Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets' response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)-1, COX-2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y₁, P2Y₁₂, CYP2C9, CYP3A4 and CYP3A5 genotypes.     

Quality of life in a heterogeneous sample of caregivers of cancer patients: an in‐depth interview study

MANCINI J., BAUMSTARCK‐BARRAU K., SIMEONI M.‐C., GROB J.‐J., MICHEL G., TARPIN C., LOUNDOU A.‐D., LAMBERT A., CLÉMENT A. & AUQUIER P. (2010) European Journal of Cancer Care
Quality of life in a heterogeneous sample of caregivers of cancer patients: an in‐depth interview study To establish the best approach to develop a quality of life (QoL) questionnaire for cancer‐patient caregivers, this study attempts to identify primary domains of QoL in terms of their impact on a purposive sample of caregivers. Seventy‐seven informal adult caregivers of cancer patients (breast cancer, paediatric haematological malignancies or melanoma) with different relationships with the patients (parents, children, spouses, siblings, and friends) were recruited at three specialised French centres and extensively interviewed. Caregivers' lives were altered in several domains: psychological well‐being, leisure and everyday activities, relationships with institutional caregivers, occupation and finances, relationships with family and friends, physical well‐being, and relationship with the patient. The relative importance of these domains varied mainly in association with the caregiver‐patient relationship. Multiple correspondence analysis identified two isolated clusters: children, and, most significantly, friends and siblings. The latter groups emphasised the repercussions on their psychological well‐being and their relationship with the patient, but were less willing to discuss the impact on their relationship with caregivers and on occupation, finances, leisure, and everyday activities. This study focuses on the caregiver's perspective and advocates the development of a short QoL core questionnaire. Additional modules should be cancer‐specific or dedicated to specifics of the caregiver‐patient relationship.     

Pharmacoeconomic considerations in treating iron overload in patients with β-thalassaemia, sickle cell disease and myelodysplastic syndromes in the US: a literature review

Patients with β-thalassaemia, sickle cell disease (SCD) and myelodysplastic syndromes (MDS) require chronic blood transfusions, which can lead to iron overload and substantial morbidity and mortality. To reduce the excess iron and its deleterious effects, available iron chelation therapy (ICT) in the US includes oral deferasirox or infusional deferoxamine (DFO). The aim of this study was to review and synthesize the available pharmacoeconomic evidence on ICT in patients with β-thalassaemia, SCD and MDS in the US. We systematically identified and reviewed pharmacoeconomic studies of ICT in patients with β-thalassaemia, SCD and MDS that either were published in MEDLINE-indexed, English-language journals from 1999 to 2009, or appeared in medical society websites and scientific meeting abstracts. We assessed available cost-of-illness, cost-of-treatment, cost-consequence, cost-effectiveness, utility and patient-satisfaction studies. The majority of the 20 identified studies assessed cost of treatment, mainly focusing on acquisition and administration costs of ICTs. Gaps in the published literature include current data on direct medical costs for patients with MDS, direct medical costs associated with complications of iron overload, direct non-medical costs, indirect costs and patient utilities. Different underlying model assumptions, methodologies and comparators were found in the cost-effectiveness studies, which yielded a broad range of incremental cost-effectiveness ratios for different ICTs. Comprehensive cost-of-illness studies are needed to address data gaps in the published literature regarding the economic burden of iron overload. Comparative-effectiveness studies that evaluate clinical, economic and patient-reported outcomes would help the medical community to better understand the value of different ICTs.     

The effect of age on outcomes of sling surgery for urinary incontinence

OBJECTIVES: To measure the effect of patient age on outcomes of sling surgery for stress urinary incontinence.
DESIGN: Analysis of Medicare claims data.
SETTING: Analysis of the 1999 to 2001 Medicare Public Use Files provided by the Centers for Medicare and Medicaid Services on a 5% national random sample of beneficiaries.
PARTICIPANTS: Women who underwent sling procedures between July 1, 1999, and December 31, 2000, were identified according to Common Procedural Terminology, Fourth Edition , code 57288 (sling operation for stress incontinence). Subjects were tracked for 6 months before surgery to identify preoperative comorbidities and for 12 months after surgery to assess short-term complications. Subjects were stratified for analysis at age 75.
MEASUREMENTS: Bivariate analyses were conducted with patients stratified at age 75, and multivariate analyses were also conducted to identify the independent effects of patient age and comorbidities on outcomes.
RESULTS: A total of 1,356 procedures were performed during the 18-month index period. This extrapolates to 27,120 procedures in all Medicare beneficiaries. At 1 year after surgery, overall outcomes in younger women (aged 65–74) were significantly better than in older women with respect to postoperative urge incontinence (20.0% vs 12.6%), treatment failure (10.5% vs 7.2%), and outlet obstruction (10.5% vs 6.6%). Older age and greater comorbidity were associated with greater risk of nonurological events (e.g., pulmonary embolism and cardiac events).
CONCLUSION: Women aged 75 and older are more likely to experience postoperative urge incontinence, treatment failure, and outlet obstruction after sling surgery. Older age and comorbidities were associated with higher rates of nonurological complications.     

Health outcomes and economic impact of therapy conversion to a biphasic insulin analog pen among privately insured patients with type 2 diabetes mellitus

STUDY OBJECTIVE: To evaluate claims-related treatment adherence, health care resource utilization, and associated costs of therapy conversion from an insulin vial and syringe to a premixed biphasic insulin analog pen device among privately insured patients with type 2 diabetes mellitus. DESIGN: Retrospective, longitudinal, intrapatient (before and after) analysis. DATA SOURCE: PharMetrics database of medical and pharmaceutical claims from 57 commercial health plans across the United States. PATIENTS: Four hundred eighty-six adult patients with a confirmed diagnosis of type 2 diabetes who converted from an insulin analog vial and syringe (233 patients) or a human insulin vial and syringe (253 patients) to a biphasic insulin analog pen device between July 1, 2001 and December 31, 2002. MEASUREMENTS AND MAIN RESULTS: All patients had no previous use of the pen device. Primary end points were medication possession ratio (MPR), a measure of adherence; hypoglycemic events; associations between treatment adherence and hypoglycemic events, and adherence and all-cause health care costs; and all-cause-attributable, hypoglycemia-attributable, and other diabetes-attributable costs. After conversion, MPR increased significantly from 59% to 68% (p<0.01). A significant decrease in the likelihood of experiencing a hypoglycemic event was also observed after conversion (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.27-0.61, p<0.05), with hypoglycemic occurrences reduced nearly two thirds among subjects with optimal adherence indicated by an MPR of 80% or greater (incidence rate ratio 0.36, 95% CI 0.11-0.76, p<0.05). Significant decreases in hypoglycemia-attributable emergency department visits (OR 0.36, 95% CI 0.16-0.84, p<0.05) and physician visits (OR 0.39, 95% CI 0.20-0.77, p<0.05) were observed. Total mean all-cause annual treatment costs were reduced by $1748/patient (p<0.01), hypoglycemia-attributable costs were reduced by $908/patient (p<0.01), and other diabetes-attributable costs were reduced by $643/patient (p<0.01). Patients with an MPR of 80% or greater were associated with significant reductions in all-cause health care costs (OR 0.55, 95% CI 0.31-0.80, p<0.05). CONCLUSION: Privately insured patients with type 2 diabetes may exhibit considerable improvements in clinical and economic outcomes after insulin therapy conversion from vial and syringe to a premixed biphasic insulin analog pen device.     

Phosphoinositide 3-kinase is involved in the induction of the human sperm acrosome reaction downstream of tyrosine phosphorylation

In somatic cells phosphoinositide 3-kinase (PI 3-kinase) is activated upon interaction with both receptor tyrosine kinases (RTK) and G- proteins resulting in the production of moieties involved in the inositol phospholipid signalling pathway. As G proteins, RTK and the inositol phospholipids have all been implicated in the human sperm acrosome reaction, experiments were carried out to determine whether PI 3-kinase was also involved in this phenomenon. Wortmannin is a selective inhibitor of PI 3-kinase and was shown to significantly inhibit the acrosome reaction induced by both mannose-bovine serum albumin (mannose-BSA) (10, 50 and 100 nM) and a polyclonal antibody raised against an extracellular region of the sperm zona receptor kinase (ZRK, at 100 nM only). Wortmannin did not inhibit the A23187- or progesterone-induced acrosome reaction. These results suggest that PI 3- kinase is involved in the human sperm acrosome reaction. The levels of tyrosine phosphorylation of sperm proteins as detected by Western blotting using antiphosphotyrosine antibodies was not affected by wortmannin in agonist (A23187 and mannose-BSA)-stimulated spermatozoa. This indicated that PI 3-kinase operates downstream of tyrosine phosphorylation in the signal transduction cascade which leads to the human sperm acrosome reaction.      

Magnetic resonance angiography

Pulse sequences that permit selective detection of moving spins in a magnetic resonance image have been developed. Experiments were performed by the authors to produce projected angiographic data without the use of contrast agents, with the intensity of each image pixel determined by the macroscopic velocity of the detected spins. With this method, suppression of nonmoving spins is essentially complete, yielding a high dynamic range in signal intensity for detected vessels. Selective detection of moving spins is not dependent on pulsatile flow. Consequently, not only arterial structures, but also venous structures can easily be visualized. High-resolution angiographic images can be obtained by combining the flow experiment with surface coil techniques.     

Pharmacokinetics of apomorphine in parkinsonian patients

Summary— Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa-induced on-off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high-performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the T_max was brief (16 ± 11 min) the drug was rapidly cleared from the plasma and had a short plasma half-life (69.7 ± 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter-subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half-life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.     

Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents

Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue- specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post- BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan- pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.