hypervariability of this region hinders its usefulness as a target for immunologic control by passive or active vaccination strategies (30,36). However, some studies have suggested that some anti-V3 antibod- ies are more broadly neutralizing (37,38). Seventy-two percent of isolates from different clades con- tain this amino acid sequence (45). The monoclonal antibody 2G12 recognizes a discontinuous epitope on gp120 that includes domains in C2, C3, C4, and V4 (46). Synergistic or additive effects were detected when two antibodies tar- geting different epitopes were combined. Two antibody combinations involving b12, 2F5, 2G12, and 694/98D (anti-V3) were most active. The synergistic effects seen in these studies are probably related to their comple- mentary activities at different epitope targets. The b12 anti- body is 10-fold less potent than the best antibodies against poliovirus and influenza A (23). Thus, by using combinations of antibodies, neutralization of virus is made more efficient, and the doses of antibodies needed to achieve maximum virus inhibi- tion are reduced. A single amino acid change in an epitope can result in escape from antibody neutralization (58–60). Thus, this potential treatment appears safe and is likely to proceed to clinical trials. Bispecific Antibodies Another approach to enhance and broaden the activities of antibodies and effector cells is the creation of bispecific antibodies (BsAbs) (79). One is through complement-mediated lysis of free virus or viral-infected cells (80,81). Antibody binding of gp120 expressed on infected cell sur- faces could inhibit fusion of cells, syncytia formation, and cell-to-cell spread to virus (84). The ability of antibodies to protect against infection has been demonstrated in these models, but the results of experiments have not been uni- versally successful. Differences in results may depend on the viral strain tested, the chal- lenge dose, the type of antibody preparation, and the dose of this product. Three of four animals were protected from infection, whereas the two control monkeys who received uninfected monkey serum before challenge became infected. Prechallenge antibody titers in individual animals did not correlate with protection. To study passive immunization against maternal-infant transmission, Van Rompay et al. They sustained low level viremias for up to 4 years after infection but had no detectable plasma viral load and no clinical illness at the time sera were obtained for the hyperimmune serum pool. Untreated neonates all became infected after viral challenge, and most died within 3 months (100). Although both monkeys became infected, one of them maintained a low virus load, with virus isolation achievable only at one time point 2 weeks after challenge (101). They are more resistant to neutralization by antibodies than T-cell laboratory-adapted strains (36,39). On the other hand, by replicating in antigen-presenting cells, they may induce enhanced immune responses when presented as vaccine.