How does quality of life of patients with systemic lupus erythematosus compare with that of other common chronic illnesses?

OBJECTIVE: Comparison of health related quality of life (HRQOL) of patients with systemic lupus erythematosus (SLE) with other common chronic illnesses. METHODS: Responses from self-administered Medical Outcomes Study Short Form-36 (SF-36) questionnaires from 90 patients with SLE, recorded in the lupus database at the University of Chicago Hospital, were analyzed. Comparative norms and domain scores for patients with other chronic diseases [hypertension, congestive heart failure (CHF), adult onset diabetes mellitus, myocardial infarction, and depression] were used and are based on the general US population. T tests were used to make comparisons. RESULTS: Patients with SLE were younger than patients with most reference chronic conditions except for depression. Their Physical Component Scores and Mental Component Scores were 30 +/- 10.5 and 45.1 +/- 11, respectively. SLE patients fared significantly worse than age matched norms from the general US population for women (p = 0.0001) in all 8 domains. Their quality of life was significantly worse than for those with hypertension, diabetes, or myocardial infarction in all domains (p < 0.004). Patients with CHF were no worse than those with SLE in regard to physical function, role-physical, role-emotional, and vitality. CHF patients fared significantly better in mental health, bodily pain, social functioning, and general health, compared to patients with SLE. Patients with depression were significantly impaired in role-emotional and mental health domains (p = 0.0001) compared to SLE patients, but were no worse (role-physical, vitality, and social functioning) and even better (physical function, bodily pain, and general health) in some. General health of SLE patients was significantly lower than all comparative groups. CONCLUSION: HRQOL of patients with SLE seems to be significantly worse and affects all health domains at an earlier age in comparison to patients with some other common chronic diseases.     

How helpful are meta-analyses in determining the best therapy of blood diseases?

Meta-analyses of data from randomized clinical trials (RCTs) are often used by hematologists to compare the efficacy of therapies of blood diseases. This is especially so when results of RCTs are not decisive. This situation in RCTs arises when the magnitude of differences in treatment outcomes between therapies tested is small, when trials are unpowered to detect differences (these are confounded) and/or when RCTs reach, or seem to reach, contradictory conclusions. Contributing to these limitations of RCTs are the relative rarity of many blood diseases, poor recruitment into RCTs and the greater interest of many hematologists in therapy strategy than in a direct comparison of alternate therapies. These limitations of RCTs are solvable, but only in part, by meta-analyses. Adding data from high-quality observational database studies(ODBs) to meta-analyses is sometimes useful in resolving controversies, but this approach also has limitations: biases may be difficult or impossible to identify and/or to adjust for. However, ODBs have large numbers of diverse subjects receiving diverse therapies and adding these data to meta-analyses sometimes gives answers more useful to clinicians than meta-analyses of RCTs alone. Side-by-side comparisons suggest analyses from high-quality ODBs often give similar conclusions as meta-analyses of high-quality RCTs. Quantification of expert opinion of high quality is also sometimes useful: experts rarely disagree under precisely defined circumstances and their consensus conclusions are often concordant with results of meta-analyses of high-quality RCTs with and without ODBs. We conclude that meta-analyses are often helpful to determine the best therapy of blood diseases. Accuracy can be improved by including data from high-quality ODBs, when appropriate, and by resolving discordances, if any, with conclusions from high-quality ODBs and from quantification of expert opinion.     

Flow cytometric measurement of platelet-leukocyte aggregates: a possible target to monitor platelet function?

Increased platelet-leukocyte-aggregate (PLA) formation has been reported in acute coronary syndromes (ACS) and during cardiopulmonary bypass, and PLA formation has been acknowledged as a possible target for antiplatelet therapy in ACS and coronary interventions. It has also been suggested as a monitoring tool for risk stratification parameters. In a controlled study design as well as under clinical conditions we investigated the effect of antiplatelet agents by flow cytometric measurement of PLA formation. We were able to demonstrate considerable reduction in PLA formation under experimental and clinical clopidogrel therapy alone or in combination with aspirin. In healthy volunteers the percentage of monocyte-PLAs decreased significantly to 55 to 75% of the baseline under clopidogrel, depending on the type and concentration of the activating agent. In patients with severe peripheral artery disease, formation of monocyte-PLAs at baseline and after stimulation with thrombin receptor activating peptide (TRAP) or adenosine diphosphate (ADP) was significantly lower under combined therapy when compared with patients under aspirin alone or without antiplatelet treatment. Flow cytometric measurement of PLA formation appears to be well suited for dose response of antiplatelet agents in healthy volunteers and a valuable tool in establishing the clinical significance of circulating PLAs. It may also be a qualified method to monitor platelet function in long-term treatment with antiplatelet agents that interfere with the degranulation process. It is not suited for acute situations.     

Inhibition of platelet function: does it offer a chance of better cancer progression control?

Thrombocytosis is frequently (10 to 57%) observed in cancer patients. Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity, growth factors, platelet-derived microparticles, and factors released from bone marrow endothelial cells as well as growth factors secreted by megakaryocytes (acting via an autocrine loop) are claimed to influence this process. The course of cancer is strongly associated with hypercoagulable state, which results from direct influences of tumor cells themselves and various indirect mechanisms. Activated platelets provide procoagulant surface amplifying the coagulation process. It is well documented that proteins of the hemostatic system influence different steps of metastasis, angiogenesis, and proteolytic events. Much less is known about the role of platelets in tumor growth and their possible contribution to prevention of tumor cells from the host immune system. Multidirectional activities of platelets during tumor development and metastatic dissemination create a possibility of introducing antiplatelet agents in anticancer therapy. The spectrum of plausible therapies includes antibodies against glycoprotein IIb-IIIa, direct thrombin inhibitors, protease activated receptor-1 targeted therapy, as well as cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors. However, there is no sufficient information on a specific type of cancer where progression does depend on platelet function. Despite numerous experimental studies conducted, to date none of the new specific antiplatelet agents were tested in clinical trials in a cancer patient population.     

How does pouch construction for a final diagnosis of Crohn's disease compare with ileoproctostomy for established Crohn's proctocolitis?

PURPOSE: There is a difference of opinion concerning the role of ileal pouch-anal anastomosis in Crohn's disease, even in the absence of small-bowel or perianal disease. One view is that ileal pouch-anal anastomosis should never be entertained, the other is that ileal pouch-anal anastomosis, like ileoproctostomy, can be justified sometimes, because it allows young people a period of stoma-free life. The aim of this study was to examine the outcome of ileal pouch-anal anastomosis and to contrast it with ileoproctostomy in patients with Crohn's disease without small-bowel or perianal disease. METHODS: Ileal pouch-anal anastomosis was performed in 23 patients with Crohn's disease (12 of whom had evidence of Crohn's disease at the time of operation and 11 who were eventually found to have Crohn's disease as a result of complications) and ileoproctostomy in 35. Patients were matched for age, gender, follow-up, and medication, but all ileoproctostomy cases had relative rectal sparing. Thus, the groups were not comparable and the reasons for ileal pouch-anal anastomosis and ileoproctostomy were therefore quite different. RESULTS: The outcome in ileal pouch-anal anastomosis at a mean follow-up of 10.2 years was pouch excision, 11 (47.8 percent); proximal stoma, 1 (4.3 percent; patient preference); average small-bowel resection, 65 cm; persistent perineal sinus, 8 of 11 having pouch excision (73 percent); and mean time in hospital, 37 (range, 8–108) days. Of those in circuit having ileal pouch-anal anastomosis (n=12), 24-hour bowel frequency was 6, with no incontinence or urgency, but 6 (50 percent) were on medication. When ileal pouch-anal anastomosis was done for Crohn's disease in the resection specimen, only 4 of 12 (33 percent) were excised compared with 7 of 11 (64 percent) in whom the diagnosis was made as a result of complications. The outcome in ileoproctostomy at a mean follow-up of 10.9 years was rectal excision in 3 (8 percent), proximal stoma in 1 (3 percent), average small-bowel resection was 15 cm, persistent perineal sinus in 1 (3 percent), and time in hospital was 21 (range, 8–36) days. Of those in circuit (n=32), 24-hour bowel frequency was 5, 2 had incontinence, 3 had urgency, and 12 (36 percent) were taking medication. CONCLUSIONS: These results indicate that the overall outcome of ileal pouch-anal anastomosis is inferior to that of ileoproctostomy, especially if Crohn's disease was diagnosed as a result of complications. Nevertheless, the functional results of those with a successful outcome are comparable.Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 24 to 29, 2000.     

How to test the effect of aspirin and clopidogrel in patients on dual antiplatelet therapy?

Dual antiplatelet therapy with clopidogrel and aspirin is frequently used for the prevention of recurrent ischemic events. Various laboratory methods are used to detect the effect of these drugs administered in monotherapy, however their value in dual therapy has not been explored. Here, we determined which methods used for testing the effect of clopidogrel or aspirin are influenced by the other antiplatelet agent. One arm of the study included 53 ischemic stroke patients being on clopidogrel monotherapy showing effective inhibition of the P2Y₁₂ ADP receptor. Laboratory tests routinely used for the detection of aspirin resistance (arachidonic acid (AA)-induced platelet aggregation/secretion, AA-induced thromboxane B₂ (TXB₂) production in platelet-rich plasma and VerifyNow Aspirin assay) were carried out on samples obtained from these patients. The other arm of the study involved 52 patients with coronary artery disease being on aspirin monotherapy. Methods used for testing the effect of clopidogrel (ADP-induced platelet aggregation and secretion, flow cytometric analysis of vasodilator-stimulated phosphoprotein (VASP) phosphorylation and a newly developed P2Y₁₂-specific platelet aggregation (ADP[PGE₁] test)) were performed on samples obtained from these patients. Clopidogrel monotherapy significantly inhibited AA-induced platelet aggregation and secretion, moreover, AA-induced TXB₂ production was also significantly decreased. VASP phosphorylation and AA-induced platelet aggregation showed fair correlation in patients taking clopidogrel only. Clopidogrel did not inhibit the VerifyNow Aspirin test significantly. Aspirin monotherapy influenced ADP-induced platelet aggregation and secretion, but did not have an effect on VASP phosphorylation and on the ADP[PGE₁] platelet aggregation test.     

How does the prognosis of diabetes compare with that of established vascular disease? Insights from the Canadian Vascular Protection (VP) Registry

Background

Diabetes mellitus is a major risk factor for atherosclerotic cardiovascular disease. In a large, prospective, practice-based registry (the Vascular Protection Registry), we enrolled patients with vascular disease and/or diabetes, and compared the following features between diabetic and non-diabetic participants: (1) risk factor profiles, (2) utilization of cardioprotective medications, and (3) cardiovascular outcomes in short-term follow-up.

Methods

Patients were enrolled by participating physicians practicing in family medicine or specialty practices across Canada. The primary outcome was a composite of the first occurrence of any of the following vascular events: myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, or death. Patients were stratified according to the presence or absence of cardiovascular disease and diabetes.

Results

In all, 3297 patients were available for analysis (972 [30%] with diabetes but no cardiovascular disease; 899 [27%] with both diabetes and cardiovascular disease; and 1425 [43%] with cardiovascular disease but no diabetes). Most of the measured risk factors were worse for patients with diabetes. Compared to non-diabetic patients, diabetes was associated with substantial undertreatment with cardioprotective medications, including antiplatelet agents, beta blockers, and statins. During a mean follow-up of 10 (SD 3.3) months, patients with both diabetes and cardiovascular disease had the worst prognosis, with the primary outcome occurring at a rate of 16.3 per 100 person-years of follow-up.

Conclusions

Patient registries provide a powerful tool for examining treatment patterns, risk factors, and outcomes. Patients with both cardiovascular disease and diabetes had the highest rates of adverse vascular outcomes. Possible reasons include relatively worse risk factor profiles and undertreatment with proven cardiovascular medications.     

How to assess the effectiveness of nasal influenza vaccines? Role and measurement of sIgA in mucosal secretions

Secretory IgAs (sIgA) constitute the principal isotype of antibodies present in nasal and mucosal secretions. They are secreted by plasma cells adjacent to the mucosal epithelial cells, the site where infection occurs, and are the main humoral mediator of mucosal immunity. Mucosally delivered vaccines, such as live attenuated influenza vaccine (LAIV), are able to mimic natural infection without causing disease or virus transmission and mainly elicit a local immune response. The measurement of sIgA concentrations in nasal swab/wash and saliva samples is therefore a valuable tool for evaluating their role in the effectiveness of such vaccines. Here, we describe two standardized assays (enzyme‐linked immunosorbent assay and microneutralization) available for the quantification of sIgA and discuss the advantages and limitations of their use.     

Personalized therapy for chronic viral hepatitis C in the naive patient: How can we optimize treatment duration as a function of viral genotype?

Pegylated interferon plus ribavirin is the standard treatment for chronic hepatitis C (CHC). It yields sustained virological response (SVR) rates of 42-52% for genotype 1, 66-72% for genotype 4, and 76-80% for genotypes 2 and 3. Hence, the patient's genotype appears to be a determining predictive factor for the SVR. We have reviewed the literature in order to determine whether a genotype-specific treatment duration should be envisaged. The largest study to date of patients infected with HCV genotype 2 or 3 confirmed the value of the standard treatment duration of 24 weeks. Shorter treatments exposed the patients to a greater risk of relapse. For genotype 1, it was possible to offer a shorter, 24-week course of treatment to the 35% of patients with an initial viral load below 600,000 IU/mL and an early virological response (EVR) at week 4 (negative PCR), resulting in an SVR of 89%. For the remaining two-thirds of genotype 1 patients with a high viral load, the treatment duration should remain at 48 weeks. A subgroup of patients - the "slow virological responders" (positive PCR at week 12 but with less than 6000 IU/mL; negative PCR at week 24) - benefited from the extension of the treatment to 72 weeks, with an SVR of 88%. For patients infected with genotype 4 virus, combination therapy should feature a ribavirin dose of more than 1000 mg/day for an optimal duration of 48 weeks.     

Challenges on the diagnostic approach of inherited platelet function disorders: Is a paradigm change necessary?

Inherited platelet function disorders (IPFD) have been assessed for more than 50 years by aggregation- and secretion-based tests. Several decision trees are available intending to standardize the investigation of IPFD. A large variability of approaches is still in use among the laboratories across the world. In spite of costly and lengthy laboratory evaluation, the results have been found inconclusive or negative in a significant part of patients having bleeding manifestations. Molecular investigation of newly identified IPFD has recently contributed to a better understanding of the complexity of platelet function. Once considered “classic” IPFDs, Glanzmann thrombasthenia and Bernard–Soulier syndrome have each had their pathophysiology reassessed and their diagnosis made more precise and informative. Megakaryopoiesis, platelet formation, and function have been found tightly interlinked, with several genes being involved in both inherited thrombocytopenias and impaired platelet function. Moreover, genetic approaches have moved from being used as confirmatory diagnostic tests to being tools for identification of genetic variants associated with bleeding disorders, even in the absence of a clear phenotype in functional testing. In this study, we aim to address some limits of the conventional tests used for the diagnosis of IPFD, and to highlight the potential contribution of recent molecular tools and opportunities to rethink the way we should approach the investigation of IPFD.     

How Constant Anatomically is the Tendon of Todaro as a Marker for the Triangle of Koch?

INTRODUCTION: Although well recognized by anatomists as a border of the triangle of Koch demarcating the location of the AV node, the tendon of Todaro is not visible in the operating room or in the catheterization laboratory. Instead, clinicians use as surrogate a projected line between the eustachian valve and the central fibrous body. The constancy of the tendon of Todaro within this border remains to be determined. MATERIALS AND RESULTS: We reexamined serial histologic sections from 25 adults and 50 infants and gross dissections in four normal hearts. The tendon of Todaro was identified in all cases and traced to the central fibrous body in all but one case. It tended to be thicker in the hearts of infants cases (0.2 to 0.8 mm vs 0.1 to 0.6 mm). The tendon and the hinge-line of the septal leaflet of the tricuspid valve were consistent as landmarks for location of the compact AV node in all the cases studied by histology. Gross dissections traced the tendon to the free edge of the eustachian valve. CONCLUSION: The tendon of Todaro is present in hearts obtained from both adults and infants. It, or its surrogate, is a reliable border for the triangle of Koch and serves as a landmark to location of the atrial components of the AV conduction axis.